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Sample records for induced hypertension pih

  1. Does palm oil vitamin E reduce the risk of pregnancy induced hypertension?

    PubMed

    Mahdy, Zaleha Abdullah; Siraj, Harlina Halizah; Khaza'ai, Huzwah; Mutalib, Mohd Sokhini Abdul; Azwar, Muhammad Hatta; Wahab, Marianah Abdul; Dali, Ahmad Zailani Hatta Md; Jaafar, Rohana; Ismail, Nor Azlin Mohd; Jamil, Muhammad Abdul; Adeeb, Nafisah

    2013-01-01

    In view of the high anti-oxidative potential oftocotrienol, the role of the tocotrienol-rich fraction (TRF) of palm oil in preventing pregnancy induced hypertension (PIH) was explored in a randomized double-blind placebo-controlled clinical trial in an urban teaching hospital. Healthy primigravidae were randomized to receive either oral TRF 100 mg daily or placebo, from early second trimester until delivery. Out of 299 women, 151 were randomized into the TRF arm and 148 into the placebo arm. A total of 15 (5.0%) developed PIH. Although there was no statistically significant difference in the incidence of PIH (4/151 or 2.6% in the TRF arm vs. 11/148 or 7.4% in the placebo arm, p = 0.058) between the two arms, there was a tendency towards a lower incidence of PIH in the TRF arm compared to the placebo arm. With TRF supplementation, the relative risk (RR) of PIH was 0.36 (95% CI 0.12-1.09). In conclusion, although TRF from palm oil does not statistically significantly reduce the risk of development of PIH in the population studied, the 64% reduction in incidence of PIH is substantial. The findings warrant further clinical trials, particularly in high risk populations. PMID:24592747

  2. Increased risk of systemic lupus erythematosus in pregnancy-induced hypertension: A nationwide population-based retrospective cohort study.

    PubMed

    Lin, Li-Te; Wang, Peng-Hui; Tsui, Kuan-Hao; Cheng, Jiin-Tsuey; Cheng, Jin-Shiung; Huang, Wei-Chun; Tang, Pei-Ling; Hu, Li-Yu

    2016-07-01

    Dysregulation of the immune system plays a role in the pathogenesis of both, pregnancy-induced hypertension (PIH) and systemic lupus erythematosus (SLE). It is well known that SLE predisposes to be complicated with PIH. However, few studies have attempted to investigate whether PIH increased subsequent SLE risk.The objectives of this study were to assess the association between PIH and subsequent SLE risk and identify predictive risk factors.Patients with newly diagnosed PIH were selected from the Taiwan National Health Insurance Research Database (NHIRD) and compared with a matched cohort without PIH based on age and the year of delivery. The incidence of new-onset SLE was evaluated in both cohorts. The overall observational period was from January 1, 2000 to December 31, 2013.Among the 23.3 million individuals registered in the NHIRD, 29,091 patients with PIH and 116,364 matched controls were identified. The incidence of SLE was higher among patients with PIH than in the matched controls (incidence rate ratio [IRR] = 4.02, 95% confidence interval [CI] 3.98-4.05, P < 0.0001). The IRR for subsequent SLE development remained significantly higher in all stratifications during the follow-up years. The multivariate Cox regression model was performed and the results showed that PIH may be an independent risk factors for the development of subsequent SLE (hazard ratio [HR] = 2.87, 95% CI 2.07-3.98, P < 0.0001). Moreover, multivariate Cox regression model was used again among the PIH cohort only in order to identify the possible risk factors for subsequent SLE in the population with PIH.Patients with PIH may have higher risk of developing newly diagnosed SLE than those without PIH. In addition, among individuals who have experienced PIH, those younger than 30 years, having experienced preeclampsia/eclampsia, single parity, preterm birth, or chronic kidney disease, may display an increased subsequent risk of SLE. PMID:27472738

  3. Parent-offspring conflict and the persistence of pregnancy-induced hypertension in modern humans.

    PubMed

    Hollegaard, Birgitte; Byars, Sean G; Lykke, Jacob; Boomsma, Jacobus J

    2013-01-01

    Preeclampsia is a major cause of perinatal mortality and disease affecting 5-10% of all pregnancies worldwide, but its etiology remains poorly understood despite considerable research effort. Parent-offspring conflict theory suggests that such hypertensive disorders of pregnancy may have evolved through the ability of fetal genes to increase maternal blood pressure as this enhances general nutrient supply. However, such mechanisms for inducing hypertension in pregnancy would need to incur sufficient offspring health benefits to compensate for the obvious risks for maternal and fetal health towards the end of pregnancy in order to explain why these disorders have not been removed by natural selection in our hunter-gatherer ancestors. We analyzed >750,000 live births in the Danish National Patient Registry and all registered medical diagnoses for up to 30 years after birth. We show that offspring exposed to pregnancy-induced hypertension (PIH) in trimester 1 had significantly reduced overall later-life disease risks, but increased risks when PIH exposure started or developed as preeclampsia in later trimesters. Similar patterns were found for first-year mortality. These results suggest that early PIH leading to improved postpartum survival and health represents a balanced compromise between the reproductive interests of parents and offspring, whereas later onset of PIH may reflect an unbalanced parent-offspring conflict at the detriment of maternal and offspring health. PMID:23451092

  4. Parent-Offspring Conflict and the Persistence of Pregnancy-Induced Hypertension in Modern Humans

    PubMed Central

    Lykke, Jacob; Boomsma, Jacobus J.

    2013-01-01

    Preeclampsia is a major cause of perinatal mortality and disease affecting 5–10% of all pregnancies worldwide, but its etiology remains poorly understood despite considerable research effort. Parent-offspring conflict theory suggests that such hypertensive disorders of pregnancy may have evolved through the ability of fetal genes to increase maternal blood pressure as this enhances general nutrient supply. However, such mechanisms for inducing hypertension in pregnancy would need to incur sufficient offspring health benefits to compensate for the obvious risks for maternal and fetal health towards the end of pregnancy in order to explain why these disorders have not been removed by natural selection in our hunter-gatherer ancestors. We analyzed >750,000 live births in the Danish National Patient Registry and all registered medical diagnoses for up to 30 years after birth. We show that offspring exposed to pregnancy-induced hypertension (PIH) in trimester 1 had significantly reduced overall later-life disease risks, but increased risks when PIH exposure started or developed as preeclampsia in later trimesters. Similar patterns were found for first-year mortality. These results suggest that early PIH leading to improved postpartum survival and health represents a balanced compromise between the reproductive interests of parents and offspring, whereas later onset of PIH may reflect an unbalanced parent-offspring conflict at the detriment of maternal and offspring health. PMID:23451092

  5. Increased Risk of Intracranial Hemorrhage in Patients With Pregnancy-Induced Hypertension

    PubMed Central

    Lin, Li-Te; Tsui, Kuan-Hao; Cheng, Jiin-Tsuey; Cheng, Jin-Shiung; Huang, Wei-Chun; Liou, Wen-Shiung; Tang, Pei-Ling

    2016-01-01

    Abstract Pregnancy-induced hypertension (PIH) may be a major predictor of pregnancy-associated intracranial hemorrhage (ICH). However, the relationship between PIH and long-term ICH risk is unknown. The objective of the study was to determine the association between PIH and ICH and to identify the predictive risk factors. Patients with newly diagnosed PIH were recruited from the Taiwan National Health Insurance Research Database. PIH patients were divided into gestational hypertension (GH) and preeclampsia groups. The 2 groups were separately compared with matched cohorts of patients without PIH based on age and date of delivery. The occurrence of ICH was evaluated in both cohorts. The overall observational period was from January 1, 2000 to December 31, 2013. Among the 23.3 million individuals registered in the National Health Insurance Research Database, 28,346 PIH patients, including 7390 with GH and 20,956 with preeclampsia, were identified. The incidences of ICH were increased in both groups (incidence rate ratio [IRR] = 3.72 in the GH group, 95% confidence interval [CI] 3.63–3.81, P < 0.0001 and IRR = 8.21 in the preeclampsia group, 95% CI 8.12–8.31, P < 0.0001, respectively). In addition, according to the results of stratification of follow-up years, both groups were associated with a highest risk of ICH at 1 to 5 years of follow-up (IRR = 11.99, 95% CI 11.16–12.88, P < 0.0001 and IRR = 21.83, 95% CI 21.24–22.44, P < 0.0001, respectively). After adjusting for age, parity, severity of PIH, number of PIH occurrences, gestational age, and comorbidities in the multivariate survival analysis using Cox regression model, age ≥30 years (hazard ratio [HR] 1.99, 95% CI 1.27–3.10, P = 0.0026), patients with preeclampsia (HR 2.18, 95% CI 1.22–3.90, P = 0.0089), multiple PIH occurrences (HR 4.08, 95% CI 1.85–9.01, P = 0.0005), hypertension (HR 4.51, 95% CI 1.89–10.74, P = 0.0007), and obesity (HR 7.21, 95

  6. Inhaled Corticosteroids Use Is Not Associated With an Increased Risk of Pregnancy-Induced Hypertension and Gestational Diabetes Mellitus

    PubMed Central

    Lee, Chang-Hoon; Kim, Jimin; Jang, Eun Jin; Lee, Joon-Ho; Kim, Yun Jung; Choi, Seongmi; Kim, Deog Kyeom; Yim, Jae-Joon; Yoon, Ho Il

    2016-01-01

    Abstract There have been concerns that systemic corticosteroid use is associated with pregnancy-induced hypertension (PIH) and diabetes mellitus. However, the relationship between inhaled corticosteroids (ICSs) and the risk of PIH has not been fully examined, and there was no study investigating the association between ICS use and the development of gestational diabetes mellitus (GDM). The aims of the study are to determine whether the use of ICSs during pregnancy increases the risk of PIH and GDM in women. We conducted 2 nested case-control studies utilizing the nationwide insurance claims database of the Health Insurance Review and Assessment Service (Seoul, Republic of Korea), in which 1,306,281 pregnant women who delivered between January 1, 2009 and December 31, 2011 were included. Among them, PIH cases and GDM cases were identified and matched controls were included. Conditional logistic regression analyses adjusted by other concomitant drugs use during and before pregnancy and confounding covariates including comorbidities were performed. Total 43,908 PIH cases and 219,534 controls, and 34,190 GDM cases and 170,934 control subjects were identified. When other concomitant drugs use during pregnancy was adjusted, ICS use was associated with an increased rate of PIH (adjusted odds ratio, 1.40 [95% CI, 1.05–1.87]). ICS medication possession ratios and cumulative doses were associated with an increased risk of PIH. However, the statistical significance was not found in other models. In both unadjusted and adjusted multivariable models, ICSs use was not associated with increase in the risk of GDM. ICSs use is not associated with an increased risk of PIH and GDM. PMID:27258493

  7. A Combined Supplementation of Omega-3 Fatty Acids and Micronutrients (Folic Acid, Vitamin B12) Reduces Oxidative Stress Markers in a Rat Model of Pregnancy Induced Hypertension

    PubMed Central

    Kemse, Nisha G.; Kale, Anvita A.; Joshi, Sadhana R.

    2014-01-01

    Objectives Our earlier studies have highlighted that an altered one carbon metabolism (vitamin B12, folic acid, and docosahexaenoic acid) is associated with preeclampsia. Preeclampsia is also known to be associated with oxidative stress and inflammation. The current study examines whether maternal folic acid, vitamin B12 and omega-3 fatty acid supplementation given either individually or in combination can ameliorate the oxidative stress markers in a rat model of pregnancy induced hypertension (PIH). Materials and Methods Pregnant Wistar rats were assigned to control and five treatment groups: PIH; PIH + vitamin B12; PIH + folic acid; PIH + Omega-3 fatty acids and PIH + combined micronutrient supplementation (vitamin B12 + folic acid + omega-3 fatty acids). L-Nitroarginine methylester (L-NAME; 50 mg/kg body weight/day) was used to induce hypertension during pregnancy. Blood Pressure (BP) was recorded during pregnancy and dams were dissected at d20 of gestation. Results Animals from the PIH group demonstrated higher (p<0.01 for both) systolic and diastolic BP; lower (p<0.01) pup weight; higher dam plasma homocysteine (p<0.05) and dam and offspring malondialdehyde (MDA) (p<0.01), lower (p<0.05) placental and offspring liver DHA and higher (p<0.01) tumor necrosis factor–alpha (TNF–ά) levels as compared to control. Individual micronutrient supplementation did not offer much benefit. In contrast, combined supplementation lowered systolic BP, homocysteine, MDA and placental TNF-ά levels in dams and liver MDA and protein carbonyl in the offspring as compared to PIH group. Conclusion Key constituents of one carbon cycle (folic acid, vitamin B12 and DHA) may play a role in reducing oxidative stress and inflammation in preeclampsia. PMID:25405347

  8. Inhaled Corticosteroids Use Is Not Associated With an Increased Risk of Pregnancy-Induced Hypertension and Gestational Diabetes Mellitus: Two Nested Case-Control Studies.

    PubMed

    Lee, Chang-Hoon; Kim, Jimin; Jang, Eun Jin; Lee, Joon-Ho; Kim, Yun Jung; Choi, Seongmi; Kim, Deog Kyeom; Yim, Jae-Joon; Yoon, Ho Il

    2016-05-01

    There have been concerns that systemic corticosteroid use is associated with pregnancy-induced hypertension (PIH) and diabetes mellitus. However, the relationship between inhaled corticosteroids (ICSs) and the risk of PIH has not been fully examined, and there was no study investigating the association between ICS use and the development of gestational diabetes mellitus (GDM). The aims of the study are to determine whether the use of ICSs during pregnancy increases the risk of PIH and GDM in women.We conducted 2 nested case-control studies utilizing the nationwide insurance claims database of the Health Insurance Review and Assessment Service (Seoul, Republic of Korea), in which 1,306,281 pregnant women who delivered between January 1, 2009 and December 31, 2011 were included. Among them, PIH cases and GDM cases were identified and matched controls were included. Conditional logistic regression analyses adjusted by other concomitant drugs use during and before pregnancy and confounding covariates including comorbidities were performed.Total 43,908 PIH cases and 219,534 controls, and 34,190 GDM cases and 170,934 control subjects were identified. When other concomitant drugs use during pregnancy was adjusted, ICS use was associated with an increased rate of PIH (adjusted odds ratio, 1.40 [95% CI, 1.05-1.87]). ICS medication possession ratios and cumulative doses were associated with an increased risk of PIH. However, the statistical significance was not found in other models. In both unadjusted and adjusted multivariable models, ICSs use was not associated with increase in the risk of GDM.ICSs use is not associated with an increased risk of PIH and GDM. PMID:27258493

  9. [Vasoactive prostanoids and inhibitors of blood coagulation in pregnancy-induced hypertension].

    PubMed

    Peterseim, H; Kemkes-Matthes, B

    1994-01-01

    The aim of the present study was to investigate the occurrence of changes in the plasma levels of vasoactive prostanoids and inhibitors of blood coagulation in normal pregnancy and in cases of pregnancy induced hypertension. Levels of the coagulation inhibitors antithrombin III, protein C, Protein S as well as the prostaglandin metabolites thromboxane B2 and 6-oxo-prostaglandin F1 alpha were measured between 13 and 37 weeks gestation in 36 primigravidae. In 8 of the examined patients persistently raised blood pressure values of 140/90 and above were measured after 20 weeks of gestation. Our results indicated that an imbalance of vasoactive prostanoids may precede the appearance of clinical symptoms of PIH. The determination of coagulation factors before blood pressure is elevated has no predictive value regarding the later development of PIH. The reduced levels of protein C associated with our PIH group are considered to be the result of an activated coagulation followed by consumption of clotting factors. Reduced measured levels of protein S in normotensive as well as hypertensive pregnancies offer an explanation for the increased risk of thromboembolic disease. This increased susceptibility to thromboembolic disorders is further enhanced by the altered balance between the platelet aggregator and vasoconstrictor thromboxane A2 and its antagonist prostacyclin. PMID:8048287

  10. Spectrum of hypertensive emergencies in pregnancy.

    PubMed

    Henry, Charles S; Biedermann, Scott A; Campbell, Michel F; Guntupalli, Jayarama S

    2004-10-01

    Hypertension in pregnancy represents a spectrum of clinical entities, including pregnancy-induced hypertension (PIH), preeclampsia, eclampsia, and hemolysis, elevated liver enzyme levels, low platelet count syndrome. Although hypertension is a common denominator in this group of disorders, the pathogenesis, clinical features, and clinical course of these disorders is variable and somewhat distinct. Therapy must be tailored to the clinical entity and the patient. The incidence and prevalence of preeclampsia and eclampsia is decreasing worldwide. This decrease partly may be caused by the improved treatment of PIH and improved obstetrical services. PMID:15388197

  11. Valproate Induced Hypertensive Urgency

    PubMed Central

    Sivananthan, Mauran

    2016-01-01

    Valproate is a medication used in the treatment of seizures, bipolar disorder, migraines, and behavioral problems. Here we present a case of an 8-year-old boy who presented with hypertensive urgency after initiation of valproate. Primary treatment of his hypertension was ineffective. Blood pressure stabilization was achieved following discontinuation of valproate. Clinicians should be aware of the risk of developing hypertensive urgency with administration of valproate. PMID:27403366

  12. Pregnancy-Induced Hypertension

    MedlinePlus

    ... upper arm. Then they listen to your blood flow with a stethoscope. High blood pressure (also called hypertension) occurs when your ... is not a good idea if you have high blood pressure during pregnancy. Your body needs salt to keep up the flow of fluid in your body, so you need ...

  13. Application of Optical Coherence Tomography and Contrast Sensitivity Test for Observing Fundus Changes of Patients With Pregnancy-Induced Hypertension Syndrome

    PubMed Central

    Wang, Zhixue; Zou, Yuanyuan; Li, Wenying; Wang, Xueyan; Zhang, Min; Wang, Wenying

    2015-01-01

    Abstract This study was aimed to investigate the fundus changes of patients with pregnancy-induced hypertension syndrome (PIHS) using optical coherence tomography (OCT) technology and contrast sensitivity (CS) tests. Ninety-eight patients with PIHS underwent routine eye examinations including vision correction, fundus examination, OCT, and CS tests. The CS test was performed at low, medium, and high frequency, respectively. Moreover, the difference in CS tests between 2 groups was analyzed by independent-samples T test. The Kruskal–Wallis rank sum test and linear regression model were used to detect the correlation of OCT with CS, respectively. Meanwhile Satterthwaite approximate T test was adopted for pairwise comparisons after nonparametric analysis of variance. The OCT test revealed that 56.76% of the examined eyes showed shallow retinal detachment in the macula lutea and around the optic disk. The differences in CS at each spatial frequency between the case and control group were statistically significant (P < 0.01). Besides, OCT manifestations were associated with CS at each spacial frequency including 1.5, 3, 6, 12, and 18 frequency (P < 0.01). And patients with abnormal manifestations of OCT showed lower CS at each spacial frequency than those without abnormal OCT manifestations. What's more the OCT manifestation 1 showed the greatest impact on CS at each spacial frequency. The results showed that abnormal OCT manifestations were correlated with CS in PIHS. OCT and CS tests might be valuable methods in observing fundus changes for PIHS patients. PMID:26554764

  14. Pheochromocytoma induced hypertension.

    PubMed

    Andrews, Deborah

    2010-12-01

    Pheochromocytoma (Pheo) is a rare tumor that develops in the core of a chromaffin cell. This article will focus on pheochromocytoma and its affect on the heart. Because the signs and symptoms of a pheochromocytoma are those of the sympathetic nervous system, this tumor is hard to detect and might not be considered early on. In addition, there are many common deferential diagnoses that may lead to a delay of the correct diagnosis of a pheochromocytoma. Uncontrollable hypertension is one of the primary effects of pheochromocytoma. A severe increase in blood pressure (hypertensive crisis) may occur and this can be a life threatening condition that leads to stroke or arrhythmias. African-Americans are disproportionately affected by hypertension and they often go undiagnosed because of a lack of resources or access to care. This tumor is difficult to detect and its effects often mimic many other diagnoses, which often leads to this tumor being a late consideration. The long-term effects of a pheochromocytoma can lead to damage to the heart muscle, congestive heart failure (CHF), increased risk of diabetes, and even death. Nurses need to be aware of the key signs and symptoms of a pheochromocytoma, and to know when testing for this tumor what symptoms should be considered. Patients who suffer from a diagnosis of this tumor need a lot of emotional support and they must follow a strict diet and medication regimen. Nurses can play a vital role in raising awareness in our community about this tumor as well as being a patient advocate. PMID:21516925

  15. Carbamazepine-induced hypertension: A rare case

    PubMed Central

    Kharb, Preeti; Mittal, Niti; Gupta, Mahesh C.

    2015-01-01

    A 74-year-old female with trigeminal neuralgia developed hypertension after the initiation of carbamazepine therapy. The time sequence of start of the suspected drug and onset of hypertension are consistent with the diagnosis. The hypertension did not resolve with antihypertensive therapy or dose reduction of carbamazepine. Patient recovered after the carbamazepine therapy was discontinued. The positive rechallenge and positive dechallenge showed association of carbamazepine therapy with hypertension as its adverse effect. This is a rare case that we report of carbamazepine-induced hypertension and this report may act as alerting mechanism to the health care professionals especially neurologists. PMID:26816475

  16. Drugs induced pulmonary arterial hypertension.

    PubMed

    Seferian, Andrei; Chaumais, Marie-Camille; Savale, Laurent; Günther, Sven; Tubert-Bitter, Pascale; Humbert, Marc; Montani, David

    2013-09-01

    Pulmonary arterial hypertension (PAH) is a rare disorder characterized by progressive obliteration of the pulmonary microvasculature, resulting in elevated pulmonary vascular resistance and premature death. According to the current classification, PAH can be associated with exposure to certain drugs or toxins, particularly appetite suppressant drugs, such as aminorex, fenfluramine derivatives and benfluorex. These drugs have been confirmed to be risk factors for PAH and were withdrawn from the market. The supposed mechanism is an increase in serotonin levels, which was demonstrated to act as a growth factor for the pulmonary arterial smooth muscle cells. Amphetamines, phentermine and mazindol were less frequently used but are also considered as possible risk factors for PAH. Dasatinib, a dual Src/Abl kinase inhibitor, used in the treatment of chronic myelogenous leukaemia was associated with cases of severe PAH, in part reversible after its withdrawal. Recently several studies raised the potential endothelial dysfunction that could be induced by interferon, and few cases of PAH have been reported with interferon therapy. Other possible risk factors for PAH include: nasal decongestants, like phenylpropanolamine, dietary supplement - L-Tryptophan, selective serotonin reuptake inhibitors, pergolide and other drugs that could act on 5HT2B receptors. Interestingly, PAH remains a rare complication of these drugs, suggesting possible individual susceptibility and further studies are needed to identify patients at risk of drugs induced PAH. PMID:23972547

  17. Application of Optical Coherence Tomography and Contrast Sensitivity Test for Observing Fundus Changes of Patients With Pregnancy-Induced Hypertension Syndrome.

    PubMed

    Wang, Zhixue; Zou, Yuanyuan; Li, Wenying; Wang, Xueyan; Zhang, Min; Wang, Wenying

    2015-11-01

    This study was aimed to investigate the fundus changes of patients with pregnancy-induced hypertension syndrome (PIHS) using optical coherence tomography (OCT) technology and contrast sensitivity (CS) tests.Ninety-eight patients with PIHS underwent routine eye examinations including vision correction, fundus examination, OCT, and CS tests. The CS test was performed at low, medium, and high frequency, respectively. Moreover, the difference in CS tests between 2 groups was analyzed by independent-samples T test. The Kruskal-Wallis rank sum test and linear regression model were used to detect the correlation of OCT with CS, respectively. Meanwhile Satterthwaite approximate T test was adopted for pairwise comparisons after nonparametric analysis of variance.The OCT test revealed that 56.76% of the examined eyes showed shallow retinal detachment in the macula lutea and around the optic disk. The differences in CS at each spatial frequency between the case and control group were statistically significant (P < 0.01). Besides, OCT manifestations were associated with CS at each spacial frequency including 1.5, 3, 6, 12, and 18 frequency (P < 0.01). And patients with abnormal manifestations of OCT showed lower CS at each spacial frequency than those without abnormal OCT manifestations. What's more the OCT manifestation 1 showed the greatest impact on CS at each spacial frequency.The results showed that abnormal OCT manifestations were correlated with CS in PIHS. OCT and CS tests might be valuable methods in observing fundus changes for PIHS patients. PMID:26554764

  18. Fish Oil Supplementation does not Reduce Risks of Gestational Diabetes Mellitus, Pregnancy-Induced Hypertension, or Pre-Eclampsia: A Meta-Analysis of Randomized Controlled Trials

    PubMed Central

    Chen, Bing; Ji, Xinran; Zhang, Lei; Hou, Zhaohui; Li, Chundong; Tong, Ying

    2015-01-01

    Background The effects of gestational supplementation with fish oil on risks for gestational diabetes mellitus (GDM), pregnancy-induced hypertension (PIH), and pre-eclampsia (PE) have not been confirmed. In this study, a meta-analysis was performed to evaluate the effect of fish oil supplementation on these gestational complications. Material/Methods Randomized controlled human trials that investigated the effects of fish oil supplementation in pregnant women were identified by a systematic search of Medline, Embase, and Cochrane’s Library, and references of related reviews and studies up to December 2014. Relative risks (RRs) for GDM, PIH, and PE were the outcomes of interest. Fixed-effects or random-effects models were applied according to the heterogeneity. Results Thirteen comparisons from 11 published articles, including more than 5000 participants, were included. The results showed that fish oil supplementation was not associated with reduced risks for GDM (RR=1.06, 95% confidence interval [CI]: 0.85–1.32, p=0.60), PIH (RR=1.03, 95% CI: 0.89–1.20, p=0.66), or PE (RR=0.93, 95% CI: 0.74–1.16, p=0.51). No statistically significant heterogeneity was detected for the comparison of each outcome. The effects of fish oil on these gestational complications were consistent between women with low-risk and high-risk pregnancies. Conclusions Gestational supplementation with fish oil during the second or third trimester of pregnancy is not associated with reduced risks for GDM, PIH, or PE. Other possible benefits of fish oil supplementation during pregnancy warrant further evaluation. PMID:26256041

  19. Fentanyl-droperidol supplementation of rapid sequence induction in the presence of severe pregnancy-induced and pregnancy-aggravated hypertension.

    PubMed

    Lawes, E G; Downing, J W; Duncan, P W; Bland, B; Lavies, N; Gane, G A

    1987-11-01

    Twenty-six patients manifesting severe pregnancy-induced (PIH) or pregnancy-aggravated (PAH) hypertension who presented for emergency Caesarean section under general anaesthesia were studied. All patients came from a previously identified high risk group--namely greater than 25 yr, multiparous and with diastolic arterial pressures sustained at greater than 120 mm Hg. Our standard accelerated induction technique for the management of severely hypertensive mothers was modified to include the use of fentanyl and droperidol before induction. This modification of the induction sequence produced a clinically significant amelioration of the reflex sympathetic hypertensive response to laryngoscopy and intubation in most mothers receiving antihypertensive therapy, without apparent deleterious effect in the immediate postoperative period to those neonates unaffected by intrauterine asphyxia. PMID:3689612

  20. Mother-induced hypertension in familial dysautonomia.

    PubMed

    Norcliffe-Kaufmann, Lucy; Palma, Jose-Alberto; Kaufmann, Horacio

    2016-02-01

    Here we report the case of a patient with familial dysautonomia (a genetic form of afferent baroreflex failure), who had severe hypertension (230/149 mmHg) induced by the stress of his mother taking his blood pressure. His hypertension subsided when he learnt to measure his blood pressure without his mother's involvement. The case highlights how the reaction to maternal stress becomes amplified when catecholamine release is no longer under baroreflex control. PMID:26589199

  1. Obesity-Induced Hypertension: Brain Signaling Pathways.

    PubMed

    do Carmo, Jussara M; da Silva, Alexandre A; Wang, Zhen; Fang, Taolin; Aberdein, Nicola; de Lara Rodriguez, Cecilia E P; Hall, John E

    2016-07-01

    Obesity greatly increases the risk for cardiovascular, metabolic, and renal diseases and is one of the most significant and preventable causes of increased blood pressure (BP) in patients with essential hypertension. This review highlights recent advances in our understanding of central nervous system (CNS) signaling pathways that contribute to the etiology and pathogenesis of obesity-induced hypertension. We discuss the role of excess adiposity and activation of the brain leptin-melanocortin system in causing increased sympathetic activity in obesity. In addition, we highlight other potential brain mechanisms by which increased weight gain modulates metabolic and cardiovascular functions. Unraveling the CNS mechanisms responsible for increased sympathetic activation and hypertension and how circulating hormones activate brain signaling pathways to control BP offer potentially important therapeutic targets for obesity and hypertension. PMID:27262997

  2. The Proteasome Subunit Rpn8 Interacts with the Small Nucleolar RNA Protein (snoRNP) Assembly Protein Pih1 and Mediates Its Ubiquitin-independent Degradation in Saccharomyces cerevisiae.

    PubMed

    Paci, Alexandr; Liu, Peter X H; Zhang, Lingjie; Zhao, Rongmin

    2016-05-27

    Pih1 is a scaffold protein of the Rvb1-Rvb2-Tah1-Pih1 (R2TP) protein complex, which is conserved in fungi and animals. The chaperone-like activity of the R2TP complex has been implicated in the assembly of multiple protein complexes, such as the small nucleolar RNA protein complex. However, the mechanism of the R2TP complex activity in vivo and the assembly of the complex itself are still largely unknown. Pih1 is an unstable protein and tends to aggregate when expressed alone. The C-terminal fragment of Pih1 contains multiple destabilization factors and acts as a degron when fused to other proteins. In this study, we investigated Pih1 interactors and identified a specific interaction between Pih1 and the proteasome subunit Rpn8 in yeast Saccharomyces cerevisiae when HSP90 co-chaperone Tah1 is depleted. By analyzing truncation mutants, we identified that the C-terminal 30 amino acids of Rpn8 are sufficient for the binding to Pih1 C terminus. With in vitro and in vivo degradation assays, we showed that the Pih1 C-terminal fragment Pih1(282-344) is able to induce a ubiquitin-independent degradation of GFP. Additionally, we demonstrated that truncation of the Rpn8 C-terminal disordered region does not affect proteasome assembly but specifically inhibits the degradation of the GFP-Pih1(282-344) fusion protein in vivo and Pih1 in vitro We propose that Pih1 is a ubiquitin-independent proteasome substrate, and the direct interaction with Rpn8 C terminus mediates its proteasomal degradation. PMID:27053109

  3. Hypoxia Inducible Factors and Hypertension: Lessons from Sleep Apnea Syndrome

    PubMed Central

    Nanduri, Jayasri; Peng, Ying-Jie; Yuan, Guoxiang; Kumar, Ganesh K.; Prabhakar, Nanduri R.

    2015-01-01

    Systemic hypertension is one of the most prevalent cardiovascular diseases. Sleep disordered breathing (SDB) with recurrent apnea is a major risk factor for developing essential hypertension. Chronic intermittent hypoxia (CIH) is a hallmark manifestation of recurrent apnea. Rodent models patterned after the O2 profiles seen with SDB patients showed that CIH is the major stimulus for causing systemic hypertension. This article reviews the physiological and molecular basis of CIH-induced hypertension. Physiological studies have identified that augmented carotid body chemosensory reflex and the resulting increase in sympathetic nerve activity is a major contributor to CIH-induced hypertension. Analysis of molecular mechanisms revealed that CIH activates hypoxia-inducible factor (HIF)-1 and suppresses HIF-2- mediated transcription. Dysregulation of HIF-1- and HIF-2- mediated transcription leads to imbalance of pro-oxidant and anti-oxidant enzyme gene expression resulting in increased reactive species (ROS) generation in the chemosensory reflex which is central for developing hypertension. PMID:25772710

  4. Mechanisms of intermittent hypoxia induced hypertension

    PubMed Central

    Bosc, Laura V González; Resta, Thomas; Walker, Benjimen; Kanagy, Nancy L

    2010-01-01

    Abstract Exposing rodents to brief episodes of hypoxia mimics the hypoxemia and the cardiovascular and metabolic effects observed in patients with obstructive sleep apnoea (OSA), a condition that affects between 5% and 20% of the population. Apart from daytime sleepiness, OSA is associated with a high incidence of systemic and pulmonary hypertension, peripheral vascular disease, stroke and sudden cardiac death. The development of animal models to study sleep apnoea has provided convincing evidence that recurrent exposure to intermittent hypoxia (IH) has significant vascular and haemodynamic impact that explain much of the cardiovascular morbidity and mortality observed in patients with sleep apnoea. However, the molecular and cellular mechanisms of how IH causes these changes is unclear and under investigation. This review focuses on the most recent findings addressing these mechanisms. It includes a discussion of the contribution of the nervous system, circulating and vascular factors, inflammatory mediators and transcription factors to IH-induced cardiovascular disease. It also highlights the importance of reactive oxygen species as a primary mediator of the systemic and pulmonary hypertension that develops in response to exposure to IH. PMID:19818095

  5. The effect of hypertensive disorders in pregnancy on small for gestational age and stillbirth: a population based study.

    PubMed

    Allen, Victoria M; Joseph, KS; Murphy, Kellie E; Magee, Laura A; Ohlsson, Arne

    2004-08-01

    BACKGROUND: Hypertensive disorders in pregnancy are leading causes of maternal, fetal and neonatal morbidity and mortality worldwide. However, studies attempting to quantify the effect of hypertension on adverse perinatal outcomes have been mostly conducted in tertiary centres. This population-based study explored the frequency of hypertensive disorders in pregnancy and the associated increase in small for gestational age (SGA) and stillbirth. METHODS: We used information on all pregnant women and births, in the Canadian province of Nova Scotia, between 1988 and 2000. Pregnancies were excluded if delivery occurred < 20 weeks, if birthweight was < 500 grams, if there was a high-order multiple pregnancy (greater than twin gestation), or a major fetal anomaly. RESULTS: The study population included 135,466 pregnancies. Of these, 7.7% had mild pregnancy-induced hypertension (PIH), 1.3% had severe PIH, 0.2% had HELLP (hemolysis, elevated liver enzymes, low platelets), 0.02% had eclampsia, 0.6% had chronic hypertension, and 0.4% had chronic hypertension with superimposed PIH. Women with any hypertension in pregnancy were 1.6 (95% CI 1.5-1.6) times more likely to have a live birth with SGA and 1.4 (95% CI 1.1-1.8) times more likely to have a stillbirth as compared with normotensive women. Adjusted analyses showed that women with gestational hypertension without proteinuria (mild PIH) and with proteinuria (severe PIH, HELLP, or eclampsia) were more likely to have infants with SGA (RR 1.5, 95% CI 1.4-1.6 and RR 3.2, 95% CI 2.8-3.6, respectively). Women with pre-existing hypertension were also more likely to give birth to an infant with SGA (RR 2.5, 95% CI 2.2-3.0) or to have a stillbirth (RR 3.2, 95% CI 1.9-5.4). CONCLUSIONS: This large, population-based study confirms and quantifies the magnitude of the excess risk of small for gestational age and stillbirth among births to women with hypertensive disease in pregnancy. PMID:15298717

  6. Maternal serum ischemia modified albumin as a marker for hypertensive disorders of pregnancy: a pilot study

    PubMed Central

    Vyakaranam, Sapna; Bhongir, Aparna Varma; Patlolla, Dakshayani; Chintapally, Rekha

    2015-01-01

    Background Hypoxia driven oxidative stress of the placenta contributes to the pathogenesis of preeclampsia. Serum Ischemia Modified Albumin (IMA) has recently emerged as an oxidative stress marker, used in diagnosis of cardiac ischemia. Aim: To determine the efficiency of serum IMA in differentiating hypertensive disorders of pregnancy (pregnancy induced hypertension, preeclampsia) from normal pregnancy. Methods It was a case control study. Pregnant women ≥32 weeks of gestation. Study population were included 3 groups, 19 Normotensive Pregnant (NP) women as controls, 18 pregnant women with Pregnancy Induced Hypertension (PIH) and 19 with preeclampsia (PE). Serum IMA was estimated by Enzyme Linked Immune Sorbent Assay (ELISA). Results were analyzed by student ‘t’test. Critical values for serum IMA were obtained by Receiver Operation Characteristics (ROC) curves. Results Serum IMA levels were significantly elevated in PE (56.84 ± 21.57 ng/ml) when compared with PIH (36.24 ± 14.51 ng/ml) and NP (35.47 ± 11.58 ng/ml) (P value <0.001). With a cutoff of 38.33 ng/ml, sensitivity and specificity for preeclampsia was 88.9% and 73.7% respectively. Conclusions Our study demonstrated that serum IMA, an oxidative stress marker is elevated in PE & PIH. Hence serum IMA can undergo further evaluation as a marker of PE. PMID:26636109

  7. New developments in the pathogenesis of obesity-induced hypertension.

    PubMed

    Kotsis, Vasilios; Nilsson, Peter; Grassi, Guido; Mancia, Giuseppe; Redon, Josep; Luft, Frank; Schmieder, Roland; Engeli, Stefan; Stabouli, Stella; Antza, Christina; Pall, Denes; Schlaich, Markus; Jordan, Jens

    2015-08-01

    Obesity is a disorder that develops from the interaction between genotype and environment involving social, behavioral, cultural, and physiological factors. Obesity increases the risk for type 2 diabetes mellitus, hypertension, cardiovascular disease, cancer, musculoskeletal disorders, chronic kidney and pulmonary disease. Although obesity is clearly associated with an increased prevalence of hypertension, many obese individuals may not develop hypertension. Protecting factors may exist and it is important to understand why obesity is not always related to hypertension. The aim of this review is to highlight the knowledge gap for the association between obesity, hypertension, and potential genetic and racial differences or environmental factors that may protect obese patients against the development of hypertension and other co-morbidities. Specific mutations in the leptin and the melaninocortin receptor genes in animal models of obesity without hypertension, the actions of α-melanocyte stimulating hormone, and SNS activity in obesity-related hypertension may promote recognition of protective and promoting factors for hypertension in obesity. Furthermore, gene-environment interactions may have the potential to modify gene expression and epigenetic mechanisms could also contribute to the heritability of obesity-induced hypertension. Finally, differences in nutrition, gut microbiota, exposure to sun light and exercise may play an important role in the presence or absence of hypertension in obesity. PMID:26103132

  8. Low incidence of hypertensive disorders of pregnancy in women treated with spiramycin for toxoplasma infection

    PubMed Central

    Todros, T; Verdiglione, P; Oggè, G; Paladini, D; Vergani, P; Cardaropoli, S

    2006-01-01

    Aims Toxoplasma infection in pregnancy is usually treated with long-term administration of the macrolide spiramycin to prevent fetal malformations. We had empirically observed that treated patients seldom developed pregnancy-induced hypertension (PIH), a common and severe disorder of pregnancy whose aetiology and pathogenesis are still debated. Some clinical and experimental data suggest that infection could play a role in its development. Methods To test this hypothesis, we studied a cohort of 417 pregnant women treated with spiramycin because of seroconversion for Toxoplasma gondii and 353 low-risk women who did not take any antibiotic during pregnancy. PIH was defined as blood pressure >140/90 mmHg on two or more occasions, occurring after 20 weeks of gestational age. Results Seventeen (5.2%) women in the control group developed PIH compared with two (0.5%) in the case group. The odds of developing the disease were significantly lower in the treated subjects (odds ratio =0.092, 95% confidence interval 0.021, 0.399; P < 0.001). Conclusions Our results suggest that antibiotic treatment during pregnancy can reduce the incidence of PIH, thus opening new perspectives in its prevention and therapy. PMID:16487228

  9. Mechanisms of obesity-induced hypertension.

    PubMed

    Kotsis, Vasilios; Stabouli, Stella; Papakatsika, Sofia; Rizos, Zoe; Parati, Gianfranco

    2010-05-01

    The relationship between obesity and hypertension is well established both in children and adults. The mechanisms through which obesity directly causes hypertension are still an area of research. Activation of the sympathetic nervous system has been considered to have an important function in the pathogenesis of obesity-related hypertension. The arterial-pressure control mechanism of diuresis and natriuresis, according to the principle of infinite feedback gain, seems to be shifted toward higher blood-pressure levels in obese individuals. During the early phases of obesity, primary sodium retention exists as a result of increase in renal tubular reabsorption. Extracellular-fluid volume is expanded and the kidney-fluid apparatus is resetted to a hypertensive level, consistent with a model of hypertension because of volume overload. Plasma renin activity, angiotensinogen, angiotensin II and aldosterone values display significant increase during obesity. Insulin resistance and inflammation may promote an altered profile of vascular function and consequently hypertension. Leptin and other neuropeptides are possible links between obesity and the development of hypertension. Obesity should be considered as a chronic medical condition, which is likely to require long-term treatment. Understanding of the mechanisms associated with obesity-related hypertension is essential for successful treatment strategies. PMID:20442753

  10. Spaceflight-Induced Intracranial Hypertension: An Overview

    NASA Technical Reports Server (NTRS)

    Traver, William J.

    2011-01-01

    This slide presentation is an overview of the some of the known results of spaceflight induced intracranial hypertension. Historical information from Gemini 5, Apollo, and the space shuttle programs indicated that some vision impairment was reported and a comparison between these historical missions and present missions is included. Optic Disc Edema, Globe Flattening, Choroidal Folds, Hyperopic Shifts and Raised Intracranial Pressure has occurred in Astronauts During and After Long Duration Space Flight. Views illustrate the occurrence of Optic Disc Edema, Globe Flattening, and Choroidal Folds. There are views of the Arachnoid Granulations and Venous return, and the question of spinal or venous compliance issues is discussed. The question of increased blood flow and its relation to increased Cerebrospinal fluid (CSF) is raised. Most observed on-orbit papilledema does not progress, and this might be a function of plateau homeostasis for the higher level of intracranial pressure. There are seven cases of astronauts experiencing in flight and post flight symptoms, which are summarized and follow-up is reviewed along with a comparison of the treatment options. The question is "is there other involvement besides vision," and other Clinical implications are raised,

  11. Functional Inducible Nitric Oxide Synthase Gene Variants Associate With Hypertension

    PubMed Central

    Nikkari, Seppo T.; Määttä, Kirsi M.; Kunnas, Tarja A.

    2015-01-01

    Abstract Increased inducible nitric oxide synthase (iNOS) activity and expression has been associated with hypertension, but less is known whether the 2 known functional polymorphic sites in the iNOS gene (g.–1026 C/A (rs2779249), g.2087 G/A (rs2297518)) affect susceptibility to hypertension. The objective of this study was to investigate the association between the genetic variants of iNOS and diagnosed hypertension in a Finnish cohort. This study included 320 hypertensive cases and 439 healthy controls. All participants were 50-year-old men and women and the data were collected from the Tampere adult population cardiovascular risk study (TAMRISK). DNA was extracted from buccal swabs and iNOS single nucleotide polymorphisms (SNPs) were analyzed using KASP genotyping PCR. Data analysis was done by logistic regression. At the age of 50 years, the SNP rs2779249 (C/A) associated significantly with hypertension (P = 0.009); specifically, subjects carrying the A-allele had higher risk of hypertension compared to those carrying the CC genotype (OR = 1.47; CI = 1.08–2.01; P = 0.015). In addition, a 15-year follow-up period (35, 40, and 45 years) of the same individuals showed that carriers of the A-allele had more often hypertension in all of the studied age-groups. The highest risk for developing hypertension was obtained among 35-year-old subjects (odds ratio [OR] 3.83; confidence interval [CI] = 1.20–12.27; P = 0.024). Those carrying variant A had also significantly higher readings of both systolic (P = 0.047) and diastolic (P = 0.048) blood pressure during the follow-up. No significant associations between rs2297518 (G/A) variants alone and hypertension were found. However, haplotype analysis of rs2779249 and rs2297518 revealed that individuals having haplotype H3 which combines both A alleles (CA–GA, 19.7% of individuals) was more commonly found in the hypertensive group than in the normotensive group (OR = 2.01; CI = 1

  12. Drug-Induced Ocular Hypertension and Angle-Closure Glaucoma.

    PubMed

    Badhu, Badri P; Bhattarai, Balkrishna; Sangraula, Himal P

    2013-01-01

    The objective of this study was to review the available literature on the drugs causing ocular hypertension and glaucoma. Electronic literature search was carried out using the Web sites www.pubmed.gov and www.google.com published through the year 2011. The search words were "drug induced ocular hypertension" and "drug induced glaucoma" used in combination. The articles published or translated into English were studied. Quite a significant number of drugs commonly prescribed by various physicians of different specialties can induce ocular hypertension or glaucoma. A brief account of various drugs that can induce ocular hypertension has been given in this article. Those drugs are parasympatholytics; steroids; anticholinergics, adrenergics, and antidepressants; cholinomimetics; antineoplastic agents; antipsychotic and antiparkinsonism agents; H1 and H2 receptor blockers; botulinum toxin, cardiac agents, and anticoagulants; silicone oil; sulfa drugs; and anesthetic agents. Rational use of these drugs and knowledge of their potential adverse effects can help prevent the devastating complications resulting in loss of vision and compromised quality of life. PMID:26108110

  13. The mechanisms underlying fructose-induced hypertension: a review

    PubMed Central

    Klein, Alice Victoria; Kiat, Hosen

    2015-01-01

    We are currently in the midst of an epidemic of metabolic disorders, which may, in part, be explained by excess fructose intake. This theory is supported by epidemiological observations as well as experimental studies in animals and humans. Rising consumption of fructose has been matched with growing rates of hypertension, leading to concern from public health experts. At this stage, the mechanisms underlying fructose-induced hypertension have not been fully characterized and the bulk of our knowledge is derived from animal models. Animal studies have shown that high-fructose diets up-regulate sodium and chloride transporters, resulting in a state of salt overload that increases blood pressure. Excess fructose has also been found to activate vasoconstrictors, inactivate vasodilators, and over-stimulate the sympathetic nervous system. Further work is required to determine the relevance of these findings to humans and to establish the level at which dietary fructose increases the risk of developing hypertension PMID:25715094

  14. Placental Growth Factor Administration Abolishes Placental Ischemia-Induced Hypertension.

    PubMed

    Spradley, Frank T; Tan, Adelene Y; Joo, Woo S; Daniels, Garrett; Kussie, Paul; Karumanchi, S Ananth; Granger, Joey P

    2016-04-01

    Preeclampsia is a pregnancy-specific disorder of new-onset hypertension. Unfortunately, the most effective treatment is early delivery of the fetus and placenta. Placental ischemia appears central to the pathogenesis of preeclampsia because placental ischemia/hypoxia induced in animals by reduced uterine perfusion pressure (RUPP) or in humans stimulates release of hypertensive placental factors into the maternal circulation. The anti-angiogenic factor soluble fms-like tyrosine kinase-1 (sFlt-1), which antagonizes and reduces bioavailable vascular endothelial growth factor and placental growth factor (PlGF), is elevated in RUPP rats and preeclampsia. Although PlGF and vascular endothelial growth factor are both natural ligands for sFlt-1, vascular endothelial growth factor also has high affinity to VEGFR2 (Flk-1) causing side effects like edema. PlGF is specific for sFlt-1. We tested the hypothesis that PlGF treatment reduces placental ischemia-induced hypertension by antagonizing sFlt-1 without adverse consequences to the mother or fetus. On gestational day 14, rats were randomized to 4 groups: normal pregnant or RUPP±infusion of recombinant human PlGF (180 μg/kg per day; AG31, a purified, recombinant human form of PlGF) for 5 days via intraperitoneal osmotic minipumps. On day 19, mean arterial blood pressure and plasma sFlt-1 were higher and glomerular filtration rate lower in RUPP than normal pregnant rats. Infusion of recombinant human PlGF abolished these changes seen with RUPP along with reducing oxidative stress. These data indicate that the increased sFlt-1 and reduced PlGF resulting from placental ischemia contribute to maternal hypertension. Our novel finding that recombinant human PlGF abolishes placental ischemia-induced hypertension, without major adverse consequences, suggests a strong therapeutic potential for this growth factor in preeclampsia. PMID:26831193

  15. Upregulated Copper Transporters in Hypoxia-Induced Pulmonary Hypertension

    PubMed Central

    Zimnicka, Adriana M.; Tang, Haiyang; Guo, Qiang; Kuhr, Frank K.; Oh, Myung-Jin; Wan, Jun; Chen, Jiwang; Smith, Kimberly A.; Fraidenburg, Dustin R.; Choudhury, Moumita S. R.; Levitan, Irena; Machado, Roberto F.; Kaplan, Jack H.; Yuan, Jason X.-J.

    2014-01-01

    Pulmonary vascular remodeling and increased arterial wall stiffness are two major causes for the elevated pulmonary vascular resistance and pulmonary arterial pressure in patients and animals with pulmonary hypertension. Cellular copper (Cu) plays an important role in angiogenesis and extracellular matrix remodeling; increased Cu in vascular smooth muscle cells has been demonstrated to be associated with atherosclerosis and hypertension in animal experiments. In this study, we show that the Cu-uptake transporter 1, CTR1, and the Cu-efflux pump, ATP7A, were both upregulated in the lung tissues and pulmonary arteries of mice with hypoxia-induced pulmonary hypertension. Hypoxia also significantly increased expression and activity of lysyl oxidase (LOX), a Cu-dependent enzyme that causes crosslinks of collagen and elastin in the extracellular matrix. In vitro experiments show that exposure to hypoxia or treatment with cobalt (CoCl2) also increased protein expression of CTR1, ATP7A, and LOX in pulmonary arterial smooth muscle cells (PASMC). In PASMC exposed to hypoxia or treated with CoCl2, we also confirmed that the Cu transport is increased using 64Cu uptake assays. Furthermore, hypoxia increased both cell migration and proliferation in a Cu-dependent manner. Downregulation of hypoxia-inducible factor 1α (HIF-1α) with siRNA significantly attenuated hypoxia-mediated upregulation of CTR1 mRNA. In summary, the data from this study indicate that increased Cu transportation due to upregulated CTR1 and ATP7A in pulmonary arteries and PASMC contributes to the development of hypoxia-induced pulmonary hypertension. The increased Cu uptake and elevated ATP7A also facilitate the increase in LOX activity and thus the increase in crosslink of extracellular matrix, and eventually leading to the increase in pulmonary arterial stiffness. PMID:24614111

  16. Sympathetic activation in rats with L-NAME-induced hypertension.

    PubMed

    Biancardi, V C; Bergamaschi, C T; Lopes, O U; Campos, R R

    2007-03-01

    We evaluated the hemodynamic pattern and the contribution of the sympathetic nervous system in conscious and anesthetized (1.4 g/kg urethane, iv) Wistar rats with L-NAME-induced hypertension (20 mg/kg daily). The basal hemodynamic profile was similar for hypertensive animals, conscious (N = 12) or anesthetized (N = 12) treated with L-NAME for 2 or 7 days: increase of total peripheral resistance associated with a decrease of cardiac output (CO) compared to normotensive animals, conscious (N = 14) or anesthetized (N = 14). Sympathetic blockade with hexamethonium essentially caused a decrease in total peripheral resistance in hypertensive animals (conscious, 2 days: from (means +/- SEM) 2.47 +/- 0.08 to 2.14 +/- 0.07; conscious, 7 days: from 2.85 +/- 0.13 to 2.07 +/- 0.33; anesthetized, 2 days: from 3.00 +/- 0.09 to 1.83 +/- 0.25 and anesthetized, 7 days: from 3.56 +/- 0.11 to 1.53 +/- 0.10 mmHg mL-1 min-1) with no change in CO in either group. However, in the normotensive group a fall in CO (conscious: from 125 +/- 4.5 to 96 +/- 4; anesthetized: from 118 +/- 1.5 to 104 +/- 5.5 mL/min) was observed. The responses after hexamethonium were more prominent in the hypertensive anesthetized group. However, no difference was observed between conscious and anesthetized normotensive rats in response to sympathetic blockade. The present study shows that the vasoconstriction in response to L-NAME was mediated by the sympathetic drive. The sympathetic tone plays an important role in the initiation and maintenance of hypertension. PMID:17334538

  17. Hypertension.

    PubMed

    Oparil, S; Calhoun, D A

    1989-03-01

    An estimated 58 million Americans are at increased risk of morbidity and premature death due to high blood pressure (BP) and require some type of therapy or systematic monitoring. This article focuses on recent advances in our understanding of the pathogenesis of hypertension, new approaches to the diagnosis and treatment of secondary hypertension, and current views of the most appropriate nonpharmacologic and pharmacologic therapy for essential hypertension. In view of the extremely high prevalence of the disorder, emphasis is placed on efficient and cost-effective strategies for diagnosing and managing the hypertensive patient. Recent evidence indicates that nonpharmacologic therapy, including dietary potassium and calcium supplements, reduction of salt intake, weight loss for the obese patient, regular exercise, a diet high in fiber and low in cholesterol and saturated fats, smoking cessation, and moderation of alcohol consumption produces significant sustained reductions in BP while reducing overall cardiovascular risk. Accordingly, nonpharmacologic antihypertensive therapy should be included in the treatment of all hypertensive patients. In persons with mild hypertension, nonpharmacologic approaches may adequately reduce BP, thereby avoiding the expense and potential side effects of drug therapy. In patients with more severe hypertension, nonpharmacologic therapy, used in conjunction with pharmacologic therapy, can reduce the dosage of antihypertensive medications necessary for BP control. Patients treated with nonpharmacologic therapy only should be followed closely, and if BP control is not satisfactory, drug therapy should be added. The large number of drugs available for use in hypertension treatment, coupled with our rapidly expanding knowledge of the pathophysiology of hypertension and of the adverse effects of these drugs in individual patient groups, make it possible to individualize antihypertensive treatment. When used as monotherapy, most agents

  18. Selenium status in U.K. pregnant women and its relationship with hypertensive conditions of pregnancy.

    PubMed

    Rayman, Margaret P; Bath, Sarah C; Westaway, Jacob; Williams, Peter; Mao, Jinyuan; Vanderlelie, Jessica J; Perkins, Anthony V; Redman, Christopher W G

    2015-01-28

    Dietary intake/status of the trace mineral Se may affect the risk of developing hypertensive conditions of pregnancy, i.e. pre-eclampsia and pregnancy-induced hypertension (PE/PIH). In the present study, we evaluated Se status in U.K. pregnant women to establish whether pre-pregnant Se status or Se supplementation affected the risk of developing PE/PIH. The samples originated from the SPRINT (Selenium in PRegnancy INTervention) study that randomised 230 U.K. primiparous women to treatment with Se (60 μg/d) or placebo from 12 weeks of gestation. Whole-blood Se concentration was measured at 12 and 35 weeks, toenail Se concentration at 16 weeks, plasma selenoprotein P (SEPP1) concentration at 35 weeks and plasma glutathione peroxidase (GPx3) activity at 12, 20 and 35 weeks. Demographic data were collected at baseline. Participants completed a FFQ. U.K. pregnant women had whole-blood Se concentration lower than the mid-range of other populations, toenail Se concentration considerably lower than U.S. women, GPx3 activity considerably lower than U.S. and Australian pregnant women, and low baseline SEPP1 concentration (median 3.00, range 0.90-5.80 mg/l). Maternal age, education and social class were positively associated with Se status. After adjustment, whole-blood Se concentration was higher in women consuming Brazil nuts (P= 0.040) and in those consuming more than two seafood portions per week (P= 0.054). A stepwise logistic regression model revealed that among the Se-related risk factors, only toenail Se (OR 0.38, 95% CI 0.17, 0.87, P= 0.021) significantly affected the OR for PE/PIH. On excluding non-compliers with Se treatment, Se supplementation also significantly reduced the OR for PE/PIH (OR 0.30, 95% CI 0.09, 1.00, P= 0.049). In conclusion, U.K. women have low Se status that increases their risk of developing PE/PIH. Therefore, U.K. women of childbearing age need to improve their Se status. PMID:25571960

  19. Hypertension.

    PubMed

    Poulter, Neil R; Prabhakaran, Dorairaj; Caulfield, Mark

    2015-08-22

    Raised blood pressure is the biggest single contributor to the global burden of disease and to global mortality. The numbers of people affected and the prevalence of high blood pressure worldwide are expected to increase over the next decade. Preventive strategies are therefore urgently needed, especially in less developed countries, and management of hypertension must be optimised. Genetic advances in some rare causes of hypertension have been made lately, but the aggregate effect on blood pressure of all the genetic loci identified to date is small. Hence, intervention on key environmental determinants and effective implementation of trial-based therapies are needed. Three-drug combinations can control hypertension in about 90% of patients but only if resources allow identification of patients and drug delivery is affordable. Furthermore, assessment of optimal drug therapy for each ethnic group is needed. PMID:25832858

  20. 76 FR 76432 - Notice of Proposed Information for Public Comment for: Capture Energy Efficiency Measures for PIH

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-12-07

    ... URBAN DEVELOPMENT Notice of Proposed Information for Public Comment for: Capture Energy Efficiency... public comments on the subject proposal. HUD is creating the Capture Energy Efficiency Measures for PIH... lists the following information: Title of Proposal: Capture Energy Efficiency Measures for PIH...

  1. Dasatinib induces lung vascular toxicity and predisposes to pulmonary hypertension.

    PubMed

    Guignabert, Christophe; Phan, Carole; Seferian, Andrei; Huertas, Alice; Tu, Ly; Thuillet, Raphaël; Sattler, Caroline; Le Hiress, Morane; Tamura, Yuichi; Jutant, Etienne-Marie; Chaumais, Marie-Camille; Bouchet, Stéphane; Manéglier, Benjamin; Molimard, Mathieu; Rousselot, Philippe; Sitbon, Olivier; Simonneau, Gérald; Montani, David; Humbert, Marc

    2016-09-01

    Pulmonary arterial hypertension (PAH) is a life-threatening disease that can be induced by dasatinib, a dual Src and BCR-ABL tyrosine kinase inhibitor that is used to treat chronic myelogenous leukemia (CML). Today, key questions remain regarding the mechanisms involved in the long-term development of dasatinib-induced PAH. Here, we demonstrated that chronic dasatinib therapy causes pulmonary endothelial damage in humans and rodents. We found that dasatinib treatment attenuated hypoxic pulmonary vasoconstriction responses and increased susceptibility to experimental pulmonary hypertension (PH) in rats, but these effects were absent in rats treated with imatinib, another BCR-ABL tyrosine kinase inhibitor. Furthermore, dasatinib treatment induced pulmonary endothelial cell apoptosis in a dose-dependent manner, while imatinib did not. Dasatinib treatment mediated endothelial cell dysfunction via increased production of ROS that was independent of Src family kinases. Consistent with these findings, we observed elevations in markers of endothelial dysfunction and vascular damage in the serum of CML patients who were treated with dasatinib, compared with CML patients treated with imatinib. Taken together, our findings indicate that dasatinib causes pulmonary vascular damage, induction of ER stress, and mitochondrial ROS production, which leads to increased susceptibility to PH development. PMID:27482885

  2. Evaluation of the Persistent Issues in History Laboratory for Virtual Field Experience (PIH-LVFE)

    ERIC Educational Resources Information Center

    Brush, Thomas; Saye, John; Kale, Ugur; Hur, Jung Won; Kohlmeier, Jada; Yerasimou, Theano; Guo, Lijiang; Symonette, Simone

    2009-01-01

    The Persistent Issues in History Laboratory for Virtual Field Experience (PIH-LVFE) combines a database of video cases of authentic classroom practices with multiple resources and tools to enable pre-service social studies teachers to virtually observe teachers implementing problem-based learning activities. In this paper, we present the results…

  3. Oleanolic acid prevents glucocorticoid-induced hypertension in rats.

    PubMed

    Bachhav, Sagar S; Patil, Savita D; Bhutada, Mukesh S; Surana, Sanjay J

    2011-10-01

    The present study was designed to evaluate the antihypertensive activity of oleanolic acid isolated from Viscum articulatum, Burm. (Loranthaceae) in glucocorticoid (dexamethasone)-induced hypertension in rats and to propose a probable mechanism of action for this effect. Male Wistar rats (300-350 g) received dexamethasone (20 μg/kg/day s.c.) or saline (vehicle) for 10 days. In a prevention study, the rats received oleanolic acid (60 mg/kg i.p.) for 5 days, followed by dexamethasone or saline for 10 days. During this period the systolic blood pressure and body weight were evaluated on alternate days. At the end of the experiment, the weight of the thymus gland, plasma nitrate/nitrite (nitric oxide metabolites) concentration and cardiac lipid peroxidation value were determined. Oleanolic acid (60 mg/kg i.p.) significantly prevented a rise in the systolic blood pressure and cardiac lipid peroxidation level after administration of dexamethasone (p < 0.01 and p < 0.05, respectively) without showing any significant effect on the dexamethasone-induced change in body and thymus weights. The decrease in concentration of plasma nitrate/nitrite due to dexamethasone was prevented significantly in the group treated with oleanolic acid (p < 0.05). These findings suggest that oleanolic acid (60 mg/kg i.p.) prevents dexamethasone-induced hypertension in rats, which may be attributed to its antioxidant and nitric oxide releasing action. PMID:21953707

  4. Exercise-Induced Systemic Venous Hypertension in the Fontan Circulation.

    PubMed

    Navaratnam, Devaraj; Fitzsimmons, Samantha; Grocott, Michael; Rossiter, Harry B; Emmanuel, Yaso; Diller, Gerard-Paul; Gordon-Walker, Timothy; Jack, Sandy; Sheron, Nick; Pappachan, John; Pratap, Jayant Nick; Vettukattil, Joseph J; Veldtman, Gruschen

    2016-05-15

    Increasingly end-organ injury is being demonstrated late after institution of the Fontan circulation, particularly liver fibrosis and cirrhosis. The exact mechanisms for these late phenomena remain largely elusive. Hypothesizing that exercise induces precipitous systemic venous hypertension and insufficient cardiac output for the exercise demand, that is, a possible mechanism for end-organ injury, we sought to demonstrate the dynamic exercise responses in systemic venous perfusion (SVP) and concurrent end-organ perfusion. Ten stable Fontan patients and 9 control subjects underwent incremental cycle ergometry-based cardiopulmonary exercise testing. SVP was monitored in the right upper limb, and regional tissue oxygen saturation was monitored in the brain and kidney using near-infrared spectroscopy. SVP rose profoundly in concert with workload in the Fontan group, described by the regression equation 15.97 + 0.073 watts per mm Hg. In contrast, SVP did not change in healthy controls. Regional renal (p <0.01) and cerebral tissue saturations (p <0.001) were significantly lower and decrease more rapidly in Fontan patients. We conclude that in a stable group of adult patients with Fontan circulation, high-intensity exercise was associated with systemic venous hypertension and reduced systemic oxygen delivery. This physiological substrate has the potential to contribute to end-organ injury. PMID:27032711

  5. Stress induced hypertensive response: should it be evaluated more carefully?

    PubMed Central

    2011-01-01

    Various diagnostic methods have been used to evaluate hypertensive patients under physical and pharmacological stress. Several studies have shown that exercise hypertension has an independent, adverse impact on outcome; however, other prognostic studies have shown that exercise hypertension is a favorable prognostic indicator and associated with good outcome. Exercise hypertension may be encountered as a warning signal of hypertension at rest and future hypertensive left ventricular hypertrophy. The results of diagnostic stress tests support that hypertensive response to exercise is frequently associated with high rate-pressure product in hypertensives. In addition to the observations on high rate-pressure product and enhanced ventricular contractility in patients with hypertension, evaluation of myocardial contractility by Doppler tissue imaging has shown hyperdynamic myocardial function under pharmacological stress. These recent quantitative data in hypertensives suggest that hyperdynamic myocardial function and high rate-pressure product response to stress may be related to exaggerated hypertension, which may have more importance than that it has been already given in clinical practice. PMID:21846346

  6. Pressure-Induced Renal Injury in Angiotensin II Versus Norepinephrine-Induced Hypertensive Rats

    PubMed Central

    Polichnowski, Aaron J.; Cowley, Allen W.

    2010-01-01

    The susceptibility to renal perfusion pressure (RPP)-induced renal injury was investigated in angiotensin II (AngII) versus norepinephrine (NE)-infused hypertensive rats. To determine the magnitude of RPP-induced injury, Sprague-Dawley rats fed a 4% salt diet were instrumented with a servocontrolled aortic balloon occluder positioned between the renal arteries to maintain RPP to the left kidney at baseline levels while the right kidney was exposed to elevated RPP during a 2 week infusion of: 1) AngII i.v. (25 ng/kg/min), 2) NE i.v. (0.5, 1, and 2 ug/kg/min on Days 1, 2, and 3-14, respectively), or saline i.v. (sham rats). Over the 14 days of AngII infusion, RPP averaged 161.5 ± 8 mmHg to uncontrolled kidneys and 121.9 ± 2 mmHg to servocontrolled kidneys. In NE-infused rats, RPP averaged 156.3 ± 3 mmHg to uncontrolled kidneys and 116.9 ± 2 mmHg to servocontrolled kidneys. RPP averaged 111.1 ± 1 mmHg to kidneys of sham rats. Interlobular arterial injury and juxtamedullary glomerulosclerosis were largely RPP-dependent in both models of hypertension. Superficial cortical glomerulosclerosis was greater and RPP-dependent in NE versus AngII-infused rats, which was primarily independent of RPP. Outer medullary tubular necrosis and interstitial fibrosis was also primarily RPP-dependent in both models of hypertension; however, the magnitude of injury was exacerbated in AngII-infused rats. We conclude that elevated RPP is the dominant cause of renal injury in both NE and AngII-induced hypertensive rats and that underlying neurohumoral factors in these models of hypertension alter the pattern and magnitude of RPP-induced renal injury. PMID:19858406

  7. Age-related autoregulatory dysfunction and cerebromicrovascular injury in mice with angiotensin II-induced hypertension

    PubMed Central

    Toth, Peter; Tucsek, Zsuzsanna; Sosnowska, Danuta; Gautam, Tripti; Mitschelen, Matthew; Tarantini, Stefano; Deak, Ferenc; Koller, Akos; Sonntag, William E; Csiszar, Anna; Ungvari, Zoltan

    2013-01-01

    Hypertension in the elderly substantially contributes to cerebromicrovascular damage and promotes the development of vascular cognitive impairment. Despite the importance of the myogenic mechanism in cerebromicrovascular protection, it is not well understood how aging affects the functional adaptation of cerebral arteries to high blood pressure. Hypertension was induced in young (3 months) and aged (24 months) C57/BL6 mice by chronic infusion of angiotensin II (AngII). In young hypertensive mice, the range of cerebral blood flow autoregulation was extended to higher pressure values, and the pressure-induced tone of middle cerebral artery (MCA) was increased. In aged hypertensive mice, autoregulation was markedly disrupted, and MCAs did not show adaptive increases in myogenic tone. In young mice, the mechanism of adaptation to hypertension involved upregulation of the 20-HETE (20-hydroxy-5,8,11,14-eicosatetraenoic acid)/transient receptor potential cation channel, subfamily C (TRPC6) pathway and this mechanism was impaired in aged hypertensive mice. Downstream consequences of cerebrovascular autoregulatory dysfunction in aged AngII-induced hypertensive mice included exacerbated disruption of the blood–brain barrier and neuroinflammation (microglia activation and upregulation of proinflammatory cytokines and chemokines), which were associated with impaired hippocampal dependent cognitive function. Collectively, aging impairs autoregulatory protection in the brain of mice with AngII-induced hypertension, potentially exacerbating cerebromicrovascular injury and neuroinflammation. PMID:23942363

  8. Carotid body overactivity induces respiratory neurone channelopathy contributing to neurogenic hypertension.

    PubMed

    Moraes, Davi J A; Machado, Benedito H; Paton, Julian F R

    2015-07-15

    Why sympathetic activity rises in neurogenic hypertension remains unknown. It has been postulated that changes in the electrical excitability of medullary pre-sympathetic neurones are the main causal mechanism for the development of sympathetic overactivity in experimental hypertension. Here we review recent data suggesting that enhanced sympathetic activity in neurogenic hypertension is, at least in part, dependent on alterations in the electrical excitability of medullary respiratory neurones and their central modulation of sympatho-excitatory networks. We also present results showing a critical role for carotid body tonicity in the aetiology of enhanced central respiratory modulation of sympathetic activity in neurogenic hypertension. We propose a novel hypothesis of respiratory neurone channelopathy induced by carotid body overactivity in neurogenic hypertension that may contribute to sympathetic excess. Moreover, our data support the notion of targeting the carotid body as a potential novel therapeutic approach for reducing sympathetic vasomotor tone in neurogenic hypertension. PMID:25900825

  9. Drug-induced pulmonary arterial hypertension: a recent outbreak.

    PubMed

    Montani, David; Seferian, Andrei; Savale, Laurent; Simonneau, Gérald; Humbert, Marc

    2013-09-01

    Pulmonary arterial hypertension (PAH) is a rare disorder characterised by progressive obliteration of the pulmonary microvasculature resulting in elevated pulmonary vascular resistance and premature death. According to the current classification PAH can be associated with exposure to certain drugs or toxins, particularly to appetite suppressant intake drugs, such as aminorex, fenfluramine derivatives and benfluorex. These drugs have been confirmed to be risk factors for PAH and were withdrawn from the market. The supposed mechanism is an increase in serotonin levels, which was demonstrated to act as a growth factor for the pulmonary artery smooth muscle cells. Amphetamines, phentermine and mazindol were less frequently used, but are considered possible risk factors, for PAH. Dasatinib, dual Src/Abl kinase inhibitor, used in the treatment of chronic myelogenous leukaemia was associated with cases of severe PAH, potentially in part reversible after dasatinib withdrawal. Recently, several studies have raised the issue of potential endothelial dysfunction that could be induced by interferon, and a few cases of PAH have been reported with interferon therapy. PAH remains a rare complication of these drugs, suggesting possible individual susceptibility, and further studies are needed to identify patients at risk of drug-induced PAH. PMID:23997051

  10. Chemotherapy-induced pulmonary hypertension: role of alkylating agents.

    PubMed

    Ranchoux, Benoît; Günther, Sven; Quarck, Rozenn; Chaumais, Marie-Camille; Dorfmüller, Peter; Antigny, Fabrice; Dumas, Sébastien J; Raymond, Nicolas; Lau, Edmund; Savale, Laurent; Jaïs, Xavier; Sitbon, Olivier; Simonneau, Gérald; Stenmark, Kurt; Cohen-Kaminsky, Sylvia; Humbert, Marc; Montani, David; Perros, Frédéric

    2015-02-01

    Pulmonary veno-occlusive disease (PVOD) is an uncommon form of pulmonary hypertension (PH) characterized by progressive obstruction of small pulmonary veins and a dismal prognosis. Limited case series have reported a possible association between different chemotherapeutic agents and PVOD. We evaluated the relationship between chemotherapeutic agents and PVOD. Cases of chemotherapy-induced PVOD from the French PH network and literature were reviewed. Consequences of chemotherapy exposure on the pulmonary vasculature and hemodynamics were investigated in three different animal models (mouse, rat, and rabbit). Thirty-seven cases of chemotherapy-associated PVOD were identified in the French PH network and systematic literature analysis. Exposure to alkylating agents was observed in 83.8% of cases, mostly represented by cyclophosphamide (43.2%). In three different animal models, cyclophosphamide was able to induce PH on the basis of hemodynamic, morphological, and biological parameters. In these models, histopathological assessment confirmed significant pulmonary venous involvement highly suggestive of PVOD. Together, clinical data and animal models demonstrated a plausible cause-effect relationship between alkylating agents and PVOD. Clinicians should be aware of this uncommon, but severe, pulmonary vascular complication of alkylating agents. PMID:25497573

  11. Evaluation of docosahexaenoic acid in a dog model of hypertension induced left ventricular hypertrophy.

    PubMed

    Stanley, William C; Cox, James W; Asemu, Girma; O'Connell, Kelly A; Dabkowski, Erinne R; Xu, Wenhong; Ribeiro, Rogerio F; Shekar, Kadambari C; Hoag, Stephen W; Rastogi, Sharad; Sabbah, Hani N; Daneault, Caroline; des Rosiers, Christine

    2013-12-01

    Marine n-3 polyunsaturated fatty acids alter cardiac phospholipids and prevent cardiac pathology in rodents subjected to pressure overload. This approach has not been evaluated in humans or large animals with hypertension-induced pathological hypertrophy. We evaluated docosahexaenoic acid (DHA) in old female dogs with hypertension caused by 16 weeks of aldosterone infusion. Aldosterone-induced hypertension resulted in concentric left ventricular (LV) hypertrophy and impaired diastolic function in placebo-treated dogs. DHA supplementation increased DHA and depleted arachidonic acid in cardiac phospholipids, but did not improve LV parameters compared to placebo. Surprisingly, DHA significantly increased serum aldosterone concentration and blood pressure compared to placebo. Cardiac mitochondrial yield was decreased in placebo-treated hypertensive dogs compared to normal animals, which was prevented by DHA. Extensive analysis of mitochondrial function found no differences between DHA and placebo groups. In conclusion, DHA did not favorably impact mitochondrial or LV function in aldosterone hypertensive dogs. PMID:24065618

  12. Ambient air pollution and pregnancy-induced hypertensive disorders: a systematic review and meta-analysis.

    PubMed

    Pedersen, Marie; Stayner, Leslie; Slama, Rémy; Sørensen, Mette; Figueras, Francesc; Nieuwenhuijsen, Mark J; Raaschou-Nielsen, Ole; Dadvand, Payam

    2014-09-01

    Pregnancy-induced hypertensive disorders can lead to maternal and perinatal morbidity and mortality, but the cause of these conditions is not well understood. We have systematically reviewed and performed a meta-analysis of epidemiological studies investigating the association between exposure to ambient air pollution and pregnancy-induced hypertensive disorders including gestational hypertension and preeclampsia. We searched electronic databases for English language studies reporting associations between ambient air pollution and pregnancy-induced hypertensive disorders published between December 2009 and December 2013. Combined risk estimates were calculated using random-effect models for each exposure that had been examined in ≥4 studies. Heterogeneity and publication bias were evaluated. A total of 17 articles evaluating the impact of nitrogen oxides (NO2, NOX), particulate matter (PM10, PM2.5), carbon monoxide (CO), ozone (O3), proximity to major roads, and traffic density met our inclusion criteria. Most studies reported that air pollution increased risk for pregnancy-induced hypertensive disorders. There was significant heterogeneity in meta-analysis, which included 16 studies reporting on gestational hypertension and preeclampsia as separate or combined outcomes; there was less heterogeneity in findings of the 10 studies reporting solely on preeclampsia. Meta-analyses showed increased risks of hypertensive disorders in pregnancy for all pollutants except CO. Random-effect meta-analysis combined odds ratio associated with a 5-μg/m3 increase in PM2.5 was 1.57 (95% confidence interval, 1.26-1.96) for combined pregnancy-induced hypertensive disorders and 1.31 (95%confidence interval, 1.14-1.50) for preeclampsia [corrected]. Our results suggest that exposure to air pollution increases the risk of pregnancy-induced hypertensive disorders. PMID:24935943

  13. Increased Klk9 Urinary Excretion Is Associated to Hypertension-Induced Cardiovascular Damage and Renal Alterations

    PubMed Central

    Blázquez-Medela, Ana M.; García-Sánchez, Omar; Quirós, Yaremi; Blanco-Gozalo, Victor; Prieto-García, Laura; Sancho-Martínez, Sandra M.; Romero, Miguel; Duarte, Juan M.; López-Hernández, Francisco J.; López-Novoa, José M.; Martínez-Salgado, Carlos

    2015-01-01

    Abstract Early detection of hypertensive end-organ damage and secondary diseases are key determinants of cardiovascular prognosis in patients suffering from arterial hypertension. Presently, there are no biomarkers for the detection of hypertensive target organ damage, most outstandingly including blood vessels, the heart, and the kidneys. We aimed to validate the usefulness of the urinary excretion of the serine protease kallikrein-related peptidase 9 (KLK9) as a biomarker of hypertension-induced target organ damage. Urinary, plasma, and renal tissue levels of KLK9 were measured by the Western blot in different rat models of hypertension, including angiotensin-II infusion, DOCA-salt, L-NAME administration, and spontaneous hypertension. Urinary levels were associated to cardiovascular and renal injury, assessed by histopathology. The origin of urinary KLK9 was investigated through in situ renal perfusion experiments. The urinary excretion of KLK9 is increased in different experimental models of hypertension in rats. The ACE inhibitor trandolapril significantly reduced arterial pressure and the urinary level of KLK9. Hypertension did not increase kidney, heart, liver, lung, or plasma KLK9 levels. Hypertension-induced increased urinary excretion of KLK9 results from specific alterations in its tubular reabsorption, even in the absence of overt nephropathy. KLK9 urinary excretion strongly correlates with cardiac hypertrophy and aortic wall thickening. KLK9 appears in the urine in the presence of hypertension as a result of subtle renal handling alterations. Urinary KLK9 might be potentially used as an indicator of hypertensive cardiac and vascular damage. PMID:26469898

  14. Urantide alleviates monocrotaline induced pulmonary arterial hypertension in Wistar rats.

    PubMed

    Mei, Yifang; Jin, Hong; Tian, Wei; Wang, Hao; Wang, Han; Zhao, Yanping; Zhang, Zhiyi; Meng, Fanchao

    2011-08-01

    Pulmonary arterial hypertension (PAH) is a serious disorder with poor prognosis. Urotensin II (UII) has been confirmed to be powerful vasoconstrictor than endothelin-1, which may play an important role in PAH development. The aim of this study is to observe the effects of urantide, a UII receptor antagonist, on monocrotaline (MCT) induced PAH in rats. 60 male Wistar rats were divided into six groups. For early treatment experiment, rats were divided into normal control group, MCT(4w) model group (MCT + saline × 3 wks from the 8th day of MCT injection) and urantide early treatment group (MCT + urantide 10 μg/kg/d × 3 wks, 1 week after MCT injection once). For late treatment experiment, rats were divided as controls, MCT(6w) model group (MCT + saline × 2 wks, 4 weeks after MCT injection once) and urantide late treatment group (MCT + urantide 10 μg/kg/d × 2 wks, 4 weeks after MCT injection once). At the end of experiments, mean pulmonary arterial pressures (mPAP) and mean blood pressure (MBP) of rats in each group were measured by catheterization. Right ventricular weight ratio was also weighed. Relaxation effects of urantide on intralobar pulmonary arterial rings of normal control and MCT(4w) model rats were investigated. Pulmonary artery remodeling was detected by hematoxylin and eosin (HE) staining and immunohistochemistry analysis. Serum nitric oxide (NO) levels in all six groups were assayed by ELISA kits. Urantide markedly reduced the mPAP levels of MCT induced PAH in both early and late treatment groups. It didn't change the MBP. Urantide dose-dependently relaxed the pulmonary arterial rings of normal control and MCT(4w) model rats. Moreover, N(G)-Nitro-l-arginine Methyl Ester (l-NAME) blocked the dilation response induced by urantide. In addition, urantide inhibited the pulmonary vascular remodeling remarkably. Serum NO level elevated in both early and late treatment rats with urantide infusion. These results suggest that urantide effectively alleviated

  15. An Observational Study of Bevacizumab-Induced Hypertension as a Clinical Biomarker of Antitumor Activity

    PubMed Central

    Coriat, Romain; Cabanes, Laure; Ropert, Stanislas; Billemont, Bertrand; Alexandre, Jérôme; Durand, Jean-Philippe; Treluyer, Jean-Marc; Knebelmann, Bertrand; Goldwasser, François

    2011-01-01

    Background. Hypertension is a common toxicity of bevacizumab, but the frequency of assessment of blood pressure and standardized grading remain to be defined. This study aimed to describe the incidence of bevacizumab-induced hypertension and factors associated with its development, then to retrospectively assess its relation with activity. Patients and methods. One hundred nineteen patients with advanced or metastatic non-small cell lung cancer, colorectal cancer, or ovarian cancer receiving bevacizumab (2.5 mg/kg per week) and chemotherapy were eligible for this analysis. Blood pressure was measured at home twice daily according to international guidelines, and graded according to the National Cancer Institute Common Toxicity Criteria (NCI-CTC), version 3.0, and the European Society of Hypertension (ESH) criteria. Results. Home-based measurements detected significantly more cases of hypertension than in-clinic measurements did, according to the ESH criteria (54.6% versus 24.4%; p < .001) or the NCI-CTC (42.9% versus 22.7%; p = .0015). Very early hypertension (within 42 days, according to the ESH criteria) but not hypertension (occurring at any time during treatment period) was predictive of response (p = .0011 and p = .26, respectively). Conclusions. Our preliminary results indicate that home-based measurement and grading according to the ESH criteria represents a reliable method to detect bevacizumab-induced hypertension. Whether hypertension is a biomarker of bevacizumab activity remains to be determined in a prospective study. PMID:21807768

  16. Genistein attenuates low temperature induced pulmonary hypertension in broiler chicks by modulating endothelial function.

    PubMed

    Yang, Ying; Gao, Mingyu; Wu, Zhenlong; Guo, Yuming

    2010-12-15

    Pulmonary arterial hypertension is characterized by high pulmonary blood pressure, vascular remodeling and right ventricular hypertrophy. In the present study, we investigated whether genistein would prevent the development of low temperature-induced pulmonary hypertension in broilers. Hemodynamic parameters, vascular remodeling, the expression of endothelial nitric oxide and endothelin-1 content in lung tissue were evaluated. The results demonstrated that genistein significantly reduced pulmonary arterial hypertension and suppressed pulmonary arterial vascular remodeling without affecting broilers' performance. The beneficial effects appeared to be mediated by restoring endothelial function especially endothelial nitric oxide and endothelin-1, two critical vasoactive molecules that associated with the development of hypertension. Genistein supplementation might be a potential therapeutic strategy for the treatment of pulmonary hypertension. PMID:20854807

  17. Obesity-induced hypertension: interaction of neurohumoral and renal mechanisms.

    PubMed

    Hall, John E; do Carmo, Jussara M; da Silva, Alexandre A; Wang, Zhen; Hall, Michael E

    2015-03-13

    Excess weight gain, especially when associated with increased visceral adiposity, is a major cause of hypertension, accounting for 65% to 75% of the risk for human primary (essential) hypertension. Increased renal tubular sodium reabsorption impairs pressure natriuresis and plays an important role in initiating obesity hypertension. The mediators of abnormal kidney function and increased blood pressure during development of obesity hypertension include (1) physical compression of the kidneys by fat in and around the kidneys, (2) activation of the renin-angiotensin-aldosterone system, and (3) increased sympathetic nervous system activity. Activation of the renin-angiotensin-aldosterone system is likely due, in part, to renal compression, as well as sympathetic nervous system activation. However, obesity also causes mineralocorticoid receptor activation independent of aldosterone or angiotensin II. The mechanisms for sympathetic nervous system activation in obesity have not been fully elucidated but may require leptin and activation of the brain melanocortin system. With prolonged obesity and development of target organ injury, especially renal injury, obesity-associated hypertension becomes more difficult to control, often requiring multiple antihypertensive drugs and treatment of other risk factors, including dyslipidemia, insulin resistance and diabetes mellitus, and inflammation. Unless effective antiobesity drugs are developed, the effect of obesity on hypertension and related cardiovascular, renal and metabolic disorders is likely to become even more important in the future as the prevalence of obesity continues to increase. PMID:25767285

  18. OBESITY-INDUCED HYPERTENSION: INTERACTION OF NEUROHUMORAL AND RENAL MECHANISMS

    PubMed Central

    Hall, John E.; do Carmo, Jussara M.; da Silva, Alexandre A.; Wang, Zhen; Hall, Michael E.

    2015-01-01

    Excess weight gain, especially when associated with increased visceral adiposity, is a major cause of hypertension, accounting for 65–75% of the risk for human primary (essential) hypertension. Increased renal tubular sodium reabsorption impairs pressure natriuresis and plays an important role in initiating obesity hypertension. The mediators of abnormal kidney function and increased blood pressure during development of obesity hypertension include 1) physical compression of the kidneys by fat in and around the kidneys, 2) activation of the renin-angiotensin-aldosterone system (RAAS), and 3) increased sympathetic nervous system (SNS) activity. Activation of the RAAS system is likely due, in part, to renal compression as well as SNS activation. However, obesity also causes mineralocorticoid receptor activation independent of aldosterone or angiotensin II. The mechanisms for SNS activation in obesity have not been fully elucidated but appear to require leptin and activation of the brain melanocortin system. With prolonged obesity and development of target organ injury, especially renal injury, obesity-associated hypertension becomes more difficult to control, often requiring multiple antihypertensive drugs and treatment of other risk factors, including dyslipidemia, insulin resistance and diabetes, and inflammation. Unless effective anti-obesity drugs are developed, the impact of obesity on hypertension and related cardiovascular, renal and metabolic disorders is likely to become even more important in the future as the prevalence of obesity continues to increase. PMID:25767285

  19. Effect of magnesium supplementation on blood rheology in NOS inhibition-induced hypertension model.

    PubMed

    Cengiz, Melike; Ülker, Pinar; Üyüklü, Mehmet; Yaraş, Nazmi; Özen, Nur; Aslan, Mutay; Özyurt, Dilek; Basralı, Filiz

    2016-01-27

    This study investigated the effects of magnesium on blood rheological properties and blood pressure in nitric oxide synthase (NOS) inhibition-induced hypertension model. Hypertension was induced by oral administration of the nonselective NOS inhibitor N-nitro-L-arginine methyl ester (L-NAME, 25 mg/kg/day) for 6 weeks and systolic blood pressure was measured by the tail-cuff method. The groups receiving magnesium supplementation were fed with rat chow containing 0.8% magnesium oxide during the experiment. At the end of experiment, blood samples were obtained from abdominal aorta, using ether anesthesia. Plasma and erythrocyte magnesium levels were determined by the atomic absorption spectrometer. RBC deformability and aggregation were determined by rotational ektacytometry. Plasma fibrinogen concentration was evaluated by ELISA. Whole blood and plasma viscosities were determined by viscometer and intracellular free Ca++ level was measured by using spectroflurometric method. Blood pressure was elevated in hypertensive groups and suppressed by magnesium therapy. Plasma viscosity and RBC aggregation were found to be higher in hypertensive rats than control animals and these parameters significantly decreased in magnesium supplemented hypertensive animals. Other measurements were not different between experimental groups. These results confirm that blood pressure, plasma viscosity and RBC aggregation increased in NOS inhibition-induced hypertension model and oral magnesium supplementation improved these parameters. PMID:26890104

  20. Nebivolol has a beneficial effect in monocrotaline-induced pulmonary hypertension.

    PubMed

    Pankey, Edward A; Edward, Justin A; Swan, Kevin W; Bourgeois, Camille R T; Bartow, Matthew J; Yoo, Daniel; Peak, Taylor A; Song, Bryant M; Chan, Ryan A; Murthy, Subramanyam N; Prieto, Minolfa C; Giles, Thomas D; Kadowitz, Philip J

    2016-07-01

    Pulmonary hypertension is a rare disorder that, without treatment, is progressive and fatal within 3-4 years. Current treatment involves a diverse group of drugs that target the pulmonary vascular bed. In addition, strategies that increase nitric oxide (NO) formation have a beneficial effect in rodents and patients. Nebivolol, a selective β1 adrenergic receptor-blocking agent reported to increase NO production and stimulate β3 receptors, has vasodilator properties suggesting that it may be beneficial in the treatment of pulmonary hypertension. The present study was undertaken to determine whether nebivolol has a beneficial effect in monocrotaline-induced (60 mg/kg) pulmonary hypertension in the rat. These results show that nebivolol treatment (10 mg/kg, once or twice daily) attenuates pulmonary hypertension, reduces right ventricular hypertrophy, and improves pulmonary artery remodeling in monocrotaline-induced pulmonary hypertension. This study demonstrates the presence of β3 adrenergic receptor immunoreactivity in pulmonary arteries and airways and that nebivolol has pulmonary vasodilator activity. Studies with β3 receptor agonists (mirabegron, BRL 37344) and antagonists suggest that β3 receptor-mediated decreases in systemic arterial pressure occur independent of NO release. Our results suggest that nebivolol, a selective vasodilating β1 receptor antagonist that stimulates β3 adrenergic receptors and induces vasodilation by increasing NO production, may be beneficial in treating pulmonary hypertensive disorders. PMID:27172427

  1. Sodium hydrosulfide prevents hypoxia-induced pulmonary arterial hypertension in broilers.

    PubMed

    Yang, Y; Zhang, B K; Liu, D; Nie, W; Yuan, J M; Wang, Z; Guo, Y M

    2012-01-01

    1. The aim of the study was to determine if H(2)S is involved in the development of hypoxia-induced pulmonary hypertension in broilers, a condition frequently observed in a variety of cardiac and pulmonary diseases. 2. Two-week-old broilers were reared under normoxic conditions or exposed to normobaric hypoxia (6 h/day) with tissue levels of H(2)S adjusted by administering sodium hydrosulfide (NaHS, 10 µmol/kg body weight/day). Mean pulmonary arterial pressure, right ventricular mass, plasma and tissue H(2)S levels, the expression of cystathionine-β-synthase (CSE) and vascular remodeling were determined at 35 d of age. 3. Exposure to hypoxia-induced pulmonary arterial hypertension was characterized by elevated pulmonary pressure, right ventricular hypertrophy and vascular remodeling. This was accompanied by decreased expression of CSE and decreased concentrations of plasma and tissue H(2)S. 4. Hypoxia-induced pulmonary hypertension was significantly reduced by administration of NaHS but this protective effect was largely abolished by D, L-propargylglycerine, an inhibitor of CSE. 5. The results indicate that H(2)S is involved in the development of hypoxia-induced pulmonary hypertension. Supplementing NaHS or H(2)S could be a strategy for reducing hypoxia-induced hypertension in broilers. PMID:23281754

  2. beta-Adrenergic and cholinergic receptors in hypertension-induced hypertrophy

    SciTech Connect

    Vatner, D.E.; Kirby, D.A.; Homcy, C.J.; Vatner, S.F.

    1985-05-01

    Perinephritic hypertension was produced in dogs by wrapping one kidney with silk and removing the contralateral kidney 1 week later. Mean arterial pressure rose from 104 +/- 3 to 156 +/- 11 mm Hg, while left ventricular free wall weight, normalized for body weight, was increased by 49%. Muscarinic, cholinergic receptor density measured with (/sup 3/H)-quinuclidinyl benzilate, fell in hypertensive left ventricles (181 +/- 19 fmol/mg, n = 6; p less than 0.01) as compared with that found in normal left ventricles (272 +/- 16 fmol/mg, n = 8), while receptor affinity was not changed. The beta-adrenergic receptor density, measured by binding studies with (/sup 3/H)-dihydroalprenolol, rose in the hypertensive left ventricles (108 +/- 10 fmol/mg, n = 7; p less than 0.01) as compared with that found in normal left ventricles (68.6 +/- 5.2 fmol/mg, n = 15), while beta-adrenergic receptor affinity decreased in the hypertensive left ventricles (10.4 +/- 1.2 nM) compared with that found in the normal left ventricles (5.0 +/- 0.7 nM). Plasma norepinephrine levels were similar in the two groups, but myocardial norepinephrine levels were depressed (p less than 0.05) in dogs with hypertension. Moderate left ventricular hypertrophy induced by long-term aortic banding in dogs resulted in elevations in beta-adrenergic receptor density (115 +/- 14 fmol/mg) and decreases in affinity (10.4 +/- 2.2 nM) similar to those observed in the dogs with left ventricular hypertrophy induced by hypertension. Thus, these results suggest that perinephritic hypertension in the dog induces divergent effects on cholinergic and beta-adrenergic receptor density. The increased beta-adrenergic receptor density and decreased affinity may be a characteristic of left ventricular hypertrophy rather than hypertension.

  3. Hypertension induced by pregnancy, oral contraceptives, and postmenopausal replacement therapy.

    PubMed

    Kaplan, N M

    1988-11-01

    Hypertension may develop during pregnancy or with the use of OC pills. Although the precise manner by which this rise in blood pressure occurs is unknown, appropriate management of the problem can protect against the consequences. The use of hormonal replacement therapy after menopause is not associated with a rise in blood pressure, and appears to provide significant protection against CHD. PMID:3067841

  4. CaMK4 Gene Deletion Induces Hypertension

    PubMed Central

    Santulli, Gaetano; Cipolletta, Ersilia; Sorriento, Daniela; Del Giudice, Carmine; Anastasio, Antonio; Monaco, Sara; Maione, Angela Serena; Condorelli, Gianluigi; Puca, Annibale; Trimarco, Bruno; Illario, Maddalena; Iaccarino, Guido

    2012-01-01

    Background The expression of calcium/calmodulin-dependent kinase IV (CaMKIV) was hitherto thought to be confined to the nervous system. However, a recent genome-wide analysis indicated an association between hypertension and a single-nucleotide polymorphism (rs10491334) of the human CaMKIV gene (CaMK4), which suggests a role for this kinase in the regulation of vascular tone. Methods and Results To directly assess the role of CaMKIV in hypertension, we characterized the cardiovascular phenotype of CaMK4−/− mice. They displayed a typical hypertensive phenotype, including high blood pressure levels, cardiac hypertrophy, vascular and kidney damage, and reduced tolerance to chronic ischemia and myocardial infarction compared with wild-type littermates. Interestingly, in vitro experiments showed the ability of this kinase to activate endothelial nitric oxide synthase. Eventually, in a population study, we found that the rs10491334 variant associates with a reduction in the expression levels of CaMKIV in lymphocytes from hypertensive patients. Conclusions Taken together, our results provide evidence that CaMKIV plays a pivotal role in blood pressure regulation through the control of endothelial nitric oxide synthase activity. (J Am Heart Assoc. 2012;1:e001081 doi: 10.1161/JAHA.112.001081.) PMID:23130158

  5. Renal Oxidative Stress Induced by Long-Term Hyperuricemia Alters Mitochondrial Function and Maintains Systemic Hypertension

    PubMed Central

    Cristóbal-García, Magdalena; García-Arroyo, Fernando E.; Arellano-Buendía, Abraham S.; Madero, Magdalena; Rodríguez-Iturbe, Bernardo; Pedraza-Chaverrí, José; Zazueta, Cecilia; Johnson, Richard J.; Sánchez Lozada, Laura-Gabriela

    2015-01-01

    We addressed if oxidative stress in the renal cortex plays a role in the induction of hypertension and mitochondrial alterations in hyperuricemia. A second objective was to evaluate whether the long-term treatment with the antioxidant Tempol prevents renal oxidative stress, mitochondrial alterations, and systemic hypertension in this model. Long-term (11-12 weeks) and short-term (3 weeks) effects of oxonic acid induced hyperuricemia were studied in rats (OA, 750 mg/kg BW), OA+Allopurinol (AP, 150 mg/L drinking water), OA+Tempol (T, 15 mg/kg BW), or vehicle. Systolic blood pressure, renal blood flow, and vascular resistance were measured. Tubular damage (urine N-acetyl-β-D-glucosaminidase) and oxidative stress markers (lipid and protein oxidation) along with ATP levels were determined in kidney tissue. Oxygen consumption, aconitase activity, and uric acid were evaluated in isolated mitochondria from renal cortex. Short-term hyperuricemia resulted in hypertension without demonstrable renal oxidative stress or mitochondrial dysfunction. Long-term hyperuricemia induced hypertension, renal vasoconstriction, tubular damage, renal cortex oxidative stress, and mitochondrial dysfunction and decreased ATP levels. Treatments with Tempol and allopurinol prevented these alterations. Renal oxidative stress induced by hyperuricemia promoted mitochondrial functional disturbances and decreased ATP content, which represent an additional pathogenic mechanism induced by chronic hyperuricemia. Hyperuricemia-related hypertension occurs before these changes are evident. PMID:25918583

  6. Rosuvastatin, sildenafil and their combination in monocrotaline-induced pulmonary hypertension in rat.

    PubMed

    Jasińska-Stroschein, Magdalena; Owczarek, Jacek; Wesołowska, Anna; Orszulak-Michalak, Daria

    2014-09-01

    There is considerable interest in the pleiotropic effects of statins and their potential role in the treatment of pulmonary hypertension. Previous experimental findings indicate that a combination of lipophilic statins with phosphodiesterase type-5 inhibitor, sildenafil, can offer preventive effects on rat monocrotaline-induced pulmonary hypertension. The present study is aimed to assess whether therapeutic regimen provides any benefits. Seven days after pulmonary hypertension induction, hydrophilic rosuvastatin and sildenafil were given for 14 days to male Wistar outbred rats. Right ventricular pressure, right ventricle mass and three biomarkers were evaluated after 21 days: brain natriuretic peptide, high-density lipoprotein cholesterol and vascular endothelial growth factor. The present study demonstrates that administration of hydrophilic statin with sildenafil results in reduction of pulmonary vascular remodeling and right ventricular pressure. The results of biochemical measurements may suggest that statins play a positive role in right ventricle function or the process of angiogenesis in pulmonary hypertension development. PMID:25296680

  7. Differential Phenotypes of Tissue-Infiltrating T Cells during Angiotensin II-Induced Hypertension in Mice

    PubMed Central

    Wei, Zihui; Spizzo, Iresha; Diep, Henry; Drummond, Grant R.; Widdop, Robert E.; Vinh, Antony

    2014-01-01

    Hypertension remains the leading risk factor for cardiovascular disease (CVD). Experimental hypertension is associated with increased T cell infiltration into blood pressure-controlling organs, such as the aorta and kidney; importantly in absence of T cells of the adaptive immune system, experimental hypertension is significantly blunted. However, the function and phenotype of these T cell infiltrates remains speculative and undefined in the setting of hypertension. The current study compared T cell-derived cytokine and reactive oxygen species (ROS) production from normotensive and hypertensive mice. Splenic, blood, aortic, kidney and brain T cells were isolated from C57BL/6J mice following 14-day vehicle or angiotensin (Ang) II (0.7 mg/kg/day, s.c.) infusion. T cell infiltration was increased in aorta, kidney and brain from hypertensive mice. Cytokine analysis in stimulated T cells indicated an overall Th1 pro-inflammatory phenotype, but a similar proportion (flow cytometry) and quantity (cytometric bead array) of IFN-γ, TNF-α, IL-4 and IL-17 between vehicle- and Ang II- treated groups. Strikingly, elevated T cell-derived production of a chemokine, chemokine C-C motif ligand 2 (CCL2), was observed in aorta (∼6-fold) and kidney in response to Ang II, but not in brain, spleen or blood. Moreover, T cell-derived ROS production in aorta was elevated ∼3 -fold in Ang II-treated mice (n = 7; P<0.05). Ang II-induced hypertension does not affect the overall T cell cytokine profile, but enhanced T cell-derived ROS production and/or leukocyte recruitment due to elevated CCL2, and this effect may be further amplified with increased infiltration of T cells. We have identified a potential hypertension-specific T cell phenotype that may represent a functional contribution of T cells to the development of hypertension, and likely several other associated vascular disorders. PMID:25501574

  8. Resveratrol affects histone 3 lysine 27 methylation of vessels and blood biomarkers in DOCA salt-induced hypertension.

    PubMed

    Han, Sevtap; Uludag, Mecit Orhan; Usanmaz, Suzan Emel; Ayaloglu-Butun, Fatma; Akcali, Kamil Can; Demirel-Yilmaz, Emine

    2015-01-01

    Hypertension is a risk factor for the cardiovascular diseases. Although, several drugs are used to treat hypertension, the success of the antihypertensive therapy is limited. Resveratrol decreases blood pressure in animal models of hypertension. This study researched the mechanisms behind the effects of resveratrol on hypertension. Hypertension was induced by using the deoxycorticosterone acetate (DOCA)-induced (15 mg/kg twice per week, subcutaneously) salt-sensitive hypertension model of Wistar rats. Hypertension caused a decrease in endothelium-dependent relaxations of the isolated thoracic aorta. Resveratrol treatment (50 mg/l in drinking water) prevented DOCA salt-induced hypertension, but did not improve endothelial dysfunction. Plasma nitric oxide (NO), asymmetric dimethylarginine (ADMA), total antioxidant capacity (TAC) and hydrogen sulfide (H2S) levels were not changed by DOCA salt application. However, treatment of resveratrol significantly decreased ADMA and increased TAC and H2S levels. NO level in circulation was not significantly changed by resveratrol. DOCA salt application and resveratrol treatment also caused an alteration in the epigenetic modification of vessels. Staining pattern of histone 3 lysine 27 methylation (H3K27me3) in the aorta and renal artery sections was changed. These results show that preventive effect of resveratrol on DOCA salt-induced hypertension might due to its action on the production of some blood biomarkers and the epigenetic modification of vessels that would focus upon new aspect of hypertension prevention and treatment. PMID:25234650

  9. Risperidone Induced Benign Intracranial Hypertension Leading to Visual Loss

    PubMed Central

    Alexander, Sushil Thomas; Kattula, Dheeraj; Mannam, Pavithra; Iyyadurai, Ramya

    2016-01-01

    Benign intracranial hypertension (BIH) is a rare but potentially serious condition causing visual loss. Occasionally, medication use has been associated with the occurrence of BIH. We report the case of a 40-year-old obese lady being treated with risperidone for schizophrenia who presented with features of BIH. We report this case, occurring for the 1st time in India, to emphasize that a commonly used atypical antipsychotic drug can rarely cause BIH leading to visual loss. PMID:27335522

  10. Asiatic acid alleviates cardiovascular remodelling in rats with L-NAME-induced hypertension.

    PubMed

    Bunbupha, Sarawoot; Prachaney, Parichat; Kukongviriyapan, Upa; Kukongviriyapan, Veerapol; Welbat, Jariya Umka; Pakdeechote, Poungrat

    2015-11-01

    A previous study demonstrated the antihypertensive effect of asiatic acid. The current study investigates the effect of asiatic acid on cardiovascular remodelling and possible mechanisms involved in Nω -nitro-L-arginine methyl ester hydrochloride (L-NAME)-induced hypertensive rats. Male Sprague-Dawley rats were treated with L-NAME (40 mg/kg per day) for 3 weeks in order to induce hypertension. Hypertensive rats were administered asiatic acid (20 mg/kg per day) or vehicle for a further 2 weeks. It was found that hypertensive rats showed high systolic blood pressure, left ventricular (LV) hypertrophy, increases in LV fibrosis, aortic wall thickness and aortic collagen deposition (P < 0.05). Moreover, decreased plasma nitrate and nitrite (NOx) and increased plasma tumor necrosis factor alpha (TNF-α) were observed in hypertensive rats (P < 0.05). This was consistent with downregulation of endothelial nitric oxide synthase (eNOS) expression and upregulation of inducible nitric oxide synthase (iNOS) expression in heart and aortic tissues (P < 0.05). Levels of malondialdehyde (MDA) in plasma, aortic and heart tissues were significantly increased in hypertensive rats (P < 0.05). Asiatic acid markedly reduced blood pressure, alleviated cardiovascular remodelling, and restored plasma NOx and TNF-α as well as eNOS/iNOS expression in heart and aortic tissues (P < 0.05). Additionally, there was a significant reduction of MDA levels in the tissues of treated hypertensive rats. In conclusion, this study demonstrates the therapeutic effects of asiatic acid on blood pressure and cardiovascular remodelling, which is possibly related to the restoration of eNOS/iNOS expression, and the resulting anti-inflammatory and antioxidant activities. PMID:26234646

  11. Vascular Endothelial Growth Factor Inhibitor-Induced Hypertension: Basics for Primary Care Providers

    PubMed Central

    Escalante, Carmen P.; Zalpour, Ali

    2011-01-01

    Frequently, primary care providers continue to manage the overall medical care of cancer patients. With newer and often more potent antitumor agents, patients may present to their local physicians with drug-induced toxicities such as hypertension induced by vascular endothelial growth factor (VEGF) inhibitors. It is imperative that these healthcare providers are aware of basic aspects of this drug class, as its use has increased significantly in the last several years. Uncontrolled or malignant hypertension due to these agents should be recognized readily and treated early to prevent more severe outcomes. This overview provides a brief background on the role of VEGF and angiogenesis in tumor metabolism as well as theories of the mechanism of VEGF inhibitors and hypertension. Helpful clinical practice aspects including the types of inhibitors used in the United States and their pharmacologic characteristics will be discussed. Also, diagnosis and treatment of hypertension induced by vascular endothelial growth factors are reviewed. A summary of key aspects of this drug class and hypertension is included. PMID:21629798

  12. 49 CFR 236.1020 - Exclusion of track segments for implementation due to cessation of PIH materials service or...

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... procedures and using the same methodology as required for safety and security route analysis under 49 CFR 172... 49 Transportation 4 2011-10-01 2011-10-01 false Exclusion of track segments for implementation due....1020 Exclusion of track segments for implementation due to cessation of PIH materials service...

  13. Neutralization by insulin of the hypertensive effect of dermcidin isoform 2: an environmentally induced diabetogenic and hypertensive protein.

    PubMed

    Ghosh, Rajeshwary; Bank, Sarbashri; Bhattacharya, Rabindra; Khan, Nighat N; Sinha, A Kumar

    2014-01-01

    The effect of dermcidin isoform 2 (dermcidin), an environmentally induced stress protein, was investigated on the genesis of diabetes mellitus and hypertension, the two major atherosclerotic risk factors. The role of dermcidin as an atherosclerotic risk factor related to the impaired systemic insulin level was investigated. Dermcidin was prepared by electrophoresis using plasma from the subjects with acute ischemic heart disease. Injection of 0.2 μM dermcidin in mice increased the blood glucose level from 98 ± 2.45 mg/dL to 350  ± 10.2 mg/dL which was normalized by the oral administration of acetyl salicylic acid (aspirin) after 24 h. Hypertensive subjects with systolic and diastolic blood pressure of 165 mm and 95 mm of Hg, respectively, had plasma dermcidin level of 95 nM. Ingestion of acetyl salicylic acid (aspirin) (150 mg/70 kg body weight) decreased the systolic and diastolic pressures to 125 mm and 80 mm of Hg, respectively, with decrease of dermcidin level to 15 nM. Incubation of kidney cortex cells with 0.2 μM dermcidin-inhibited synthesis of (r)-cortexin, an antihypertensive protein, and the basal (r)-cortexin level was reduced from 33 nM to 15 nM. Addition of 25 μunits of insulin/mL was found to reverse the inhibition of cortexin synthesis. The effect of dermcidin as a diabetogenic and a hypertensive agent could be controlled either by aspirin or by insulin. PMID:24649391

  14. Neutralization by Insulin of the Hypertensive Effect of Dermcidin Isoform 2: An Environmentally Induced Diabetogenic and Hypertensive Protein

    PubMed Central

    Bank, Sarbashri; Bhattacharya, Rabindra; Khan, Nighat N.; Sinha, A. Kumar

    2014-01-01

    The effect of dermcidin isoform 2 (dermcidin), an environmentally induced stress protein, was investigated on the genesis of diabetes mellitus and hypertension, the two major atherosclerotic risk factors. The role of dermcidin as an atherosclerotic risk factor related to the impaired systemic insulin level was investigated. Dermcidin was prepared by electrophoresis using plasma from the subjects with acute ischemic heart disease. Injection of 0.2 μM dermcidin in mice increased the blood glucose level from 98 ± 2.45 mg/dL to 350  ± 10.2 mg/dL which was normalized by the oral administration of acetyl salicylic acid (aspirin) after 24 h. Hypertensive subjects with systolic and diastolic blood pressure of 165 mm and 95 mm of Hg, respectively, had plasma dermcidin level of 95 nM. Ingestion of acetyl salicylic acid (aspirin) (150 mg/70 kg body weight) decreased the systolic and diastolic pressures to 125 mm and 80 mm of Hg, respectively, with decrease of dermcidin level to 15 nM. Incubation of kidney cortex cells with 0.2 μM dermcidin-inhibited synthesis of (r)-cortexin, an antihypertensive protein, and the basal (r)-cortexin level was reduced from 33 nM to 15 nM. Addition of 25 μunits of insulin/mL was found to reverse the inhibition of cortexin synthesis. The effect of dermcidin as a diabetogenic and a hypertensive agent could be controlled either by aspirin or by insulin. PMID:24649391

  15. Role of the Gut Microbiome in Obstructive Sleep Apnea-Induced Hypertension.

    PubMed

    Durgan, David J; Ganesh, Bhanu P; Cope, Julia L; Ajami, Nadim J; Phillips, Sharon C; Petrosino, Joseph F; Hollister, Emily B; Bryan, Robert M

    2016-02-01

    Individuals suffering from obstructive sleep apnea (OSA) are at increased risk for systemic hypertension. The importance of a healthy gut microbiota, and detriment of a dysbiotic microbiota, on host physiology is becoming increasingly evident. We tested the hypothesis that gut dysbiosis contributes to hypertension observed with OSA. OSA was modeled in rats by inflating a tracheal balloon during the sleep cycle (10-s inflations, 60 per hour). On normal chow diet, OSA had no effect on blood pressure; however, in rats fed a high-fat diet, blood pressure increased 24 and 29 mm Hg after 7 and 14 days of OSA, respectively (P<0.05 each). Bacterial community characterization was performed on fecal pellets isolated before and after 14 days of OSA in chow and high-fat fed rats. High-fat diet and OSA led to significant alterations of the gut microbiota, including decreases in bacterial taxa known to produce the short chain fatty acid butyrate (P<0.05). Finally, transplant of dysbiotic cecal contents from hypertensive OSA rats on high-fat diet into OSA recipient rats on normal chow diet (shown to be normotensive) resulted in hypertension similar to that of the donor (increased 14 and 32 mm Hg after 7 and 14 days of OSA, respectively; P<0.05). These studies demonstrate a causal relationship between gut dysbiosis and hypertension, and suggest that manipulation of the microbiota may be a viable treatment for OSA-induced, and possibly other forms of, hypertension. PMID:26711739

  16. Resolution of pulmonary hypertension complication during venovenous perfusion-induced systemic hyperthermia application.

    PubMed

    Ballard-Croft, Cherry; Wang, Dongfang; Jones, Cameron; Wang, Jingkun; Pollock, Robert; Jubak, Bob; Topaz, Stephen; Zwischenberger, Joseph B

    2013-01-01

    We are developing a venovenous perfusion-induced systemic hyperthermia (vv-PISH) system for advanced cancer treatment. The vv-PISH system consistently delivered hyperthermia to adult healthy swine, but significant pulmonary hypertension developed during the heating phase. The goal of this study was to develop a method to prevent pulmonary hypertension. We hypothesized that pulmonary hypertension results from decreased priming solution air solubility, which causes pulmonary gas embolism. Healthy adult sheep (n = 3) were used to establish a standard vv-PISH sheep model without priming solution preheating. In subsequent sheep (n = 7), the priming solution was preheated (42-46°C) and the hyperthermia circuit flushed with CO2. All sheep survived the experiment and achieved 2 hours of 42°C hyperthermia. In the group lacking priming solution preheating, significant pulmonary hypertension (35-44 mm Hg) developed. In the sheep with priming solution preheating, pulmonary artery pressure was very stable without pulmonary hypertension. Blood electrolytes were in physiologic range, and complete blood counts were unaffected by hyperthermia. Blood chemistries revealed no significant liver or kidney damage. Our simple strategy of priming solution preheating completely resolved the problem of pulmonary hypertension as a milestone toward developing a safe and easy-to-use vv-PISH system for cancer treatment. PMID:23820278

  17. Long Noncoding RNA-GAS5: A Novel Regulator of Hypertension-Induced Vascular Remodeling.

    PubMed

    Wang, Yang-Ning-Zhi; Shan, Kun; Yao, Mu-Di; Yao, Jin; Wang, Jia-Jian; Li, Xiang; Liu, Ban; Zhang, Yang-Yang; Ji, Yong; Jiang, Qin; Yan, Biao

    2016-09-01

    Vascular remodeling is an important pathological feature of hypertension, leading to increased vascular resistance and reduced compliance. Endothelial cell (EC) and vascular smooth muscle cell (VSMC) dysfunction is involved in vascular remodeling. Long noncoding RNAs are potential regulators of EC and VSMC function. Herein, we determined whether long noncoding RNA-growth arrest-specific 5 (GAS5) is involved in hypertension-related vascular remodeling. We revealed that GAS5 knockdown aggravated hypertension-induced microvascular dysfunction as shown by increased retinal neovascularization and capillary leakage. GAS5 regulated the remodeling of arteries, including caudal arteries, carotid arteries, renal arteries, and thoracic arteries. GAS5 was mainly expressed in ECs and VSMCs, and its expression was significantly downregulated in hypertension. GAS5 knockdown affected endothelial activation, endothelial proliferation, VSMC phenotypic conversion, and EC-VSMC communication in vivo and in vitro. Mechanistically, GAS5 regulated EC and VSMC function through β-catenin signaling. This study identified GAS5 as a critical regulator in hypertension and demonstrated the potential of gene therapy and drug development for treating hypertension. PMID:27432865

  18. Effects of propranolol and sucralfate on ethanol-induced gastric mucosal damage in chronic portal hypertensive rats.

    PubMed

    Geoffroy, P; Duchateau, A; Thiéfin, G; Zeitoun, P

    1987-10-01

    In a rat model of chronic portal hypertension we studied ethanol-induced gastric mucosal damage and the effects of pretreatment by propranolol and sucralfate. Susceptibility to ethanol was increased in chronic portal hypertensive rats compared with sham-operated rats (55 +/- 8% vs. 25 +/- 4%). Both acute pretreatment (10 min) and chronic pretreatment (3 weeks) with propranolol reduced gastric mucosal injury induced by ethanol in portal hypertensive rats, compared with saline-treated rats. Acute and chronic pretreatment with propranolol had no protective effect in sham-operated rats. In portal hypertensive rats, sucralfate in two different doses (500 and 125 mg/kg) protected the gastric mucosa against ethanol-induced gastric injury compared with animals receiving saline (2 +/- 1% and 3 +/- 2% vs. 25 +/- 3%). Sucralfate at the higher dose did not reduce portal pressure in portal hypertensive rats. We conclude that: (1) chronic portal hypertension increases ethanol-induced gastric damage; (2) acute and chronic propranolol treatment reduces ethanol-induced gastric injury in portal hypertensive rats, probably by decreasing portal hypertension; (3) sucralfate has a cytoprotective effect in portal hypertensive rats without reducing portal pressure. These results suggest a potential application of sucralfate in patients otherwise treated by sclerotherapy. PMID:3693860

  19. Periostin expression induced by oxidative stress contributes to myocardial fibrosis in a rat model of high salt-induced hypertension

    PubMed Central

    WU, HAN; CHEN, LIANG; XIE, JUN; LI, RAN; LI, GUAN-NAN; CHEN, QIN-HUA; ZHANG, XIN-LIN; KANG, LI-NA; XU, BIAO

    2016-01-01

    Periostin is an extracellular matrix protein involved in fibrosis. The present study investigated the importance of periostin in hypertension-induced myocardial fibrosis. Rats were randomly divided into either the normal group (0.4% NaCl diet; n=8) or hypertension group (8% NaCl diet; n=8). For 36 weeks, the blood pressure and heart rate of the rats were monitored. At week 36, the hearts were extracted for further analysis. Masson's staining and western blotting were performed to determine the levels of periostin protein expression, oxidative stress and fibrosis. In addition, fibroblasts were isolated from adult rats and cultured in vitro, and following treatment with angiotensin II (Ang II) and N-acetyl-L-cysteine (NAC), western blotting, immunofluorescence and 2′,7′ dichlorodihydrofluorescin staining were performed to examine reactive oxygen species production, and periostin and α-smooth muscle actin (α-SMA) expression levels. The results demonstrated that periostin expression and oxidative stress were increased in hypertensive hearts compared with normal hearts. The in vitro experiments demonstrated that Ang II upregulated the expression levels of periostin and α-SMA compared with the control, whereas, pretreatment with NAC inhibited oxidative stress, periostin and α-SMA expression in fibroblasts. In conclusion, the results of the current study suggested that oxidative stress-induced periostin is involved in myocardial fibrosis and hypertension. The present study demonstrated that periostin inhibition may be a promising approach for the inhibition of hypertension-induced cardiac remodeling. PMID:27220372

  20. Genetic variant predicts bevacizumab-induced hypertension in ECOG-5103 and ECOG-2100

    PubMed Central

    Schneider, B P; Li, L; Shen, F; Miller, K D; Radovich, M; O'Neill, A; Gray, R J; Lane, D; Flockhart, D A; Jiang, G; Wang, Z; Lai, D; Koller, D; Pratt, J H; Dang, C T; Northfelt, D; Perez, E A; Shenkier, T; Cobleigh, M; Smith, M L; Railey, E; Partridge, A; Gralow, J; Sparano, J; Davidson, N E; Foroud, T; Sledge, G W

    2014-01-01

    Background: Bevacizumab has broad anti-tumour activity, but substantial risk of hypertension. No reliable markers are available for predicting bevacizumab-induced hypertension. Methods: A genome-wide association study (GWAS) was performed in the phase III bevacizumab-based adjuvant breast cancer trial, ECOG-5103, to evaluate for an association between genotypes and hypertension. GWAS was conducted in those who had experienced systolic blood pressure (SBP) >160 mm Hg during therapy using binary analysis and a cumulative dose model for the total exposure of bevacizumab. Common toxicity criteria (CTC) grade 3–5 hypertension was also assessed. Candidate SNP validation was performed in the randomised phase III trial, ECOG-2100. Results: When using the phenotype of SBP>160 mm Hg, the most significant association in SV2C (rs6453204) approached and met genome-wide significance in the binary model (P=6.0 × 10−8; OR=3.3) and in the cumulative dose model (P=4.7 × 10−8; HR=2.2), respectively. Similar associations with rs6453204 were seen for CTC grade 3–5 hypertension but did not meet genome-wide significance. Validation study from ECOG-2100 demonstrated a statistically significant association between this SNP and grade 3/4 hypertension using the binary model (P-value=0.037; OR=2.4). Conclusions: A genetic variant in SV2C predicted clinically relevant bevacizumab-induced hypertension in two independent, randomised phase III trials. PMID:25117820

  1. Renal Transcriptome Analysis of Programmed Hypertension Induced by Maternal Nutritional Insults

    PubMed Central

    Tain, You-Lin; Hsu, Chien-Ning; Chan, Julie Y. H.; Huang, Li-Tung

    2015-01-01

    Maternal nutrition can affect development, leading to long-term effects on the health of offspring. The most common outcome is programmed hypertension. We examined whether alterations in renal transcriptome are responsible for generating programmed hypertension among four different models using next-generation RNA sequencing (NGS) technology. Pregnant Sprague-Dawley rats received 50% caloric restriction (CR), intraperitoneal injection of 45 mg/kg streptozotocin, 60% high-fructose (HF) diet, or 1% NaCl in drinking water to conduct CR, diabetes, HF, or high-salt models, respectively. All four models induced programmed hypertension in adult male offspring. We observed 16 shared genes in a two-week-old kidney among four different models. The identified differential expressed genes (DEGs) that are related to the regulation of blood pressure included Adrb3, Alb, Apoe, Calca, Kng1, Adm2, Guca2b, Hba2, Hba-a2, and Ppara. The peroxisome proliferator-activated receptor (PPAR) signaling pathway and glutathione metabolism pathway were shared by the CR, diabetes, and HF models. Conclusively, a variety of maternal nutritional insults induced the same phenotype—programmed hypertension with differential alterations of renal transcriptome in adult male offspring. The roles of DEGs identified by the NGS in this study deserve further clarification to develop ideal maternal dietary interventions and thus spare the next generations from the burden of hypertension. PMID:26247937

  2. Renal Transcriptome Analysis of Programmed Hypertension Induced by Maternal Nutritional Insults.

    PubMed

    Tain, You-Lin; Hsu, Chien-Ning; Chan, Julie Y H; Huang, Li-Tung

    2015-01-01

    Maternal nutrition can affect development, leading to long-term effects on the health of offspring. The most common outcome is programmed hypertension. We examined whether alterations in renal transcriptome are responsible for generating programmed hypertension among four different models using next-generation RNA sequencing (NGS) technology. Pregnant Sprague-Dawley rats received 50% caloric restriction (CR), intraperitoneal injection of 45 mg/kg streptozotocin, 60% high-fructose (HF) diet, or 1% NaCl in drinking water to conduct CR, diabetes, HF, or high-salt models, respectively. All four models induced programmed hypertension in adult male offspring. We observed 16 shared genes in a two-week-old kidney among four different models. The identified differential expressed genes (DEGs) that are related to the regulation of blood pressure included Adrb3, Alb, Apoe, Calca, Kng1, Adm2, Guca2b, Hba2, Hba-a2, and Ppara. The peroxisome proliferator-activated receptor (PPAR) signaling pathway and glutathione metabolism pathway were shared by the CR, diabetes, and HF models. Conclusively, a variety of maternal nutritional insults induced the same phenotype-programmed hypertension with differential alterations of renal transcriptome in adult male offspring. The roles of DEGs identified by the NGS in this study deserve further clarification to develop ideal maternal dietary interventions and thus spare the next generations from the burden of hypertension. PMID:26247937

  3. Hepatoprotective Effect of Silymarin (Silybum marianum) on Hepatotoxicity Induced by Acetaminophen in Spontaneously Hypertensive Rats

    PubMed Central

    Cardia, Gabriel Fernando Esteves; da Rocha, Bruno Ambrósio; Aguiar, Rafael Pazzinatto; Spironello, Ricardo Alexandre; Caparroz-Assef, Silvana Martins; Bersani-Amado, Ciomar Aparecida; Cuman, Roberto Kenji Nakamura

    2015-01-01

    This study was aimed to investigate the effect of Silymarin (SLM) on the hypertension state and the liver function changes induced by acetaminophen (APAP) in spontaneously hypertensive rat (SHR). Animals normotensive (N) or hypertensive (SHR) were treated or not with APAP (3 g/kg, oral) or previously treated with SLM. Twelve hours after APAP administration, plasmatic levels of liver function markers: alanine aminotransferase (ALT), aspartate aminotransferase (AST), glucose (GLU), gamma glutamyl transferase (γ-GT), and alkaline phosphatase (ALP) of all groups, were determined. Liver injury was assessed using histological studies. Samples of their livers were then used to determine the myeloperoxidase (MPO) activity and nitric oxide (NO) production and were also sectioned for histological analysis. No differences were observed for ALT, γ-GT, and GLU levels between SHR and normotensive rats groups. However, AST and ALP levels were increased in hypertensive animals. APAP treatment promoted an increase in ALT and AST in both SHR and N. However, only for SHR, γ-GT levels were increased. The inflammatory response evaluated by MPO activity and NO production showed that SHR was more susceptible to APAP effect, by increasing leucocyte infiltration. Silymarin treatment (Legalon) restored the hepatocyte functional and histopathological alterations induced by APAP in normotensive and hypertensive animals. PMID:25821491

  4. Pharmacological treatment of antipsychotic-induced dyslipidemia and hypertension.

    PubMed

    Tse, Lurdes; Procyshyn, Ric M; Fredrikson, Diane H; Boyda, Heidi N; Honer, William G; Barr, Alasdair M

    2014-05-01

    Second-generation antipsychotics (SGAs) are associated with significant comorbid metabolic abnormalities. Adjunct medications may be prescribed to treat these metabolic side effects, but the evidence supporting this practice (especially for the management of antipsychotic-associated dyslipidemia and hypertension) is limited. The purpose of this review was to evaluate the effects of adjunct medications on triglyceride, total cholesterol, low-density lipoprotein, high-density lipoprotein, and blood pressure levels in participants taking SGAs for psychosis. Studies were systematically searched and evaluated. Studies were included for review if participants were taking SGAs and if lipid and/or blood pressure levels were included as outcome measures. Statins, conventional lipid-lowering agents, fluvoxamine, ramelteon, topiramate, valsartan, telmisartan, omega-3 fatty acids, metformin (including both immediate-release and extended-release formulations), and a combination of metformin-sibutramine seemed to have beneficial effects on lipid levels. Valsartan, telmisartan, and topiramate appeared to be effective for controlling increases in blood pressure. The literature on adjunct medications for the treatment of antipsychotic-associated dyslipidemia and hypertension is not exhaustive, and long-term randomized-controlled trials would offer valuable results. PMID:24169026

  5. Postnatal dexamethasone-induced programmed hypertension is related to the regulation of melatonin and its receptors.

    PubMed

    Chang, Hsin-Yu; Tain, You-Lin

    2016-04-01

    Adulthood hypertension can be programmed by glucocorticoid exposure in early life. We found that maternal melatonin therapy prevents postnatal dexamethasone (DEX)-induced programmed hypertension. Melatonin acts through specific receptors, including MT1 and MT2 membrane receptors, and retinoid related orphan nuclear receptors of the RZR/ROR family. Thus we tested whether postnatal DEX-induced hypertension is related to changes of melatonin receptors in the kidney and heart, which was preserved by maternal melatonin therapy. Male neonates were assigned to four groups (n=6-8/group): control, DEX, control+melatonin (MEL), and DEX+MEL. Male rat pups were injected i.p. with DEX on d 1 (0.5mg/kg BW), d 2 (0.3mg/kg BW), and d 3 (0.1mg/kg BW) after birth. Melatonin was administered in drinking water (0.01%) during the lactation period. We found DEX group developed hypertension at 16weeks of age, which melatonin therapy prevented. Postnatal DEX treatment increased mRNA expression of MT1 and MT2, while decreased RORα and RZRβ in the kidney. These changes were prevented by melatonin therapy. Postnatal DEX decreased protein level of MT2 in the kidney, which was attenuated by melatonin therapy. Renal protein level of RORα was higher in DEX+MEL group compared to control and DEX group. Renal melatonin level was higher in the MEL and DEX+MEL groups compared to control. We concluded that melatonin therapy has long-term protection on postnatal DEX-induced programmed hypertension, which is associated with regulation on melatonin receptors in the kidney. Our findings would offer potential therapeutic approaches to prevent programmed hypertension in premature baby receiving glucocorticoids. PMID:26921678

  6. Prevalence of hypertension and noise-induced hearing loss in Chinese coal miners

    PubMed Central

    Liu, Jing; Xu, Ming; Ding, Lu; Zhang, Hengdong; Pan, Liping; Liu, Qingdong; Ding, Enming; Zhao, Qiuni; Wang, Boshen; Han, Lei

    2016-01-01

    Background Owing to inconsistent epidemiologic evidence and the presence of confounding factors, the relation between occupational noise exposure and hypertension still remained unclear. We aimed to assess whether Chinese coal miners were at risk of developing hypertension and noise induced hearing loss (NIHL), and whether occupational noise exposure was a risk factor of hypertension. Methods A questionnaire was designed to collect information from 738 study participants, all of whom were employees from the Datun Xuzhou Coal Company. The participants were divided into a noise-exposed group and a control group based on the noise level to which they were exposed in the workplace. The differences in the mean of systolic blood pressure (SBP) and diastolic blood pressure (DBP) were compared between the noise-exposed and control groups. Also the prevalence and age-adjusted odds ratio (OR) [95% confidence intervals (CIs)] of audiometric deficit and hypertension was compared in the study. Binary logistic regression was used to assess the relation between occupational noise level and hypertension while controlling for potential confounding factors. Results Hypertension was more prevalent in noise-exposed group than the control group, 29.2% vs. 21.2% (P=0.012). The noise-exposed group faced an increased risk of hypertension (age-adjusted OR =1.52, 95% CI =1.07–2.15) when the control group was used as reference. The mean values of SBP and DBP of the noise-exposed groups were significantly higher than the control group (P=0.006 and P=0.002 respectively). Hearing loss at low frequencies was significantly more prevalent in the noise-exposed group than the control group, 12.8% vs. 7.4% (P=0.015), while the noise-exposed group faced the increased risk of hearing loss at low frequencies (age-adjusted OR =1.81, 95% CI =1.10–2.96). LEX, 8h (OR =1.036, 95% CI =1.012–1.060) was an independent risk of hypertension when controlling for potential confounding factors. Conclusions We

  7. Update of Targeted Therapy-Induced Hypertension: Basics for Non-Oncology Providers.

    PubMed

    Escalante, Carmen P; Lu, Maggie; Marten, Claire A

    2016-01-01

    Over the past several years, cancer treatments have expanded from usual chemotherapy standards with introduction of newer targeted therapies. As with chemotherapy, the targeted therapies also have unique side effects affecting various organ systems producing toxicities, such as cardiac and renal. This manuscript focuses on hypertension induced by vascular endothelial growth factor (VEGF) inhibitors and tyrosine kinase inhibitors (TKI). Hypertension due to these cancer therapies is important because these agents are now frequently used in common cancers. In addition, patients with cancer may not be treated in a comprehensive cancer center with experts available to manage the cancer and other side effects either from the malignancy or treatment of the malignancy. Especially in rural areas, patients are often managed or co-managed by a primary care provider with input from an oncologist that may not be nearby. Our aim is to provide an overview of the latest Federal Drug Administration (FDA) approved VEGF inhibitors and TKI's causing hypertension so that others managing patients on these treatments may easily recognize hypertension attributable to these agents and feel comfortable and confident in providing appropriate management and treatment of this side effect. This update includes characteristics, such as mechanism of action, metabolism and route of administration, and management and treatment of hypertension with aspects such as the timing, duration and monitoring of these agents. In addition, an algorithm for monitoring and treating hypertension before, during and after treatment with these therapies is included. It is imperative for patients to have hypertension promptly treated to prevent complications so they may continue with these agents with the least interruption or discontinuation of treatment, ensuring the best benefit available in their cancer trajectory. PMID:26931476

  8. Antioxidant Effects of Bovine Lactoferrin on Dexamethasone-Induced Hypertension in Rat

    PubMed Central

    Safaeian, Leila; Zabolian, Hadi

    2014-01-01

    Dexamethasone- (Dex-) induced hypertension is associated with enhanced oxidative stress. Lactoferrin (LF) is an iron-binding glycoprotein with antihypertensive properties. In this study, we investigated the effect of chronic administration of LF on oxidative stress and hypertension upon Dex administration. Male Wistar rats were treated by Dex (30 μg/kg/day subcutaneously) or saline for 14 days. Oral bovine LF (30, 100, 300 mg/kg) was given from day 8 to 14 in a reversal study. In a prevention study, rats received 4 days of LF treatment followed by Dex and continued during the test period. Systolic blood pressure (SBP) was measured using tail-cuff method. Thymus weight was used as a marker of glucocorticoid activity. Plasma hydrogen peroxide (H2O2) concentration and ferric reducing antioxidant power (FRAP) value were determined. Dexamethasone significantly increased SBP and plasma H2O2 level and decreased thymus and body weights. LF lowered (P < 0.01) and dose dependently prevented (P < 0.001) Dex-induced hypertension. LF prevented body weight loss and significantly reduced the elevated plasma H2O2 and increased FRAP values. Chronic administration of LF strongly reduced the blood pressure and production of ROS and improved antioxidant capacity in Dex-induced hypertension, suggesting the role of inhibition of oxidative stress as another mechanism of antihypertensive action of LF. PMID:24587916

  9. A clinical evaluation of the "roll-over test" for pregnancy-induced hypertension.

    PubMed

    Gusdon, J P; Anderson, S G; May, W J

    1977-01-01

    A study of the capability of the roll-over test to predict pregnancy-induced hypertension was undertaken using our private patients. Sixty primigravid and 60 multigravid patients were studied between the twenty-eighth and thirty-second week of gestations. These patients were chosen at random by one of our two nurses who conducted all these studies. All results were recorded but were not available to the physicians. Eighteen months later, after all study patients had delivered, the hospital charts and the patients' office records were evaluated to determine if preganancy-induced hypertension had occurred. In primigravid patients a positive test accurately predicted the later development of pregnancy-induced hypertension only 50 per cent of the time while a negative test accurately predicted that it would not develop 93 per cent of the time. In multigravid patients, only 25 per cent of the patients who had positive tests later developed hypertension. The negative test in multigravid patients was accurate 94 per cent of the time. PMID:831479

  10. Resistin Induces Hypertension and Insulin Resistance in Mice via a TLR4-Dependent Pathway.

    PubMed

    Jiang, Yun; Lu, Linfang; Hu, Youtao; Li, Qiang; An, Chaoqiang; Yu, Xiaolan; Shu, Le; Chen, Ao; Niu, Congcong; Zhou, Lei; Yang, Zaiqing

    2016-01-01

    Resistin, an adipokine involved in insulin resistance (IR) and diabetes, has recently been reported to play a role in cardiovascular events. However, its effect on blood pressure (BP) and the underlying mechanisms remain unclear. In the present study, we showed that resistin induces hypertension and IR in wild type (WT) mice, but not in tlr4(-/-) mice. Resistin upregulated angiotensinogen (Agt) expression in WT mice, whereas it had no effect on tlr4(-/-) mice, or in mice treated with the angiotensin-converting enzyme inhibitor perindopril. Real-time PCR and chromatin immunoprecipitation further confirmed that resistin activates the renin-angiotensin system (RAS) via the TLR4/P65/Agt pathway. This finding suggested an essential role of resistin in linking IR and hypertension, which may offer a novel target in clinic on the study of the association between diabetes and hypertension. PMID:26917360

  11. Resistin Induces Hypertension and Insulin Resistance in Mice via a TLR4-Dependent Pathway

    PubMed Central

    Jiang, Yun; Lu, Linfang; Hu, Youtao; Li, Qiang; An, Chaoqiang; Yu, Xiaolan; Shu, Le; Chen, Ao; Niu, Congcong; Zhou, Lei; Yang, Zaiqing

    2016-01-01

    Resistin, an adipokine involved in insulin resistance (IR) and diabetes, has recently been reported to play a role in cardiovascular events. However, its effect on blood pressure (BP) and the underlying mechanisms remain unclear. In the present study, we showed that resistin induces hypertension and IR in wild type (WT) mice, but not in tlr4−/− mice. Resistin upregulated angiotensinogen (Agt) expression in WT mice, whereas it had no effect on tlr4−/− mice, or in mice treated with the angiotensin-converting enzyme inhibitor perindopril. Real-time PCR and chromatin immunoprecipitation further confirmed that resistin activates the renin-angiotensin system (RAS) via the TLR4/P65/Agt pathway. This finding suggested an essential role of resistin in linking IR and hypertension, which may offer a novel target in clinic on the study of the association between diabetes and hypertension. PMID:26917360

  12. Therapeutic Benefits of Induced Pluripotent Stem Cells in Monocrotaline-Induced Pulmonary Arterial Hypertension.

    PubMed

    Huang, Wei-Chun; Ke, Meng-Wei; Cheng, Chin-Chang; Chiou, Shih-Hwa; Wann, Shue-Ren; Shu, Chih-Wen; Chiou, Kuan-Rau; Tseng, Ching-Jiunn; Pan, Hung-Wei; Mar, Guang-Yuan; Liu, Chun-Peng

    2016-01-01

    Pulmonary arterial hypertension (PAH) is characterized by progressive increases in vascular resistance and the remodeling of pulmonary arteries. The accumulation of inflammatory cells in the lung and elevated levels of inflammatory cytokines in the bloodstream suggest that inflammation may play a role in PAH. In this study, the benefits of induced pluripotent stem cells (iPSCs) and iPSC-conditioned medium (iPSC CM) were explored in monocrotaline (MCT)-induced PAH rats. We demonstrated that both iPSCs and iPSC CM significantly reduced the right ventricular systolic pressure and ameliorated the hypertrophy of the right ventricle in MCT-induced PAH rats in models of both disease prevention and disease reversal. In the prevention of MCT-induced PAH, iPSC-based therapy led to the decreased accumulation of inflammatory cells and down-regulated the expression of the IL-1β, IL-6, IL-12α, IL-12β, IL-23 and IFNγ genes in lung specimens, which implied that iPSC-based therapy may be involved in the regulation of inflammation. NF-κB signaling is essential to the inflammatory cascade, which is activated via the phosphorylation of the NF-κB molecule. Using the chemical inhibitor specifically blocked the phosphorylation of NF-κB, and in vitro assays of cultured human M1 macrophages implied that the anti-inflammation effect of iPSC-based therapy may contribute to the disturbance of NF-κB activation. Here, we showed that iPSC-based therapy could restore the hemodynamic function of right ventricle with benefits for preventing the ongoing inflammation in the lungs of MCT-induced PAH rats by regulating NF-κB phosphorylation. PMID:26840075

  13. Decreased pituitary response to insulin-induced hypoglycaemia in young lean male patients with essential hypertension.

    PubMed

    Radikova, Z; Penesova, A; Cizmarova, E; Huckova, M; Kvetnansky, R; Vigas, M; Koska, J

    2006-07-01

    Essential hypertension is associated with changes in central catecholaminergic pathways which might also be reflected in the pituitary response to stress stimuli. The aim of this study was to determine whether the response of pituitary hormones, cortisol, plasma renin activity, aldosterone and catecholamines to insulin-induced hypoglycaemia is changed in hypertension. We studied 22 young lean male patients with newly diagnosed untreated essential hypertension and 19 healthy normotensive, age- and body mass index (BMI)-matched controls. All subjects underwent an insulin tolerance test (0.1 IU insulin/kg body weight intravenously) with blood sampling before and 15, 30, 45, 60 and 90 min after insulin administration. Increased baseline levels of norepinephrine (P<0.05), increased response of norepinephrine (P<0.001) and decreased response of growth hormone (P<0.001), prolactin (P<0.001), adrenocorticotropic hormone (P<0.05) and cortisol (P<0.001) were found in hypertensive patients when compared to normotensive controls. Increased norepinephrine levels and a decreased pituitary response to metabolic stress stimuli may represent another manifestation of chronically increased sympathetic tone in early hypertension. PMID:16617309

  14. Renal Deletion of 12 kDa FK506-Binding Protein Attenuates Tacrolimus-Induced Hypertension.

    PubMed

    Lazelle, Rebecca A; McCully, Belinda H; Terker, Andrew S; Himmerkus, Nina; Blankenstein, Katharina I; Mutig, Kerim; Bleich, Markus; Bachmann, Sebastian; Yang, Chao-Ling; Ellison, David H

    2016-05-01

    Tacrolimus is a widely used immunosuppressive drug that inhibits the phosphatase calcineurin when bound to the 12 kDa FK506-binding protein (FKBP12). When this binding occurs in T cells, it leads to immunosuppression. Tacrolimus also causes side effects, however, such as hypertension and hyperkalemia. Previously, we reported that tacrolimus stimulates the renal thiazide-sensitive sodium chloride cotransporter (NCC), which is necessary for the development of hypertension. However, it was unclear if tacrolimus-induced hypertension resulted from tacrolimus effects in renal epithelial cells directly or in extrarenal tissues, and whether inhibition of calcineurin was required. To address these questions, we developed a mouse model in which FKBP12 could be deleted along the nephron. FKBP12 disruption alone did not cause phenotypic effects. When treated with tacrolimus, however, BP and the renal abundance of phosphorylated NCC were lower in mice lacking FKBP12 along the nephron than in control mice. Mice lacking FKBP12 along the nephron also maintained a normal relationship between plasma potassium levels and the abundance of phosphorylated NCC with tacrolimus treatment. In cultured cells, tacrolimus inhibited dephosphorylation of NCC. Together, these results suggest that tacrolimus causes hypertension predominantly by inhibiting calcineurin directly in cells expressing NCC, indicating thiazide diuretics may be particularly effective for lowering BP in tacrolimus-treated patients with hypertension. PMID:26432904

  15. Fractal Dimension in Quantifying Experimental-Pulmonary-Hypertension-Induced Cardiac Dysfunction in Rats

    PubMed Central

    Pacagnelli, Francis Lopes; Sabela, Ana Karênina Dias de Almeida; Mariano, Thaoan Bruno; Ozaki, Guilherme Akio Tamura; Castoldi, Robson Chacon; do Carmo, Edna Maria; Carvalho, Robson Francisco; Tomasi, Loreta Casquel; Okoshi, Katashi; Vanderlei, Luiz Carlos Marques

    2016-01-01

    Background Right-sided heart failure has high morbidity and mortality, and may be caused by pulmonary arterial hypertension. Fractal dimension is a differentiated and innovative method used in histological evaluations that allows the characterization of irregular and complex structures and the quantification of structural tissue changes. Objective To assess the use of fractal dimension in cardiomyocytes of rats with monocrotaline-induced pulmonary arterial hypertension, in addition to providing histological and functional analysis. Methods Male Wistar rats were divided into 2 groups: control (C; n = 8) and monocrotaline-induced pulmonary arterial hypertension (M; n = 8). Five weeks after pulmonary arterial hypertension induction with monocrotaline, echocardiography was performed and the animals were euthanized. The heart was dissected, the ventricles weighed to assess anatomical parameters, and histological slides were prepared and stained with hematoxylin/eosin for fractal dimension analysis, performed using box-counting method. Data normality was tested (Shapiro-Wilk test), and the groups were compared with non-paired Student t test or Mann Whitney test (p < 0.05). Results Higher fractal dimension values were observed in group M as compared to group C (1.39 ± 0.05 vs. 1.37 ± 0.04; p < 0.05). Echocardiography showed lower pulmonary artery flow velocity, pulmonary acceleration time and ejection time values in group M, suggesting function worsening in those animals. Conclusion The changes observed confirm pulmonary-arterial-hypertension-induced cardiac dysfunction, and point to fractal dimension as an effective method to evaluate cardiac morphological changes induced by ventricular dysfunction. PMID:27223643

  16. Neutrophil Depletion Attenuates Placental Ischemia-Induced Hypertension in the Rat.

    PubMed

    Regal, Jean F; Lillegard, Kathryn E; Bauer, Ashley J; Elmquist, Barbara J; Loeks-Johnson, Alex C; Gilbert, Jeffrey S

    2015-01-01

    Preeclampsia is characterized by reduced placental perfusion with placental ischemia and hypertension during pregnancy. Preeclamptic women also exhibit a heightened inflammatory state and greater number of neutrophils in the vasculature compared to normal pregnancy. Since neutrophils are associated with tissue injury and inflammation, we hypothesized that neutrophils are critical to placental ischemia-induced hypertension and fetal demise. Using the reduced uteroplacental perfusion pressure (RUPP) model of placental ischemia-induced hypertension in the rat, we determined the effect of neutrophil depletion on blood pressure and fetal resorptions. Neutrophils were depleted with repeated injections of polyclonal rabbit anti-rat polymorphonuclear leukocyte (PMN) antibody (antiPMN). Rats received either antiPMN or normal rabbit serum (Control) on 13.5, 15.5, 17.5, and 18.5 days post conception (dpc). On 14.5 dpc, rats underwent either Sham surgery or clip placement on ovarian arteries and abdominal aorta to reduce uterine perfusion pressure (RUPP). On 18.5 dpc, carotid arterial catheters were placed and mean arterial pressure (MAP) was measured on 19.5 dpc. Neutrophil-depleted rats had reduced circulating neutrophils from 14.5 to 19.5 dpc compared to Control, as well as decreased neutrophils in lung and placenta on 19.5 dpc. MAP increased in RUPP Control vs Sham Control rats, and neutrophil depletion attenuated this increase in MAP in RUPP rats without any effect on Sham rats. The RUPP-induced increase in fetal resorptions and complement activation product C3a were not affected by neutrophil depletion. Thus, these data are the first to indicate that neutrophils play an important role in RUPP hypertension and that cells of the innate immune system may significantly contribute to pregnancy-induced hypertension. PMID:26135305

  17. Oxidant and enzymatic antioxidant status (gene expression and activity) in the brain of chickens with cold-induced pulmonary hypertension

    NASA Astrophysics Data System (ADS)

    Hassanpour, Hossein; Khalaji-Pirbalouty, Valiallah; Nasiri, Leila; Mohebbi, Abdonnaser; Bahadoran, Shahab

    2015-11-01

    To evaluate oxidant and antioxidant status of the brain (hindbrain, midbrain, and forebrain) in chickens with cold-induced pulmonary hypertension, the measurements of lipid peroxidation, protein oxidation, antioxidant capacity, enzymatic activity, and gene expression (for catalase, glutathione peroxidase, and superoxide dismutases) were done. There were high lipid peroxidation/protein oxidation and low antioxidant capacity in the hindbrain of cold-induced pulmonary hypertensive chickens compared to control ( P < 0.05). In the hypertensive chickens, superoxide dismutase activity was decreased (forebrain, midbrain, and hindbrain), while catalase activity was increased (forebrain and midbrain) ( P < 0.05). Glutathione peroxidase activity did not change. Relative gene expression of catalase and superoxide dismutases (1 and 2) was downregulated, while glutathione peroxidase was upregulated in the brain of the cold-induced pulmonary hypertensive chickens. Probably, these situations in the oxidant and antioxidant status of the brain especially hindbrain may change its function at cardiovascular center and sympathetic nervous system to exacerbate pulmonary hypertension.

  18. Prevention of hypertension is associated with reduced susceptibility to histamine-induced arrhythmias in SHR.

    PubMed

    Cameron, J S; Antonik, L J

    1988-07-01

    Two groups of spontaneously hypertensive rats (SHR) were treated with alpha-methyldopa (2.5 g/L in drinking water) for 12-17 weeks. One group was treated during the normal time course for development of hypertension and myocardial hypertrophy (beginning at age 4 weeks), while the other was treated after stabilization of hypertension/hypertrophy (21 weeks). Appropriate age-matched controls (WKY strain) also were treated. Intracellular microelectrodes were used to monitor action potential configuration, automaticity, and the incidence of arrhythmias (including delayed afterdepolarizations and repetitive tachyarrhythmias) in isolated left ventricles from each group. The younger rats did not develop hypertension of left ventricular hypertrophy; susceptibility of isolated left ventricles to histamine-induced (10(-5) M) arrhythmogenesis was significantly reduced. The older rats showed decreased blood pressure, although not to normal levels; further left ventricular hypertrophy was prevented, though the existing enlargement did not regress. These hearts were as susceptible to the development of histamine-induced arrhythmias as were hearts of untreated SHR. Enhanced susceptibility to arrhythmias in hypertrophied hearts reflects a preventable alteration of the myocardial cell membrane that occurs during the course of blood pressure elevation. This change may be associated with defective sarcolemmal calcium transport in hypertrophied myocardium. PMID:2970857

  19. The Effect of Magnesium on Visual Evoked Potentials in L-NAME-Induced Hypertensive Rats.

    PubMed

    Ozsoy, Ozlem; Aras, Sinem; Ulker Karadamar, Pinar; Nasircilar Ulker, Seher; Kocer, Gunnur; Senturk, Umit Kemal; Basrali, Filiz; Yargicoglu, Piraye; Ozyurt, Dilek; Agar, Aysel

    2016-08-01

    In the literature, although there are many studies regarding complications of hypertension, information concerning its influence on visual evoked potentials (VEPs) is limited. This study aims to clarify the possible therapeutic effects of the preferential magnesium (Mg) treatment on VEPs in an experimental hypertension model. Rats were divided into four groups as follows: control, Mg treated (Mg), N(omega)-nitro-L-arginine methyl ester (L-NAME) hypertension, and L-NAME hypertension + Mg treated (L-NAME + Mg). Hypertension was induced by L-NAME which was given to rats orally over 6 weeks (25 mg/kg/day in drinking water). A magnesium-enriched diet (0.8 g/kg) was given to treatment groups for 6 weeks. Systolic blood pressure (SBP) was determined by using the tail-cuff method. Flash VEPs were recorded. Our results revealed that the SBP was significantly increased in the L-NAME group compared to control. Magnesium treatment significantly attenuated SBP in the hypertensive rats compared to the L-NAME group. The mean latencies of P1, N1, P2, N2, and P3 components were significantly prolonged in hypertensive rats compared to control. Treatment with Mg provided a significant decrease in the latencies of P1, N1, P2, N2, and P3 potentials in the L-NAME + Mg group compared to the L-NAME group. Plasma Mg levels were increased in the L-NAME + Mg group compared to the L-NAME group. No change was detected in the Mg levels of the brains in all experimental groups. Magnesium treatment had no effect on the brain nitrate/nitrite and thiobarbituric acid-reactive substances (TBARS) levels in hypertensive rats compared to non-treated rats. There was a positive correlation between the brain TBARS levels and SBP of the rats. The present study suggests that Mg supplementation has the potential to prevent VEP changes in the L-NAME-induced hypertension model. PMID:26701333

  20. Alcohol-induced hypertension: an important healthcare target in Belgium.

    PubMed

    Collart, F; de Timary, P; Dom, G; Dor, B D; Duprez, D; Lengelé, J-P; Matthys, F; Peuskens, H; Rehm, J; Stärkel, P

    2015-12-01

    Excessive alcohol intake is one of the leading causes of premature death in Europe and particularly in Belgium. Belgian people are consuming more alcohol per year than the European average. It is well established that excessive alcohol consumption is a significant predictor of the development of hypertension (HTN). Two million adults in Belgium suffer from HTN and this number will increase to three million by 2025. Less than 50% of Belgian people treated for HTN are well-controlled. Alcohol reduction in patients with HTN can significantly lower systolic and diastolic blood pressure. After reviewing the epidemiology of HTN and alcohol disorders in Belgium, this paper will focus on the rationale for alcohol screening and brief intervention in primary care. It will also describe the barriers to alcohol screening, and what could be the benefits of alcohol screening for our healthcare system. The authors believe that early identification through alcohol screening and brief intervention in general practice can help to improve the management of patients with HTN, to reach the targets of the WHO Global Action Plan, i.e., a 25% relative reduction in the risk of premature mortality from cardiovascular diseases, cancer, diabetes or chronic respiratory diseases. They are also convinced that this would allow achieving major healthcare savings. PMID:26135944

  1. Mechanisms of lead-induced hypertension and cardiovascular disease

    PubMed Central

    Vaziri, Nosratola D.

    2008-01-01

    Lead is a ubiquitous environmental toxin that is capable of causing numerous acute and chronic illnesses. Population studies have demonstrated a link between lead exposure and subsequent development of hypertension (HTN) and cardiovascular disease. In vivo and in vitro studies have shown that chronic lead exposure causes HTN and cardiovascular disease by promoting oxidative stress, limiting nitric oxide availability, impairing nitric oxide signaling, augmenting adrenergic activity, increasing endothelin production, altering the renin-angiotensin system, raising vasoconstrictor prostaglandins, lowering vasodilator prostaglandins, promoting inflammation, disturbing vascular smooth muscle Ca2+ signaling, diminishing endothelium-dependent vasorelaxation, and modifying the vascular response to vasoactive agonists. Moreover, lead has been shown to cause endothelial injury, impede endothelial repair, inhibit angiogenesis, reduce endothelial cell growth, suppress proteoglycan production, stimulate vascular smooth muscle cell proliferation and phenotypic transformation, reduce tissue plasminogen activator, and raise plasminogen activator inhibitor-1 production. Via these and other actions, lead exposure causes HTN and promotes arteriosclerosis, atherosclerosis, thrombosis, and cardiovascular disease. In conclusion, studies performed in experimental animals, isolated tissues, and cultured cells have provided compelling evidence that chronic exposure to low levels of lead can cause HTN, endothelial injury/dysfunction, arteriosclerosis, and cardiovascular disease. More importantly, these studies have elucidated the cellular and molecular mechanisms of lead's action on cardiovascular/renal systems, a task that is impossible to accomplish using clinical and epidemiological investigations alone. PMID:18567711

  2. Inhaled tezosentan reduces pulmonary hypertension in endotoxin-induced lung injury.

    PubMed

    Persson, Björn P; Rossi, Patrik; Weitzberg, Eddie; Oldner, Anders

    2009-10-01

    The vasoconstrictive and proinflammatory peptide endothelin 1 (ET-1) is highly involved in the pathogenesis of sepsis and associated lung injury. Systemic administration of ET-receptor antagonists has been beneficial in experimental pulmonary hypertension. We wanted to study the effects of inhaled tezosentan, a dual endothelin-receptor antagonist on endotoxin-induced pulmonary hypertension, deterioration of gas exchange, and edema formation. After 2 h of endotoxemia, 28 anesthetized, mechanically ventilated pigs were randomized to either inhaled tezosentan 0.5 mg x kg (TEZO(0.5), n = 7), 0.05 mg x kg (TEZO(0.05), n = 7), intravenous 0.5 mg x kg (TEZO(iv), n = 7), or control (n = 7). Cardiopulmonary hemodynamics and gas-exchange parameters were recorded as well as extravascular lung water and pulmonary capillary pressure. In addition, plasma levels of tezosentan and ET-1 were analyzed. The protocol lasted for 5 h. Endotoxin-induced pulmonary hypertension (mean pulmonary artery pressure) was efficiently reduced by all treatments (TEZO(0.5) 24 +/- 2, TEZO(0.05) 27 +/- 2, TEZO(iv) 26 +/- 1, and control 37 +/- 2 mmHg at 4 h). TEZO(0.5) and TEZO(iv) also reduced pulmonary capillary pressure. All treatments led to a modest reduction in extravascular lung water, whereas no effects were noted on oxygenation or systemic circulation. Despite similar effects on pulmonary hypertension systemic treatment resulted in significantly higher plasma levels of ET-1 (twofold) and tezosentan (10- to 100-fold). Inhalation of the dual ET-receptor antagonist tezosentan was feasible and efficiently counteracted endotoxin-induced pulmonary hypertension. These effects were obtained with only minor systemic uptake of tezosentan and without affecting circulating levels of plasma ET-1 as compared with intravenous administration. PMID:19197226

  3. Loss of functional endothelial connexin40 results in exercise-induced hypertension in mice.

    PubMed

    Morton, Susan K; Chaston, Daniel J; Howitt, Lauren; Heisler, Jillian; Nicholson, Bruce J; Fairweather, Stephen; Bröer, Stefan; Ashton, Anthony W; Matthaei, Klaus I; Hill, Caryl E

    2015-03-01

    During activity, coordinated vasodilation of microcirculatory networks with upstream supply vessels increases blood flow to skeletal and cardiac muscles and reduces peripheral resistance. Endothelial dysfunction in humans attenuates activity-dependent vasodilation, resulting in exercise-induced hypertension in otherwise normotensive individuals. Underpinning activity-dependent hyperemia is an ascending vasodilation in which the endothelial gap junction protein, connexin (Cx)40, plays an essential role. Because exercise-induced hypertension is proposed as a forerunner to clinical hypertension, we hypothesized that endothelial disruption of Cx40 function in mice may create an animal model of this condition. To this end, we created mice in which a mutant Cx40T152A was expressed alongside wildtype Cx40 selectively in the endothelium. Expression of the Cx40T152A transgene in Xenopus oocytes and mouse coronary endothelial cells in vitro impaired both electric and chemical conductance and acted as a dominant-negative against wildtype Cx40, Cx43, and Cx45, but not Cx37. Endothelial expression of Cx40T152A in Cx40T152ATg mice attenuated ascending vasodilation, without effect on radial coupling through myoendothelial gap junctions. Using radiotelemetry, Cx40T152ATg mice showed an activity-dependent increase in blood pressure, which was significantly greater than in wildtype mice, but significantly less than in chronically hypertensive, Cx40knockout mice. The increase in heart rate with activity was also greater than in wildtype or Cx40knockout mice. We conclude that the endothelial Cx40T152A mutation attenuates activity-dependent vasodilation, producing a model of exercise-induced hypertension. These data highlight the importance of endothelial coupling through Cx40 in regulating blood pressure during activity. PMID:25547341

  4. Carotid Body Ablation Abrogates Hypertension and Autonomic Alterations Induced by Intermittent Hypoxia in Rats.

    PubMed

    Del Rio, Rodrigo; Andrade, David C; Lucero, Claudia; Arias, Paulina; Iturriaga, Rodrigo

    2016-08-01

    Chronic intermittent hypoxia (CIH), the main feature of obstructive sleep apnea, enhances carotid body (CB) chemosensory responses to hypoxia and produces autonomic dysfunction, cardiac arrhythmias, and hypertension. We tested whether autonomic alterations, arrhythmogenesis, and the progression of hypertension induced by CIH depend on the enhanced CB chemosensory drive, by ablation of the CB chemoreceptors. Male Sprague-Dawley rats were exposed to control (Sham) conditions for 7 days and then to CIH (5% O2, 12/h 8 h/d) for a total of 28 days. At 21 days of CIH exposure, rats underwent bilateral CB ablation and then exposed to CIH for 7 additional days. Arterial blood pressure and ventilatory chemoreflex response to hypoxia were measured in conscious rats. In addition, cardiac autonomic imbalance, cardiac baroreflex gain, and arrhythmia score were assessed during the length of the experiments. In separate experimental series, we measured extracellular matrix remodeling content in cardiac atrial tissue and systemic oxidative stress. CIH induced hypertension, enhanced ventilatory response to hypoxia, induced autonomic imbalance toward sympathetic preponderance, reduced baroreflex gain, and increased arrhythmias and atrial fibrosis. CB ablation normalized blood pressure, reduced ventilatory response to hypoxia, and restored cardiac autonomic and baroreflex function. In addition, CB ablation reduced the number of arrhythmias, but not extracellular matrix remodeling or systemic oxidative stress, suggesting that reductions in arrhythmia incidence during CIH were related to normalization of cardiac autonomic balance. Present results show that autonomic alterations induced by CIH are critically dependent on the CB and support a main role for the CB in the CIH-induced hypertension. PMID:27381902

  5. Arginase inhibition protects against hypoxia‑induced pulmonary arterial hypertension.

    PubMed

    Jiang, Wenjin; Sun, Bolin; Song, Xuepeng; Zheng, Yanbo; Wang, Ligang; Wang, Tao; Liu, Sheng

    2015-09-01

    The present study aimed to determine the role of arginase (Arg) in pulmonary arterial hypertension (PAH). In vitro, human pulmonary artery smooth muscle cells (HPASMCs) were cultured under hypoxic conditions with, or without, the Arg inhibitor, S‑(2‑boronoethyl)‑l‑cysteine (BEC), for 48 h, following which the proliferation of the HPASMCs was determined using MTT and cell counting assays. For the in vivo investigation, 30 male rats were randomly divided into the following three groups (n=10 per group): i) control group, ii) PAH group and iii) BEC group, in which the right ventricle systolic pressure (RVSP) of the rats was assessed. The levels of cyclin D1, cyclin‑dependent kinase (CDK)4 and p27 were measured in vitro and in vivo. The phosphorylation levels of Akt and extracellular‑related kinase (ERK) were also measured in HPASMCs. In vitro, compared with the hypoxia group, Arg inhibition reduced HPASMC proliferation and reduced the expression levels of cyclin D1, CDK4, phosphorylated (p‑)Akt and p‑ERK. By contrast, Arg inhibition increased the expression of p27. In vivo, compared with the control group, the expression levels of cyclin D1 and CDK4 were reduced in the PAH group, however, the expression of p27 and the RVSP increased. In the BEC group, the opposite effects were observed. Therefore, it was suggested that Arg inhibition may reduce the RVSP of PAH rats and reduce HPASMC proliferation by decreasing the expression levels of cyclin D1 and CDK4, increasing the expression of p27, and partly reducing the phosphorylation of Akt and ERK. PMID:26126810

  6. Low ethanol intake prevents salt-induced hypertension in WKY rats.

    PubMed

    Vasdev, Sudesh; Gill, Vicki; Parai, Sushil; Gadag, Veeresh

    2006-07-01

    Low alcohol intake in humans lowers the risk of coronary heart disease and may lower blood pressure. In hypertension, insulin resistance with altered glucose metabolism leads to increased formation of aldehydes. We have shown that chronic low alcohol intake decreased systolic blood pressure (SBP) and tissue aldehyde conjugates in spontaneously hypertensive rats and demonstrated a strong link between elevated tissue aldehyde conjugates and hypertension in salt-induced hypertensive Wistar-Kyoto (WKY) rats. This study investigated the antihypertensive effect of chronic low alcohol consumption in high salt-treated WKY rats and its effect on tissue aldehyde conjugates, platelet cytosolic free calcium ([Ca2+]i, and renal vascular changes. Animals, aged 7 weeks, were divided into three groups of six animals each. The control group was given normal salt diet (0.7% NaCl) and regular drinking water; the high salt group was given a high salt diet (8% NaCl) and regular drinking water; the high salt + ethanol group was given a high salt diet and 0.25% ethanol in drinking water. After 10 weeks, SBP, platelet [Ca2+]i, and tissue aldehyde conjugates were significantly higher in rats in the high salt group as compared with controls. Animals on high salt diets also showed smooth muscle cell hyperplasia in the small arteries and arterioles of the kidney. Ethanol supplementation prevented the increase in SBP and platelet [Ca2+]i and aldehyde conjugates in liver and aorta. Kidney aldehyde conjugates and renal vascular changes were attenuated. These results suggest that chronic low ethanol intake prevents salt-induced hypertension and attenuates renal vascular changes in WKY rats by preventing an increase in tissue aldehyde conjugates and cytosolic [Ca2+]i. PMID:16685463

  7. Prostatic Relaxation Induced by Loperamide Is Reduced in Spontaneously Hypertensive Rats

    PubMed Central

    Lee, Liang-Ming; Lu, Chih-Cheng; Chung, Hsien-Hui; Cheng, Juei-Tang

    2012-01-01

    This paper shows a new finding about the decrease of relaxative response to loperamide in prostate of spontaneously hypertensive rats (SHR) as compare to normal rats (WKY). Authors demonstrated the reduction of ATP-sensitive potassium channels is resposible for this change using immunoblotting analysis and the decrease of action induced by diazoxide. This view is not mentioned before and is the first one reporting this result. PMID:22645476

  8. The glucocorticoid receptor in the distal nephron is not necessary for the development or maintenance of dexamethasone-induced hypertension

    PubMed Central

    Goodwin, Julie E.; Zhang, Junhui; Velazquez, Heino; Geller, David S.

    2010-01-01

    Glucocorticoids are used as a treatment for a variety of conditions and hypertension is a well-recognized side effect of their use. The mechanism of glucocorticoid-induced hypertension is incompletely understood and has traditionally been attributed to promiscuous activation of the mineralocorticoid receptor by cortisol. Multiple lines of evidence, however, point to the glucocorticoid receptor as an important mediator as well. We have developed a mouse model of glucocorticoid-induced hypertension, which is dependent on the glucocorticoid receptor. To determine the site(s) of glucocorticoid receptor action relevant to the development of hypertension, we studied glucocorticoid-induced hypertension in a mouse with a tissue-specific knockout of the glucocorticoid receptor in the distal nephron. Although knockout mice had similar body weight, nephron number and renal histology compared to littermate controls, their baseline blood pressure was mildly elevated. Nevertheless, distal nephron glucocorticoid receptor knockout mice and controls had a similar hypertensive response to dexamethasone. Urinary excretion of electrolytes, both before and after administration of glucocorticoid was also indistinguishable between the two groups. We conclude that the glucocorticoid receptor in the distal nephron is not necessary for the development or maintenance of dexamethasone-induced hypertension in our model. PMID:20188070

  9. Experimental TIPS with spiral Z-stents in swine with and without induced portal hypertension

    SciTech Connect

    Kichikawa, Kimihiko; Saxon, Richard R.; Nishimine, Kiyoshi; Nishida, Norifumi; Uchida, Barry T.

    1997-05-15

    Purpose. To assess the suitability of spiral Z-stents for transjugular intrahepatic portosystemic shunt (TIPS) and the influence of portal hypertension on shunt patency in young swine. Methods. TIPS were established using spiral Z-stents in 14 domestic swine. In 7 animals, the portal venous pressure was normal; in the other 7, acute portal hypertension was induced by embolization of portal vein branches. Follow-up portal venography and histologic evaluations were done from 1 hr to 12 weeks after TIPS. Results. Follow-up transhepatic portal venograms showed progressive narrowing of the shunt, most priminent in the midportion of the tract. Ingrowth of liver parenchyma between the stent wires found after 3 weeks led to progressive shunt narrowing and shunt occlusion by 12 weeks. A pseudointima grew rapidly inside the stent, peaked in thickness around 4 weeks, and decreased later. Acutely created portal hypertension rapidly returned to normal and there was no difference in TIPS patency between the two groups of animals. Conclusion. Although the spiral Z-stent can be used as a device for creation of TIPS in patients with cirrhotic livers, it is associated with extensive liver ingrowth in swine that leads to rapid shunt occlusion. Portal hypertension was only transient in this model.

  10. In vivo left ventricular function and collagen expression in aldosterone/salt-induced hypertension.

    PubMed

    Ramirez-Gil, J F; Delcayre, C; Robert, V; Wassef, M; Trouve, P; Mougenot, N; Charlemagne, D; Lechat, P

    1998-12-01

    Cardiac fibrosis is linked to aldosterone-induced hypertension, but the effects on in vivo left ventricular (LV) function are not established. We studied the relations between in vivo LV function and aldosterone/salt cardiac fibrosis. Adult guinea pigs (GPs) were treated for 3 months with an aldosterone infusion and high-salt diet. This treatment induced arterial hypertension (+35%) and moderate LV hypertrophy (LVH; +60%) without right ventricular (RV) hypertrophy. Echo-Doppler LV assessment demonstrated unaltered cardiac output, stroke volume, or LV relaxation. Type I collagen messenger RNA (mRNA) was significantly increased in both ventricles (LV, +48%; RV, +77%) and accompanied by a significant increase in total collagen deposition (LV, from 0.52% in controls to 4.4% in treated GPs; RV, from 0.82 to 5.5% in treated GPs). Plasma norepinephrine levels increased 2.6-fold (p < 0.01) and correlated with the increase in collagen deposition in both ventricles. Collagen content was not correlated with hypertension or LVH. We conclude that aldosterone administration induces cardiac collagen accumulation and a sympathetic stimulation, which might preserve systolic and diastolic function. PMID:9869498

  11. p66Shc regulates renal vascular tone in hypertension-induced nephropathy.

    PubMed

    Miller, Bradley; Palygin, Oleg; Rufanova, Victoriya A; Chong, Andrew; Lazar, Jozef; Jacob, Howard J; Mattson, David; Roman, Richard J; Williams, Jan M; Cowley, Allen W; Geurts, Aron M; Staruschenko, Alexander; Imig, John D; Sorokin, Andrey

    2016-07-01

    Renal preglomerular arterioles regulate vascular tone to ensure a large pressure gradient over short distances, a function that is extremely important for maintaining renal microcirculation. Regulation of renal microvascular tone is impaired in salt-sensitive (SS) hypertension-induced nephropathy, but the molecular mechanisms contributing to this impairment remain elusive. Here, we assessed the contribution of the SH2 adaptor protein p66Shc (encoded by Shc1) in regulating renal vascular tone and the development of renal vascular dysfunction associated with hypertension-induced nephropathy. We generated a panel of mutant rat strains in which specific modifications of Shc1 were introduced into the Dahl SS rats. In SS rats, overexpression of p66Shc was linked to increased renal damage. Conversely, deletion of p66Shc from these rats restored the myogenic responsiveness of renal preglomerular arterioles ex vivo and promoted cellular contraction in primary vascular smooth muscle cells (SMCs) that were isolated from renal vessels. In primary SMCs, p66Shc restricted the activation of transient receptor potential cation channels to attenuate cytosolic Ca2+ influx, implicating a mechanism by which overexpression of p66Shc impairs renal vascular reactivity. These results establish the adaptor protein p66Shc as a regulator of renal vascular tone and a driver of impaired renal vascular function in hypertension-induced nephropathy. PMID:27270176

  12. Heme biosynthesis modulation via δ-aminolevulinic acid administration attenuates chronic hypoxia-induced pulmonary hypertension

    PubMed Central

    Alhawaj, Raed; Patel, Dhara; Kelly, Melissa R.; Sun, Dong

    2015-01-01

    This study examines how heme biosynthesis modulation with δ-aminolevulinic acid (ALA) potentially functions to prevent 21-day hypoxia (10% oxygen)-induced pulmonary hypertension in mice and the effects of 24-h organoid culture with bovine pulmonary arteries (BPA) with the hypoxia and pulmonary hypertension mediator endothelin-1 (ET-1), with a focus on changes in superoxide and regulation of micro-RNA 204 (miR204) expression by src kinase phosphorylation of signal transducer and activator of transcription-3 (STAT3). The treatment of mice with ALA attenuated pulmonary hypertension (assessed through echo Doppler flow of the pulmonary valve, and direct measurements of right ventricular systolic pressure and right ventricular hypertrophy), increases in pulmonary arterial superoxide (detected by lucigenin), and decreases in lung miR204 and mitochondrial superoxide dismutase (SOD2) expression. ALA treatment of BPA attenuated ET-1-induced increases in mitochondrial superoxide (detected by MitoSox), STAT3 phosphorylation, and decreases in miR204 and SOD2 expression. Because ALA increases BPA protoporphyrin IX (a stimulator of guanylate cyclase) and cGMP-mediated protein kinase G (PKG) activity, the effects of the PKG activator 8-bromo-cGMP were examined and found to also attenuate the ET-1-induced increase in superoxide. ET-1 increased superoxide production and the detection of protoporphyrin IX fluorescence, suggesting oxidant conditions might impair heme biosynthesis by ferrochelatase. However, chronic hypoxia actually increased ferrochelatase activity in mouse pulmonary arteries. Thus, a reversal of factors increasing mitochondrial superoxide and oxidant effects that potentially influence remodeling signaling related to miR204 expression and perhaps iron availability needed for the biosynthesis of heme by the ferrochelatase reaction could be factors in the beneficial actions of ALA in pulmonary hypertension. PMID:25659899

  13. A Novel Model of Dexamethasone-Induced Hypertension: Use in Investigating the Role of Tyrosine Hydroxylase.

    PubMed

    Soto-Piña, Alexandra E; Franklin, Cynthia; Rani, C S Sheela; Gottlieb, Helmut; Hinojosa-Laborde, Carmen; Strong, Randy

    2016-09-01

    Our objective was to study hypertension induced by chronic administration of synthetic glucocorticoid, dexamethasone (DEX), under nonstressful conditions and examine the role of catecholamine biosynthesis. To achieve this, we did the following: 1) used radiotelemetry to record mean arterial pressure (MAP) and heart rate (HR) in freely moving rats, and 2) administered different doses of DEX in drinking water. To evaluate the involvement of tyrosine hydroxylase (TH), the rate-limiting step in catecholamine biosynthesis, we treated rats with the TH inhibitor, α-methyl-para-tyrosine (α-MPT), for 3 days prior to administration of DEX and assessed TH mRNA and protein expression by quantitative real-time polymerase chain reaction and Western blot in the adrenal medulla. We observed a dose-dependent elevation in blood pressure with a DEX dose of 0.3 mg/kg administered for 10 days, significantly increasing MAP by +15.0 ± 1.1 mm Hg, while concomitantly reducing HR. Although this DEX treatment also significantly decreased body weight, pair-fed animals that showed similar decreases in body weight due to lowered food intake were not hypertensive, suggesting that body weight changes may not account for DEX-induced hypertension. Chronic DEX treatment significantly increased the TH mRNA and protein levels in the adrenal medulla, and α-MPT administration not only reduced DEX pressor effects, but also inhibited TH (serine(40)) phosphorylation. Our study thus validates a novel model to study hypertension induced by chronic intake of DEX in freely moving rats not subject to the confounding factors of previous models and establishes its dependence on concomitant activation of peripheral catecholamine biosynthesis. PMID:27405316

  14. Tetrahydrocurcumin Protects against Cadmium-Induced Hypertension, Raised Arterial Stiffness and Vascular Remodeling in Mice

    PubMed Central

    Sangartit, Weerapon; Kukongviriyapan, Upa; Donpunha, Wanida; Pakdeechote, Poungrat; Kukongviriyapan, Veerapol; Surawattanawan, Praphassorn; Greenwald, Stephen E.

    2014-01-01

    Background Cadmium (Cd) is a nonessential heavy metal, causing oxidative damage to various tissues and associated with hypertension. Tetrahydrocurcumin (THU), a major metabolite of curcumin, has been demonstrated to be an antioxidant, anti-diabetic, anti-hypertensive and anti-inflammatory agent. In this study, we investigated the protective effect of THU against Cd-induced hypertension, raised arterial stiffness and vascular remodeling in mice. Methods Male ICR mice received CdCl2 (100 mg/l) via drinking water for 8 weeks. THU was administered intragastrically at dose of 50 or 100 mg/kg/day concurrently with Cd treatment. Results Administration of CdCl2 significantly increased arterial blood pressure, blunted vascular responses to vasoactive agents, increased aortic stiffness, and induced hypertrophic aortic wall remodeling by increasing number of smooth muscle cells and collagen deposition, decreasing elastin, and increasing matrix metalloproteinase (MMP)-2 and MMP-9 levels in the aortic medial wall. Supplementation with THU significantly decreased blood pressure, improved vascular responsiveness, and reversed the structural and mechanical alterations of the aortas, including collagen and elastin deposition. The reduction on the adverse response of Cd treatment was associated with upregulated eNOS and downregulated iNOS protein expressions, increased nitrate/nitrite level, alleviated oxidative stress and enhanced antioxidant glutathione. Moreover, THU also reduced the accumulation of Cd in the blood and tissues. Conclusions Our results suggest that THU ameliorates cadmium-induced hypertension, vascular dysfunction, and arterial stiffness in mice through enhancing NO bioavailability, attenuating oxidative stress, improving vascular remodeling and decreasing Cd accumulation in other tissues. THU has a beneficial effect in moderating the vascular alterations associated with Cd exposure. PMID:25502771

  15. Oral oestrogen reverses ovariectomy-induced morning surge hypertension in growth-restricted mice.

    PubMed

    Haskell, Sarah E; Peotta, Veronica; Reinking, Benjamin E; Zhang, Catherine; Zhu, Vivian; Kenkel, Elizabeth J; Roghair, Robert D

    2016-04-01

    Perinatal growth restriction (GR) is associated with heightened sympathetic tone and hypertension. We have previously shown that naturally occurring neonatal GR programmes hypertension in male but not female mice. We therefore hypothesized that intact ovarian function or post-ovariectomy (OVX) oestrogen administration protects GR female mice from hypertension. Utilizing a non-interventional model that categorizes mice with weanling weights below the tenth percentile as GR, control and GR adult mice were studied at three distinct time points: baseline, post-OVX and post-OVX with oral oestrogen replacement. OVX elicited hypertension in GR mice that was significantly exacerbated by psychomotor arousal (systolic blood pressure at light to dark transition: control 122 ± 2; GR 119 ± 2; control-OVX 116 ± 3; GR-OVX 126 ± 3 mmHg). Oestrogen partially normalized the rising blood pressure surge seen in GR-OVX mice (23 ± 7% reduction). GR mice had left ventricular hypertrophy, and GR-OVX mice in particular had exaggerated bradycardic responses to sympathetic blockade. For GR mice, a baseline increase in baroreceptor reflex sensitivity and high frequency spectral power support a vagal compensatory mechanism, and that compensation was lost following OVX. For GR mice, the OVX-induced parasympathetic withdrawal was partially restored by oestrogen (40 ± 25% increase in high frequency spectral power, P<0.05). In conclusion, GR alters cardiac morphology and cardiovascular regulation. The haemodynamic consequences of GR are attenuated in ovarian-sufficient or oestrogen-replete females. Further investigations are needed to define the role of hormone replacement therapy targeted towards young women with oestrogen deficiency and additional cardiovascular risk factors, including perinatal GR, cardiac hypertrophy and morning surge hypertension. PMID:26795436

  16. Lack of Bcr and Abr Promotes Hypoxia-Induced Pulmonary Hypertension in Mice

    PubMed Central

    Lim, Min; Arutyunyan, Anna; Groffen, John; Heisterkamp, Nora

    2012-01-01

    Background Bcr and Abr are GTPase activating proteins that specifically downregulate activity of the small GTPase Rac in restricted cell types in vivo. Rac1 is expressed in smooth muscle cells, a critical cell type involved in the pathogenesis of pulmonary hypertension. The molecular mechanisms that underlie hypoxia-associated pulmonary hypertension are not well-defined. Methodology/Principal Findings Bcr and abr null mutant mice were compared to wild type controls for the development of pulmonary hypertension after exposure to hypoxia. Also, pulmonary arterial smooth muscle cells from those mice were cultured in hypoxia and examined for proliferation, p38 activation and IL-6 production. Mice lacking Bcr or Abr exposed to hypoxia developed increased right ventricular pressure, hypertrophy and pulmonary vascular remodeling. Perivascular leukocyte infiltration in the lungs was increased, and under hypoxia bcr−/− and abr−/− macrophages generated more reactive oxygen species. Consistent with a contribution of inflammation and oxidative stress in pulmonary hypertension-associated vascular damage, Bcr and Abr-deficient animals showed elevated endothelial leakage after hypoxia exposure. Hypoxia-treated pulmonary arterial smooth muscle cells from Bcr- or Abr-deficient mice also proliferated faster than those of wild type mice. Moreover, activated Rac1, phosphorylated p38 and interleukin 6 were increased in these cells in the absence of Bcr or Abr. Inhibition of Rac1 activation with Z62954982, a novel Rac inhibitor, decreased proliferation, p38 phosphorylation and IL-6 levels in pulmonary arterial smooth muscle cells exposed to hypoxia. Conclusions Bcr and Abr play a critical role in down-regulating hypoxia-induced pulmonary hypertension by deactivating Rac1 and, through this, reducing both oxidative stress generated by leukocytes as well as p38 phosphorylation, IL-6 production and proliferation of pulmonary arterial smooth muscle cells. PMID:23152932

  17. Association of plasma antibodies against the inducible Hsp70 with hypertension and harsh working conditions.

    PubMed

    Wu, T; Ma, J; Chen, S; Sun, Y; Xiao, C; Gao, Y; Wang, R; Poudrier, J; Dargis, M; Currie, R W; Tanguay, R M

    2001-10-01

    Autoantibodies against certain stress or heat shock proteins (Hsps) may play a role in the pathogenesis and/ or prognosis of some diseases. Using immunoblotting with human recombinant Hsps and univariate and multivariate logistic regression models, we have investigated the presence of antibodies against Hsp70, the inducible member of the 70-kDa family of heat shock proteins, and analyzed its possible association with hypertension and working conditions. Plasma and serum were collected from 764 steel mill workers from 6 work sites exposed to (1) severe noise; (2) severe noise and dust; (3) noise, dust, and heat; (4) noise and heat; (5) severe noise and heat; and (6) office conditions (control). Workers with prolonged exposure to stresses such as noise, dust, and high temperature and a combination of these in the workplace had a high incidence (26.6% to 40.2%) of antibodies to Hsp70 compared to the lowest incidence (18.6%) of antibodies to Hsp70 in the control group of office workers. Moreover, there was a statistical association of antibodies against Hsp70 with hypertension. The statistical correlation between the presence of antibodies to Hsp70 and hypertension is higher in the group of workers with blood pressure of 160/95 mmHg than in the 140/90-mmHg group after excluding possible effects of the workplace stresses. These results suggest that harsh workplace conditions can increase the production of antibodies against Hsp70 and that the presence of antibodies to this stress protein may be associated with hypertension. The precise mechanism for the elevation of antibodies against Hsps by environmental and workplace stresses and their relation to hypertension remains to be established. PMID:11795477

  18. Histone deacetylase inhibitor, CG200745, attenuates cardiac hypertrophy and fibrosis in DOCA-induced hypertensive rats

    PubMed Central

    Lee, Eunjo; Song, Min-ji; Lee, Hae-Ahm; Kang, Seol-Hee; Kim, Mina; Yang, Eun Kyoung; Lee, Do Young; Ro, Seonggu; Cho, Joong Myung

    2016-01-01

    CG200745 is a novel inhibitor of histone deacetylases (HDACs), initially developed for treatment of various hematological and solid cancers. Because it is water-soluble, it can be administered orally. We hypothesized that the HDAC inhibitor, CG200745, attenuates cardiac hypertrophy and fibrosis in deoxycorticosterone acetate (DOCA)-induced hypertensive rats. For establishment of hypertension, 40 mg/kg of DOCA was subcutaneously injected four times weekly into Sprague-Dawley rats. All the rats used in this study including those in the sham group had been unilaterally nephrectomized and allowed free access to drinking water containing 1% NaCl. Systolic blood pressure was measured by the tail-cuff method. Blood chemistry including sodium, potassium, glucose, triglyceride, and cholesterol levels was analyzed. Sections of the heart were visualized after trichrome and hematoxylin and eosin stain. The expression of hypertrophic genes such as atrial natriuretic peptide A (Nppa) and atrial natriuretic peptide B (Nppb) in addition to fibrotic genes such as Collagen-1, Collagen-3, connective tissue growth factor (Ctgf), and Fibronectin were measured by quantitative real-time PCR (qRT-PCR). Injection of DOCA increased systolic blood pressure, heart weight, and cardiac fibrosis, which was attenuated by CG200745. Neither DOCA nor CG200745 affected body weight, vascular contraction and relaxation responses, and blood chemistry. Injection of DOCA increased expression of both hypertrophic and fibrotic genes, which was abrogated by CG200745. These results indicate that CG200745 attenuates cardiac hypertrophy and fibrosis in DOCA-induced hypertensive rats. PMID:27610034

  19. Growth hormone secretagogue receptor deficiency in mice protects against obesity‐induced hypertension

    PubMed Central

    Harris, Louise E.; Morgan, David G.; Balthasar, Nina

    2014-01-01

    Abstract Growth hormone secretagogue receptor (GHS‐R) signaling has been associated with growth hormone release, increases in food intake and pleiotropic cardiovascular effects. Recent data demonstrated that acute GHS‐R antagonism leads to increases in mean arterial pressure mediated by the sympathetic nervous system in rats; a highly undesirable effect if GHS‐R antagonism was to be used as a therapeutic approach to reducing food intake in an already obese, hypertensive patient population. However, our data in conscious, freely moving GHS‐R deficient mice demonstrate that chronic absence of GHS‐R signaling is protective against obesity‐induced hypertension. GHS‐R deficiency leads to reduced systolic blood pressure variability (SBPV); in response to acute high‐fat diet (HFD)‐feeding, increases in the sympathetic control of SBPV are suppressed in GHS‐R KO mice. Our data further suggest that GHS‐R signaling dampens the immediate HFD‐mediated increase in spontaneous baroreflex sensitivity. In diet‐induced obesity, absence of GHS‐R signaling leads to reductions in obesity‐mediated hypertension and tachycardia. Collectively, our findings thus suggest that chronic blockade of GHS‐R signaling may not result in adverse cardiovascular effects in obesity. PMID:24760503

  20. Protective Effect of Salicornia europaea Extracts on High Salt Intake-Induced Vascular Dysfunction and Hypertension

    PubMed Central

    Panth, Nisha; Park, Sin-Hee; Kim, Hyun Jung; Kim, Deuk-Hoi; Oak, Min-Ho

    2016-01-01

    High salt intake causes and aggravates arterial hypertension and vascular dysfunction. We investigated the effect of Salicornia europaea extracts (SE) on vascular function and blood pressure. SE constituents were analyzed using high performance liquid chromatography, and SE’s effect on vascular function was evaluated in isolated porcine coronary arteries. SE’s vascular protective effect was also evaluated in vivo using normotensive and spontaneous hypertensive rats (SHRs). SE mainly contained sodium chloride (55.6%), 5-(hydroxymethyl)furfural, p-coumaric acid, and trans-ferulic acid. High sodium (160 mmol/L) induced vascular dysfunction; however, SE containing the same quantity of sodium did not cause vascular dysfunction. Among the compounds in SE, trans-ferulic acid accounts for the vascular protective effect. Normotensive rats fed a high-salt diet showed significantly increased systolic blood pressure (SBP), diastolic blood pressure (DBP), and mean arterial pressure (MAP), which decreased significantly in the SE-treated groups. In SHRs, high edible salt intake significantly increased SBP, DBP, and MAP, but SE intake was associated with a significantly lower MAP. Thus, SE did not induce vascular dysfunction, and trans-ferulic acid might be at least partly responsible for the vasoprotective effect of SE. Taken together, SE could be used as an alternative to purified salt to prevent and ameliorate hypertension. PMID:27455235

  1. Effect of aerosolized milrinone during drug-induced pulmonary hypertension in lambs.

    PubMed

    Gelvez, Javier; Fakioglu, Harun; Olarte, Jose L; Soliz, Amed; Totapally, Balagangadhar R; Torbati, Dan

    2004-07-01

    We tested whether aerosolized milrinone in lambs selectively reduces drug-induced acute pulmonary hypertension without reducing the mean systemic blood pressure (MSBP). Seven, 2-3-week-old lambs were anesthetized (50 mg/kg ketamine), paralyzed (0.1 mg/kg vecuronium bromide) and mechanically ventilated. A femoral artery, pulmonary artery, and jugular vein were catheterized for continuous monitoring of MSBP, mean pulmonary artery pressure, periodic gas-exchange analyses, and determination of cardiac output by thermodilution technique. An Airlife Misty nebulizer was used in a dry state to establish a stable baseline of an inspired fraction of oxygen (FiO(2)) at 0.21. Acute pulmonary hypertension with hypoxemia was then induced by increasing the mean pulmonary artery pressure up to 30-35% of the MSBP using 2-6 microg/kg/min of Thromboxane A(2) mimetic (U-46619), intravenously. The lambs were then subjected to 15 min of saline nebulization without milrinone followed by 30 min saline nebulization with a relatively high concentration of milrinone (10 mg/ml, total dose of 40 mg). Aerosolized milrinone had no effect on systemic or pulmonary artery pressure during combined acute pulmonary hypertension and hypoxemia. We speculate that our nebulization procedures failed to deliver sufficient amount of milrinone for producing a detectable hemodynamic effect. PMID:15082033

  2. Protective Effect of Salicornia europaea Extracts on High Salt Intake-Induced Vascular Dysfunction and Hypertension.

    PubMed

    Panth, Nisha; Park, Sin-Hee; Kim, Hyun Jung; Kim, Deuk-Hoi; Oak, Min-Ho

    2016-01-01

    High salt intake causes and aggravates arterial hypertension and vascular dysfunction. We investigated the effect of Salicornia europaea extracts (SE) on vascular function and blood pressure. SE constituents were analyzed using high performance liquid chromatography, and SE's effect on vascular function was evaluated in isolated porcine coronary arteries. SE's vascular protective effect was also evaluated in vivo using normotensive and spontaneous hypertensive rats (SHRs). SE mainly contained sodium chloride (55.6%), 5-(hydroxymethyl)furfural, p-coumaric acid, and trans-ferulic acid. High sodium (160 mmol/L) induced vascular dysfunction; however, SE containing the same quantity of sodium did not cause vascular dysfunction. Among the compounds in SE, trans-ferulic acid accounts for the vascular protective effect. Normotensive rats fed a high-salt diet showed significantly increased systolic blood pressure (SBP), diastolic blood pressure (DBP), and mean arterial pressure (MAP), which decreased significantly in the SE-treated groups. In SHRs, high edible salt intake significantly increased SBP, DBP, and MAP, but SE intake was associated with a significantly lower MAP. Thus, SE did not induce vascular dysfunction, and trans-ferulic acid might be at least partly responsible for the vasoprotective effect of SE. Taken together, SE could be used as an alternative to purified salt to prevent and ameliorate hypertension. PMID:27455235

  3. Hypoxia inducible factor signaling and experimental persistent pulmonary hypertension of the newborn

    PubMed Central

    Wedgwood, Stephen; Lakshminrusimha, Satyan; Schumacker, Paul T.; Steinhorn, Robin H.

    2015-01-01

    Background: Mitochondrial reactive oxygen species (ROS) levels and nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB) activity are increased in a lamb model of persistent pulmonary hypertension of the newborn (PPHN). These events can trigger hypoxia inducible factor (HIF) signaling in response to hypoxia, which has been shown to contribute to pulmonary vascular remodeling in rodent models of pulmonary hypertension. However, the role of HIF signaling in chronic intrauterine pulmonary hypertension is not well understood. Aim: To determine if HIF signaling is increased in the lamb model of PPHN, and to identify the underlying mechanisms. Results: PPHN was induced in lambs by antenatal ligation of the ductus arteriosus at 128 days gestation. After 9 days, lungs and pulmonary artery smooth muscle cells (PASMC) were isolated from control and PPHN lambs. HIF-1α expression was increased in PPHN lungs and HIF activity was increased in PPHN PASMC relative to controls. Hypoxia increased HIF activity to a greater degree in PPHN vs. control PASMC. Control PASMC were exposed to cyclic stretch at 1 Hz and 15% elongation for 24 h, as an in vitro model of vascular stress. Stretch increased HIF activity, which was attenuated by inhibition of mitochondrial complex III and NFκB. Conclusion: Increased HIF signaling in PPHN is triggered by stretch, via mechanisms involving mitochondrial ROS and NFκB. Hypoxia substantially amplifies HIF activity in PPHN vascular cells. Targeting these signaling molecules may attenuate and reverse pulmonary vascular remodeling associated with PPHN. PMID:25814954

  4. Histone deacetylase inhibitor, CG200745, attenuates cardiac hypertrophy and fibrosis in DOCA-induced hypertensive rats.

    PubMed

    Lee, Eunjo; Song, Min-Ji; Lee, Hae-Ahm; Kang, Seol-Hee; Kim, Mina; Yang, Eun Kyoung; Lee, Do Young; Ro, Seonggu; Cho, Joong Myung; Kim, Inkyeom

    2016-09-01

    CG200745 is a novel inhibitor of histone deacetylases (HDACs), initially developed for treatment of various hematological and solid cancers. Because it is water-soluble, it can be administered orally. We hypothesized that the HDAC inhibitor, CG200745, attenuates cardiac hypertrophy and fibrosis in deoxycorticosterone acetate (DOCA)-induced hypertensive rats. For establishment of hypertension, 40 mg/kg of DOCA was subcutaneously injected four times weekly into Sprague-Dawley rats. All the rats used in this study including those in the sham group had been unilaterally nephrectomized and allowed free access to drinking water containing 1% NaCl. Systolic blood pressure was measured by the tail-cuff method. Blood chemistry including sodium, potassium, glucose, triglyceride, and cholesterol levels was analyzed. Sections of the heart were visualized after trichrome and hematoxylin and eosin stain. The expression of hypertrophic genes such as atrial natriuretic peptide A (Nppa) and atrial natriuretic peptide B (Nppb) in addition to fibrotic genes such as Collagen-1, Collagen-3, connective tissue growth factor (Ctgf), and Fibronectin were measured by quantitative real-time PCR (qRT-PCR). Injection of DOCA increased systolic blood pressure, heart weight, and cardiac fibrosis, which was attenuated by CG200745. Neither DOCA nor CG200745 affected body weight, vascular contraction and relaxation responses, and blood chemistry. Injection of DOCA increased expression of both hypertrophic and fibrotic genes, which was abrogated by CG200745. These results indicate that CG200745 attenuates cardiac hypertrophy and fibrosis in DOCA-induced hypertensive rats. PMID:27610034

  5. Pulmonary hypertension

    MedlinePlus

    Pulmonary arterial hypertension; Sporadic primary pulmonary hypertension; Familial primary pulmonary hypertension; Idiopathic pulmonary arterial hypertension; Primary pulmonary hypertension; PPH; Secondary pulmonary ...

  6. Intermittent Hypoxia-Induced Carotid Body Chemosensory Potentiation and Hypertension Are Critically Dependent on Peroxynitrite Formation

    PubMed Central

    Moya, Esteban A.; Arias, Paulina; Varela, Carlos; Oyarce, María P.; Del Rio, Rodrigo; Iturriaga, Rodrigo

    2016-01-01

    Oxidative stress is involved in the development of carotid body (CB) chemosensory potentiation and systemic hypertension induced by chronic intermittent hypoxia (CIH), the main feature of obstructive sleep apnea. We tested whether peroxynitrite (ONOO−), a highly reactive nitrogen species, is involved in the enhanced CB oxygen chemosensitivity and the hypertension during CIH. Accordingly, we studied effects of Ebselen, an ONOO− scavenger, on 3-nitrotyrosine immunoreactivity (3-NT-ir) in the CB, the CB chemosensory discharge, and arterial blood pressure (BP) in rats exposed to CIH. Male Sprague-Dawley rats were exposed to CIH (5% O2, 12 times/h, 8 h/day) for 7 days. Ebselen (10 mg/kg/day) was administrated using osmotic minipumps and BP measured with radiotelemetry. Compared to the sham animals, CIH-treated rats showed increased 3-NT-ir within the CB, enhanced CB chemosensory responses to hypoxia, increased BP response to acute hypoxia, and hypertension. Rats treated with Ebselen and exposed to CIH displayed a significant reduction in 3-NT-ir levels (60.8 ± 14.9 versus 22.9 ± 4.2 a.u.), reduced CB chemosensory response to 5% O2 (266.5 ± 13.4 versus 168.6 ± 16.8 Hz), and decreased mean BP (116.9 ± 13.2 versus 82.1 ± 5.1 mmHg). Our results suggest that CIH-induced CB chemosensory potentiation and hypertension are critically dependent on ONOO− formation. PMID:26798430

  7. Thrombospondin-1 null mice are resistant to hypoxia-induced pulmonary hypertension

    PubMed Central

    2010-01-01

    Background and objective Chronic hypoxia induces pulmonary hypertension in mice. Smooth muscle cell hyperplasia and medial thickening characterize the vasculature of these animals. Thrombospondin-1 null (TSP-1-/-) mice spontaneously develop pulmonary smooth muscle cell hyperplasia and medial thickening. In addition, TSP-1 produced by the pulmonary endothelium inhibits pulmonary artery smooth muscle cell growth. Based on these observations we sought to describe the pulmonary vascular changes in TSP-1-/- mice exposed to chronic hypoxia. Methods We exposed TSP-1-/- and wild type (WT) mice to a fraction of inspired oxygen (FiO2) of 0.1 for up to six weeks. Pulmonary vascular remodeling was evaluated using tissue morphometrics. Additionally, right ventricle systolic pressures (RVSP) and right ventricular hypertrophy by right ventricle/left ventricle + septum ratios (RV/LV+S) were measured to evaluate pulmonary hypertensive changes. Finally, acute pulmonary vasoconstriction response in both TSP-1-/- and WT mice was evaluated by acute hypoxia and U-46619 (a prostaglandin F2 analog) response. Results In hypoxia, TSP-1-/- mice had significantly lower RVSP, RV/LV+S ratios and less pulmonary vascular remodeling when compared to WT mice. TSP-1-/- mice also had significantly lower RVSP in response to acute pulmonary vasoconstriction challenges than their WT counterparts. Conclusion TSP-1-/- mice had diminished pulmonary vasoconstriction response and were less responsive to hypoxia-induced pulmonary hypertension than their wild type counterparts. This observation suggests that TSP-1 could play an active role in the pathogenesis of pulmonary hypertension associated with hypoxia. PMID:20441584

  8. Activity of endothelium-derived hyperpolarizing factor is augmented in monocrotaline-induced pulmonary hypertension of rat lungs.

    PubMed

    Morio, Yoshiteru; Homma, Noriyuki; Takahashi, Hideki; Yamamoto, Akihito; Nagaoka, Tetsutaro; Sato, Koichi; Muramatsu, Masashi; Fukuchi, Yoshinosuke

    2007-01-01

    The mechanism of endothelium-dependent vasodilator signaling involves three components such as nitric oxide, prostacyclin, and endothelium-derived hyperpolarizing factor (EDHF). Although EDHF is distinct from nitric oxide and prostacyclin, it requires activation of Ca(2+)-sensitive K(+) channels (K(Ca)) and cytochrome P(450) metabolites. However, the physiological role of EDHF in the pulmonary circulation is unclear. Thus, we tested if EDHF would regulate vascular tone in rat lungs of control and monocrotaline (MCT)-induced pulmonary hypertension. Inhibition of EDHF with a combination of K(Ca) blockers, charybdotoxin (50 nM) plus apamin (50 nM), increased baseline vascular tone in MCT-induced hypertensive lungs. Thapsigargin (TG; 100 nM), an inhibitor of Ca-ATPase, caused greater EDHF-mediated vasodilation in MCT-induced hypertensive lungs. TG-induced vasodilation was abolished with the charybdotoxin-apamin combination. Sulfaphenazole (10 muM), a cytochrome P(450) inhibitor, reduced the TG-induced vasodilation in MCT-induced hypertensive lungs. RT-PCR analysis exhibited an increase in K(Ca) mRNA in MCT-treated lungs. These results indicate the augmentation of tonic EDHF activity, at least in part, through the alteration in cytochrome P(450) metabolites and the upregulation of K(Ca) expression in MCT-induced pulmonary hypertension. PMID:17438361

  9. “A small leak will sink a great ship”: hypoxia-inducible factor and group III pulmonary hypertension

    PubMed Central

    Bryant, Andrew J.; Scott, Edward W.

    2016-01-01

    Pulmonary hypertension complicating idiopathic pulmonary fibrosis, also known as secondary pulmonary hypertension, represents a major source of morbidity and mortality in affected patients. While the study of primary pulmonary arterial hypertension has yielded several therapies, the same is not true for the treatment of pulmonary hypertension secondary to pulmonary fibrosis. Recent studies have indicated an important role of hypoxia-inducible factor (HIF) – a regulatory protein that is vital in adaptation to hypoxic conditions – in the development of secondary pulmonary hypertension. HIF influences development of hypoxia-induced pulmonary hypertension through alteration in voltage-gated potassium channels and homeostatic calcium regulation, resulting in disruption of endothelial cell-cell communication, and eventual vascular remodeling. This article summarizes salient literature related to HIF and secondary pulmonary hypertension, in addition to proposing a final common pathway in known mechanistic pathways that result in endothelial barrier integrity loss – vascular “leak” – primarily through a shared endothelial-epithelial signaling protein family, CCN.

  10. The effects of acute intermittent hypoxia on cardiovascular parameters in normotensive and chronic hypobaric hypoxia-induced hypertensive rabbits.

    PubMed

    Yaman, Muhittin O; Guner, Ibrahim; Uzun, Hafize; Sahin, Gulderen; Yelmen, Nermin

    2014-01-01

    The effects of both chronic hypoxia and acute intermittent hypoxia (AIH) on cardiovascular system are unclear. We designed this study to develop a rabbit model of hypertension by exposure to chronic hypobaric hypoxia (CHH) and to investigate the effects of AIH on hypertensive rabbits. Present study was performed in 13 albino rabbits that divided into CHH and control groups. To develop hypertension, the rabbits were placed in a hypobaric chamber (390 mmHg; 22 hours/day, 30 days). Afterwards, AIH protocol was applied (8% FIO2 (Fraction of Inspired Oxygen) 1 min + 5 min normoxia, 20 cycles, 2 hours) to rabbits anesthetized with urethane and alpha-chloralose. Mean arterial pressure (MAP), heart rate (HR) and hematocrit values have been determined. Also asymmetric dimethylarginine (ADMA), endothelial nitric oxide synthase (eNOS), endothelin-1 and norepinephrine values have been analyzed in blood. We developed a model of hypertension in rabbits via exposure to severe CHH and we believe that ADMA is an important parameter in the development and permanence of CHH-induced hypertension. The main finding of this sudy was the depressor effect of AIH on blood pressure and heart rate in CHH- induced hypertension model. Finally, we believe that AIH protocol may be applicable for prevention and treatment of hypertension if properly developed. PMID:24448370

  11. Endotoxin-induced acute lung injury is enhanced in rats with spontaneous hypertension.

    PubMed

    Liu, Demeral D; Hsu, Yung Hsiang; Chen, Hsing I

    2007-01-01

    1. Acute lung injury (ALI), or acute respiratory distress syndrome, is a major cause of mortality in endotoxaemia. The present study tested whether the endotoxaemia-induced changes and associated ALI were enhanced in rats with established hypertension and to examine the possible mechanisms involved. 2. Fifty spontaneously hypertensive rats (SHR) and the same number of normotensive Wistar Kyoto (WKY) rats, aged 12-15 weeks, were used. The experiments were performed in conscious, unanaesthetized rats. Endotoxaemia was produced by intravenous lipopolysaccharide (LPS; 10 mg/kg). N(G)-Nitro-L-arginine methyl ester (L-NAME; 10 mg/kg, i.v.), L-N(6)-(1-iminoethyl)-lysine (L-Nil; 5 mg/kg, i.v.) and 3-morpholinosydnonimine (SIN-1; 5 mg/kg, i.v.) were given 5 min before LPS to observe the effects of nitric oxide synthase (NOS) inhibition and nitric oxide (NO) donation. 3. We monitored arterial pressure and heart rate and evaluated ALI by determining the lung weight/bodyweight ratio, lung weight gain, leakage of Evans blue dye, the protein concentration in bronchoalveolar lavage and histopathological examination. Plasma nitrate/nitrite, methyl guanidine, pro-inflammatory cytokines, including tumour necrosis factor-alpha and interleukin-1beta, and lung tissue cGMP were determined. Expression of mRNA for inducible and endothelial NOS was examined using reverse transcription-polymerase chain reaction. 4. Lipopolysaccharide caused systemic hypotension, ALI and increases in plasma nitrate/nitrite, methyl guanidine, pro-inflammatory cytokines and lung cGMP content. The LPS-induced changes were greater in SHR than in WKY rats. Pretreatment with L-NAME or L-Nil attenuated, whereas the NO donor SIN-1 aggravated, the endotoxin-induced changes. 5. In conclusion, rats with genetic hypertension are more susceptible to endotoxaemia and this results in a greater extent of ALI compared with normotensive WKY rats. PMID:17201737

  12. Mice lacking the Raf-1 kinase inhibitor protein exhibit exaggerated hypoxia-induced pulmonary hypertension

    PubMed Central

    Morecroft, I; Doyle, B; Nilsen, M; Kolch, W; Mair, K; MacLean, MR

    2011-01-01

    BACKGROUND AND PURPOSE Increased pulmonary vascular remodelling, pulmonary arterial pressure and pulmonary vascular resistance characterize the development of pulmonary arterial hypertension (PAH). Activation of the Raf/mitogen-activated protein kinase/extracellular signal-regulated kinase (ERK)1/2 is thought to play an important role in PAH and Raf-1 kinase inhibitor protein (RKIP), negatively regulates this pathway. This study investigated whether genetic deletion of RKIP (and hence ERK1/2 up-regulation) resulted in a pulmonary hypertensive phenotype in mice and investigated a role for RKIP in mitogen-regulated proliferative responses in lung fibroblasts. EXPERIMENTAL APPROACH Pulmonary vascular haemodynamics and remodelling were assessed in mice genetically deficient in RKIP (RKIP−/−) after 2 weeks of either normoxia or hypoxia. Immunoblotting and immunohistochemistry were used to examine phosphorylation of Raf-1, RKIP and ERK1/2 in mouse pulmonary arteries. In vitro, RKIP inhibition of mitogen signalling was analysed in CCL39 hamster lung fibroblasts. KEY RESULTS RKIP−/− mice demonstrated elevated indices of PAH and ERK1/2 phosphorylation compared with wild-type (WT) mice. Hypoxic RKIP−/− mice exhibited exaggerated PAH indices. Hypoxia increased phosphorylation of Raf-1, RKIP and ERK1/2 in WT mouse pulmonary arteries and Raf-1 phosphorylation in RKIP−/− mouse pulmonary arteries. In CCL39 cells, inhibition of RKIP potentiated mitogen-induced proliferation and phosphorylation of RKIP, and Raf-1. CONCLUSIONS AND IMPLICATIONS The lack of RKIP protein resulted in a pulmonary hypertensive phenotype, exaggerated in hypoxia. Hypoxia induced phosphorylation of RKIP signalling elements in WT pulmonary arteries. RKIP inhibition potentiated mitogen-induced proliferation in lung fibroblasts. These results provide evidence for the involvement of RKIP in suppressing the development of hypoxia-induced PAH in mice. PMID:21385176

  13. Clopidogrel preserves whole kidney autoregulatory behavior in ANG II-induced hypertension

    PubMed Central

    Osmond, David A.; Zhang, Shali; Pollock, Jennifer S.; Yamamoto, Tatsuo; De Miguel, Carmen

    2014-01-01

    This study tested the hypothesis that P2Y12 receptor blockade with clopidogrel preserves renal autoregulatory ability during ANG II-induced hypertension. Clopidogrel was administered orally to male Sprague-Dawley rats chronically infused with ANG II. After 14 days of treatment, whole kidney autoregulation of renal blood flow was assessed in vivo in pentobarbital-anesthetized rats using an ultrasonic flow probe placed around the left renal artery. In ANG II-vehicle-treated rats, decreasing arterial pressure over a range from 160 to 100 mmHg resulted in a 25 ± 5% decrease in renal blood flow, demonstrating a significant loss of autoregulation with an autoregulatory index of 0.66 ± 0.15. However, clopidogrel treatment preserved autoregulatory behavior in ANG II-treated rats to levels indistinguishable from normotensive sham-operated (sham) rats (autoregulatory index: 0.04 ± 0.14). Compared with normotensive sham-vehicle-treated rats, ANG II infusion increased renal CD3-positive T cell infiltration by 66 ± 6%, induced significant thickening of the preglomerular vessels and glomerular basement membrane and increased glomerular collagen I deposition, tubulointerstitial fibrosis, damage to the proximal tubular brush border, and protein excretion. Clopidogrel significantly reduced renal infiltration of T cells by 39 ± 9% and prevented interstitial artery thickening, ANG II-induced damage to the glomerular basement membrane, deposition of collagen type I, and tubulointerstitial fibrosis, despite the maintenance of hypertension. These data demonstrate that systemic P2Y12 receptor blockade with clopidogrel protects against impairment of autoregulatory behavior and renal vascular injury in ANG II-induced hypertension, possibly by reducing renal T cell infiltration. PMID:24477682

  14. Role of α1D -adrenoceptors in vascular wall hypertrophy during angiotensin II-induced hypertension.

    PubMed

    Gallardo-Ortíz, I A; Rodríguez-Hernández, S N; López-Guerrero, J J; Del Valle-Mondragón, L; López-Sánchez, P; Touyz, R M; Villalobos-Molina, R

    2015-09-01

    The in vivo effect of continuous angiotensin II (Ang II) infusion on arterial blood pressure, vascular hypertrophy and α1 -adrenoceptors (α1 -ARs) expression was explored. Alzet(®) minipumps filled with Ang II (200 ng kg(-1)  min(-1) ) were subcutaneously implanted in male Wistar rats (3 months-old). Groups of rats were also treated with losartan, an AT1 R antagonist, or with BMY 7378, a selective α1D -AR antagonist. Blood pressure was measured by tail-cuff; after 2 or 4 weeks of treatment, vessels were isolated for functional and structural analyses. Angiotensin II increased systolic blood pressure. Phenylephrine-induced contraction in aorta was greater (40% higher) in Ang II-treated rats than in the controls, and similar effect occurred with KCl 80 mm. Responses in tail arteries were not significantly different among the different groups. Angiotensin II decreased α1D -ARs without modifying the other α1 -ARs and induced an increase in media thickness (hypertrophy) in aorta, while no structural change occurred in tail artery. Losartan prevented and reversed hypertension and hypertrophy, while BMY 7378 prevented and reversed the aorta's hypertrophic response, without preventing or reversing hypertension. Findings indicate that Ang II-induced aortic hypertrophic response involves Ang II-AT1 Rs and α1D -ARs. Angiotensin II-induced α1D -AR-mediated vascular remodeling occurs independently of hypertension. Findings identify a α1D -AR-mediated process whereby Ang II influences aortic hypertrophy independently of blood pressure elevation. PMID:26845248

  15. Melatonin attenuates hypertension-induced renal injury partially through inhibiting oxidative stress in rats

    PubMed Central

    QIAO, YU-FENG; GUO, WEN-JUAN; LI, LU; SHAO, SHAN; QIAO, XI; SHAO, JIN-JIN; ZHANG, QIONG; LI, RONG-SHAN; WANG, LI-HUA

    2016-01-01

    The aim of the present study was to investigate the protective effects of melatonin (MLT) on hypertension-induced renal injury and identify its mechanism of action. Twenty-four healthy male Wistar rats were divided into a sham control group (n=8), which was subjected to sham operation and received vehicle treatment (physiological saline intraperitoneally at 0.1 ml/100 g), a vehicle group (n=8), which was subjected to occlusion of the left renal artery and vehicle treatment, and the MLT group (n=8), which was subjected to occlusion of the left renal artery and treated with MLT (10 mg/kg/day). Pathological features of the renal tissues were determined using hematoxylin and eosin staining and Masson staining. Urine protein, serum creatinine (Scr), superoxide dismutase (SOD) and malondialdehyde (MDA) were determined. Immunohistochemical analysis was performed to determine the expression of heme oxygenase-1 (HO-1), intercellular adhesion molecule-1 (ICAM-1), inducible nitric oxide synthase (iNOS) and endothelial nitric oxide synthase (eNOS). Furthermore, reverse transcription polymerase chain reaction was conducted to determine the mRNA expression of HO-1, ICAM-1, eNOS and iNOS. A marked decrease in blood pressure was noticed in the MLT group at week 4 compared with that of the vehicle group (P<0.01). Furthermore, MLT treatment attenuated the infiltration of inflammatory cells and oedema/atrophy of renal tubules. MLT attenuated hypertension-induced increases in urine protein excretion, serum creatinine and MDA as well as decreases in SOD activity in renal tissues. Furthermore, MLT attenuated hypertension-induced increases in iNOS and ICAM-1 as well as decreases in eNOS and HO-1 expression at the mRNA and protein level. In conclusion, the results of the present study indicated that MLT had protective roles in hypertension-induced renal injury. Its mechanism of action is, at least in part, associated with the inhibition of oxidative stress. PMID:26531807

  16. Nox2 Deficiency Prevents Hypertension-Induced Vascular Dysfunction and Hypertrophy in Cerebral Arterioles

    PubMed Central

    Chan, Siu-Lung; Baumbach, Gary L.

    2013-01-01

    Oxidative stress is involved in many hypertension-related vascular diseases in the brain, including stroke and dementia. Thus, we examined the role of genetic deficiency of NADPH oxidase subunit Nox2 in the function and structure of cerebral arterioles during hypertension. Arterial pressure was increased in right-sided cerebral arterioles with transverse aortic banding for 4 weeks in 8-week-old wild-type (WT) and Nox2-deficient (-/y) mice. Mice were given NG-nitro-L-arginine methyl ester (L-NAME, 10 mg/kg) or vehicle to drink. We measured the reactivity in cerebral arterioles through open cranial window in anesthetized mice and wall cross-sectional area and superoxide levels ex vivo. Aortic constriction increased systolic and pulse pressures in right-sided carotid arteries in all groups of mice. Ethidium fluorescence showed increased superoxide in right-sided cerebral arterioles in WT, but not in Nox2-/y mice. Dilation to acetylcholine, but not sodium nitroprusside, was reduced, and cross-sectional areas were increased in the right-sided arterioles in WT, but were unchanged in Nox2-/y mice. L-NAME reduced dilation to acetylcholine but did not result in hypertrophy in right-sided arterioles of Nox2-/y  mice. In conclusion, hypertension-induced superoxide production derived from Nox2-containing NADPH oxidase promotes hypertrophy and causes endothelial dysfunction in cerebral arterioles, possibly involving interaction with nitric oxide. PMID:23573415

  17. Does copper enhance the antihypertensive effect of Elaeocarpus ganitrus in experimentally induced hypertensive rats?

    PubMed Central

    Barve, Kalyani H; Chodankar, Rahul

    2014-01-01

    Ayurveda, one of the traditional systems of medicine of India, reports that the seeds of Elaeocarpus ganitrus Linn. (Tilaceae) can be used for the treatment of hypertension. The main aim is to evaluate the antihypertensive effect of Elaeocarpus ganitrus (Rudraksha) seeds. Powdered seeds were extracted by maceration, overnight, using water, in copper (E1) and glass vessel (E2) and analyzed for antihypertensive activity in cadmium chloride (1 mg/kg intraperitoneally, for a period of 15 days) induced hypertensive male Wistar rats at three dose levels. E1 was administered at the dose of 5, 10, and 15 mg/kg and E2 at dose of 10, 20, and 30 mg/kg. All the data were analyzed using one way analysis of variance (ANOVA) followed by Dunnett's multiple comparison test. E1 and E2 did not show any toxicity at the dose of 5 g/kg in rats. It was found that 15 mg/kg of E1 and 30 mg/kg of E2 decreases the blood pressure by 30.20 mmHg and 28.96 mmHg, respectively, in hypertensive rats. Thus, it can be said that 15 mg/kg of E1 produced similar decrease in blood pressure as was observed with 30 mg/kg of E2. Copper ions in E1 might be additively affecting the reduction in blood pressure with the usage of Elaeocarpus ganitrus extracts. PMID:24948856

  18. Aluminum Trichloride Induces Hypertension and Disturbs the Function of Erythrocyte Membrane in Male Rats.

    PubMed

    Zhang, Qiuyue; Cao, Zheng; Sun, Xudong; Zuang, Cuicui; Huang, Wanyue; Li, Yanfei

    2016-05-01

    Aluminum (Al) is the most abundant metal in the earth's crust. Al accumulates in erythrocyte and causes toxicity on erythrocyte membrane. The dysfunction of erythrocyte membrane is a potential risk to hypertension. The high Al content in plasma was associated with hypertension. To investigate the effect of AlCl3 on blood pressure and the function of erythrocyte membrane, the rats were intragastrically exposed to 0, 64(1/20 LD50), 128(1/10 LD50), and 256(1/5 LD50) mg/kg body weight AlCl3 in double distilled water for 120 days, respectively. Then, we determined the systolic and mean arterial blood pressures of rats, the osmotic fragility, the percentage of membrane proteins, the activities of Na(+)/K(+)-ATPase, Mg(2+)-ATPase, Ca(2+)-ATPase, catalase (CAT), superoxide dismutase (SOD) and glutathione peroxidase (GSH-pX), and malondialdehyde (MDA) content of the erythrocyte membrane in this experiment. The results showed that AlCl3 elevated the systolic and mean arterial blood pressure of rats, increased the osmotic fragility, decreased the percentage of membrane protein, inhibited the activities of Na(+)/K(+)-ATPase, Mg(2+)-ATPase, Ca(2+)-ATPase, CAT, SOD and GSH-pX, and increased the MDA content of erythrocyte membrane. These results indicate that AlCl3 may induce hypertension by disturbing the function of erythrocyte membrane. PMID:26354416

  19. Comparison of enalapril and valsartan in cyclosporine A-induced hypertension and nephrotoxicity in spontaneously hypertensive rats on high-sodium diet

    PubMed Central

    Lassila, Markus; Finckenberg, Piet; Pere, Anna-Kaisa; Krogerus, Leena; Ahonen, Juhani; Vapaatalo, Heikki; Nurminen, Marja-Leena

    2000-01-01

    We compared the effects of the angiotensin converting enzyme (ACE) inhibitor enalapril and the angiotensin AT1 receptor antagonist valsartan in cyclosporine A (CsA)-induced hypertension and nephrotoxicity in spontaneously hypertensive rats (SHR).SHR (8–9 weeks old) on high-sodium diet were given CsA (5 mg kg−1d −1 s.c.) for 6 weeks. The rats were treated concomitantly either with enalapril (30 mg kg−1d −1 p.o.) or valsartan (3 or 30 mg kg−1 d −1 p.o.). To evaluate the role of bradykinin in the action of enalapril, some rats received a bradykinin B2 receptor antagonist icatibant (HOE 140, 500 μg kg−1 d −1 s.c.) during the last 2 weeks of enalapril treatment.Blood pressure was recorded every second week by tail cuff method. Renal function was measured by serum creatinine, creatinine clearance and urinary excretion of proteins at the end of the experiment. The activity of the renal kallikrein-kinin system was estimated by urinary kallikrein excretion.CsA caused hypertension, impaired renal function and induced morphological nephrotoxicity with glomerular damage and interstitial fibrosis.Enalapril and the lower dose of valsartan attenuated the CsA-induced hypertension to the same extent, while the higher dose of valsartan totally abolished it. Icatibant did not reduce the antihypertensive effect of enalapril. Urinary kallikrein excretion was similar in all groups. Enalapril and valsartan equally prevented the CsA-induced deterioration of kidney function and morphology.The renin-angiotensin but not the kallikrein-kinin system plays a crucial role in CsA-toxicity during high intake of sodium in SHR. PMID:10903974

  20. An Intact Median Preoptic Nucleus is Necessary for Chronic Angiotensin II-Induced Hypertension

    PubMed Central

    Ployngam, Trasida; Collister, John P.

    2007-01-01

    The median preoptic nucleus (MnPO) receives afferent input from the subfornical organ, a circumventricular organ that has been shown to be necessary in mediating the full chronic hypertensive response to angiotensin II (ANG II) administration. In addition, intravenous ANG II infusion has been shown to cause activation of a number of neurons in both the dorsal and ventral part of MnPO. Taken together, we hypothesized that the MnPO is necessary for the full hypertensive response observed during chronic ANG II-induced hypertension. To test this hypothesis, male Sprague Dawley rats were subjected to either sham (SHAM) or electrolytic lesion of both the dorsal and ventral part of the MnPO (MnPOx). During the same surgery, rats were instrumented with venous catheters, and radiotelemetric transducers for the intravenous administration of ANG II and the measurement of blood pressure and heart rate, respectively. Rats were then given a week recovery period. After 3 days of saline control infusion, ANG II was intravenously infused (10 ng ˙ kg−1˙ min−1) in both sham and MnPOx animals for 10 consecutive days, and followed by 3 recovery days. By day 7 of Ang II infusion, MAP had increased 38 ± 3 mmHg in sham lesion rats (n=6), but MAP of MnPOx rats (>90% MnPO ablated; n=5) had only increased 18 ± 2 mmHg. This trend continued through day 10 of ANG II treatment. These results support the hypothesis that the MnPO is necessary for the chronic hypertensive response to ANG II administration. PMID:17618605

  1. Renovascular hypertension identified by captopril-induced changes in the renogram

    SciTech Connect

    Geyskes, G.G.; Oei, H.Y.; Puylaert, C.B.; Mees, E.J.

    1987-05-01

    Radioisotope renography was performed in 21 patients with hypertension and unilateral renal artery stenosis with and without premedication with 25 mg of captopril, and the results were compared with the effect of percutaneous transluminal angioplasty on the blood pressure, assessed 6 weeks after angioplasty. Angioplasty caused a considerable decrease in blood pressure in 15 of the 21 patients. In 12 of these 15 patients, captopril induced changes in the time-activity curves of the affected kidney only, suggesting deterioration of the excretory function of that kidney, while the function of the contralateral kidney remained normal. After angioplasty the asymmetry in the time-activity curves diminished despite identical pretreatment with captopril. Such captopril-induced unilateral impairment of the renal function was not seen in the six patients with unilateral renal artery stenosis whose blood pressure did not change after percutaneous transluminal angioplasty or in 13 patients with hypertension and normal renal arteries. The functional impairment of the affected kidneys was characterized by a decrease of /sup 99m/Tc-diethylenetriamine pentaacetic acid uptake and a delay of /sup 131/I-hippurate excretion, while the /sup 131/I-hippurate uptake remained unaffected. These data are in agreement with a reduced glomerular filtration rate and diuresis during preservation of the renal blood flow, changes that can be expected after converting enzyme inhibition in a kidney with low perfusion and an active, renin-mediated autoregulation of the glomerular filtration rate. These data suggest that functional captopril-induced unilateral changes, shown by split renal function studies with noninvasive gamma camera scintigraphy, can be used as a diagnostic test for renovascular hypertension caused by unilateral renal artery stenosis.

  2. Gremlin Induces Ocular Hypertension in Mice Through Smad3-Dependent Signaling

    PubMed Central

    McDowell, Colleen M.; Hernandez, Humberto; Mao, Weiming; Clark, Abbot F.

    2015-01-01

    Purpose Transforming growth factor–β2 induces extracellular matrix (ECM) remodeling, which likely contributes to the defective function of the trabecular meshwork (TM) leading to glaucomatous ocular hypertension. Bone morphogenetic proteins (BMPs) inhibit these profibrotic effects of TGFβ2. The BMP antagonist gremlin is elevated in glaucomatous TM cells and increases IOP in an ex vivo perfusion culture model. The purpose of this study was to determine whether gremlin regulates ECM proteins in the TM, signals through the Smad3-dependent pathway, and induces ocular hypertension in mice. Methods Ad5.Gremlin or Ad5.TGFβ2 was injected intravitreally into one eye of each mouse. Intraocular pressure measurements were taken using a TonoLab tonometer. Gremlin, TGFβ2, fibronectin (FN), and collagen-1 (Col-1) expression in the TM was determined by immunofluorescence, Western immunoblot, and quantitative (q)PCR analyses. Results Ad5.Gremlin or Ad5.TGFβ2 each caused significant IOP elevation in mice. Immunofluorescence and Western blot analysis demonstrated that gremlin and TGFβ2 reciprocally increased the expression of each other, and both increased FN expression in the TM and surrounding tissues. Ad5.Gremlin elevated IOP and increased Fn and Col-1 gene expression in the TM of Smad3 wild-type (WT) mice, but had no effect in Smad3 HET or Smad3 KO mice. Conclusions Our results demonstrate that intravitreal injections of either Ad5.Gremlin or Ad5.TGFβ2 elevate IOP and upregulate the ECM protein FN in the TM of mice. These data show that gremlin signals through the Smad3-dependent pathway in the TM to elevate IOP. We determined for the first time gremlin's role in inducing ocular hypertension in an in vivo model system. PMID:26284554

  3. Diesel exhaust induced pulmonary and cardiovascular impairment: The role of hypertension intervention

    SciTech Connect

    Kodavanti, Urmila P.; Thomas, Ronald F.; Ledbetter, Allen D.; Schladweiler, Mette C.; Bass, Virginia; Krantz, Q. Todd; King, Charly; Nyska, Abraham; Richards, Judy E.; Andrews, Debora; Gilmour, M. Ian

    2013-04-15

    Exposure to diesel exhaust (DE) and associated gases is linked to cardiovascular impairments; however, the susceptibility of hypertensive individuals is poorly understood. The objectives of this study were (1) to determine cardiopulmonary effects of gas-phase versus whole-DE and (2) to examine the contribution of systemic hypertension in pulmonary and cardiovascular effects. Male Wistar Kyoto (WKY) rats were treated with hydralazine to reduce blood pressure (BP) or L-NAME to increase BP. Spontaneously hypertensive (SH) rats were treated with hydralazine to reduce BP. Control and drug-pretreated rats were exposed to air, particle-filtered exhaust (gas), or whole DE (1500 μg/m{sup 3}), 4 h/day for 2 days or 5 days/week for 4 weeks. Acute and 4-week gas and DE exposures increased neutrophils and γ-glutamyl transferase (γ-GT) activity in lavage fluid of WKY and SH rats. DE (4 weeks) caused pulmonary albumin leakage and inflammation in SH rats. Two-day DE increased serum fatty acid binding protein-3 (FABP-3) in WKY. Marked increases occurred in aortic mRNA after 4-week DE in SH (eNOS, TF, tPA, TNF-α, MMP-2, RAGE, and HMGB-1). Hydralazine decreased BP in SH while L-NAME tended to increase BP in WKY; however, neither changed inflammation nor BALF γ-GT. DE-induced and baseline BALF albumin leakage was reduced by hydralazine in SH rats and increased by L-NAME in WKY rats. Hydralazine pretreatment reversed DE-induced TF, tPA, TNF-α, and MMP-2 expression but not eNOS, RAGE, and HMGB-1. ET-1 was decreased by HYD. In conclusion, antihypertensive drug treatment reduces gas and DE-induced pulmonary protein leakage and expression of vascular atherogenic markers. - Highlights: ► Acute diesel exhaust exposure induces pulmonary inflammation in healthy rats. ► In hypertensive rats diesel exhaust effects are seen only after long term exposure. ► Normalizing blood pressure reverses lung protein leakage caused by diesel exhaust. ► Normalizing blood pressure reverses

  4. Serial nephelometric urine IgG measurement and the management of pregnancy-induced hypertension.

    PubMed

    Eden, R D; Wahbeh, C J; Williams, A Y; Easley, H A; Gall, S A

    1984-04-15

    Serial IgG analysis was performed on the urine and serum of 16 patients with pregnancy-induced hypertension. Significant immunoglobulinuria developed prior to the development of azotemia, significantly decreased creatinine clearance, significant proteinuria (greater than or equal to 3+ dipstick or greater than or equal to 5 gm per 24-hour urine collection), or oliguria. Nephelometric measurement of urine IgG concentrations appears to be a rapid and accurate method for confirming the severity of clinical disease, the degree of renal involvement, the benefit of treatment modalities on renal function, and the likelihood of postpartum maternal morbidity. PMID:6711642

  5. Protective effects of methylsulfonylmethane on hemodynamics and oxidative stress in monocrotaline-induced pulmonary hypertensive rats.

    PubMed

    Mohammadi, Sadollah; Najafi, Moslem; Hamzeiy, Hossein; Maleki-Dizaji, Nasrin; Pezeshkian, Masoud; Sadeghi-Bazargani, Homayon; Darabi, Masoud; Mostafalou, Sara; Bohlooli, Shahab; Garjani, Alireza

    2012-01-01

    Methylsulfonylmethane (MSM) is naturally occurring organic sulfur that is known as a potent antioxidant/anti-inflammatory compound. The aim of this study was to investigate the effect of MSM on hemodynamics functions and oxidative stress in rats with monocrotaline- (MCT-) induced pulmonary arterial hypertension (PAH). Wistar rats were randomly assigned to 38-days treatment. MSM was administered to rats at 100, 200, and 400 mg/kg/day doses 10 days before a single dose of 60 mg/kg, IP, MCT. Hemodynamics of ventricles were determined by Powerlab AD instrument. Blood samples were obtained to evaluate changes in the antioxidative system including activities of catalase (CAT), superoxide dismutase (SOD), glutathione peroxidase (GPx), and the level of reduced glutathione (GSH) and malondialdehyde (MDA). Improvements in cardiopulmonary hemodynamics were observed in the MSM-treated pulmonary arterial hypertensive rats, with a significant reduction in right ventricular systolic pressure (RSVP) and an increase in the mean arterial pressure (MAP). The values of CAT, SOD, GSH-px activities, and GSH were significantly lower in MCT-induced PAH (P < 0.01), but they were recovered to control levels of MSM-treated groups. Our present results suggest that long-term administration of the MSM attenuates MCT-induced PAH in rats through modulation of oxidative stress and antioxidant defense. PMID:23118745

  6. Treatment of sunitinib-induced hypertension in solid tumor by nitric oxide donors.

    PubMed

    León-Mateos, L; Mosquera, J; Antón Aparicio, L

    2015-12-01

    Vascular endothelial growth factor (VEGF) and its receptor (VEGFR) are overexpressed in the majority of renal cell carcinomas. This characteristic has supported the rationale of targeting VEGF-driven tumour vascularization, especially in clear cell RCC. VEGF-inhibiting strategies include the use of tyrosine kinase inhibitors (sunitinib, axitinib, pazopanib, and sorafenib) and neutralizing antibodies such as bevacizumab. Hypertension (HTN) is one of the most common adverse effects of angiogenesis inhibitors. HTN observed in clinical trials appears to correlate with the potency of VEGF kinase inhibitor against VEGFR-2: agents with higher potency are associated with a higher incidence of HTN. Although the exact mechanism by tyrosine kinase inhibitors induce HTN has not yet been completely clarified, two key hypotheses have been postulated. First, some studies have pointed to a VEGF inhibitors-induced decrease in nitric oxide synthase (NOS) and nitric oxide (NO) production, that can result in vasoconstriction and increased blood pressure. VEGF, mediated by PI3K/Akt and MAPK pathway, upregulates the endothelial nitric oxide synthase enzyme leading to up-regulation of NO production. So inhibition of signaling through the VEGF pathway would lead to a decrease in NO production, resulting in an increase in vascular resistance and blood pressure. Secondly a decrease in the number of microvascular endothelial cells and subsequent depletion of normal microvessel density (rarefaction) occurs upon VEGF signaling inhibition. NO donors could be successfully used not only for the treatment of developed angiogenesis-inhibitor-induced hypertension but also for preventive effects. PMID:26386874

  7. Apigenin ameliorates hypertension-induced cardiac hypertrophy and down-regulates cardiac hypoxia inducible factor-lα in rats.

    PubMed

    Zhu, Zeng-Yan; Gao, Tian; Huang, Yan; Xue, Jie; Xie, Mei-Lin

    2016-04-20

    Apigenin is a natural flavonoid compound that can inhibit hypoxia-inducible factor (HIF)-1α expression in cultured tumor cells under hypoxic conditions. Hypertension-induced cardiac hypertrophy is always accompanied by abnormal myocardial glucolipid metabolism due to an increase of HIF-1α. However, whether or not apigenin may ameliorate the cardiac hypertrophy and abnormal myocardial glucolipid metabolism remains unknown. This study aimed to examine the effects of apigenin. Rats with cardiac hypertrophy induced by renovascular hypertension were treated with apigenin 50-100 mg kg(-1) (the doses can be achieved by pharmacological or dietary supplementation for an adult person) by gavage for 4 weeks. The results showed that after treatment with apigenin, the blood pressure, heart weight, heart weight index, cardiomyocyte cross-sectional area, serum angiotensin II, and serum and myocardial free fatty acids were reduced. It is important to note that apigenin decreased the expression level of myocardial HIF-1α protein. Moreover, apigenin simultaneously increased the expression levels of myocardial peroxisome proliferator-activated receptor (PPAR) α, carnitine palmitoyltransferase (CPT)-1, and pyruvate dehydrogenase kinase (PDK)-4 proteins and decreased the expression levels of myocardial PPARγ, glycerol-3-phosphate acyltransferase genes (GPAT), and glucose transporter (GLUT)-4 proteins. These findings demonstrated that apigenin could improve hypertensive cardiac hypertrophy and abnormal myocardial glucolipid metabolism in rats, and its mechanisms might be associated with the down-regulation of myocardial HIF-1α expression and, subsequently increasing the expressions of myocardial PPARα and its target genes CPT-1 and PDK-4, and decreasing the expressions of myocardial PPARγ and its target genes GPAT and GLUT-4. PMID:26987380

  8. 20-HETE induces remodeling of renal resistance arteries independent of blood pressure elevation in hypertension.

    PubMed

    Ding, Yan; Wu, Cheng-Chia; Garcia, Victor; Dimitrova, Irina; Weidenhammer, Adam; Joseph, Gregory; Zhang, Frank; Manthati, Vijay L; Falck, John R; Capdevila, Jorge H; Schwartzman, Michal L

    2013-09-01

    20-Hydroxyeicosatetraenoic acid (20-HETE) is a cytochrome P-450 (Cyp)-derived arachidonic acid metabolite that has been shown to increase smooth muscle contractions and proliferation, stimulate endothelial dysfunction and activation, and promote hypertension. We examined if 20-HETE contributes to microvascular remodeling in hypertension. In Sprague-Dawley rats, administration of the 20-HETE biosynthesis inhibitor HET0016 or the 20-HETE antagonist N-20-hydroxyeicosa-6(Z),15(Z)-dienoic acid (20-HEDE) prevented 5α-dihydrotestosterone (DHT)-induced increases in blood pressure as well as abrogated DHT-induced increases in the media-to-lumen ratio (M/L), media thickness, and collagen IV deposition in renal interlobar arteries. Reserpine prevented blood pressure elevation in DHT-treated rats but did not affect microvascular remodeling (M/L, media thickness, and collagen deposition); under these conditions, treatment with the 20-HETE antagonist attenuated microvascular remodeling, suggesting that 20-HETE contributes to DHT-induced vascular remodeling independent of blood pressure elevation. In Cyp4a14(-/-) mice, which display androgen-driven and 20-HETE-dependent hypertension, treatment with the 20-HETE antagonist abolished remodeling of renal resistance arteries measured as media thickness (24 ± 1 vs. 15 ± 1 μm) and M/L (0.29 ± 0.03 vs. 0.17 ± 0.01). Moreover, in Cyp4a12 transgenic mice in which the expression of Cyp4a12-20-HETE synthase is driven by a tetracycline-sensitive promoter, treatment with doxycycline resulted in blood pressure elevation (140 ± 4 vs. 92 ± 5 mmHg) and a significant increase in remodeling of renal resistance arteries (media thickness: 23 ± 1 vs. 16 ± 1 μm; M/L: 0.39 ± 0.04 vs. 0.23 ± 0.02); these increases were abrogated by cotreatment with 20-HEDE. This study demonstrated that 20-HETE is a key regulator of microvascular remodeling in hypertension; its effect is independent of blood pressure elevation and androgen levels. PMID

  9. 20-HETE induces remodeling of renal resistance arteries independent of blood pressure elevation in hypertension

    PubMed Central

    Ding, Yan; Wu, Cheng-Chia; Garcia, Victor; Dimitrova, Irina; Weidenhammer, Adam; Joseph, Gregory; Zhang, Frank; Manthati, Vijay L.; Falck, John R.; Capdevila, Jorge H.

    2013-01-01

    20-Hydroxyeicosatetraenoic acid (20-HETE) is a cytochrome P-450 (Cyp)-derived arachidonic acid metabolite that has been shown to increase smooth muscle contractions and proliferation, stimulate endothelial dysfunction and activation, and promote hypertension. We examined if 20-HETE contributes to microvascular remodeling in hypertension. In Sprague-Dawley rats, administration of the 20-HETE biosynthesis inhibitor HET0016 or the 20-HETE antagonist N-20-hydroxyeicosa-6(Z),15(Z)-dienoic acid (20-HEDE) prevented 5α-dihydrotestosterone (DHT)-induced increases in blood pressure as well as abrogated DHT-induced increases in the media-to-lumen ratio (M/L), media thickness, and collagen IV deposition in renal interlobar arteries. Reserpine prevented blood pressure elevation in DHT-treated rats but did not affect microvascular remodeling (M/L, media thickness, and collagen deposition); under these conditions, treatment with the 20-HETE antagonist attenuated microvascular remodeling, suggesting that 20-HETE contributes to DHT-induced vascular remodeling independent of blood pressure elevation. In Cyp4a14−/− mice, which display androgen-driven and 20-HETE-dependent hypertension, treatment with the 20-HETE antagonist abolished remodeling of renal resistance arteries measured as media thickness (24 ± 1 vs. 15 ± 1 μm) and M/L (0.29 ± 0.03 vs. 0.17 ± 0.01). Moreover, in Cyp4a12 transgenic mice in which the expression of Cyp4a12–20-HETE synthase is driven by a tetracycline-sensitive promoter, treatment with doxycycline resulted in blood pressure elevation (140 ± 4 vs. 92 ± 5 mmHg) and a significant increase in remodeling of renal resistance arteries (media thickness: 23 ± 1 vs. 16 ± 1 μm; M/L: 0.39 ± 0.04 vs. 0.23 ± 0.02); these increases were abrogated by cotreatment with 20-HEDE. This study demonstrated that 20-HETE is a key regulator of microvascular remodeling in hypertension; its effect is independent of blood pressure elevation and androgen levels. PMID

  10. Interleukin-17A Regulates Renal Sodium Transporters and Renal Injury in Angiotensin II-Induced Hypertension.

    PubMed

    Norlander, Allison E; Saleh, Mohamed A; Kamat, Nikhil V; Ko, Benjamin; Gnecco, Juan; Zhu, Linjue; Dale, Bethany L; Iwakura, Yoichiro; Hoover, Robert S; McDonough, Alicia A; Madhur, Meena S

    2016-07-01

    Angiotensin II-induced hypertension is associated with an increase in T-cell production of interleukin-17A (IL-17A). Recently, we reported that IL-17A(-/-) mice exhibit blunted hypertension, preserved natriuresis in response to a saline challenge, and decreased renal sodium hydrogen exchanger 3 expression after 2 weeks of angiotensin II infusion compared with wild-type mice. In the current study, we performed renal transporter profiling in mice deficient in IL-17A or the related isoform, IL-17F, after 4 weeks of Ang II infusion, the time when the blood pressure reduction in IL-17A(-/-) mice is most prominent. Deficiency of IL-17A abolished the activation of distal tubule transporters, specifically the sodium-chloride cotransporter and the epithelial sodium channel and protected mice from glomerular and tubular injury. In human proximal tubule (HK-2) cells, IL-17A increased sodium hydrogen exchanger 3 expression through a serum and glucocorticoid-regulated kinase 1-dependent pathway. In mouse distal convoluted tubule cells, IL-17A increased sodium-chloride cotransporter activity in a serum and glucocorticoid-regulated kinase 1/Nedd4-2-dependent pathway. In both cell types, acute treatment with IL-17A induced phosphorylation of serum and glucocorticoid-regulated kinase 1 at serine 78, and treatment with a serum and glucocorticoid-regulated kinase 1 inhibitor blocked the effects of IL-17A on sodium hydrogen exchanger 3 and sodium-chloride cotransporter. Interestingly, both HK-2 and mouse distal convoluted tubule 15 cells produce endogenous IL-17A. IL17F had little or no effect on blood pressure or renal sodium transporter abundance. These studies provide a mechanistic link by which IL-17A modulates renal sodium transport and suggest that IL-17A inhibition may improve renal function in hypertension and other autoimmune disorders. PMID:27141060

  11. Targeted activation of endothelin-1 exacerbates hypoxia-induced pulmonary hypertension

    SciTech Connect

    Satwiko, Muhammad Gahan; Ikeda, Koji; Nakayama, Kazuhiko; Yagi, Keiko; Hocher, Berthold; Hirata, Ken-ichi; Emoto, Noriaki

    2015-09-25

    Pulmonary arterial hypertension (PAH) is a fatal disease that eventually results in right heart failure and death. Current pharmacologic therapies for PAH are limited, and there are no drugs that could completely cure PAH. Enhanced activity of endothelin system has been implicated in PAH severity and endothelin receptor antagonists have been used clinically to treat PAH. However, there is limited experimental evidence on the direct role of enhanced endothelin system activity in PAH. Here, we investigated the correlation between endothelin-1 (ET-1) and PAH using ET-1 transgenic (ETTG) mice. Exposure to chronic hypoxia increased right ventricular pressure and pulmonary arterial wall thickness in ETTG mice compared to those in wild type mice. Of note, ETTG mice exhibited modest but significant increase in right ventricular pressure and vessel wall thickness relative to wild type mice even under normoxic conditions. To induce severe PAH, we administered SU5416, a vascular endothelial growth factor receptor inhibitor, combined with exposure to chronic hypoxia. Treatment with SU5416 modestly aggravated hypoxia-induced pulmonary hypertension, right ventricular hypertrophy, and pulmonary arterial vessel wall thickening in ETTG mice in association with increased interleukin-6 expression in blood vessels. However, there was no sign of obliterative endothelial cell proliferation and plexiform lesion formation in the lungs. These results demonstrated that enhanced endothelin system activity could be a causative factor in the development of PAH and provided rationale for the inhibition of endothelin system to treat PAH. - Highlights: • Role of endothelin-1 in pulmonary arterial hypertension (PAH) was investigated. • The endothelin-1 transgenic (ETTG) and wild type (WT) mice were analyzed. • ETTG mice spontaneously developed PAH under normoxia conditions. • SU5416 further aggravated PAH in ETTG mice. • Enhanced endothelin system activity could be a causative factor in

  12. Pneumonectomy combined with SU5416 induces severe pulmonary hypertension in rats.

    PubMed

    Happé, C M; de Raaf, M A; Rol, N; Schalij, I; Vonk-Noordegraaf, A; Westerhof, N; Voelkel, N F; de Man, F S; Bogaard, H J

    2016-06-01

    The SU5416 + hypoxia (SuHx) rat model is a commonly used model of severe pulmonary arterial hypertension. While it is known that exposure to hypoxia can be replaced by another type of hit (e.g., ovalbumin sensitization) it is unknown whether abnormal pulmonary blood flow (PBF), which has long been known to invoke pathological changes in the pulmonary vasculature, can replace the hypoxic exposure. Here we studied if a combination of SU5416 administration combined with pneumonectomy (PNx), to induce abnormal PBF in the contralateral lung, is sufficient to induce severe pulmonary arterial hypertension (PAH) in rats. Sprague Dawley rats were subjected to SuPNx protocol (SU5416 + combined with left pneumonectomy) or standard SuHx protocol, and comparisons between models were made at week 2 and 6 postinitiation. Both SuHx and SuPNx models displayed extensive obliterative vascular remodeling leading to an increased right ventricular systolic pressure at week 6 Similar inflammatory response in the lung vasculature of both models was observed alongside increased endothelial cell proliferation and apoptosis. This study describes the SuPNx model, which features severe PAH at 6 wk and could serve as an alternative to the SuHx model. Our study, together with previous studies on experimental models of pulmonary hypertension, shows that the typical histopathological findings of PAH, including obliterative lesions, inflammation, increased cell turnover, and ongoing apoptosis, represent a final common pathway of a disease that can evolve as a consequence of a variety of insults to the lung vasculature. PMID:27036867

  13. A longitudinal study of maternal digoxin-like immunoreactive substances in normotensive pregnancy and pregnancy-induced hypertension.

    PubMed

    Kerkez, S A; Poston, L; Wolfe, C D; Quartero, H W; Carabelli, P; Petruckevitch, A; Hilton, P J

    1990-03-01

    The serum of women in the third trimester of pregnancy demonstrates cross-reactivity with some commercially available antibodies to digoxin. A number of studies have suggested that levels of this digoxin-like immunoreactive substance(s) are further increased in patients with pregnancy-induced hypertension, and some have proposed that the digoxin-like immunoreactive substance could be useful as a predictor of pregnancy-induced hypertension. We measured digoxin-like immunoreactive substance levels every 2 weeks throughout the third trimester in 170 women; of these, 20 developed hypertension. Digoxin-like immunoreactive substance levels rose with gestational age. A graph of the slope of digoxin-like immunoreactive substance plotted against gestational age was fitted for the results obtained from each woman. There was no significant difference in the mean rate of increase of digoxin-like immunoreactive substance level per week between pregnancy-induced hypertension and normotensive pregnancy, nor was there any difference between these two groups at any gestational age studied. These results suggest that measuring digoxin-like immunoreactive substance levels is not useful as a predictor of pregnancy-induced hypertension. PMID:2316589

  14. Ocular Hypertension

    MedlinePlus

    ... Español Eye Health / Eye Health A-Z Ocular Hypertension Sections What Is Ocular Hypertension? Ocular Hypertension Causes ... Hypertension Diagnosis Ocular Hypertension Treatment What Is Ocular Hypertension? Written by: Kierstan Boyd Reviewed by: J Kevin ...

  15. Melatonin attenuates hypertension-induced renal injury partially through inhibiting oxidative stress in rats.

    PubMed

    Qiao, Yu-Feng; Guo, Wen-Juan; Li, Lu; Shao, Shan; Qiao, Xi; Shao, Jin-Jin; Zhang, Qiong; Li, Rong-Shan; Wang, Li-Hua

    2016-01-01

    The aim of the present study was to investigate the protective effects of melatonin (MLT) on hypertension-induced renal injury and identify its mechanism of action. Twenty-four healthy male Wistar rats were divided into a sham control group (n=8), which was subjected to sham operation and received vehicle treatment (physiological saline intraperitoneally at 0.1 ml/100 g), a vehicle group (n=8), which was subjected to occlusion of the left renal artery and vehicle treatment, and the MLT group (n=8), which was subjected to occlusion of the left renal artery and treated with MLT (10 mg/kg/day). Pathological features of the renal tissues were determined using hematoxylin and eosin staining and Masson staining. Urine protein, serum creatinine (Scr), superoxide dismutase (SOD) and malondialdehyde (MDA) were determined. Immunohistochemical analysis was performed to determine the expression of heme oxygenase‑1 (HO‑1), intercellular adhesion molecule‑1 (ICAM‑1), inducible nitric oxide synthase (iNOS) and endothelial nitric oxide synthase (eNOS). Furthermore, reverse transcription polymerase chain reaction was conducted to determine the mRNA expression of HO‑1, ICAM‑1, eNOS and iNOS. A marked decrease in blood pressure was noticed in the MLT group at week 4 compared with that of the vehicle group (P<0.01). Furthermore, MLT treatment attenuated the infiltration of inflammatory cells and oedema/atrophy of renal tubules. MLT attenuated hypertension-induced increases in urine protein excretion, serum creatinine and MDA as well as decreases in SOD activity in renal tissues. Furthermore, MLT attenuated hypertension-induced increases in iNOS and ICAM‑1 as well as decreases in eNOS and HO‑1 expression at the mRNA and protein level. In conclusion, the results of the present study indicated that MLT had protective roles in hypertension‑induced renal injury. Its mechanism of action is, at least in part, associated with the inhibition of oxidative stress. PMID:26531807

  16. Role of Menkes ATPase in Angiotensin II-Induced Hypertension: A Key Modulator for Extracellular SOD Function

    PubMed Central

    Qin, Zhenyu; Gongora, Maria Carolina; Ozumi, Kiyoshi; Itoh, Shinichi; Akram, Kamran; Ushio-Fukai, Masuko; Harrison, David G.; Fukai, Tohru

    2009-01-01

    The extracellular superoxide dismutase (SOD3), a secretory copper-containing enzyme, regulates angiotensin II (Ang II)–induced hypertension by modulating levels of extracellular superoxide anion. The present study was designed to determine the role of the copper transporter Menkes ATPase (MNK) in Ang II–induced SOD3 activity and hypertension in vivo. Here we show that chronic Ang II infusion enhanced systolic blood pressure and vascular superoxide anion production in MNK mutant (MNKmut) mice as compared with those in wild-type mice, which are associated with impaired acetylcholine-induced endothelium-dependent vasorelaxation in MNKmut mice. These effects in MNKmut mice are rescued by infusion of the SOD mimetic Tempol. By contrast, norepinephrine-induced hypertension, which is not associated with an increase in vascular superoxide anion production, is not affected in MNKmut mice. Mechanistically, basal and Ang II infusion-induced increase in vascular SOD3-specific activity is significantly inhibited in MNKmut mice. Coimmunoprecipitation analysis reveals that Ang II stimulation promotes association of MNK with SOD3 in cultured vascular smooth muscle cell and in mouse aortas, which may contribute to SOD3-specific activity by increasing copper delivery to SOD3 through MNK. In summary, MNK plays an important role in modulating Ang II–induced hypertension and endothelial function by regulating SOD3 activity and vascular superoxide anion production and becomes a potential therapeutic target for oxidant stress-dependent cardiovascular diseases. PMID:18768397

  17. GPER activation ameliorates aortic remodeling induced by salt-sensitive hypertension.

    PubMed

    Liu, Liu; Kashyap, Shreya; Murphy, Brennah; Hutson, Dillion D; Budish, Rebecca A; Trimmer, Emma H; Zimmerman, Margaret A; Trask, Aaron J; Miller, Kristin S; Chappell, Mark C; Lindsey, Sarah H

    2016-04-15

    The mRen2 female rat is an estrogen- and salt-sensitive model of hypertension that reflects the higher pressure and salt sensitivity associated with menopause. We previously showed that the G protein-coupled estrogen receptor (GPER) mediates estrogenic effects in this model. The current study hypothesized that GPER protects against vascular injury during salt loading. Intact mRen2 female rats were fed a normal (NS; 0.5% Na(+)) or high-salt diet (HS; 4% Na(+)) for 10 wk, which significantly increased systolic blood pressure (149 ± 5 vs. 224 ± 8 mmHg;P< 0.001). Treatment with the selective GPER agonist G-1 for 2 wk did not alter salt-sensitive hypertension (216 ± 4 mmHg;P> 0.05) or ex vivo vascular responses to angiotensin II or phenylephrine (P> 0.05). However, G-1 significantly attenuated salt-induced aortic remodeling assessed by media-to-lumen ratio (NS: 0.43; HS+veh: 0.89; HS+G-1: 0.61;P< 0.05). Aortic thickening was not accompanied by changes in collagen, elastin, or medial proliferation. However, HS induced increases in medial layer glycosaminoglycans (0.07 vs. 0.42 mm(2);P< 0.001) and lipid peroxidation (0.11 vs. 0.51 mm(2);P< 0.01), both of which were reduced by G-1 (0.20 mm(2)and 0.23 mm(2); both P< 0.05). We conclude that GPER's beneficial actions in the aorta of salt-loaded mRen2 females occur independently of changes in blood pressure and vasoreactivity. GPER-induced attenuation of aortic remodeling was associated with a reduction in oxidative stress and decreased accumulation of glycosaminoglycans. Endogenous activation of GPER may protect females from salt- and pressure-induced vascular damage. PMID:26873963

  18. Transient Receptor Potential Melastatin 7 Cation Channel Kinase: New Player in Angiotensin II-Induced Hypertension.

    PubMed

    Antunes, Tayze T; Callera, Glaucia E; He, Ying; Yogi, Alvaro; Ryazanov, Alexey G; Ryazanova, Lillia V; Zhai, Alexander; Stewart, Duncan J; Shrier, Alvin; Touyz, Rhian M

    2016-04-01

    Transient receptor potential melastatin 7 (TRPM7) is a bifunctional protein comprising a magnesium (Mg(2+))/cation channel and a kinase domain. We previously demonstrated that vasoactive agents regulate vascular TRPM7. Whether TRPM7 plays a role in the pathophysiology of hypertension and associated cardiovascular dysfunction is unknown. We studied TRPM7 kinase-deficient mice (TRPM7Δkinase; heterozygous for TRPM7 kinase) and wild-type (WT) mice infused with angiotensin II (Ang II; 400 ng/kg per minute, 4 weeks). TRPM7 kinase expression was lower in heart and aorta from TRPM7Δkinase versus WT mice, effects that were further reduced by Ang II infusion. Plasma Mg(2+) was lower in TRPM7Δkinase versus WT mice in basal and stimulated conditions. Ang II increased blood pressure in both strains with exaggerated responses in TRPM7Δkinase versus WT groups (P<0.05). Acetylcholine-induced vasorelaxation was reduced in Ang II-infused TRPM7Δkinase mice, an effect associated with Akt and endothelial nitric oxide synthase downregulation. Vascular cell adhesion molecule-1 expression was increased in Ang II-infused TRPM7 kinase-deficient mice. TRPM7 kinase targets, calpain, and annexin-1, were activated by Ang II in WT but not in TRPM7Δkinase mice. Echocardiographic and histopathologic analysis demonstrated cardiac hypertrophy and left ventricular dysfunction in Ang II-treated groups. In TRPM7 kinase-deficient mice, Ang II-induced cardiac functional and structural effects were amplified compared with WT counterparts. Our data demonstrate that in TRPM7Δkinase mice, Ang II-induced hypertension is exaggerated, cardiac remodeling and left ventricular dysfunction are amplified, and endothelial function is impaired. These processes are associated with hypomagnesemia, blunted TRPM7 kinase expression/signaling, endothelial nitric oxide synthase downregulation, and proinflammatory vascular responses. Our findings identify TRPM7 kinase as a novel player in Ang II-induced hypertension

  19. Activation of Central PPAR-γ Attenuates Angiotensin II-Induced Hypertension

    PubMed Central

    Yu, Yang; Xue, Bao-Jian; Wei, Shun-Guang; Zhang, Zhi-Hua; Beltz, Terry G; Guo, Fang; Johnson, Alan Kim; Felder, Robert B

    2015-01-01

    Inflammation and renin-angiotensin system activity in the brain contribute to hypertension through effects on fluid intake, vasopressin release, and sympathetic nerve activity. We recently reported that activation of brain peroxisome proliferator-activated receptor (PPAR)-γ in heart failure rats reduced inflammation and renin-angiotensin system activity in the hypothalamic paraventricular nucleus and ameliorated the peripheral manifestations of heart failure. We hypothesized that activation of brain PPAR-γ might have beneficial effects in angiotensin II-induced hypertension. Sprague-Dawley rats received a 2-week subcutaneous infusion of angiotensin II (120 ng/kg/min) combined with a continuous intracerebroventricular infusion of vehicle, the PPAR-γ agonist pioglitazone (3 nmol/h) or the PPAR-γ antagonist GW9662 (7 nmol/h). Angiotensin II+vehicle rats had increased mean blood pressure, increased sympathetic drive as indicated by the mean blood pressure response to ganglionic blockade, and increased water consumption. PPAR-γ mRNA in subfornical organ and hypothalamic paraventricular nucleus was unchanged, but PPAR-γ DNA binding activity was reduced. mRNA for interleukin-1β, tumor necrosis factor-α, cyclooxygenase-2 and angiotensin II type-1 receptor was augmented in both nuclei, and hypothalamic paraventricular nucleus neuronal activity was increased. The plasma vasopressin response to a 6-hour water restriction also increased. These responses to angiotensin II were exacerbated by GW9662 and ameliorated by pioglitazone, which increased PPAR-γ mRNA and PPAR-γ DNA binding activity in subfornical organ and hypothalamic paraventricular nucleus. Pioglitazone and GW9662 had no effects on control rats. The results suggest that activating brain PPAR-γ to reduce central inflammation and brain renin-angiotensin system activity may be a useful adjunct in the treatment of angiotensin II-dependent hypertension. PMID:26101342

  20. Serelaxin reduces oxidative stress and asymmetric dimethylarginine in angiotensin II-induced hypertension.

    PubMed

    Sasser, Jennifer M; Cunningham, Mark W; Baylis, Chris

    2014-12-15

    Recent findings suggest the therapeutic action of relaxin during hypertension is dependent on nitric oxide synthase (NOS) activation; however, the mechanisms underlying the beneficial effects of relaxin on the NOS system have not been fully elucidated. We hypothesized that the protective effects of relaxin include reducing both oxidative stress and the endogenous NOS inhibitor asymmetric dimethylarginine (ADMA). We examined the effect of Serelaxin [human recombinant relaxin-2 (RLX)] in male Sprague-Dawley rats given high-dose angiotensin (ANG) II (400 ng·kg(-1)·min(-1) sc) for 6 wk or shams. RLX was administered (4 μg/h sc) to half of the rats in each group after 2 wk of ANG II for the remaining 4 wk. ANG II induced hypertension and proteinuria, reduced NO oxidation products (NOx), and increased oxidative stress (NADPH oxidase activity, thiobarbituric acid-reactive substances, and 8-isoprostane excretion) and plasma ADMA. While RLX had no effect on sham rats, RLX attenuated the ANG II-dependent hypertension (165 ± 5 vs. 135 ± 13 mmHg, P < 0.05) and proteinuria at 6 wk (62 ± 6 vs. 41 ± 4 mg·day(-1)·100 g(-1), P < 0.05) and normalized oxidative stress and circulating ADMA, in association with restored NOx excretion and kidney cortex NOx. We found that RLX had no impact on the ADMA-regulatory enzymes protein arginine methyltransferase and dimethylarginine-dimethylaminohydrolase (DDAH). Furthermore, RLX treatment did not increase DDAH activity in kidney cortex or liver. These data suggest that benefits of RLX treatment include reduced ADMA levels and increased NO bioavailability, possibly due to its antioxidant effects. PMID:25298524

  1. Activation of central PPAR-γ attenuates angiotensin II-induced hypertension.

    PubMed

    Yu, Yang; Xue, Bao-Jian; Wei, Shun-Guang; Zhang, Zhi-Hua; Beltz, Terry G; Guo, Fang; Johnson, Alan Kim; Felder, Robert B

    2015-08-01

    Inflammation and renin-angiotensin system activity in the brain contribute to hypertension through effects on fluid intake, vasopressin release, and sympathetic nerve activity. We recently reported that activation of brain peroxisome proliferator-activated receptor (PPAR)-γ in heart failure rats reduced inflammation and renin-angiotensin system activity in the hypothalamic paraventricular nucleus and ameliorated the peripheral manifestations of heart failure. We hypothesized that the activation of brain PPAR-γ might have beneficial effects in angiotensin II-induced hypertension. Sprague-Dawley rats received a 2-week subcutaneous infusion of angiotensin II (120 ng/kg per minute) combined with a continuous intracerebroventricular infusion of vehicle, the PPAR-γ agonist pioglitazone (3 nmol/h) or the PPAR-γ antagonist GW9662 (7 nmol/h). Angiotensin II+vehicle rats had increased mean blood pressure, increased sympathetic drive as indicated by the mean blood pressure response to ganglionic blockade, and increased water consumption. PPAR-γ mRNA in subfornical organ and hypothalamic paraventricular nucleus was unchanged, but PPAR-γ DNA-binding activity was reduced. mRNA for interleukin-1β, tumor necrosis factor-α, cyclooxygenase-2, and angiotensin II type 1 receptor was augmented in both nuclei, and hypothalamic paraventricular nucleus neuronal activity was increased. The plasma vasopressin response to a 6-hour water restriction also increased. These responses to angiotensin II were exacerbated by GW9662 and ameliorated by pioglitazone, which increased PPAR-γ mRNA and PPAR-γ DNA-binding activity in subfornical organ and hypothalamic paraventricular nucleus. Pioglitazone and GW9662 had no effects on control rats. The results suggest that activating brain PPAR-γ to reduce central inflammation and brain renin-angiotensin system activity may be a useful adjunct in the treatment of angiotensin II-dependent hypertension. PMID:26101342

  2. New Insights on the Maternal Diet Induced-Hypertension: Potential Role of the Phenotypic Plasticity and Sympathetic-Respiratory Overactivity

    PubMed Central

    Costa-Silva, João H.; de Brito-Alves, José L.; Barros, Monique Assis de V.; Nogueira, Viviane Oliveira; Paulino-Silva, Kássya M.; de Oliveira-Lira, Allan; Nobre, Isabele G.; Fragoso, Jéssica; Leandro, Carol G.

    2015-01-01

    Systemic arterial hypertension (SAH) is an important risk factor for cardiovascular disease and affects worldwide population. Current environment including life style coupled with genetic programming have been attributed to the rising incidence of hypertension. Besides, environmental conditions during perinatal development such as maternal malnutrition can program changes in the integration among renal, neural, and endocrine system leading to hypertension. This phenomenon is termed phenotypic plasticity and refers to the adjustment of a phenotype in response to environmental stimuli without genetic change, following a novel or unusual input during development. Human and animal studies indicate that fetal exposure to an adverse maternal environment may alter the renal morphology and physiology that contribute to the development of hypertension. Recently, it has been shown that the maternal protein restriction alter the central control of SAH by a mechanism that include respiratory dysfunction and enhanced sympathetic-respiratory coupling at early life, which may contribute to adult hypertension. This review will address the new insights on the maternal diet induced-hypertension that include the potential role of the phenotypic plasticity, specifically the perinatal protein malnutrition, and sympathetic-respiratory overactivity. PMID:26635631

  3. Dietary saffron reduced the blood pressure and prevented remodeling of the aorta in L-NAME-induced hypertensive rats

    PubMed Central

    Nasiri, Zohreh; Sameni, Hamid Reza; Vakili, Abedin; Jarrahi, Morteza; Khorasani, Mahdi Zahedi

    2015-01-01

    Objective(s): The aim of this study was to investigate the effects of nutritional saffron (Crocus sativus L.) stigma hydroalcoholic extract on blood pressure (BP) and histology of the aorta in normotensive and hypertensive rats. Materials and Methods: Saffron (200 mg/kg/day) was given orally for 5 weeks to normotensive and hypertensive rats. Hypertension was induced by NG-nitro-L-arginine methyl ester (L-NAME; 40 mg/kg/day) administration in drinking water, and BP was measured weekly. Histological examination of the thoracic aorta included staining with hematoxylin and eosin, orcein, and periodic acid Schiff methods. Results: Saffron had no effect on normotensive rats, but on hypertensive rats, prevented BP elevation form the third week of treatment (P<0.001). Furthermore, saffron reduced the cross-section area, media thickness, and elastic lamellae number of the aorta (P<0.05). Conclusion: Nutritional saffron prevented BP increases and remodeling of the aorta in hypertensive rats. It may be useful for preventing hypertension. PMID:26949504

  4. Effect of Lysyl Oxidase Inhibition on Angiotensin II-Induced Arterial Hypertension, Remodeling, and Stiffness

    PubMed Central

    Eberson, Lance S.; Sanchez, Pablo A.; Majeed, Beenish A.; Tawinwung, Supannikar; Secomb, Timothy W.; Larson, Douglas F.

    2015-01-01

    It is well accepted that angiotensin II (Ang II) induces altered vascular stiffness through responses including both structural and material remodeling. Concurrent with remodeling is the induction of the enzyme lysyl oxidase (LOX) through which ECM proteins are cross-linked. The study objective was to determine the effect of LOX mediated cross-linking on vascular mechanical properties. Three-month old mice were chronically treated with Ang II with or without the LOX blocker, β -aminopropionitrile (BAPN), for 14 days. Pulse wave velocity (PWV) from Doppler measurements of the aortic flow wave was used to quantify in vivo vascular stiffness in terms of an effective Young’s modulus. The increase in effective Young’s modulus with Ang II administration was abolished with the addition of BAPN, suggesting that the material properties are a major controlling element in vascular stiffness. BAPN inhibited the Ang II induced collagen cross-link formation by 2-fold and PWV by 44% (P<0.05). Consistent with this observation, morphometric analysis showed that BAPN did not affect the Ang II mediated increase in medial thickness but significantly reduced the adventitial thickness. Since the hypertensive state contributes to the measured in vivo PWV stiffness, we removed the Ang II infusion pumps on Day 14 and achieved normal arterial blood pressures. With pump removal we observed a decrease of the PWV in the Ang II group to 25% above that of the control values (P=0.002), with a complete return to control values in the Ang II plus BAPN group. In conclusion, we have shown that the increase in vascular stiffness with 14 day Ang II administration results from a combination of hypertension-induced wall strain, adventitial wall thickening and Ang II mediated LOX ECM cross-linking, which is a major material source of vascular stiffening, and that the increased PWV was significantly inhibited with co-administration of BAPN. PMID:25875748

  5. Inactivation of p53 Is Sufficient to Induce Development of Pulmonary Hypertension in Rats

    PubMed Central

    Jacquin, S.; Rincheval, V.; Mignotte, B.; Richard, S.; Humbert, M.; Mercier, O.; Londoño-Vallejo, A.; Fadel, E.; Eddahibi, S.

    2015-01-01

    Objective Pulmonary artery smooth muscle cells (PA-SMCs) in pulmonary arterial hypertension (PAH) show similarities to cancer cells. Due to the growth-suppressive and pro-apoptotic effects of p53 and its inactivation in cancer, we hypothesized that the p53 pathway could be altered in PAH. We therefore explored the involvement of p53 in the monocrotaline (MCT) rat model of pulmonary hypertension (PH) and the pathophysiological consequences of p53 inactivation in response to animal treatment with pifithrin-α (PFT, an inhibitor of p53 activity). Methods and Results PH development was assessed by pulmonary arterial pressure, right ventricular hypertrophy and arterial wall thickness. The effect of MCT and PFT on lung p53 pathway expression was evaluated by western blot. Fourteen days of daily PFT treatment (2.2 mg/kg/day), similar to a single injection of MCT (60 mg/kg), induced PH and aggravated MCT-induced PH. In the first week after MCT administration and prior to PH development, p53, p21 and MDM2 protein levels were significantly reduced; whereas PFT administration effectively altered the protein level of p53 targets. Anti-apoptotic and pro-proliferative effects of PFT were revealed by TUNEL and MTT assays on cultured human PA-SMCs treated with 50 μM PFT. Conclusions Pharmacological inactivation of p53 is sufficient to induce PH with a chronic treatment by PFT, an effect related to its anti-apoptotic and pro-proliferative properties. The p53 pathway was down-regulated during the first week in the rat MCT model. These in vivo experiments implicate the p53 pathway at the initiation stages of PH pathogenesis. PMID:26121334

  6. Chronic Normobaric Hypoxia Induces Pulmonary Hypertension in Rats: Role of NF-κB.

    PubMed

    Fan, Junming; Fan, Xiaofang; Li, Yang; Ding, Lu; Zheng, Qingqing; Guo, Jinbin; Xia, Dongmei; Xue, Feng; Wang, Yongyu; Liu, Shufang; Gong, Yongsheng

    2016-03-01

    Junming Fan, Xiaofang Fan, Yang Li, Lu Ding, Qingqing Zheng, Jinbin Guo, Dongmei Xia, Feng Xue, Yongyu Wang, Shufang Liu, and Yongsheng Gong. Chronic normobaric hypoxia induces pulmonary hypertension in rats: role of NF-κB. High Alt Med Biol 17:43-49, 2016.-To investigate whether nuclear factor-kappa B (NF-κB) activation is involved in chronic normobaric hypoxia-induced pulmonary hypertension (PH), rats were treated with saline or an NF-κB inhibitor, pyrrolidine dithiocarbamate (PDTC, 150 mg/kg, sc, twice daily), and exposed to normoxia or chronic normobaric hypoxia with a fraction of inspired oxygen of ∼0.1 for 14 days. Lung tissue levels of NF-κB activity, and interleukin (IL)-1β, IL-6, and cyclooxygenase-2 mRNAs, were determined, and mean pulmonary arterial pressure, right ventricular hypertrophy, and right heart function were evaluated. Compared to the normoxia exposure group, rats exposed to chronic normobaric hypoxia showed an increased NF-κB activity, measured by increased nuclear translocation of p50 and p65 proteins, an increased inflammatory gene expression in the lungs, elevated mean pulmonary arterial blood pressure and mean right ventricular pressure, right ventricular hypertrophy, as assessed by right ventricle-to-left ventricle plus septum weight ratio, and right heart dysfunction. Treatment of hypoxia-exposed rats with PDTC inhibited NF-κB activity, decreased pulmonary arterial blood pressure and right ventricular pressure, and ameliorated right ventricular hypertrophy and right heart dysfunction. Hypoxia exposure increased protein kinase C activity and promoted pulmonary artery smooth muscle cell proliferation in vitro. Our data suggest that NF-κB activation may contribute to chronic normobaric hypoxia-induced PH. PMID:26788753

  7. Mechanisms underlying the cerebral microvascular responses to angiotensin II-induced hypertension.

    PubMed

    Vital, Shantel A; Terao, Satoshi; Nagai, Mutsumi; Granger, D Neil

    2010-11-01

    Angiotensin II (AngII) and AngII type-1 receptors (AT1r) have been implicated in the pathogenesis of hypertension and ischemic stroke. The objectives of this study was to determine if/how chronic AngII administration affects blood-brain barrier (BBB) function and blood cell adhesion in the cerebral microvasculature. AngII-loaded osmotic pumps were implanted in wild type (WT) and mutant mice. Leukocyte and platelet adhesion were monitored in cerebral venules by intravital microscopy and BBB permeability detected by Evans blue leakage. AngII (two week) infusion increased blood pressure in WT mice. This was accompanied by an increased BBB permeability and a high density of adherent leukocytes and platelets. AT1r (on the vessel wall, but not on blood cells) was largely responsible for the microvascular responses to AngII. Immunodeficient (Rag-1(-/-) ) mice exhibited blunted blood cell recruitment responses without a change in BBB permeability. A similar protection pattern was noted in RANTES(-/-) and P-selectin(-/-) mice, with bone marrow chimeras (blood cell deficiency only) yielding responses comparable to the respective knockouts. These findings implicate AT1r in the microvascular dysfunction associated with AngII-induced hypertension and suggest that immune cells and blood cell-associated RANTES and P-selectin contribute to the blood cell recruitment, but not the BBB failure, elicited by AngII. PMID:21044218

  8. Calorie Restriction Attenuates Monocrotaline-induced Pulmonary Arterial Hypertension in Rats

    PubMed Central

    Ding, Mingge; Lei, Jingyi; Qu, Yinxian; Zhang, Huan; Xin, Weichuan; Ma, Feng; Liu, Shuwen; Li, Zhichao; Jin, Faguang

    2015-01-01

    Abstract: Calorie restriction (CR) is one of the most effective nonpharmacological interventions protecting against cardiovascular disease, such as hypertension in the systemic circulation. However, whether CR could attenuate pulmonary arterial hypertension (PAH) is largely unknown. The PAH model was developed by subjecting the rats to a single subcutaneous injection of monocrotaline. CR lowered mean pulmonary arterial pressure (mPAP) and reduced vascular remodeling and right ventricular hypertrophy in PAH rats. Meanwhile, CR attenuated endothelial dysfunction as evidenced by increased relaxation in response to acetylcholine. The beneficial effects of CR were associated with restored sirtuin-1 (SIRT1) expression and endothelial nitric oxide synthase (eNOS) phosphorylation and reduced eNOS acetylation in pulmonary arteries of PAH rats. To further clarify the role of SIRT1 in the protective effects of CR, adenoviral vectors for overexpression of SIRT1 were administered intratracheally at 1 day before monocrotaline injection. Overexpression of SIRT1 exhibited similar beneficial effects on mPAP and endothelial function, and increased eNOS phosphorylation and reduced eNOS acetylation in the absence of CR. Moreover, SIRT1 overexpression attenuated the increase in mPAP in hypoxia-induced PAH animals. Overall, the present data demonstrate that CR may serve as an effective treatment of PAH, and targeting the SIRT1/eNOS pathway may improve treatment of PAH. PMID:25636073

  9. Thrombospondin-4 knockout in hypertension protects small-artery endothelial function but induces aortic aneurysms.

    PubMed

    Palao, Teresa; Rippe, Catarina; van Veen, Henk; VanBavel, Ed; Swärd, Karl; Bakker, Erik N T P

    2016-06-01

    Thrombospondin-4 (TSP-4) is a multidomain calcium-binding protein that has both intracellular and extracellular functions. As an extracellular matrix protein, it is involved in remodeling processes. Previous work showed that, in the cardiovascular system, TSP-4 expression is induced in the heart in response to experimental pressure overload and infarction injury. Intracellularly, it mediates the endoplasmic reticulum stress response in the heart. In this study, we explored the role of TSP-4 in hypertension. For this purpose, wild-type and TSP-4 knockout (Thbs4(-/-)) mice were treated with angiotensin II (ANG II). Hearts from ANG II-treated Thbs4(-/-) mice showed an exaggerated hypertrophic response. Interestingly, aortas from Thbs4(-/-) mice treated with ANG II showed a high incidence of aneurysms. In resistance arteries, ANG II-treated wild-type mice showed impaired endothelial-dependent relaxation. This was not observed in ANG II-treated Thbs4(-/-) mice or in untreated controls. No differences were found in the passive pressure-diameter curves or stress-strain relationships, although ANG II-treated Thbs4(-/-) mice showed a tendency to be less stiff, associated with thicker diameters of the collagen fibers as revealed by electron microscopy. We conclude that TSP-4 plays a role in hypertension, affecting cardiac hypertrophy, aortic aneurysm formation, as well as endothelial-dependent relaxation in resistance arteries. PMID:26968543

  10. Phenylalanine improves dilation and blood pressure in GTP cyclohydrolase inhibition-induced hypertensive rats.

    PubMed

    Mitchell, Brett M; Dorrance, Anne M; Webb, R Clinton

    2004-06-01

    GTP cyclohydrolase (GTPCH), the rate-limiting enzyme in the production of the nitric oxide synthase cofactor tetrahydrobiopterin (BH4), is partly regulated by the GTPCH feedback regulatory protein (GFRP). GFRP can inhibit GTPCH by end-product negative feedback, and L-phenylalanine (L-Phe) reverses this inhibition and increases BH4 biosynthesis in vitro. We hypothesized that L-Phe would increase endothelium-dependent relaxation and decrease blood pressure in rats made hypertensive by GTPCH inhibition. Di-amino-hydroxypyrimidine (DAHP, 10 mmol/L), a known inhibitor of GTPCH, was given with or without L-Phe or D-Phe (2 mmol/L) in the drinking water of rats for 3 days and blood pressure was measured via tail-cuff. Endothelium-intact aortic segments were hung in organ chambers for measurement of isometric force generation. Systolic blood pressure was increased significantly in DAHP-treated rats compared with controls. The addition of L-Phe attenuated the hypertensive effect, whereas D-Phe had no effect. Acetylcholine- and A23187-induced relaxation was decreased in aortas from DAHP-treated rats compared with controls, but was restored in aortas from DAHP+L-Phe-treated rats. Following NOS inhibition, sensitivity to sodium nitroprusside was increased in aortas from DAHP-treated rats, but restored in DAHP+L-Phe-treated rats. These results suggest that L-Phe can reverse GTPCH inhibition in vivo leading to increased vasodilation and decreased blood pressure. PMID:15167268

  11. Glucocorticoid-induced fetal origins of adult hypertension: Association with epigenetic events.

    PubMed

    Anwar, M Akhtar; Saleh, Alaaeldin I; Al Olabi, Reem; Al Shehabi, Tuqa S; Eid, Ali H

    2016-07-01

    Hypertension is a predominant risk factor for cardiovascular diseases and a major health care burden. Accumulating epidemiological and experimental evidence suggest that adult-onset hypertension may have its origins during early development. Upon exposure to glucocorticoids, the fetus develops hypertension, and the offspring may be programmed to continue the hypertensive trajectory into adulthood. Elevated oxidative stress and deranged nitric oxide system are not only hallmarks of adult hypertension but are also observed earlier in life. Endothelial dysfunction and remodeling of the vasculature, which are robustly associated with increased incidence of hypertension, are likely to have been pre-programmed during fetal life. Apparently, genomic, non-genomic, and epigenomic factors play a significant role in the development of hypertension, including glucocorticoid-driven effects on blood pressure. In this review, we discuss the involvement of the aforementioned participants in the pathophysiology of hypertension and suggest therapeutic opportunities for targeting epigenome modifiers, potentially for personalized medicine. PMID:26903240

  12. Intracerebroventricular infusion of the (Pro)renin receptor antagonist PRO20 attenuates deoxycorticosterone acetate-salt-induced hypertension.

    PubMed

    Li, Wencheng; Sullivan, Michelle N; Zhang, Sheng; Worker, Caleb J; Xiong, Zhenggang; Speth, Robert C; Feng, Yumei

    2015-02-01

    We previously reported that binding of prorenin to the (pro)renin receptor (PRR) plays a major role in brain angiotensin II formation and the development of deoxycorticosterone acetate (DOCA)-salt hypertension. Here, we designed and developed an antagonistic peptide, PRO20, to block prorenin binding to the PRR. Fluorescently labeled PRO20 bound to both mouse and human brain tissues with dissociation constants of 4.4 and 1.8 nmol/L, respectively. This binding was blocked by coincubation with prorenin and was diminished in brains of neuron-specific PRR-knockout mice, indicating specificity of PRO20 for PRR. In cultured human neuroblastoma cells, PRO20 blocked prorenin-induced calcium influx in a concentration- and AT(1) receptor-dependent manner. Intracerebroventricular infusion of PRO20 dose-dependently inhibited prorenin-induced hypertension in C57Bl6/J mice. Furthermore, acute intracerebroventricular infusion of PRO20 reduced blood pressure in both DOCA-salt and genetically hypertensive mice. Chronic intracerebroventricular infusion of PRO20 attenuated the development of hypertension and the increase in brain hypothalamic angiotensin II levels induced by DOCA-salt. In addition, chronic intracerebroventricular infusion of PRO20 improved autonomic function and spontaneous baroreflex sensitivity in mice treated with DOCA-salt. In summary, PRO20 binds to both mouse and human PRRs and decreases angiotensin II formation and hypertension induced by either prorenin or DOCA-salt. Our findings highlight the value of the novel PRR antagonist, PRO20, as a lead compound for a novel class of antihypertensive agents and as a research tool to establish the validity of brain PRR antagonism as a strategy for treating hypertension. PMID:25421983

  13. Effects of lung recruitment maneuvers on splanchnic organ perfusion during endotoxin-induced pulmonary arterial hypertension.

    PubMed

    Daudel, Fritz; Gorrasi, José; Bracht, Hendrik; Brandt, Sebastian; Krejci, Vladimir; Jakob, Stephan M; Takala, Jukka; Rothen, Hans Ulrich

    2010-11-01

    Lung recruitment maneuvers (RMs), used to reopen atelectatic lung units and to improve oxygenation during mechanical ventilation, may result in hemodynamic impairment. We hypothesize that pulmonary arterial hypertension aggravates the consequences of RMs in the splanchnic circulation. Twelve anesthetized pigs underwent laparotomy and prolonged postoperative ventilation. Systemic, regional, and organ blood flows were monitored. After 6 h (= baseline), a recruitment maneuver was performed with sustained inflation of the lungs. Thereafter, the pigs were randomly assigned to group C (control, n = 6) or group E with endotoxin-induced pulmonary arterial hypertension (n = 6). Endotoxemia resulted in a normotensive and hyperdynamic state and a deterioration of the oxygenation index by 33%. The RM was then repeated in both groups. Pulmonary artery pressure increased during lipopolysaccharide infusion from 17 ± 2 mmHg (mean ± SD) to 31 ± 10 mmHg and remained unchanged in controls (P < 0.05). During endotoxemia, RM decreased aortic pulse pressure from 37 ± 14 mmHg to 27 ± 13 mmHg (mean ± SD, P = 0.024). The blood flows of the renal artery, hepatic artery, celiac trunk, superior mesenteric artery, and portal vein decreased to 71% ± 21%, 69% ± 20%, 76% ± 16%, 79% ± 18%, and 81% ± 12%, respectively, of baseline flows before RM (P < 0.05 all). Organ perfusion of kidney cortex, kidney medulla, liver, and jejunal mucosa in group E decreased to 65% ± 19%, 77% ± 13%, 66% ± 26%, and 71% ± 12%, respectively, of baseline flows (P < 0.05 all). The corresponding recovery to at least 90% of baseline regional blood flow and organ perfusion lasted 1 to 5 min. Importantly, the decreases in regional blood flows and organ perfusion and the time to recovery of these flows did not differ from the controls. In conclusion, lipopolysaccharide-induced pulmonary arterial hypertension does not aggravate the RM-induced significant but short-lasting decreases in systemic, regional, and

  14. Obesity-induced hypertension develops in young rats independently of the renin-angiotensin-aldosterone system.

    PubMed

    Smith, Anita D; Brands, Michael W; Wang, Mong-Heng; Dorrance, Anne M

    2006-03-01

    A correlation exists between obesity and hypertension. In the currently available models of diet-induced obesity, the treatment of rats with a high fat (HF) diet does not begin until adulthood. Our aim was to develop and characterize a model of pre-pubescent obesity-induced hypertension. Male Sprague-Dawley rats were fed a HF diet (35% fat) for 10 weeks, beginning at age 3 weeks. Blood pressure was measured by tail-cuff, and a terminal blood sample was obtained to measure fasting blood glucose, insulin, plasma renin, aldosterone, thiobarbitutic acid reactive substances (TBARS), and free 8-isoprostanes levels. The vascular reactivity in the aorta was assessed using a myograph. Blood pressure was increased in rats fed the HF diet (HF, 161 +/- 2 mm Hg vs. control, 137 +/- 2 mm Hg, P < 0.05). Blood glucose (HF, 155 +/- 4 mg/dL vs. control, 123 +/- 5 mg/dL, P < 0.05), insulin (HF, 232 +/- 63 pM vs. control, 60 +/- 11 pM, P < 0.05), TBARS (expressed as nM of malondialdehyde [MDA]/ml [HF, 1.8 +/- 0.37 nM MDA/ml vs. control 1.05 +/- 0.09 nM MDA/ml, P < 0.05]), and free 8-isoprostanes (HF, 229 +/- 68 pg/ml vs. control, 112 +/- 9 pg/ml, P < 0.05) levels were elevated in the HF diet group. Interestingly, plasma renin and aldosterone levels were not different between the groups. The maximum vasoconstriction to phenylephrine (10(-4) M) was increased in the HF diet group (HF, 26.1 +/- 1.5 mN vs. control 22.3 +/- 1.2 mN, P < 0.05). In conclusion, pre-pubescent rats become hypertensive and have increased oxidative stress and enhanced vasoconstriction when fed a HF diet. Surprisingly, this occurs without the increase in renin or aldosterone levels seen in the adult models of diet-induced obesity. PMID:16514174

  15. Maternal Melatonin Therapy Rescues Prenatal Dexamethasone and Postnatal High-Fat Diet Induced Programmed Hypertension in Male Rat Offspring

    PubMed Central

    Tain, You-Lin; Sheen, Jiunn-Ming; Yu, Hong-Ren; Chen, Chih-Cheng; Tiao, Mao-Meng; Hsu, Chien-Ning; Lin, Yu-Ju; Kuo, Kuang-Che; Huang, Li-Tung

    2015-01-01

    Prenatal dexamethasone (DEX) exposure and high-fat (HF) intake are linked to hypertension. We examined whether maternal melatonin therapy prevents programmed hypertension synergistically induced by prenatal DEX plus postnatal HF in adult offspring. We also examined whether DEX and melatonin causes renal programming using next-generation RNA sequencing (NGS) technology. Pregnant Sprague-Dawley rats received intraperitoneal dexamethasone (0.1 mg/kg) or vehicle from gestational day 16 to 22. In the melatonin-treatment groups (M), rats received 0.01% melatonin in drinking water during their entire pregnancy and lactation. Male offspring were assigned to five groups: control, DEX, HF, DEX+HF, and DEX+HF+M. Male offspring in the HF group were fed a HF diet from weaning to 4 months of age. Prenatal DEX and postnatal HF diet synergistically induced programmed hypertension in adult offspring, which melatonin prevented. Maternal melatonin treatment modified over 3000 renal transcripts in the developing offspring kidney. Our NGS data indicate that PPAR signaling and fatty acid metabolism are two significantly regulated pathways. In addition, maternal melatonin therapy elicits longstanding alterations on renal programming, including regulation of the melatonin signaling pathway and upregulation of Agtr1b and Mas1 expression in the renin-angiotensin system (RAS), to protect male offspring against programmed hypertension. Postnatal HF aggravates prenatal DEX induced programmed hypertension in adult offspring, which melatonin prevented. The protective effects of melatonin on programmed hypertension is associated with regulation of the RAS and melatonin receptors. The long-term effects of maternal melatonin therapy on renal transcriptome require further clarification. PMID:26696906

  16. CYP4A2-Induced Hypertension is 20-HETE and Angiotensin II-Dependent

    PubMed Central

    Sodhi, Komal; Wu, Cheng-Chia; Cheng, Jennifer; Gotlinger, Katherine; Inoue, Kazuyoshi; Goli, Mohan; Falck, John R.; Abraham, Nader G.; Schwartzman, Michal L.

    2010-01-01

    We have previously shown that increased vascular endothelial expression of CYP4A2 leads to 20-HETE-dependent hypertension. The renin-angiotensin system (RAS) is a key regulator of blood pressure. In this study, we examined possible interactions between 20-HETE and RAS. In normotensive (110±3 mmHg) Sprague Dawley rats transduced with a lentivirus expressing the CYP4A2 cDNA under the control of an endothelial-specific promoter (VECAD-4A2), systolic blood pressure increased rapidly, reaching 139±1, 145±3 and 150±2 mmHg at 3, 5 and 10 days after transduction; blood pressure remained elevated, thereafter, with maximum levels of 163±3 mmHg. Treatment with lisinopril, losartan or the 20-HETE antagonist 20-hydroxyeicosa-6(Z), 15(Z)-dienoic acid (20-HEDE) decreased blood pressure to control values, but blood pressure returned to its high levels after cessation of treatment. Endothelial-specific overexpression of CYP4A2 resulted in increased expression of vascular angiotensin converting enzyme (ACE) and angiotensin II type 1 receptor (AT1R) and increased levels of plasma and tissue Angiotensin II; all were attenuated by treatment with HET0016, an inhibitor of 20-HETE synthesis, or with 20-HEDE. In cultured endothelial cells, 20-HETE specifically and potently induced ACE expression without altering the expression of ACE2, angiotensinogen or angiotensin II receptors. This is the first study to demonstrate that 20-HETE, a key constrictor eicosanoid in the microcirculation, induces ACE and AT1R expression and increases Angiotensin II levels, suggesting that the mechanisms by which 20-HETE promotes hypertension include activation of RAS that is likely initiated at the level of ACE induction. PMID:20837888

  17. Carotid body remodelling in l-NAME-induced hypertension in the rat.

    PubMed

    Felix, A S; Rocha, V N; Nascimento, A L R; de Carvalho, J J

    2012-05-01

    The carotid body (CB) is a chemoreceptor organ located at the bifurcation of the common carotid artery. It is made up of the carotid glomus, a structure containing type 1 cells surrounded by type 2 cells. The aim of this study was to evaluate the morphological changes of the CB and carotid glomus in the rat model of l-NAME-induced hypertension. Male Wistar rats were divided in two groups: control untreated rats (C) and rats receiving l-NAME 40 mg/kg/day (LN) for 6 weeks. At the end of the experiment, the systolic blood pressure was 63% higher in the LN group compared with the C group. Morphometric analysis showed that the area of the CB was 29% greater in the LN group compared with the C group. The density of nuclei in the CB was similar between groups, but it was 31% less in the carotid glomus of the LN group. Cells in the CB of the LN group displayed cytoplasmic vacuolation and expressed several biogenic amines. There were more elastic fibres, proteoglycans and collagen fibres in the LN group compared with the C group. Immunohistochemistry showed increased expression of nuclear factor kB, substance P, vascular endothelial growth factor and neuronal nitric oxide synthase in the LN group, while expression of the protein gene product 9.5 was decreased. l-NAME alters cell morphology and the expression of extracellular matrix molecules in the CB and carotid glomus in rats with l-NAME-induced hypertension. PMID:21899859

  18. Pulmonary Hypertension

    PubMed Central

    Newman, John H.

    2005-01-01

    The modern era in cardiopulmonary medicine began in the 1940s, when Cournand and Richards pioneered right-heart catheterization. Until that time, no direct measurement of central vascular pressure had been performed in humans. Right-heart catheterization ignited an explosion of insights into function and dysfunction of the pulmonary circulation, cardiac performance, ventilation–perfusion relationships, lung–heart interactions, valvular function, and congenital heart disease. It marked the beginnings of angiocardiography with its diagnostic implications for diseases of the left heart and peripheral circulation. Pulmonary hypertension was discovered to be the consequence of a large variety of diseases that either raised pressure downstream of the pulmonary capillaries, induced vasoconstriction, increased blood flow to the lung, or obstructed the pulmonary vessels, either by embolism or in situ fibrosis. Hypoxic vasoconstriction was found to be a major cause of acute and chronic pulmonary hypertension, and surprising vasoreactivity of the pulmonary vascular bed was discovered to be present in many cases of severe pulmonary hypertension, initially in mitral stenosis. Diseases as disparate as scleroderma, cystic fibrosis, kyphoscoliosis, sleep apnea, and sickle cell disease were found to have shared consequences in the pulmonary circulation. Some of the achievements of Cournand and Richards and their scientific descendents are discussed in this article, including success in the diagnosis and treatment of idiopathic pulmonary arterial hypertension, chronic thromboembolic pulmonary hypertension, and management of hypoxic pulmonary hypertension. PMID:15994464

  19. Role of digitalis-like substance in the hypertension of streptozotocin-induced diabetes and simulated weightlessness in rats

    NASA Technical Reports Server (NTRS)

    Pamnani, M. B.; Chen, S.; Haddy, F. J.; Yuan, C.; Mo, Z.

    1998-01-01

    We have examined the role of plasma Na+-K+ pump inhibitor (SPI) in the hypertension of streptozotocin induced insulin dependent diabetes (IDDM) in reduced renal mass rats. The increase in blood pressure (BP) was associated with an increase in extracellular fluid volume (ECFV), and SPI and a decrease in myocardial Na+,K+ATPase (NKA) activity, suggesting that increased SPI, which inhibits cardiovascular muscle (CVM) cell NKA activity, may be involved in the mechanism of IDDM-hypertension. In a second study, using prolonged suspension resulted in a decrease in cardiac NKA activity, suggesting that cardiovascular deconditioning following space flight might in part result from insufficient SPI.

  20. Structural and functional prevention of hypoxia-induced pulmonary hypertension by individualized exercise training in mice.

    PubMed

    Weissmann, Norbert; Peters, Dorothea M; Klöpping, Christina; Krüger, Karsten; Pilat, Christian; Katta, Susmitha; Seimetz, Michael; Ghofrani, Hossein A; Schermuly, Ralph T; Witzenrath, Martin; Seeger, Werner; Grimminger, Friedrich; Mooren, Frank C

    2014-06-01

    Pulmonary hypertension (PH) is a disease with a poor prognosis characterized by a vascular remodeling process and an increase in pulmonary vascular resistance. While a variety of reports demonstrated that exercise training exerts beneficial effects on exercise performance and quality of life in PH patients, it is not known how physical exercise affects vascular remodeling processes occurring in hypoxia-induced PH. Therefore, we investigated the effect of individualized exercise training on the development of hypoxia-induced PH in mice. Training effects were compared with pharmacological treatment with the phosphodiesterase 5 inhibitor Sildenafil or a combination of training plus Sildenafil. Trained mice who received Sildenafil showed a significantly improved walking distance (from 88.9 ± 8.1 to 146.4 ± 13.1 m) and maximum oxygen consumption (from 93.3 ± 2.9 to 105.5 ± 2.2% in combination with Sildenafil, to 102.2 ± 3.0% with placebo) compared with sedentary controls. Right ventricular systolic pressure, measured by telemetry, was at the level of healthy normoxic animals, whereas right heart hypertrophy did not benefit from training. Most interestingly, the increase in small pulmonary vessel muscularization was prevented by training. Respective counterregulatory processes were detected for the nitric oxide-soluble guanylate cyclase-phosphodiesterase system. We conclude that individualized daily exercise can prevent vascular remodeling in hypoxia-induced PH. PMID:24705723

  1. Inhibition of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) reverses experimental pulmonary hypertension.

    PubMed

    Hameed, Abdul G; Arnold, Nadine D; Chamberlain, Janet; Pickworth, Josephine A; Paiva, Claudia; Dawson, Sarah; Cross, Simon; Long, Lu; Zhao, Lan; Morrell, Nicholas W; Crossman, David C; Newman, Christopher M H; Kiely, David G; Francis, Sheila E; Lawrie, Allan

    2012-10-22

    Pulmonary arterial hypertension (PAH) is a life-threatening disease characterized by the progressive narrowing and occlusion of small pulmonary arteries. Current therapies fail to fully reverse this vascular remodeling. Identifying key pathways in disease pathogenesis is therefore required for the development of new-targeted therapeutics. We have previously reported tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) immunoreactivity within pulmonary vascular lesions from patients with idiopathic PAH and animal models. Because TRAIL can induce both endothelial cell apoptosis and smooth muscle cell proliferation in the systemic circulation, we hypothesized that TRAIL is an important mediator in the pathogenesis of PAH. We demonstrate for the first time that TRAIL is a potent stimulus for pulmonary vascular remodeling in human cells and rodent models. Furthermore, antibody blockade or genetic deletion of TRAIL prevents the development of PAH in three independent rodent models. Finally, anti-TRAIL antibody treatment of rodents with established PAH reverses pulmonary vascular remodeling by reducing proliferation and inducing apoptosis, improves hemodynamic indices, and significantly increases survival. These preclinical investigations are the first to demonstrate the importance of TRAIL in PAH pathogenesis and highlight its potential as a novel therapeutic target to direct future translational therapies. PMID:23071256

  2. Inhibition of tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) reverses experimental pulmonary hypertension

    PubMed Central

    Hameed, Abdul G.; Arnold, Nadine D.; Chamberlain, Janet; Pickworth, Josephine A.; Paiva, Claudia; Dawson, Sarah; Cross, Simon; Long, Lu; Zhao, Lan; Morrell, Nicholas W.; Crossman, David C.; Newman, Christopher M.H.; Kiely, David G.; Francis, Sheila E.

    2012-01-01

    Pulmonary arterial hypertension (PAH) is a life-threatening disease characterized by the progressive narrowing and occlusion of small pulmonary arteries. Current therapies fail to fully reverse this vascular remodeling. Identifying key pathways in disease pathogenesis is therefore required for the development of new-targeted therapeutics. We have previously reported tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) immunoreactivity within pulmonary vascular lesions from patients with idiopathic PAH and animal models. Because TRAIL can induce both endothelial cell apoptosis and smooth muscle cell proliferation in the systemic circulation, we hypothesized that TRAIL is an important mediator in the pathogenesis of PAH. We demonstrate for the first time that TRAIL is a potent stimulus for pulmonary vascular remodeling in human cells and rodent models. Furthermore, antibody blockade or genetic deletion of TRAIL prevents the development of PAH in three independent rodent models. Finally, anti-TRAIL antibody treatment of rodents with established PAH reverses pulmonary vascular remodeling by reducing proliferation and inducing apoptosis, improves hemodynamic indices, and significantly increases survival. These preclinical investigations are the first to demonstrate the importance of TRAIL in PAH pathogenesis and highlight its potential as a novel therapeutic target to direct future translational therapies. PMID:23071256

  3. Thymosin Beta 4 Protects Mice from Monocrotaline-Induced Pulmonary Hypertension and Right Ventricular Hypertrophy

    PubMed Central

    Wu, Liling; Gupta, Sudhiranjan

    2014-01-01

    Pulmonary hypertension (PH) is a progressive vascular disease of pulmonary arteries that impedes ejection of blood by the right ventricle. As a result there is an increase in pulmonary vascular resistance and pulmonary arterial pressure causing right ventricular hypertrophy (RVH) and RV failure. The pathology of PAH involves vascular cell remodeling including pulmonary arterial endothelial cell (PAEC) dysfunction and pulmonary arterial smooth muscle cell (PASMC) proliferation. Current therapies are limited to reverse the vascular remodeling. Investigating a key molecule is required for development of new therapeutic intervention. Thymosin beta-4 (Tβ4) is a ubiquitous G-actin sequestering protein with diverse biological function and promotes wound healing and modulates inflammatory responses. However, it remains unknown whether Tβ4 has any protective role in PH. The purpose of this study is to evaluate the whether Tβ4 can be used as a vascular-protective agent. In monocrotaline (MCT)-induced PH mouse model, we showed that mice treated with Tβ4 significantly attenuated the systolic pressure and RVH, compared to the MCT treated mice. Our data revealed for the first time that Tβ4 selectively targets Notch3-Col 3A-CTGF gene axis in preventing MCT-induced PH and RVH. Our study may provide pre-clinical evidence for Tβ4 and may consider as vasculo-protective agent for the treatment of PH induced RVH. PMID:25412097

  4. Hypoxia-inducible factors in human pulmonary arterial hypertension: a link to the intrinsic myeloid abnormalities.

    PubMed

    Farha, Samar; Asosingh, Kewal; Xu, Weiling; Sharp, Jacqueline; George, Deepa; Comhair, Suzy; Park, Margaret; Tang, W H Wilson; Loyd, James E; Theil, Karl; Tubbs, Raymond; Hsi, Eric; Lichtin, Alan; Erzurum, Serpil C

    2011-03-31

    Pulmonary arterial hypertension (PAH) is a proliferative vasculopathy characterized by high circulating CD34(+)CD133(+) proangiogenic progenitors, and endothelial cells that have pathologic expression of hypoxia-inducible factor 1 α (HIF-1α). Here, CD34(+)CD133(+) progenitor cell numbers are shown to be higher in PAH bone marrow, blood, and pulmonary arteries than in healthy controls. The HIF-inducible myeloid-activating factors erythropoietin, stem cell factor (SCF), and hepatocyte growth factor (HGF) are also present at higher than normal levels in PAH blood, and related to disease severity. Primary endothelial cells harvested from human PAH lungs produce greater HGF and progenitor recruitment factor stromal-derived factor 1 α (SDF-1α) than control lung endothelial cells, and thus may contribute to bone marrow activation. Even though PAH patients had normal numbers of circulating blood elements, hematopoietic alterations in myeloid and erythroid lineages and reticulin fibrosis identified a subclinical myeloproliferative process. Unexpectedly, evaluation of bone marrow progenitors and reticulin in nonaffected family members of patients with familial PAH revealed similar myeloid abnormalities. Altogether, the results show that PAH is linked to myeloid abnormalities, some of which may be related to increased production of HIF-inducible factors by diseased pulmonary vasculature, but findings in nonaffected family suggest myeloid abnormalities may be intrinsic to the disease process. PMID:21258008

  5. Hypoxia-inducible factors in human pulmonary arterial hypertension: a link to the intrinsic myeloid abnormalities

    PubMed Central

    Asosingh, Kewal; Xu, Weiling; Sharp, Jacqueline; George, Deepa; Comhair, Suzy; Park, Margaret; Tang, W. H. Wilson; Loyd, James E.; Theil, Karl; Tubbs, Raymond; Hsi, Eric; Lichtin, Alan

    2011-01-01

    Pulmonary arterial hypertension (PAH) is a proliferative vasculopathy characterized by high circulating CD34+CD133+ proangiogenic progenitors, and endothelial cells that have pathologic expression of hypoxia-inducible factor 1 α (HIF-1α). Here, CD34+CD133+ progenitor cell numbers are shown to be higher in PAH bone marrow, blood, and pulmonary arteries than in healthy controls. The HIF-inducible myeloid-activating factors erythropoietin, stem cell factor (SCF), and hepatocyte growth factor (HGF) are also present at higher than normal levels in PAH blood, and related to disease severity. Primary endothelial cells harvested from human PAH lungs produce greater HGF and progenitor recruitment factor stromal-derived factor 1 α (SDF-1α) than control lung endothelial cells, and thus may contribute to bone marrow activation. Even though PAH patients had normal numbers of circulating blood elements, hematopoietic alterations in myeloid and erythroid lineages and reticulin fibrosis identified a subclinical myeloproliferative process. Unexpectedly, evaluation of bone marrow progenitors and reticulin in nonaffected family members of patients with familial PAH revealed similar myeloid abnormalities. Altogether, the results show that PAH is linked to myeloid abnormalities, some of which may be related to increased production of HIF-inducible factors by diseased pulmonary vasculature, but findings in nonaffected family suggest myeloid abnormalities may be intrinsic to the disease process. PMID:21258008

  6. Endothelin-1 receptor antagonist BQ123 prevents pulmonary artery hypertension induced by low ambient temperature in broilers.

    PubMed

    Yang, Ying; Qiao, Jian; Wu, Zhenlong; Chen, Yue; Gao, Mingyu; Ou, Deyuan; Wang, Huiyu

    2005-12-01

    Evidence has indicated that endothelin-1 is related to the pathogenesis of hypertension. To characterize the role of endothelin-1 (ET-1) in the development of pulmonary hypertension syndrome in broilers, the blockade effect of ETA receptor (ET(A)) antagonist, BQ123, on blood pressure in experimental models of pulmonary hypertension was examined. Birds were locally anesthetized and instrumented with venous catheters for pulmonary arterial pressure (PAP) and right ventricular pressure (RVP), followed by packed cell volume (PCV) and Ascites heart index (AHI) measured, after exposed to low ambient temperature for 7 or 14 d. In treated groups, BQ123 (0.4 or 2.0 microg each time, 2 times a day), administered in abdominal cavities for 7 or 14 d during birds kept in low ambient temperature, prevented both PAP and RVP increasing, especially the high dose BQ123 lowered PAP and RVP to normotensive levels as that in control under normal temperature, whereas significant increases (p<0.05) were found in the two parameters of broilers in both untreated and saline treated group under low ambient temperature compared with those of birds in control. Furthermore, there was also a reduction in low ambient temperature-induced right ventricular hypertrophy in the groups administered BQ123. The preventive effect of BQ123 suggests that ET-1 is associated with the development of broilers' pulmonary hypertension, which leads to the development of ascites, and BQ123 can prevent the occurrence of pulmonary hypertension. PMID:16327149

  7. Effect of chronic sodium nitrite therapy on monocrotaline-induced pulmonary hypertension.

    PubMed

    Pankey, Edward A; Badejo, Adeleke M; Casey, David B; Lasker, George F; Riehl, Russel A; Murthy, Subramanyam N; Nossaman, Bobby D; Kadowitz, Philip J

    2012-06-30

    Pulmonary hypertension (PH) is a rare disorder that without treatment is progressive and often fatal within 3 years. The treatment of PH involves the use of a diverse group of drugs and lung transplantation. Although nitrite was once thought to be an inactive metabolite of endothelial-derived nitric oxide (NO), there is increasing evidence that nitrite may be useful in the treatment of PH, but the mechanism by which nitrite exerts its beneficial effect remains uncertain. The purpose of this study was to investigate the effect of chronic sodium nitrite treatment in a PH model in the rat. Following induction of PH with a single injection of monocrotaline, 60 mg; daily ip injections of sodium nitrite (3mg/kg) starting on day 14 and continuing for 21 days, resulted in a significantly lower pulmonary arterial pressure on day 35 when compared to values in untreated animals with monocrotaline-induced PH. In monocrotaline-treated rats, daily treatment with ip nitrite injections for 21 days decreased right ventricular mass and pathologic changes in small pulmonary arteries. Nitrite therapy did not change systemic arterial pressure or cardiac output when values were measured on day 35. The decreases in pulmonary arterial pressure in response to iv injections of sodium nitroprusside, sodium nitrite, and BAY 41-8543 were not different in rats with monocrotaline-induced pulmonary hypertension and rats with chronic nitrite therapy when compared to responses in animals in which pulmonary arterial pressure was increased with U46619. These findings are consistent with the hypothesis that the mechanisms that convert nitrite to vasoactive NO, activate soluble guanylyl cyclase and mediate the vasodilator response to NO or an NO derivative are not impaired. The present data are consistent with the results of a previous study in monocrotaline-induced PH in which systemic arterial pressure and cardiac output were not evaluated and are consistent with the hypothesis that nitrite is

  8. Effect of Chronic Sodium Nitrite Therapy on Monocrotaline-Induced Pulmonary Hypertension

    PubMed Central

    Pankey, Edward A.; Badejo, Adeleke M.; Casey, David B.; Lasker, George F.; Riehl, Russel A.; Murthy, Subramanyam N.; Nossaman, Bobby D.; Kadowitz, Philip J.

    2012-01-01

    Pulmonary hypertension (PH) is a rare disorder that without treatment is progressive and often fatal within 3 years. The treatment of PH involves the use of a diverse group of drugs and lung transplantation. Although nitrite was once thought to be an inactive metabolite of endothelial-derived nitric oxide (NO), there is increasing evidence that nitrite may be useful in the treatment of PH, but the mechanism by which nitrite exerts its beneficial effect remains uncertain. The purpose of this study was to investigate the effect of chronic sodium nitrite treatment in a PH model in the rat. Following induction of PH with a single injection of monocrotaline, 60 mg; daily ip injections of sodium nitrite (3 mg/kg) starting on day 14 and continuing for 21 days, resulted in a significantly lower pulmonary arterial pressure on day 35 when compared to values in untreated animals with monocrotaline-induced PH. In monocrotaline-treated rats, daily treatment with ip nitrite injections for 21 days decreased right ventricular mass and pathologic changes in small pulmonary arteries. Nitrite therapy did not change systemic arterial pressure or cardiac output when values were measured on day 35. The decreases in pulmonary arterial pressure in response to iv injections of sodium nitroprusside, sodium nitrite, and BAY 41-8543 were not different in rats with monocrotaline-induced pulmonary hypertension and rats with chronic nitrite therapy when compared to responses in animals in which pulmonary arterial pressure was increased with U46619. These findings are consistent with the hypothesis that the mechanisms that convert nitrite to vasoactive NO, activate soluble guanylyl cyclase and mediate the vasodilator response to NO or an NO derivative are not impaired. The present data are consistent with the results of a previous study in monocrotaline-induced PH in which systemic arterial pressure and cardiac output were not evaluated and are consistent with the hypothesis that nitrite is

  9. Calcilytics enhance sildenafil-induced antiproliferation in idiopathic pulmonary arterial hypertension.

    PubMed

    Yamamura, Aya; Yagi, Satomi; Ohara, Naoki; Tsukamoto, Kikuo

    2016-08-01

    Idiopathic pulmonary arterial hypertension (IPAH) is a progressive and fatal disease of the pulmonary artery resulting from currently unidentified etiology. IPAH is pathologically characterized as sustained vasoconstriction and vascular remodeling of the pulmonary artery. Phosphodiesterase type 5 (PDE5) inhibitors have been clinically used in the treatment of IPAH. Recently, we have shown that Ca(2+)-sensing receptor (CaSR) antagonists, or calcilytics, inhibit excessive cell proliferation of pulmonary arterial smooth muscle cells (PASMCs) from IPAH patients. In this study, the additive or synergistic effect of calcilytics on antiproliferation following PDE5 inhibition was examined in IPAH-PASMCs by MTT assay. Treatment with sildenafil blocked the excessive cell proliferation of IPAH-PASMCs in a concentration-dependent manner with an IC50 value of 16.9μM. However, sildenafil (0.03-100μM) did not affect the cell growth of PASMCs from normal subjects and patients with chronic thromboembolic pulmonary hypertension (CTEPH). Co-treatment with 0.3μM NPS2143, a calcilytic, additively enhanced the antiproliferative effect induced by sildenafil (3 or 30μM) in IPAH-PASMCs. Additionally, the inhibitory effect of calcilytics, NPS2143 or Calhex 231 (1 or 10μM), on excessive cell proliferation of IPAH-PASMCs was synergistic increased in the presence of 1μM sildenafil. Similar results were obtained by BrdU incorporation assay. These findings reveal that calcilytics additively/synergistically enhance the antiproliferative activity mediated by PDE5 inhibition, suggesting that a combination therapy of a PDE5 inhibitor with a calcilytic may be useful as a novel therapeutic approach for IPAH. PMID:27164419

  10. Effects of equol on deoxycorticosterone acetate salt-induced hypertension and associated vascular dementia in rats.

    PubMed

    Liu, Te-Hua; Tsai, Tsung-Yu

    2016-08-10

    Oxidative stress is the major cause of neuronal cell degeneration observed in neurodegenerative diseases including vascular dementia (VaD), and hypertension has been found to increase the probability of VaD. Here, we investigated the effects of equol in deoxycorticosterone acetate (DOCA)-salt-induced hypertensive rats (DHRs) and the associated VaD. The systolic blood pressure of rats treated with low- (10 mg per kg body weight) and high-dose (20 mg per kg body weight) equol for 4 weeks was lower than that of the control group by 12.18 and 17.48% in a dose-dependent manner, respectively (p < 0.05), which was regulated by inhibiting angiotensin-converting enzyme (ACE) activity and increasing the nitric oxide (NO) production. Equol-treated DHRs showed a significant decrease in both the swimming distance and time required to reach the escape platform (78.20 to 82.56%, p < 0.05). In addition, the probe trial session and working memory test indicated that equol improved the long- and short-term memory of the rats. Moreover, the brain antioxidant activity was increased by elevating the activities of superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx) levels, and the malondialdehyde (MDA) content and acetylcholinesterase (AChE) activity were decreased, indicating that equol suppressed oxidative stress. In conclusion, we demonstrated that equol exhibited comparable blood pressure (BP)-lowering and VaD-improving effects with the clinically used drug, lisinopril in DHRs while there was a positive correlation between the doses. Therefore, this bioactive compound may be useful for developing functional foods, thereby extending the application of equol-containing crops. PMID:27435368

  11. High dietary phosphate intake induces hypertension and augments exercise pressor reflex function in rats.

    PubMed

    Mizuno, Masaki; Mitchell, Jere H; Crawford, Scott; Huang, Chou-Long; Maalouf, Naim; Hu, Ming-Chang; Moe, Orson W; Smith, Scott A; Vongpatanasin, Wanpen

    2016-07-01

    An increasing number of studies have linked high dietary phosphate (Pi) intake to hypertension. It is well established that the rise in sympathetic nerve activity (SNA) and blood pressure (BP) during physical exertion is exaggerated in many forms of hypertension, which are primarily mediated by an overactive skeletal muscle exercise pressor reflex (EPR). However, it remains unknown whether high dietary Pi intake potentiates the EPR-mediated SNA and BP response to exercise. Accordingly, we measured renal SNA (RSNA) and mean BP (MBP) in normotensive Sprague-Dawley rats fed a normal Pi diet (0.6%, n = 13) or high Pi diet (1.2%, n = 13) for 3 mo. As previously reported, we found that resting BP was significantly increased by 1.2% Pi diet in both conscious and anesthetized animals. Activation of the EPR by electrically induced hindlimb contraction triggered greater increases in ΔRSNA and ΔMBP in the 1.2% compared with 0.6% Pi group (126 ± 25 vs. 42 ± 9%; 44 ± 5 vs. 14 ± 2 mmHg, respectively, P < 0.01). Activation of the muscle mechanoreflex, a component of the EPR, by passively stretching hindlimb muscle also evoked greater increases in ΔRSNA and ΔMBP in the 1.2% compared with 0.6% Pi group (109 ± 27 vs. 24 ± 7%, 38 ± 7 vs. 8 ± 2 mmHg, respectively, P < 0.01). A similar response was produced by hindlimb intra-arterial capsaicin administration to stimulate the metaboreflex arm of the EPR. Thus, our data demonstrate a novel action of dietary Pi loading in augmenting EPR function through overactivation of both the muscle mechanoreflex and metaboreflex. PMID:27170660

  12. Insulin nonattenuation of vasoactive agent-induced responses in mesangial cells from spontaneously hypertensive rats.

    PubMed

    Inishi, Y; Okuda, T; Arakawa, T; Yasuda, C; Ohara, M; Kurokawa, K

    1995-03-01

    We recently found that insulin attenuates intracellular calcium transients and cell contraction caused by vasoactive agents in cultured rat mesangial cells. Because altered glomerular function may be causally related to the evolution of hypertension, we examined in the present study the effects of insulin on the functions of mesangial cells derived from spontaneously hypertensive rats (SHR) of 4- and 8-weeks of age. Age-matched Wistar Kyoto rats (WKY) were used as controls. Intracellular calcium concentration ([Ca2+]i) was measured with Fura-2 method in suspended mesangial cells. Pretreatment of mesangial cells with 5 micrograms/ml insulin for 120 minutes did not affect basal [Ca2+]i in either WKY or SHR mesangial cells. However, insulin pretreatment significantly attenuated [Ca2+]i transients to vasoactive agents in WKY mesangial cells. In contrast, [Ca2+]i transients to these agents were not attenuated by insulin in SHR mesangial cells. Additionally, SHR mesangial cell contraction in response to angiotensin II (Ang II) was not altered by insulin, while WKY mesangial cell contraction to Ang II was, as in normal Wistar rats, significantly reduced by insulin. Since we previously showed the possibility that the attenuation of calcium signal by insulin is via insulin-like growth factor I (IGF-I) receptor, we also examined the effect of IGF-I. In contrast to WKY mesangial cells, IGF-I-induced attenuation of [Ca2+]i responses to platelet activating factor was absent in SHR mesangial cells. [125I]-IGF-I binding in SHR mesangial cells was not significantly different from that in WKY mesangial cells.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:7752589

  13. Regular exercise alleviates renovascular hypertension-induced cardiac/endothelial dysfunction and oxidative injury in rats.

    PubMed

    Kumral, Z N O; Sener, G; Ozgur, S; Koc, M; Suleymanoglu, S; Hurdag, C; Yegen, B C

    2016-02-01

    The importance of physical activity in the management of renovascular diseases is well-known, but lacks evidence of underlying mechanisms. The purpose of the study was to elucidate the protective/therapeutic effects of regular exercise on experimental renovascular hypertension (RVH)-induced oxidative stress and cardiac dysfunction. Wistar albino rats underwent a RVH surgery (2K1C, Goldblatt). Three weeks later half of the rats started swimming exercise for 9 weeks (n = 15), while the sedentary RVH group (n = 15) had no exercise during that period. Sham-operated control rats (n = 10), had the similar surgical procedures but the left renal artery was left unclipped. Body weights were monitored, and blood pressures were measured weekly using tail-cuff. Echocardiographic evaluation was performed on the 3(rd) week and on the 12(th) week of the experiment before the rats were decapitated. Heart and thoracic aorta were removed and serum was collected, while aortic samples were put in a 10% formaldehyde solution for immunochemistry. Cardiac tissue samples obtained from each animal were used for the determination of tissue myeloperoxidase (MPO) and catalase (CAT) activities, malondialdehyde (MDA), and glutathione (GSH) levels. In the sedentary RVH group, aortic contractile response (contraction/relaxation in isolated organ bath), left ventricular diastolic and systolic dimensions, and immunohistochemical staining of aortic inducible nitric oxide synthase (iNOS) were increased, while ejection fraction and aortic endothelial nitric oxide synthase (eNOS) staining were decreased. RVH in the sedentary rats resulted in increased pro-inflammatory cytokines (TNF-α, IL-2, IL-6), lipid peroxidation (malondialdehyde) and neutrophil infiltration (myeloperoxidase activity) along with reductions in antioxidant glutathione and catalase levels in the cardiac tissue. Exercise after RVH increased the immunhistochemical staining of aortic eNOS, decreased iNOS staining and reversed the

  14. Effect of deoxycorticosterone acetate-salt-induced hypertension on diabetic peripheral neuropathy in alloxan-induced diabetic WBN/Kob rats.

    PubMed

    Ozaki, Kiyokazu; Hamano, Hiroko; Matsuura, Tetsuro; Narama, Isao

    2016-01-01

    The relationship between hypertension and diabetic peripheral neuropathy (DPN) has recently been reported in clinical research, but it remains unclear whether hypertension is a risk factor for DPN. To investigate the effects of hypertension on DPN, we analyzed morphological features of peripheral nerves in diabetic rats with hypertension. Male WBN/Kob rats were divided into 2 groups: alloxan-induced diabetic rats with deoxycorticosterone acetate-salt (DOCA-salt) treatment (ADN group) and nondiabetic rats with DOCA-salt treatment (DN group). Sciatic, tibial (motor) and sural (sensory) nerves were subjected to qualitative and quantitative histomorphological analysis. Systolic blood pressure in the two groups exhibited a higher value (>140 mmHg), but there was no significant difference between the two groups. Endoneurial blood vessels in both groups presented endothelial hypertrophy and narrowing of the vascular lumen. Electron microscopically, duplication of basal lamina surrounding the endothelium and pericyte of the endoneurial vessels was observed, and this lesion appeared to be more frequent and severe in the ADN group than the DN group. Many nerve fibers of the ADN and DN groups showed an almost normal appearance, whereas morphometrical analysis of the tibial nerve showed a significant shift to smaller fiber and myelin sizes in the ADN group compared with DN group. In sural nerve, the fiber and axon-size significantly shifted to a smaller size in ADN group compared with the DN group. These results suggest that combined diabetes and hypertension could induce mild peripheral nerve lesions with vascular changes. PMID:26989296

  15. Effect of deoxycorticosterone acetate-salt-induced hypertension on diabetic peripheral neuropathy in alloxan-induced diabetic WBN/Kob rats

    PubMed Central

    Ozaki, Kiyokazu; Hamano, Hiroko; Matsuura, Tetsuro; Narama, Isao

    2015-01-01

    The relationship between hypertension and diabetic peripheral neuropathy (DPN) has recently been reported in clinical research, but it remains unclear whether hypertension is a risk factor for DPN. To investigate the effects of hypertension on DPN, we analyzed morphological features of peripheral nerves in diabetic rats with hypertension. Male WBN/Kob rats were divided into 2 groups: alloxan-induced diabetic rats with deoxycorticosterone acetate-salt (DOCA-salt) treatment (ADN group) and nondiabetic rats with DOCA-salt treatment (DN group). Sciatic, tibial (motor) and sural (sensory) nerves were subjected to qualitative and quantitative histomorphological analysis. Systolic blood pressure in the two groups exhibited a higher value (>140 mmHg), but there was no significant difference between the two groups. Endoneurial blood vessels in both groups presented endothelial hypertrophy and narrowing of the vascular lumen. Electron microscopically, duplication of basal lamina surrounding the endothelium and pericyte of the endoneurial vessels was observed, and this lesion appeared to be more frequent and severe in the ADN group than the DN group. Many nerve fibers of the ADN and DN groups showed an almost normal appearance, whereas morphometrical analysis of the tibial nerve showed a significant shift to smaller fiber and myelin sizes in the ADN group compared with DN group. In sural nerve, the fiber and axon-size significantly shifted to a smaller size in ADN group compared with the DN group. These results suggest that combined diabetes and hypertension could induce mild peripheral nerve lesions with vascular changes. PMID:26989296

  16. Effects of bulbus Fritillaria water extract on blood pressure and renal functions in the L-NAME-induced hypertensive rats.

    PubMed

    Kang, Dae Gill; Sohn, Eun Jin; Lee, Yun Mi; Lee, An Sook; Han, Jong Hyun; Kim, Tai Yo; Lee, Ho Sub

    2004-03-01

    A pharmacological inhibition of nitric oxide synthase (NOS) in rats produces renal vasoconstriction, renal dysfunction, and hypertension. The present study was aimed at investigating whether Bulbus Fritillaria water extract (BFWE) ameliorates NG-nitro-L-arginine methylester (L-NAME)-induced hypertension. Treatment of rats with L-NAME (60 mg/l drinking water, 4 weeks) caused a sustained increase in systolic blood pressure (SBP). The NO concentration in plasma and NO productions in the vascular tissues of the L-NAME-treated group were significantly reduced as compared with those in the control, whereas the expressions of NOS proteins were not altered. BFWE restored SBP to normal level in the L-NAME-treated hypertensive rats. Moreover, BFWE was able to preserve the vascular NO production and plasma NO metabolites concentration without changes of the expression NOS proteins. The renal functional parameters including urinary volume, sodium excretion, and creatinine clearance (Ccr) were significantly restored in rats co-treated with BFWE and L-NAME compared to the L-NAME-treated group. Taken together, these results suggest that BFWE prevents the increase of SBP in the L-NAME-induced hypertension that may have been caused by enhanced generation of vascular NO and amelioration of renal functions. PMID:15036467

  17. Pulmonary Artery Denervation Reduces Pulmonary Artery Pressure and Induces Histological Changes in an Acute Porcine Model of Pulmonary Hypertension

    PubMed Central

    Arnold, Nadine D.; Chang, William; Watson, Oliver; Swift, Andrew J.; Condliffe, Robin; Elliot, Charlie A.; Kiely, David G.; Suvarna, S. Kim; Gunn, Julian; Lawrie, Allan

    2015-01-01

    Background— Pulmonary arterial hypertension is a devastating disease with high morbidity and mortality and limited treatment options. Recent studies have shown that pulmonary artery denervation improves pulmonary hemodynamics in an experimental model and in an early clinical trial. We aimed to evaluate the nerve distribution around the pulmonary artery, to determine the effect of radiofrequency pulmonary artery denervation on acute pulmonary hypertension induced by vasoconstriction, and to demonstrate denervation of the pulmonary artery at a histological level. Methods and Results— Histological evaluation identified a circumferential distribution of nerves around the proximal pulmonary arteries. Nerves were smaller in diameter, greater in number, and located in closer proximity to the luminal aspect of the pulmonary arterial wall beyond the pulmonary artery bifurcation. To determine the effect of pulmonary arterial denervation acute pulmonary hypertension was induced in 8 pigs by intravenous infusion of thromboxane A2 analogue. Animals were assigned to either pulmonary artery denervation, using a prototype radiofrequency catheter and generator, or a sham procedure. Pulmonary artery denervation resulted in reduced mean pulmonary artery pressure and pulmonary vascular resistance and increased cardiac output. Ablation lesions on the luminal surface of the pulmonary artery were accompanied by histological and biochemical alteration in adventitial nerves and correlated with improved hemodynamic parameters. Conclusions— Pulmonary artery denervation offers the possibility of a new treatment option for patients with pulmonary arterial hypertension. Further work is required to determine the long-term efficacy and safety. PMID:26553697

  18. 4-Phenylbutyric Acid Induces Protection against Pulmonary Arterial Hypertension in Rats

    PubMed Central

    Long, Mei; Wang, Jie; Liu, Fen; Gai, Min-Tao; Aierken, Alidan; Li, Ming-Yuan; Li, Qian; Wu, Lei-Qi; Ma, Yi-Tong; Hujiaaihemaiti, Minawaer

    2016-01-01

    Background Endoplasmic reticulum (ER) stress has been implicated in the pathophysiology of various pulmonary diseases via the activation of the unfolded protein response. However, the role of ER stress in pulmonary arterial hypertension (PAH) remains unclear. The well-known chemical chaperone 4-phenylbutyric acid (4-PBA) inhibits ER stress signaling. We hypothesized that known chemical chaperones, including 4-PBA, would inhibit the activation of ER stress and prevent and/or reverse PAH. Methods and Results Male Wistar rats were randomly divided into four groups: a normal control group (NORMAL group), a PAH group, and two PAH model plus 4-PBA treatment groups. The latter two groups included rats receiving 4-PBA by gavage each day as a preventive measure (the PRE group, with PBA starting on the day of PAH induction and continuing for 4 weeks) or as a reversal measure (the REV group, with PBA starting on the third week of PAH induction and continuing for 2 weeks). The PAH model was induced by intraperitoneally administering monocrotaline. The mean pulmonary artery pressure and mean right ventricular pressure were lower in the REV and PRE groups than in the NORMAL group. Furthermore, 4-PBA improved pulmonary arterial remodeling and suppressed the expression of ER stress indicators. Conclusion Our findings indicate that PAH induces ER stress and provokes pulmonary arterial and right ventricular remodeling. Additionally, we show that attenuation of ER stress has the potential to be an effective therapeutic strategy for protecting pulmonary arteries. PMID:27304885

  19. The anti-hypertensive drug reserpine induces neuronal cell death through inhibition of autophagic flux.

    PubMed

    Lee, Kang Il; Kim, Min Ju; Koh, Hyongjong; Lee, Jin I; Namkoong, Sim; Oh, Won Keun; Park, Junsoo

    2015-07-10

    Reserpine is a well-known medicine for the treatment of hypertension and schizophrenia, but its administration can induce Parkinson's disease (PD)-like symptoms in humans and animals. Reserpine inhibits the vesicular transporter of monoamines and depletes the brain of monoamines such as dopamine. However, the cellular function of reserpine is not fully understood. In this report, we present one possible mechanism by which reserpine may contribute to PD-like symptoms. Reserpine treatment induced the formation of enlarged autophagosomes by inhibiting the autophagic flux and led to accumulation of p62, an autophagy adapter molecule. In particular, reserpine treatment increased the level of α-synuclein protein and led to accumulation of α-synuclein in autophagosomes. Treatment with rapamycin enhanced the effect of reserpine by further increasing the level of α-synuclein and neuronal cell death. Drosophila raised on media containing reserpine showed loss of dopaminergic neurons. Furthermore, cotreatment with reserpine and rapamycin aggravated the loss of dopaminergic neurons. Our results suggest that reserpine contributes to the loss of dopaminergic neurons by interfering with autophagic flux. PMID:25976674

  20. Role of vascular endothelial growth factor signaling in Schistosoma-induced experimental pulmonary hypertension

    PubMed Central

    2014-01-01

    Abstract There is significant evidence that Th2 (T helper 2)-mediated inflammation supports the pathogenesis of both human and experimental animal models of pulmonary hypertension (PH). A key immune regulator is vascular endothelial growth factor (VEGF), which is produced by Th2 inflammation and can itself contribute to Th2 pulmonary responses. In this study, we interrogated the role of VEGF signaling in a murine model of schistosomiasis-induced PH with a phenotype of significant intrapulmonary Th2 inflammation, vascular remodeling, and elevated right ventricular pressures. We found that VEGF receptor blockade partially suppressed the levels of the Th2 inflammatory cytokines interleukin (IL)-4 and IL-13 in both the lung and the liver after Schistosoma mansoni exposure and suppressed pulmonary vascular remodeling. These findings suggest that VEGF positively contributes to schistosomiasis-induced vascular inflammation and remodeling, and they also provide evidence for a VEGF-dependent signaling pathway necessary for pulmonary vascular remodeling and inflammation in this model. PMID:25006448

  1. Attenuated muscle metaboreflex-induced pressor response during postexercise muscle ischemia in renovascular hypertension

    PubMed Central

    Spranger, Marty D.; Kaur, Jasdeep; Sala-Mercado, Javier A.; Machado, Tiago M.; Krishnan, Abhinav C.; Alvarez, Alberto

    2015-01-01

    During dynamic exercise, muscle metaboreflex activation (MMA; induced via partial hindlimb ischemia) markedly increases mean arterial pressure (MAP), and MAP is sustained when the ischemia is maintained following the cessation of exercise (postexercise muscle ischemia, PEMI). We previously reported that the sustained pressor response during PEMI in normal individuals is driven by a sustained increase in cardiac output (CO) with no peripheral vasoconstriction. However, we have recently shown that the rise in CO with MMA is significantly blunted in hypertension (HTN). The mechanisms sustaining the pressor response during PEMI in HTN are unknown. In six chronically instrumented canines, hemodynamic responses were observed during rest, mild exercise (3.2 km/h), MMA, and PEMI in the same animals before and after the induction of HTN [Goldblatt two kidney, one clip (2K1C)]. In controls, MAP, CO and HR increased with MMA (+52 ± 6 mmHg, +2.1 ± 0.3 l/min, and +37 ± 7 beats per minute). After induction of HTN, MAP at rest increased from 97 ± 3 to 130 ± 4 mmHg, and the metaboreflex responses were markedly attenuated (+32 ± 5 mmHg, +0.6 ± 0.2 l/min, and +11 ± 3 bpm). During PEMI in HTN, HR and CO were not sustained, and MAP fell to normal recovery levels. We conclude that the attenuated metaboreflex-induced HR, CO, and MAP responses are not sustained during PEMI in HTN. PMID:25632024

  2. ANG II-induced hypertension in the VCD mouse model of menopause is prevented by estrogen replacement during perimenopause.

    PubMed

    Pollow, Dennis P; Romero-Aleshire, Melissa J; Sanchez, Jessica N; Konhilas, John P; Brooks, Heddwen L

    2015-12-15

    Premenopausal females are resistant to the development of hypertension, and this protection is lost after the onset of menopause, resulting in a sharp increase in disease onset and severity. However, it is unknown how a fluctuating ovarian hormone environment during the transition from perimenopause to menopause impacts the onset of hypertension, and whether interventions during perimenopause prevent disease onset after menopause. A gradual transition to menopause was induced by repeated daily injections of 4-vinylcyclohexene diepoxide (VCD). ANG II (800 ng·kg(-1)·min(-1)) was infused into perimenopausal and menopausal female mice for 14 days. A separate cohort of mice received 17β-estradiol replacement during perimenopause. ANG II infusion produced significantly higher mean arterial pressure (MAP) in menopausal vs. cycling females, and 17β-estradiol replacement prevented this increase. In contrast, MAP was not significantly different when ANG II was infused into perimenopausal and cycling females, suggesting that female resistance to ANG II-induced hypertension is intact during perimenopause. ANG II infusion caused a significant glomerular hypertrophy, and hypertrophy was not impacted by hormonal status. Expression levels of aquaporin-2 (AQP2), a collecting duct protein, have been suggested to reflect blood pressure. AQP2 protein expression was significantly downregulated in the renal cortex of the ANG II-infused menopause group, where blood pressure was increased. AQP2 expression levels were restored to control levels with 17β-estradiol replacement. This study indicates that the changing hormonal environment in the VCD model of menopause impacts the severity of ANG II-induced hypertension. These data highlight the utility of the ovary-intact VCD model of menopause as a clinically relevant model to investigate the physiological mechanisms of hypertension that occur in women during the transition into menopause. PMID:26491098

  3. Attenuation of the extract from Moringa oleifera on monocrotaline-induced pulmonary hypertension in rats.

    PubMed

    Chen, Kang-Hu; Chen, Yi-Jui; Yang, Chao-Hsun; Liu, Kuo-Wei; Chang, Junn-Liang; Pan, Shwu-Fen; Lin, Tzer-Bin; Chen, Mei-Jung

    2012-02-29

    The purpose of this study was to determine the effects of an extract from Moringa oleifera (MO) on the development of monocrotaline (MCT)-induced pulmonary hypertension (PH) in Wistar rats. An ethanol extraction was performed on dried MO leaves, and HPLC analysis identified niaziridin and niazirin in the extract. PH was induced with a single subcutaneous injection of MCT (60 mg/kg) which resulted in increases in pulmonary arterial blood pressure (Ppa) and in thickening of the pulmonary arterial medial layer in the rats. Three weeks after induction, acute administration of the MO extract to the rats decreased Ppa in a dose-dependent manner that reached statistical significance at a dose of 4.5 mg of freeze-dried extract per kg body weight. The reduction in Ppa suggested that the extract directly relaxed the pulmonary arteries. To assay the effects of chronic administration of the MO extract on PH, control, MCT and MCT+MO groups were designated. Rats in the control group received a saline injection; the MCT and MCT+MO groups received MCT to induce PH. During the third week after MCT treatment, the MCT+MO group received daily i.p. injections of the MO extract (4.5 mg of freeze-dried extract/kg of body weight). Compared to the control group, the MCT group had higher Ppa and thicker medial layers in the pulmonary arteries. Chronic treatments with the MO extract reversed the MCT-induced changes. Additionally, the MCT group had a significant elevation in superoxide dismutase activity when normalized by the MO extract treatments. In conclusion, the MO extract successfully attenuated the development of PH via direct vasodilatation and a potential increase in antioxidant activity. PMID:22242951

  4. Adipocyte deficiency of angiotensinogen prevents obesity-induced hypertension in male mice.

    PubMed

    Yiannikouris, Frederique; Gupte, Manisha; Putnam, Kelly; Thatcher, Sean; Charnigo, Richard; Rateri, Debra L; Daugherty, Alan; Cassis, Lisa A

    2012-12-01

    Previous studies demonstrated that diet-induced obesity increased plasma angiotensin II concentrations and elevated systolic blood pressures in male mice. Adipocytes express angiotensinogen and secrete angiotensin peptides. We hypothesize that adipocyte-derived angiotensin II mediates obesity-induced increases in systolic blood pressure in male high fat-fed C57BL/6 mice. Systolic blood pressure was measured by radiotelemetry during week 16 of low-fat or high-fat feeding in Agt(fl/fl) and adipocyte angiotensinogen-deficient mice (Agt(aP2)). Adipocyte angiotensinogen deficiency had no effect on diet-induced obesity. Basal 24-hour systolic blood pressure was not different in low fat-fed Agt(fl/fl) compared with Agt(aP2) mice (124 ± 3 versus 128 ± 3 mm Hg, respectively). In Agt(fl/fl) mice, high-fat feeding significantly increased systolic blood pressure (24 hours; 134 ± 2 mm Hg; P<0.05). In contrast, high fat-fed Agt(aP2) mice did not exhibit an increase in systolic blood pressure (126 ± 2 mm Hg). Plasma angiotensin II concentrations were increased by high-fat feeding in Agt(fl/fl) mice (low fat, 32 ± 14; high fat, 219 ± 58 pg/mL; P<0.05). In contrast, high fat-fed Agt(aP2) mice did not exhibit elevated plasma angiotensin II concentrations (high fat, 18 ± 7 pg/mL). Similarly, adipose tissue concentrations of angiotensin II were significantly decreased in low fat- and high fat-fed Agt(aP2) mice compared with controls. In conclusion, adipocyte angiotensinogen deficiency prevented high fat-induced elevations in plasma angiotensin II concentrations and systolic blood pressure. These results suggest that adipose tissue serves as a major source of angiotensin II in the development of obesity hypertension. PMID:23108647

  5. Overexpression of VEGF-C attenuates chronic high salt intake-induced left ventricular maladaptive remodeling in spontaneously hypertensive rats.

    PubMed

    Yang, Guo-Hong; Zhou, Xin; Ji, Wen-Jie; Zeng, Shan; Dong, Yan; Tian, Lu; Bi, Ying; Guo, Zhao-Zeng; Gao, Fei; Chen, Hong; Jiang, Tie-Min; Li, Yu-Ming

    2014-02-15

    Recent studies have shown that the tonicity-responsive enhancer binding protein (TonEBP)/vascular endothelial growth factor-C (VEGF-C) signaling pathway-induced lymphangiogenesis provides a buffering mechanism for high salt (HS) intake-induced elevation of blood pressure (BP). Moreover, blocking of TonEBP/VEGF-C signaling by mononuclear phagocyte depletion can induce salt-sensitive hypertension in rats. We hypothesized that HS intake could have an impact on cardiac lymphangiogenesis, and regulation of VEGF-C bioactivity, which is largely through the main receptor for VEGFR-3, may modulate HS intake-induced left ventricular remodeling. We demonstrated upregulation of TonEBP, increased macrophage infiltration, and enhanced lymphangiogenesis in the left ventricles of spontaneously hypertensive rats (SHR) that were fed a HS diet (8.0% NaCl). Then, retrovirus vectors capable of overexpression (ΔNΔC/VEGF-C/Cys152Ser, used for overexpressing VEGF-C) and blocking (VEGFR-3-Rg, used for trapping of bioactive VEGF-C) of VEGF-C and control vector (pLPCX) were intravenously administered to SHR from week 9 of a 12-wk HS loading period. At the end of the HS challenge, overexpression of VEGF-C led to enhanced cardiac lymphangiogenesis, decreased myocardial fibrosis, and macrophage infiltration, preserved left ventricular functions, as well as decreased blood pressure level compared with the HS group and the control vector-treated HS group. In contrast, systemic blocking of VEGF-C was associated with elevation of blood pressure level and an exacerbation of hypertensive left ventricular remodeling, as indicated by increased fibrosis and macrophage infiltration, and diminished lymphangiogenesis. Hence, our findings highlight that VEGF-C/VEGFR-3 is a promising therapeutic target to attenuate hypertensive left ventricular remodeling induced by HS intake, presumably via blood pressure-dependent and -independent mechanisms. PMID:24337460

  6. Arginase inhibition prevents bleomycin-induced pulmonary hypertension, vascular remodeling, and collagen deposition in neonatal rat lungs.

    PubMed

    Grasemann, Hartmut; Dhaliwal, Rupinder; Ivanovska, Julijana; Kantores, Crystal; McNamara, Patrick J; Scott, Jeremy A; Belik, Jaques; Jankov, Robert P

    2015-03-15

    Arginase is an enzyme that limits substrate L-arginine bioavailability for the production of nitric oxide by the nitric oxide synthases and produces L-ornithine, which is a precursor for collagen formation and tissue remodeling. We studied the pulmonary vascular effects of arginase inhibition in an established model of repeated systemic bleomycin sulfate administration in neonatal rats that results in pulmonary hypertension and lung injury mimicking the characteristics typical of bronchopulmonary dysplasia. We report that arginase expression is increased in the lungs of bleomycin-exposed neonatal rats and that treatment with the arginase inhibitor amino-2-borono-6-hexanoic acid prevented the bleomycin-induced development of pulmonary hypertension and deposition of collagen. Arginase inhibition resulted in increased L-arginine and L-arginine bioavailability and increased pulmonary nitric oxide production. Arginase inhibition also normalized the expression of inducible nitric oxide synthase, and reduced bleomycin-induced nitrative stress while having no effect on bleomycin-induced inflammation. Our data suggest that arginase is a promising target for therapeutic interventions in neonates aimed at preventing lung vascular remodeling and pulmonary hypertension. PMID:25595650

  7. Anti-pressor effects of whole body exposure to static magnetic field on pharmacologically induced hypertension in conscious rabbits.

    PubMed

    Okano, Hideyuki; Ohkubo, Chiyoji

    2003-02-01

    Acute effects of whole body exposure to static magnetic field (SMF) on pharmacologically induced hypertension in a conscious rabbit were evaluated. Hypertensive and vasoconstrictive actions were induced by norepinephrine (NE) or a nonselective nitric oxide synthase (NOS) inhibitor, N(omega)-nitro-l-arginine methyl ester (l-NAME). The hemodynamics in a central artery of the ear lobe was measured continuously and analyzed by penetrating microphotoelectric plethysmography (MPPG). Concurrently, blood pressure (BP) changes in a central artery, contralateral to that of the MPPG measured ear lobe, were monitored. Magnetic flux densities were 5.5 mT (Bmax), the magnetic gradient peaked in the throat at the level of approximately 0.09 mT/mm, and the duration of exposure was 30 min. The results demonstrated that under normal physiological conditions without treatment of pharmacological agents, there were no statistically significant differences in the hemodynamics and BP changes between the sham and the SMF exposure alone. Under pharmacologically induced hypertensive conditions, the whole body exposure to nonuniform SMF with peak magnetic gradient in the carotid sinus baroreceptor significantly attenuated the vasoconstriction and suppressed the elevation of BPs. These findings suggest that antipressor effects of the SMF on the hemodynamics under NE or l-NAME induced high vascular tone might be, in part, dependent on modulation of NE mediated response in conjunction with alteration in NOS activity, thereby modulating BPs. PMID:12524681

  8. Imperatorin derivative OW1 inhibits the upregulation of TGF-β and MMP-2 in renovascular hypertension-induced cardiac remodeling

    PubMed Central

    ZHOU, NAN; ZHU, YANING; ZHANG, PENG; ZHANG, YU; ZHOU, MINGYAO; WANG, TAO; HE, LANGCHONG

    2016-01-01

    Chronic hypertension induces vascular and cardiac remodeling. OW1 is a novel imperatorin derivative that was previously reported to inhibit vascular remodeling and improve kidney function affected by hypertension. In the present study, the effect of OW1 on the cardiac remodeling induced by hypertension was investigated. OW1 inhibited vascular smooth muscle cell (VSMC) proliferation and the phenotypic modulation of VSMCs induced by angiotensin II (Ang II). The OW1-induced vasodilatation of rat cardiac arteries was evaluated in vitro. Renovascular hypertensive rats were developed using the two-kidney one-clip method and treated with OW1 (40 or 80 mg/kg/day) or nifedipine (30 mg/kg per day) for 5 weeks. OW1 markedly reduced the systolic and diastolic blood pressure compared with that in the hypertension group or the respective baseline value during the first week. OW1 also reduced cardiac weight, and the concentrations of Ang II, aldosterone and transforming growth factor-β1 (TGF-β1). Histological examination demonstrated that OW1 exerted an inhibitory effect on vascular and cardiac remodeling. These inhibitory effects were associated with decreased cardiac levels of Ang II, matrix metalloproteinase-2 and TGF-β1 in the hypertensive rats. In summary, OW1 exhibited a clear antihypertensive effect. More importantly, it inhibited vascular and cardiovascular remodeling, which may reduce the risk of hypertension-induced cardiovascular diseases. These results have potential implications in the development of new antihypertensive drugs. PMID:27168797

  9. [Role of endogenous hydrogen sulfide in pulmonary hypertension induced by lipopolysaccharide].

    PubMed

    Huang, Xin-Li; Zhou, Xiao-Hong; Wei, Peng; Zhang, Xiao-Jing; Meng, Xiang-Yan; Xian, Xiao-Hui

    2008-04-25

    The purpose of the present study was to explore the role of endogenous hydrogen sulfide (H2S) in pulmonary arterial hypertension induced by endotoxin. Adult male Sprague-Dawley (SD) rats were randomly divided into four groups: Control group (0.5 mL/kg body weight of normal saline, i.v.), lipopolysaccharide (LPS)-treated group (5 mg/kg body weight of LPS, i.v.), LPS + NaHS (5 mg/kg body weight of LPS, i.v., and 28 μmol/kg body weight of NaHS, i.p.) and LPS + PPG group (5 mg/kg body weight of LPS, i.v., and 30 μmol/kg body weight of PPG, i.p.). Rats were anesthetized with 20% urethane (1 g/kg body weight, i.p.). A polyethylene catheter was inserted into the pulmonary artery through the right external jugular vein to measure the mean pulmonary arterial pressure (mPAP) for 7 h, and then the pulmonary artery was isolated rapidly by the method described previously. Pulmonary arterial activity was detected. H2S concentration and cystathionine γ-lyase (CSE) activity in pulmonary artery tissues were determined by biochemical method. CSE mRNA expression was detected by competitive reverse transcriptase-polymerase chain reaction (RT-PCR). Compared with control, LPS significantly increased mPAP [(1.82±0.29) kPa vs (1.43±0.26) kPa, P<0.01], decreased H2S production [(26.33±7.84) vs (42.92±8.73) pmol/g wet tissue per minute, P<0.01), and reduced endothelium-dependent relaxation response [(75.72±7.22)% vs (86.40±4.40) %, P<0.01) induced by ACh (1×10(-6) mol/L). These effects were partly reversed by co-administration of NaHS and enhanced by co-administration of PPG. Both CSE activity and CSE mRNA expression were consistent with H2S production. It is suggested that the inhibitory effect of LPS on endothelium-dependent relaxation results in pulmonary hypertension, which might be mediated through H(2)S. PMID:18425308

  10. Right ventricular cyclic nucleotide signaling is decreased in hyperoxia-induced pulmonary hypertension in neonatal mice

    PubMed Central

    Heilman, Rachel P.; Lagoski, Megan B.; Lee, Keng Jin; Taylor, Joann M.; Kim, Gina A.; Berkelhamer, Sara K.; Steinhorn, Robin H.

    2015-01-01

    Pulmonary hypertension (PH) and right ventricular hypertrophy (RVH) affect 25–35% of premature infants with significant bronchopulmonary dysplasia (BPD), increasing morbidity and mortality. We sought to determine the role of phosphodiesterase 5 (PDE5) in the right ventricle (RV) and left ventricle (LV) in a hyperoxia-induced neonatal mouse model of PH and RVH. After birth, C57BL/6 mice were placed in room air (RA) or 75% O2 (CH) for 14 days to induce PH and RVH. Mice were euthanized at 14 days or recovered in RA for 14 days or 42 days prior to euthanasia at 28 or 56 days of age. Some pups received sildenafil or vehicle (3 mg·kg−1·dose−1 sc) every other day from P0. RVH was assessed by Fulton's index [RV wt/(LV + septum) wt]. PDE5 protein expression was analyzed via Western blot, PDE5 activity was measured by commercially available assay, and cGMP was measured by enzyme-linked immunoassay. Hyperoxia induced RVH in mice after 14 days, and RVH did not resolve until 56 days of age. Hyperoxia increased PDE5 expression and activity in RV, but not LV + S, after 14 days. PDE5 expression normalized by 28 days of age, but PDE5 activity did not normalize until 56 days of age. Sildenafil given during hyperoxia prevented RVH, decreased RV PDE5 activity, and increased RV cGMP levels. Mice with cardiac-specific overexpression of PDE5 had increased RVH in RA. These findings suggest normal RV PDE5 function is disrupted by hyperoxia, and elevated PDE5 contributes to RVH and remodeling. Therefore, in addition to impacting the pulmonary vasculature, sildenafil also targets PDE5 in the neonatal mouse RV and decreases RVH. PMID:25862831

  11. Nox2-Induced Production of Mitochondrial Superoxide in Angiotensin II-Mediated Endothelial Oxidative Stress and Hypertension

    PubMed Central

    Dikalov, Sergey I.; Bikineyeva, Alfiya; Hilenski, Lula; Lassègue, Bernard; Griendling, Kathy K.; Harrison, David G.; Dikalova, Anna E.

    2014-01-01

    Abstract Aims: Angiotensin II (AngII)-induced superoxide (O2•−) production by the NADPH oxidases and mitochondria has been implicated in the pathogenesis of endothelial dysfunction and hypertension. In this work, we investigated the specific molecular mechanisms responsible for the stimulation of mitochondrial O2•− and its downstream targets using cultured human aortic endothelial cells and a mouse model of AngII-induced hypertension. Results: Western blot analysis showed that Nox2 and Nox4 were present in the cytoplasm but not in the mitochondria. Depletion of Nox2, but not Nox1, Nox4, or Nox5, using siRNA inhibits AngII-induced O2•− production in both mitochondria and cytoplasm. Nox2 depletion in gp91phox knockout mice inhibited AngII-induced cellular and mitochondrial O2•− and attenuated hypertension. Inhibition of mitochondrial reverse electron transfer with malonate, malate, or rotenone attenuated AngII-induced cytoplasmic and mitochondrial O2•− production. Inhibition of the mitochondrial ATP-sensitive potassium channel (mitoK+ATP) with 5-hydroxydecanoic acid or specific PKCɛ peptide antagonist (EAVSLKPT) reduced AngII-induced H2O2 in isolated mitochondria and diminished cytoplasmic O2•−. The mitoK+ATP agonist diazoxide increased mitochondrial O2•−, cytoplasmic c-Src phosphorylation and cytoplasmic O2•− suggesting feed-forward regulation of cellular O2•− by mitochondrial reactive oxygen species (ROS). Treatment of AngII-infused mice with malate reduced blood pressure and enhanced the antihypertensive effect of mitoTEMPO. Mitochondria-targeted H2O2 scavenger mitoEbselen attenuated redox-dependent c-Src and inhibited AngII-induced cellular O2•−, diminished aortic H2O2, and reduced blood pressure in hypertensive mice. Innovation and Conclusions: These studies show that Nox2 stimulates mitochondrial ROS by activating reverse electron transfer and both mitochondrial O2•− and reverse electron transfer may represent new

  12. The protective effect of a buckwheat-enriched diet on renal injury in high salt-induced hypertension in rats.

    PubMed

    Cheng, Dai; Zhang, Xinyu; Meng, Meng; Han, Lirong; Li, Zheng; Hou, Lihua; Qi, Wentao; Wang, Chunling

    2016-08-10

    An excess of dietary salt is the most common factor that contributes to the pathogenesis of hypertension. Dietary management is deemed critical to prevent and treat hypertension. We aimed at evaluating the preventive effect of the buckwheat (BW)-enriched diet on high salt-induced elevation of blood pressure (BP) and renal injury in order to provide a new focus on the design of strategies to prevent hypertension. Control, high salt (HS)-treated (8%), HS + tartary buckwheat (TB) (8% HS + 15% TB), and a group of HS + common buckwheat (CB) (8% HS + 15% CB) rats were used for 7 weeks. BP was monitored periodically during the study by the tail cuff method. HS intake caused a significant increase of BP, the level of serum Na(+) compared to the control group. BW significantly prevented the increase of BP, attenuated oxidative damage, and improved Na(+)/K(+)-ATPase activity in HS treated rats. These results show that a diet supplemented with whole BW has beneficial effects on hypertension, by decreasing blood pressure values and oxidative stress. PMID:27457879

  13. Etanercept reduces late endotoxin-induced pulmonary hypertension in the pig.

    PubMed

    Mutschler, D; Wikström, G; Lind, L; Larsson, A; Lagrange, A; Eriksson, M

    2006-09-01

    To evaluate whether etanercept, a tumor necrosis factor (TNF)-blocking agent, may counteract hemodynamic deterioration in endotoxemic shock, we designed a prospective, randomized placebo-controlled trial with parallel groups, consisting of 13 pigs aged 10-14 weeks receiving general anesthesia. Five pigs were given 25 mg of etanercept, 1 h before the start of a 4-h continuous infusion of endotoxin. Another 5 pigs were given the corresponding volume of saline, 1 h before the start of a 4-h continuous infusion of endotoxin. Three pigs were given 25 mg of etanercept, 1 hr before the start of a 4-h continuous infusion of saline. At 1 h of endotoxemia, mean pulmonary arterial pressure (MPAP) and pulmonary vascular resistance index (PVRI) increased identically in both groups of pigs receiving endotoxin. Thereafter, two distinct different patterns in hemodynamics were observed. TNF-blocked pigs showed significantly lower MPAP and PVRI compared to controls. In the etanercept-treated endotoxemic pigs, Doppler analysis of the diastolic mitral inflow demonstrated a significantly increased E/A-ratio (early mitral wave inflow was divided by the atrial wave) at 2 h. The TNFblocking agent etanercept normalized two hemodynamic features of endotoxin-induced septic shock in pigs: (1) the sustained pulmonary hypertension and (2) diastolic dysfunction. PMID:16978070

  14. Cold-restraint induced gastric lesions in normotensive and spontaneously hypertensive rats

    SciTech Connect

    Athey, G.R.; Iams, S.G.

    1981-02-23

    Spontaneously hypertensive (SHR) rats and normotensive Wistar-Kyoto (WKY) rats were subjected to 2 hr of cold-restraint stress at 4-6/sup o/C following a 24 hr fast. WKY rats had a significantly greater incidence and degree of ulceration of the gastric glandular mucosa than did SHR rats. Mean arterial pressure, obtained from a chronic arterial cannula, fell during 2 hr of cold-restraint stress in both SHR and WKY rats. Heart rate was unchanged in WKY but fell significantly in SHR. Plasma norepinephrine (NE) and epinephrine (E), determined by radioenzymatic assay, increased significantly following stress. Increased levels of NE remained similar for both SHR and WKY rats, while post-stress levels of E for the SHR rats greatly exceeded E levels for WKY rats. A greater degree of hypothermia was also noted in SHR rats. Decreased stress induced ulcerogenesis in the SHR may be due to the well-known altered hemodynamic and autonomic nervous system reactivity in this strain or other factors not yet discovered.

  15. Sleep and Pregnancy-Induced Hypertension: A Possible Target for Intervention?

    PubMed Central

    Haney, Alyssa; Buysse, Daniel J.; Okun, Michele

    2013-01-01

    Sleep disturbances in the general population are associated with elevated blood pressure. This may be due to several mechanisms, including sympathetic activation and hypothalamic-pituitary-adrenal (HPA) axis disturbance. Elevated blood pressure in pregnancy can have devastating effects on both maternal and fetal health and is associated with increased risk for preeclampsia and poor delivery outcomes. Preliminary evidence suggests that mechanisms linking sleep and blood pressure in the general population may also hold in the pregnant population. However, the effects of disturbed sleep on physiologic mechanisms that may directly influence blood pressure in pregnancy have not been well studied. The role that sleep disturbance plays in gestational blood pressure elevation and its subsequent consequences warrant further investigation. This review evaluates the current literature on sleep disturbance and elevated blood pressure in pregnancy and proposes possible treatment interventions. Citation: Haney A; Buysse DJ; Okun M. Sleep and pregnancy-induced hypertension: a possible target for intervention? J Clin Sleep Med 2013;9(12):1349-1356. PMID:24340300

  16. Effects of Lactobacillus plantarum TWK10-Fermented Soymilk on Deoxycorticosterone Acetate-Salt-Induced Hypertension and Associated Dementia in Rats

    PubMed Central

    Liu, Te-Hua; Chiou, Jiachi; Tsai, Tsung-Yu

    2016-01-01

    Oxidative stress resulting from excessive production of reactive oxygen species is the major mediator of neuronal cell degeneration observed in neurodegenerative diseases, such as Alzheimer’s disease (AD) and vascular dementia (VaD). Additionally, hypertension has been shown to be a positive risk factor for VaD. Therefore, the objective of this study was to investigate the effects of Lactobacillus plantarum strain TWK10 (TWK10)-fermented soymilk on the protection of PC-12 cells in H2O2-, oxygen-glucose deprivation (OGD)- and deoxycorticosterone acetate (DOCA)-salt-induced rat models of VaD. Notably, the viabilities of H2O2-treated PC-12 cells and OGD model were significantly increased by treatment with TWK10-fermented soymilk ethanol extract (p < 0.05). In addition, oral administration of TWK10-fermented soymilk extract in DOCA-salt hypertension-induced VaD rats resulted in a significant decrease in blood pressure (p < 0.05), which was regulated by inhibiting ACE activity and promoting NO production, in addition to decreased escape latency and increased target crossing (p < 0.05). In conclusion, these results demonstrated that TWK10-fermented soymilk extract could improve learning and memory in DOCA-salt hypertension-induced VaD rats by acting as a blood pressure-lowering and neuroprotective agent. PMID:27144579

  17. Altered lymphatic function and architecture in salt-induced hypertension assessed by near-infrared fluorescence imaging

    NASA Astrophysics Data System (ADS)

    Kwon, Sunkuk; Agollah, Germaine D.; Chan, Wenyaw; Sevick-Muraca, Eva M.

    2012-08-01

    The lymphatic system plays an important role in maintaining the fluid homeostasis between the blood vascular and interstitial tissue compartment and there is recent evidence that its transport capabilities may regulate blood pressure in salt-induced hypertension. Yet, there is little known how the lymphatic contractile function and architecture responds to dietary salt-intake. Thus, we longitudinally characterized lymphatic contractile function and vessel remodeling noninvasively using dynamic near-infrared fluorescence imaging in animal models of salt-induced hypertension. The lymphatics of mice and rats were imaged following intradermal injection of indocyanine green to the ear tip or the base of the tail before and during two weeks of either a high salt diet (HSD) or normal chow. Our noninvasive imaging data demonstrated dilated lymphatic vessels in the skin of mice and rats on a HSD as compared to their baseline levels. In addition, our dynamic imaging results showed increased lymphatic contraction frequency in HSD-fed mice and rats. Lymphatic contractile function and vessel remodeling occurs in response to salt-induced hypertension suggesting a possible role for the lymphatics in the regulation of vascular blood pressure.

  18. Effects of Lactobacillus plantarum TWK10-Fermented Soymilk on Deoxycorticosterone Acetate-Salt-Induced Hypertension and Associated Dementia in Rats.

    PubMed

    Liu, Te-Hua; Chiou, Jiachi; Tsai, Tsung-Yu

    2016-01-01

    Oxidative stress resulting from excessive production of reactive oxygen species is the major mediator of neuronal cell degeneration observed in neurodegenerative diseases, such as Alzheimer's disease (AD) and vascular dementia (VaD). Additionally, hypertension has been shown to be a positive risk factor for VaD. Therefore, the objective of this study was to investigate the effects of Lactobacillus plantarum strain TWK10 (TWK10)-fermented soymilk on the protection of PC-12 cells in H₂O₂-, oxygen-glucose deprivation (OGD)- and deoxycorticosterone acetate (DOCA)-salt-induced rat models of VaD. Notably, the viabilities of H₂O₂-treated PC-12 cells and OGD model were significantly increased by treatment with TWK10-fermented soymilk ethanol extract (p < 0.05). In addition, oral administration of TWK10-fermented soymilk extract in DOCA-salt hypertension-induced VaD rats resulted in a significant decrease in blood pressure (p < 0.05), which was regulated by inhibiting ACE activity and promoting NO production, in addition to decreased escape latency and increased target crossing (p < 0.05). In conclusion, these results demonstrated that TWK10-fermented soymilk extract could improve learning and memory in DOCA-salt hypertension-induced VaD rats by acting as a blood pressure-lowering and neuroprotective agent. PMID:27144579

  19. Calcium antagonists, diltiazem and nifedipine, protect broilers against low temperature-induced pulmonary hypertension and pulmonary vascular remodeling.

    PubMed

    Yang, Ying; Gao, Mingyu; Guo, Yuming; Qiao, Jian

    2010-08-01

    This study was designed to determine whether calcium antagonists, diltiazem and nifedipine, can depress low temperature-induced pulmonary hypertension (PH) in broilers (also known as ascites) and to characterize their efficacy on hemodynamics and pulmonary artery function. Chicks were randomly allocated into six experimental groups and orally administered with vehicle, 5.0 mg/kg body weight (BW)/12 h nifedipine or 15.0 mg/kg BW/12 h diltiazem from 16 to 43 days of age under low temperature. The mean pulmonary arterial pressure (mPAP), the ascites heart index (AHI), the erythrocyte packed cell volume (PCV) and the relative percentage of medial pulmonary artery thickness were examined on days 29, 36 and 43. The data showed that administration of diltiazem protected broilers from low temperature-induced pulmonary hypertension and vascular remodeling. Although nifedipine prevented mPAP from increasing during the early stage, it did not suppress the development of PH during the late stage and did not keep heart rate (HR), PCV, AHI and the thickness of pulmonary small artery smooth muscle layer at the normal levels. Taken together, our results showed that diltiazem can effectively prevent low temperature-induced pulmonary hypertension in broilers with fewer side-effects and may be a potential compound for the prevention of this disease in poultry industry. PMID:20662820

  20. Intrarenal mouse renin-angiotensin system during ANG II-induced hypertension and ACE inhibition.

    PubMed

    Gonzalez-Villalobos, Romer A; Satou, Ryousuke; Ohashi, Naro; Semprun-Prieto, Laura C; Katsurada, Akemi; Kim, Catherine; Upchurch, G M; Prieto, Minolfa C; Kobori, Hiroyuki; Navar, L Gabriel

    2010-01-01

    Angiotensin-converting enzyme (ACE) inhibition (ACEi) ameliorates the development of hypertension and the intrarenal ANG II augmentation in ANG II-infused mice. To determine if these effects are associated with changes in the mouse intrarenal renin-angiotensin system, the expression of angiotensinogen (AGT), renin, ACE, angiotensin type 1 receptor (AT(1)R) mRNA (by quanitative RT-PCR) and protein [by Western blot (WB) and/or immunohistochemistry (IHC)] were analyzed. C57BL/6J male mice (9-12 wk old) were distributed as controls (n = 10), ANG II infused (ANG II = 8, 400 ng x kg(-1) x min(-1) for 12 days), ACEi only (ACEi = 10, lisinopril, 100 mg/l), and ANG II infused + ACEi (ANG II + ACEi = 11). When compared with controls (1.00), AGT protein (by WB) was increased by ANG II (1.29 +/- 0.13, P < 0.05), and this was not prevented by ACEi (ACEi + ANG II, 1.31 +/- 0.14, P < 0.05). ACE protein (by WB) was increased by ANG II (1.21 +/- 0.08, P < 0.05), and it was reduced by ACEi alone (0.88 +/- 0.07, P < 0.05) or in combination with ANG II (0.80 +/- 0.07, P < 0.05). AT(1)R protein (by WB) was increased by ANG II (1.27 +/- 0.06, P < 0.05) and ACEi (1.17 +/- 0.06, P < 0.05) but not ANG II + ACEi [1.15 +/- 0.06, not significant (NS)]. Tubular renin protein (semiquantified by IHC) was increased by ANG II (1.49 +/- 0.23, P < 0.05) and ACEi (1.57 +/- 0.15, P < 0.05), but not ANG II + ACEi (1.10 +/- 0.15, NS). No significant changes were observed in AGT, ACE, or AT(1)R mRNA. In summary, reduced responses of intrarenal tubular renin, ACE, and the AT(1)R protein to the stimulatory effects of chronic ANG II infusions, in the presence of ACEi, are associated with the effects of this treatment to ameliorate augmentations in blood pressure and intrarenal ANG II content during ANG II-induced hypertension. PMID:19846570

  1. Intrarenal mouse renin-angiotensin system during ANG II-induced hypertension and ACE inhibition

    PubMed Central

    Satou, Ryousuke; Ohashi, Naro; Semprun-Prieto, Laura C.; Katsurada, Akemi; Kim, Catherine; Upchurch, G. M.; Prieto, Minolfa C.; Kobori, Hiroyuki; Navar, L. Gabriel

    2010-01-01

    Angiotensin-converting enzyme (ACE) inhibition (ACEi) ameliorates the development of hypertension and the intrarenal ANG II augmentation in ANG II-infused mice. To determine if these effects are associated with changes in the mouse intrarenal renin-angiotensin system, the expression of angiotensinogen (AGT), renin, ACE, angiotensin type 1 receptor (AT1R) mRNA (by quanitative RT-PCR) and protein [by Western blot (WB) and/or immunohistochemistry (IHC)] were analyzed. C57BL/6J male mice (9–12 wk old) were distributed as controls (n = 10), ANG II infused (ANG II = 8, 400 ng·kg−1·min−1 for 12 days), ACEi only (ACEi = 10, lisinopril, 100 mg/l), and ANG II infused + ACEi (ANG II + ACEi = 11). When compared with controls (1.00), AGT protein (by WB) was increased by ANG II (1.29 ± 0.13, P < 0.05), and this was not prevented by ACEi (ACEi + ANG II, 1.31 ± 0.14, P < 0.05). ACE protein (by WB) was increased by ANG II (1.21 ± 0.08, P < 0.05), and it was reduced by ACEi alone (0.88 ± 0.07, P < 0.05) or in combination with ANG II (0.80 ± 0.07, P < 0.05). AT1R protein (by WB) was increased by ANG II (1.27 ± 0.06, P < 0.05) and ACEi (1.17 ± 0.06, P < 0.05) but not ANG II + ACEi [1.15 ± 0.06, not significant (NS)]. Tubular renin protein (semiquantified by IHC) was increased by ANG II (1.49 ± 0.23, P < 0.05) and ACEi (1.57 ± 0.15, P < 0.05), but not ANG II + ACEi (1.10 ± 0.15, NS). No significant changes were observed in AGT, ACE, or AT1R mRNA. In summary, reduced responses of intrarenal tubular renin, ACE, and the AT1R protein to the stimulatory effects of chronic ANG II infusions, in the presence of ACEi, are associated with the effects of this treatment to ameliorate augmentations in blood pressure and intrarenal ANG II content during ANG II-induced hypertension. PMID:19846570

  2. Characteristics of renal sympathetic nerve single units in rabbits with angiotensin-induced hypertension.

    PubMed

    Burke, Sandra L; Lukoshkova, Elena V; Head, Geoffrey A

    2016-01-01

    We examined the effect of chronic angiotensin (Ang II)-induced hypertension on activity of postganglionic renal sympathetic units to determine whether altered whole renal nerve activity is due to recruitment or changes in firing frequency. Rabbits were treated with a low (20 ng kg(-1) min(-1), 8 weeks) or high dose (50 ng kg(-1) min(-1), 4 weeks) of Ang II before the experiment under chloralose-urethane anaesthesia. Spontaneously active units were detected from multiunit recordings using an algorithm that separated units by action potential shape using templates that matched spikes within a prescribed standard deviation. Multiunit sympathetic nerve activity was 40% higher in rabbits treated with low-dose Ang II than in sham (P = 0.012) but not different in high-dose Ang II. Resting firing frequency was similar in sham rabbits (1.00 ± 0.09 spikes s(-1), n = 144) and in those treated with high-dose Ang II (1.10 ± 0.08 spikes s(-1), n = 112) but was lower with low-dose Ang II (0.65 ± 0.08 spikes s(-1), n = 149, P < 0.05). Unit firing rhythmicity was linked to the cardiac cycle and was similar in sham and low-dose Ang II groups but 29-32% lower in rabbits treated with high-dose Ang II (P < 0.001). Cardiac linkage followed a similar pattern during hypoxia. All units showed baroreceptor dependency. Baroreflex gain and range were reduced and curves shifted to the right in Ang II groups. Firing frequency during hypoxia increased by +39% in low-dose Ang II and +82% in shams, but the greatest increase was in the high-dose Ang II group (+103%, P(dose) = 0.001). Responses to hypercapnia were similar in all groups. Increases in sympathetic outflow in hypertension caused by low-dose chronic Ang II administration are due to recruitment of neurons, but high-dose Ang II increases firing frequency in response to chemoreceptor stimuli independently of the arterial baroreceptors. PMID:26467849

  3. Purinergic contraction of the rat vas deferens in L-NAME-induced hypertension: effect of sildenafil.

    PubMed

    Gur, Serap; Sikka, Suresh C; Knight, Gillian E; Burnstock, Geoffrey; Hellstrom, Wayne J G

    2010-05-01

    Hypertension (HTN) is a risk factor for erectile dysfunction, but its effect on vas deferens (VD) contractility and the ejaculatory response has not been delineated. NG-nitro-L-arginine methyl ester (L-NAME), a nitric oxide synthase inhibitor, was used for induction of nitric oxide (NO)-deficient HTN. Our aim was to evaluate the effects of L-NAME-induced HTN on rat VD contractility and to determine whether sildenafil affects VD contractility. A total of 36 male rats were divided into (1) control, (2) L-NAME-HTN, (3) sildenafil treated L-NAME-HTN groups. Group 2 was treated with L-NAME (40 mg kg(-1) per day) in drinking water for 4 weeks. Group 3 received sildenafil (1.5 mg kg(-1) per day, by oral gavage) concomitantly with L-NAME. The prostatic portion of the VD was subjected to electrical field stimulation (EFS, 1-20 Hz), and the P2X(1) agonist alpha,beta-methylene ATP (alpha,beta-meATP, 100 micromol L(-1)-1 micromol L(-1)) and the alpha1-adrenoceptor agonist phenylephrine (Phe, 100 micromol L(-1)-1 mmol L(-1)) were used to construct concentration-response curves. These experiments were repeated in the presence of P2X receptor antagonist, pyridoxalphosphate-6-azophenyl-2',4'-disulfonic acid (PPADS, 30 micromol L(-1)). VD contractions in response to EFS, alpha,beta-meATP and Phe were significantly enhanced by L-NAME. Sildenafil treatment in the L-NAME group improved the contractile response of VD to EFS (20 Hz). In the presence of PPADS, the enhanced contractile response of VD to EFS and alpha,beta-meATP in hypertensive rats was reversed. In the rat model of chronic NO depletion, the purinergic and adrenergic components and EFS affect VD contractility. The VD contractile response may be mediated more by the purinergic system than the adrenergic system, and sildenafil may alter the ejaculatory response in men with PE. PMID:20305675

  4. Age- and hypertension-induced changes in abnormal contractions in rat aorta.

    PubMed

    Abeywardena, Mahinda Y; Jablonskis, Lina T; Head, Richard J

    2002-12-01

    The current investigation explored the potential age-dependant modulation of abnormal spontaneous constrictions (thromboxane-like) in the spontaneously hypertensive rat (SHR) aorta, observed only after the inhibition of endogenous production of nitric oxide (NO). Aortic rings from SHR and Wistar-Kyoto (WKY) control rats of varying ages (4, 8, 12, and 18 months) were mounted in organ baths, and changes in tension were monitored. Inhibition of NO with Nomega-nitro-L-arginine (NOLA) unmasked a slow contraction, which appeared to be age dependent (p < 0.05). This contraction was found in SHRs of all age groups and in older WKY rats. Denuding the endothelium in young SHRs did not influence the constriction, confirming a nonendothelial cell origin, while in the older groups this led to a 30-40% reduction in contraction. Comparable attenuation of the constrictor response was observed after incubation of endothelium intact rings with superoxide dismutase (100 U/ml) or 3-amino-1,2,4-triazole. Of the residual activity that was unaffected by free radical scavengers or de-endothelialization, 60-70% was sensitive to cyclooxygenase inhibition by indomethacin and/or ibuprofen. The thromboxane (TxA ) receptor antagonist SQ29548 induced a complete reversal of the abnormal constriction. In contrast, thromboxane synthetase inhibition had no effect, ruling out any involvement of TxA in mediating this abnormality. Collectively, these observations support the view that as compared with the normotensive setting, contraction induced by NO inhibition in the SHR develops prematurely and deteriorates more rapidly during the aging process. In aged rats, prostaglandin endoperoxide intermediates PGG /H and endothelium-derived free radicals rather than TxA per se appear to contribute to the NOLA-dependent TxA -like vasoconstriction. PMID:12451327

  5. Role of ASIC1 in the development of chronic hypoxia-induced pulmonary hypertension

    PubMed Central

    Nitta, Carlos H.; Osmond, David A.; Herbert, Lindsay M.; Beasley, Britta F.; Resta, Thomas C.; Walker, Benjimen R.

    2013-01-01

    Chronic hypoxia (CH) associated with respiratory disease results in elevated pulmonary vascular intracellular Ca2+ concentration, which elicits enhanced vasoconstriction and promotes vascular arterial remodeling and thus has important implications in the development of pulmonary hypertension (PH). Store-operated Ca2+ entry (SOCE) contributes to this elevated intracellular Ca2+ concentration and has also been linked to acute hypoxic pulmonary vasoconstriction (HPV). Since our laboratory has recently demonstrated an important role for acid-sensing ion channel 1 (ASIC1) in mediating SOCE, we hypothesized that ASIC1 contributes to both HPV and the development of CH-induced PH. To test this hypothesis, we examined responses to acute hypoxia in isolated lungs and assessed the effects of CH on indexes of PH, arterial remodeling, and vasoconstrictor reactivity in wild-type (ASIC1+/+) and ASIC1 knockout (ASIC1−/−) mice. Restoration of ASIC1 expression in pulmonary arterial smooth muscle cells from ASIC1−/− mice rescued SOCE, confirming the requirement for ASIC1 in this response. HPV responses were blunted in lungs from ASIC1−/− mice. Both SOCE and receptor-mediated Ca2+ entry, along with agonist-dependent vasoconstrictor responses, were diminished in small pulmonary arteries from control ASIC−/− mice compared with ASIC+/+ mice. The effects of CH to augment receptor-mediated vasoconstrictor and SOCE responses in vessels from ASIC1+/+ mice were not observed after CH in ASIC1−/− mice. In addition, ASIC1−/− mice exhibited diminished right ventricular systolic pressure, right ventricular hypertrophy, and arterial remodeling in response to CH compared with ASIC1+/+ mice. Taken together, these data demonstrate an important role for ASIC1 in both HPV and the development of CH-induced PH. PMID:24186095

  6. Atorvastatin ameliorates arsenic-induced hypertension and enhancement of vascular redox signaling in rats

    SciTech Connect

    Sarath, Thengumpallil Sasindran; Waghe, Prashantkumar; Gupta, Priyanka; Choudhury, Soumen; Kannan, Kandasamy; Pillai, Ayyappan Harikrishna; Harikumar, Sankaran Kutty; Mishra, Santosh Kumar; Sarkar, Souvendra Nath

    2014-11-01

    Chronic arsenic exposure has been linked to elevated blood pressure and cardiovascular diseases, while statins reduce the incidence of cardiovascular disease predominantly by their low density lipoprotein-lowering effect. Besides, statins have other beneficial effects, including antioxidant and anti-inflammatory activities. We evaluated whether atorvastatin, a widely used statin, can ameliorate arsenic-induced increase in blood pressure and alteration in lipid profile and also whether the amelioration could relate to altered NO and ROS signaling. Rats were exposed to sodium arsenite (100 ppm) through drinking water for 90 consecutive days. Atorvastatin (10 mg/kg bw, orally) was administered once daily during the last 30 days of arsenic exposure. On the 91st day, blood was collected for lipid profile. Western blot of iNOS and eNOS protein, NO and 3-nitrotyrosine production, Nox-4 and p22Phox mRNA expression, Nox activity, ROS generation, lipid peroxidation and antioxidants were evaluated in thoracic aorta. Arsenic increased systolic, diastolic and mean arterial blood pressure, while it decreased HDL-C and increased LDL-C, total cholesterol and triglycerides in serum. Arsenic down-regulated eNOS and up-regulated iNOS protein expression and increased basal NO and 3-nitrotyrosine level. Arsenic increased aortic Nox-4 and p22Phox mRNA expression, Nox activity, ROS generation and lipid peroxidation. Further, arsenic decreased the activities of superoxide dismutase, catalase, and glutathione peroxidase and depleted aortic GSH content. Atorvastatin regularized blood pressure, improved lipid profile and attenuated arsenic-mediated redox alterations. The results demonstrate that atorvastatin has the potential to ameliorate arsenic-induced hypertension by improving lipid profile, aortic NO signaling and restoring vascular redox homeostasis. - Highlights: • Arsenic increased systolic, diastolic and mean arterial blood pressure and caused dyslipidemia. • Arsenic increased

  7. Hypoxia-induced pulmonary arterial hypertension augments lung injury and airway reactivity caused by ozone exposure.

    PubMed

    Zychowski, Katherine E; Lucas, Selita N; Sanchez, Bethany; Herbert, Guy; Campen, Matthew J

    2016-08-15

    Ozone (O3)-related cardiorespiratory effects are a growing public health concern. Ground level O3 can exacerbate pre-existing respiratory conditions; however, research regarding therapeutic interventions to reduce O3-induced lung injury is limited. In patients with chronic obstructive pulmonary disease, hypoxia-associated pulmonary hypertension (HPH) is a frequent comorbidity that is difficult to treat clinically, yet associated with increased mortality and frequency of exacerbations. In this study, we hypothesized that established HPH would confer vulnerability to acute O3 pulmonary toxicity. Additionally, we tested whether improvement of pulmonary endothelial barrier integrity via rho-kinase inhibition could mitigate pulmonary inflammation and injury. To determine if O3 exacerbated HPH, male C57BL/6 mice were subject to either 3 weeks continuous normoxia (20.9% O2) or hypoxia (10.0% O2), followed by a 4-h exposure to either 1ppm O3 or filtered air (FA). As an additional experimental intervention fasudil (20mg/kg) was administered intraperitoneally prior to and after O3 exposures. As expected, hypoxia significantly increased right ventricular pressure and hypertrophy. O3 exposure in normoxic mice caused lung inflammation but not injury, as indicated by increased cellularity and edema in the lung. However, in hypoxic mice, O3 exposure led to increased inflammation and edema, along with a profound increase in airway hyperresponsiveness to methacholine. Fasudil administration resulted in reduced O3-induced lung injury via the enhancement of pulmonary endothelial barrier integrity. These results indicate that increased pulmonary vascular pressure may enhance lung injury, inflammation and edema when exposed to pollutants, and that enhancement of pulmonary endothelial barrier integrity may alleviate such vulnerability. PMID:27286659

  8. A Magnetic Microbead Occlusion Model to Induce Ocular Hypertension-Dependent Glaucoma in Mice

    PubMed Central

    Cueva Vargas, Jorge L.; Di Polo, Adriana

    2016-01-01

    The use of rodent models of glaucoma has been essential to understand the molecular mechanisms that underlie the pathophysiology of this multifactorial neurodegenerative disease. With the advent of numerous transgenic mouse lines, there is increasing interest in inducible murine models of ocular hypertension. Here, we present an occlusion model of glaucoma based on the injection of magnetic microbeads into the anterior chamber of the eye using a modified microneedle with a facetted bevel. The magnetic microbeads are attracted to the iridocorneal angle using a handheld magnet to block the drainage of aqueous humour from the anterior chamber. This disruption in aqueous dynamics results in a steady elevation of intraocular pressure, which subsequently leads to the loss of retinal ganglion cells, as observed in human glaucoma patients. The microbead occlusion model presented in this manuscript is simple compared to other inducible models of glaucoma and also highly effective and reproducible. Importantly, the modifications presented here minimize common issues that often arise in occlusion models. First, the use of a bevelled glass microneedle prevents backflow of microbeads and ensures that minimal damage occurs to the cornea during the injection, thus reducing injury-related effects. Second, the use of magnetic microbeads ensures the ability to attract most beads to the iridocorneal angle, effectively reducing the number of beads floating in the anterior chamber avoiding contact with other structures (e.g., iris, lens). Lastly, the use of a handheld magnet allows flexibility when handling the small mouse eye to efficiently direct the magnetic microbeads and ensure that there is little reflux of the microbeads from the eye when the microneedle is withdrawn. In summary, the microbead occlusion mouse model presented here is a powerful investigative tool to study neurodegenerative changes that occur during the onset and progression of glaucoma. PMID:27077732

  9. Emission-particle-induced ventilatory abnormalities in a rat model of pulmonary hypertension.

    PubMed Central

    Gardner, Sarah Y; McGee, John K; Kodavanti, Urmila P; Ledbetter, Allen; Everitt, Jeffrey I; Winsett, Darrell W; Doerfler, Donald L; Costa, Daniel L

    2004-01-01

    Preexistent cardiopulmonary disease in humans appears to enhance susceptibility to the adverse effects of ambient particulate matter. Previous studies in this laboratory have demonstrated enhanced inflammation and mortality after intratracheal instillation (IT) and inhalation (INH) of residual oil fly ash (ROFA) in a rat model of pulmonary hypertension induced by monocrotaline (MCT). The present study was conducted to examine the effects of ROFA in this model on ventilatory function in unanesthetized, unrestrained animals. Sixty-day-old male CD rats were injected with MCT (60 mg/kg) or vehicle (VEH) intraperitoneally 10 days before IT of ROFA (8.3 mg/kg) or saline (SAL) (control) or nose-only INH of ROFA [15 mg/m3 for 6 hr on 3 consecutive days or air (control)]. At 24 and 72 hr after exposure, rats were studied individually in a simultaneous gas uptake/whole-body plethysmograph. Lungs were removed at 72 hr for histology. Pulmonary test results showed that tidal volume (VT) decreased 24 hr after IT of ROFA in MCT-treated rats. Breathing frequency, minute volume (VE), and the ventilatory equivalent for oxygen increased in MCT- and VEH-treated rats 24 hr after IT or INH of ROFA and remained elevated 72 hr post-IT. O2 uptake (VO2) decreased after IT of ROFA in MCT-treated rats. Carbon monoxide uptake decreased 24 hr after IT of ROFA, returning to control values in VEH-treated rats but remaining low in MCT-treated rats 72 hr post-IT. ROFA exposure induced histologic changes and abnormalities in several ventilatory parameters, many of which were enhanced by MCT treatment. PMID:15175175

  10. Obesity-induced hypertension: role of sympathetic nervous system, leptin, and melanocortins.

    PubMed

    Hall, John E; da Silva, Alexandre A; do Carmo, Jussara M; Dubinion, John; Hamza, Shereen; Munusamy, Shankar; Smith, Grant; Stec, David E

    2010-06-01

    Excess weight gain contributes to increased blood pressure in most patients with essential hypertension. Although the mechanisms of obesity hypertension are not fully understood, increased renal sodium reabsorption and impaired pressure natriuresis play key roles. Several mechanisms contribute to altered kidney function and hypertension in obesity, including activation of the sympathetic nervous system, which appears to be mediated in part by increased levels of the adipocyte-derived hormone leptin, stimulation of pro-opiomelanocortin neurons, and subsequent activation of central nervous system melanocortin 4 receptors. PMID:20348094

  11. Pregnancy-Induced Hypertensive Disorders before and after a National Economic Collapse: A Population Based Cohort Study

    PubMed Central

    Eiríksdóttir, Védís Helga; Valdimarsdóttir, Unnur Anna; Ásgeirsdóttir, Tinna Laufey; Hauksdóttir, Arna; Lund, Sigrún Helga; Bjarnadóttir, Ragnheiður Ingibjörg; Cnattingius, Sven; Zoëga, Helga

    2015-01-01

    Background Data on the potential influence of macroeconomic recessions on maternal diseases during pregnancy are scarce. We aimed to assess potential change in prevalence of pregnancy-induced hypertensive disorders (preeclampsia and gestational hypertension) during the first years of the major national economic recession in Iceland, which started abruptly in October 2008. Methods and Findings Women whose pregnancies resulted in live singleton births in Iceland in 2005–2012 constituted the study population (N = 35,211). Data on pregnancy-induced hypertensive disorders were obtained from the Icelandic Medical Birth Register and use of antihypertensive drugs during pregnancy, including β-blockers and calcium channel blockers, from the Icelandic Medicines Register. With the pre-collapse period as reference, we used logistic regression analysis to assess change in pregnancy-induced hypertensive disorders and use of antihypertensives during the first four years after the economic collapse, adjusting for demographic and pregnancy characteristics, taking aggregate economic indicators into account. Compared with the pre-collapse period, we observed an increased prevalence of gestational hypertension in the first year following the economic collapse (2.4% vs. 3.9%; adjusted odds ratio [aOR] 1.47; 95 percent confidence interval [95%CI] 1.13–1.91) but not in the subsequent years. The association disappeared completely when we adjusted for aggregate unemployment rate (aOR 1.04; 95% CI 0.74–1.47). Similarly, there was an increase in prescription fills of β-blockers in the first year following the collapse (1.9% vs.3.1%; aOR 1.43; 95% CI 1.07–1.90), which disappeared after adjusting for aggregate unemployment rate (aOR 1.05; 95% CI 0.72–1.54). No changes were observed for preeclampsia or use of calcium channel blockers between the pre- and post-collapse periods. Conclusions Our data suggest a transient increased risk of gestational hypertension and use of

  12. Constriction rate variation produced by partial ligation of the portal vein at pre-hepatic portal hypertension induced in rats

    PubMed Central

    RODRIGUES, Daren Athiê Boy; da SILVA, Aline Riquena; SERIGIOLLE, Leonardo Carvalho; FIDALGO, Ramiro de Sousa; FAVERO, Sergio San Gregorio; LEME, Pedro Luiz Squilacci

    2014-01-01

    Background Partial portal vein ligation causes an increase in portal pressure that remains stable even after the appearance of collateral circulation, with functional adaptation to prolonged decrease in portal blood flow. Aim To assess whether different constriction rates produced by partial ligation of the vein interfere with the results of this experimental model in rats. Methods Three groups of five rats each were used; in group 1 (sham-operated), dissection and measurement of portal vein diameters were performed. Portal hypertension was induced by partial portal vein ligation, reducing its size to 0.9 mm in the remaining 10 animals, regardless of the initial diameter of the veins. Five animals with portal hypertension (group 2) underwent reoperation after 15 days and the rats in group 3 after 30 days. The calculation of the constriction rate was performed using a specific mathematical formula (1 - π r 2 / π R2) x 100% and the statistical analysis with the Student t test. Results The initial diameter of the animal's portal vein was 2.06 mm, with an average constriction rate of the 55.88%; although the diameter of the veins and the constriction rate in group 2 were lower than in group 3 (2.06 mm - 55,25% and 2.08 mm - 56.51%, respectively), portal hypertension was induced in all rats and no significant macroscopic differences were found between the animals that were reoperated after 15 days and after 30 days respectively, being the shorter period considered enough for the evaluation. Comparing the initial diameter of the vein and the rate of constriction performed in groups 2 and 3, no statistic significance was found (p>0.05). Conclusion Pre-hepatic portal hypertension in rat can be induced by the reduction of the portal vein diameter to 0.9 mm, regardless the initial diameter of the vein and the vessel constriction rate. PMID:25626939

  13. Targeting mitochondrial reactive oxygen species to modulate hypoxia-induced pulmonary hypertension.

    PubMed

    Adesina, Sherry E; Kang, Bum-Yong; Bijli, Kaiser M; Ma, Jing; Cheng, Juan; Murphy, Tamara C; Michael Hart, C; Sutliff, Roy L

    2015-10-01

    Pulmonary hypertension (PH) is characterized by increased pulmonary vascular remodeling, resistance, and pressures. Reactive oxygen species (ROS) contribute to PH-associated vascular dysfunction. NADPH oxidases (Nox) and mitochondria are major sources of superoxide (O(2)(•-)) and hydrogen peroxide (H(2)O(2)) in pulmonary vascular cells. Hypoxia, a common stimulus of PH, increases Nox expression and mitochondrial ROS (mtROS) production. The interactions between these two sources of ROS generation continue to be defined. We hypothesized that mitochondria-derived O(2)(•-) (mtO(2)(•-)) and H(2)O(2) (mtH(2)O(2)) increase Nox expression to promote PH pathogenesis and that mitochondria-targeted antioxidants can reduce mtROS, Nox expression, and hypoxia-induced PH. Exposure of human pulmonary artery endothelial cells to hypoxia for 72 h increased mtO(2)(•-) and mtH(2)O(2). To assess the contribution of mtO(2)(•-) and mtH(2)O(2) to hypoxia-induced PH, mice that overexpress superoxide dismutase 2 (Tg(hSOD2)) or mitochondria-targeted catalase (MCAT) were exposed to normoxia (21% O(2)) or hypoxia (10% O(2)) for three weeks. Compared with hypoxic control mice, MCAT mice developed smaller hypoxia-induced increases in RVSP, α-SMA staining, extracellular H(2)O(2) (Amplex Red), Nox2 and Nox4 (qRT-PCR and Western blot), or cyclinD1 and PCNA (Western blot). In contrast, Tg(hSOD2) mice experienced exacerbated responses to hypoxia. These studies demonstrate that hypoxia increases mtO(2)(•-) and mtH(2)O(2). Targeting mtH(2)O(2) attenuates PH pathogenesis, whereas targeting mtO(2)(•-) exacerbates PH. These differences in PH pathogenesis were mirrored by RVSP, vessel muscularization, levels of Nox2 and Nox4, proliferation, and H(2)O(2) release. These studies suggest that targeted reductions in mtH(2)O(2) generation may be particularly effective in preventing hypoxia-induced PH. PMID:26073127

  14. Inhibition of neutral sphingomyelinase decreases elevated levels of inducible nitric oxide synthase and apoptotic cell death in ocular hypertensive rats

    SciTech Connect

    Aslan, Mutay; Basaranlar, Goksun; Unal, Mustafa; Ciftcioglu, Akif; Derin, Narin; Mutus, Bulent

    2014-11-01

    Endoplasmic reticulum (ER) stress and excessive nitric oxide production via induction of inducible nitric oxide synthase (NOS2) have been implicated in the pathogenesis of neuronal retinal cell death in ocular hypertension. Neutral sphingomyelinase (N-SMase)/ceramide pathway can regulate NOS2 expression, hence this study determined the role of selective neutral sphingomyelinase (N-SMase) inhibition on retinal NOS2 levels, ER stress, apoptosis and visual evoked potentials (VEPs) in a rat model of elevated intraocular pressure (EIOP). NOS2 expression and retinal protein nitration were significantly greater in EIOP and significantly decreased with N-SMase inhibition. A significant increase was observed in retinal ER stress markers pPERK, CHOP and GRP78 in EIOP, which were not significantly altered by N-SMase inhibition. Retinal TUNEL staining showed increased apoptosis in all EIOP groups; however N-SMase inhibition significantly decreased the percent of apoptotic cells in EIOP. Caspase-3, -8 and -9 activities were significantly increased in EIOP and returned to baseline levels following N-SMase inhibition. Latencies of all VEP components were significantly prolonged in EIOP and shortened following N-SMase inhibition. Data confirm the role of nitrative injury in EIOP and highlight the protective effect of N-SMase inhibition in EIOP via down-regulation of NOS2 levels and nitrative stress. - Highlights: • Inhibition of N-SMase decreases NOS2 levels in ocular hypertension. • Inhibition of N-SMase decreases protein nitration in ocular hypertension. • Inhibition of N-SMase decreases caspase activation in ocular hypertension. • Inhibition of N-SMase decreases apoptosis in ocular hypertension.

  15. Molecular mechanisms of hypoxia-inducible factor-induced pulmonary arterial smooth muscle cell alterations in pulmonary hypertension.

    PubMed

    Veith, Christine; Schermuly, Ralph T; Brandes, Ralf P; Weissmann, Norbert

    2016-03-01

    Oxygen (O2) is essential for the viability and function of most metazoan organisms and thus is closely monitored at both the organismal and the cellular levels. However, alveoli often encounter decreased O2 levels (hypoxia), leading to activation of physiological or pathophysiological responses in the pulmonary arteries. Such changes are achieved by activation of transcription factors. The hypoxia-inducible factors (HIFs) are the most prominent hypoxia-regulated transcription factors in this regard. HIFs bind to hypoxia-response elements (HREs) in the promoter region of target genes, whose expression and translation allows the organism, amongst other factors, to cope with decreased environmental O2 partial pressure (pO2). However, prolonged HIF activation can contribute to major structural alterations, especially in the lung, resulting in the development of pulmonary hypertension (PH). PH is characterized by a rise in pulmonary arterial pressure associated with pulmonary arterial remodelling, concomitant with a reduced intravascular lumen area. Patients with PH develop right heart hypertrophy and eventually die from right heart failure. Thus, understanding the molecular mechanisms of HIF regulation in PH is critical for the identification of novel therapeutic strategies. This review addresses the relationship of hypoxia and the HIF system with pulmonary arterial dysfunction in PH. We particularly focus on the cellular and molecular mechanisms underlying the HIF-driven pathophysiological processes. PMID:26228924

  16. Insight into molecular mechanisms of ultrafine carbon particle induced cardiovascular impairments in spontaneously hypertensive rats.

    EPA Science Inventory

    Rationale: Exposure to ambient particulate matter is a risk factor for cardiopulmonary disease as identified in several epidemiological studies. Radio telemetric analysis detected increased heart rate and blood pressure in Spontaneously Hypertensive Rats (SHR) following inhalatio...

  17. Optical cryoimaging of rat kidney and the effective role of chromosome 13 in salt-induced hypertension

    NASA Astrophysics Data System (ADS)

    Salehpour, F.; Yang, C.; Kurth, T.; Cowley, A. W.; Ranji, M.

    2015-03-01

    The objective of this work is to assess oxidative stress levels in salt-sensitive hypertension animal model using 3D optical cryoimager to image mitochondrial redox ratio. We studied Dahl salt-induced (SS) rats, and compared the results with a consomic SS rat strain (SSBN13). The SSBN13 strain was developed by the introgression of chromosome from the Brown Norway (BN) rat into the salt-sensitive (SS) genetic background and exhibits significant protection from salt induced hypertension1 . These two groups were fed on a high salt diet of 8.0% NaCl for one week. Mitochondrial redox ratio (NADH/FAD=NADH RR), was used as a quantitative marker of the oxidative stress in kidney tissue. Maximum intensity projected images and their corresponding histograms in each group were acquired from each kidney group. The result showed a 49% decrease in mitochondrial redox ratio of SS compared to SSBN13 translated to an increase in the level of oxidative stress of the tissue. Therefore, the results quantify oxidative stress levels and its effect on mitochondrial redox in salt sensitive hypertension.

  18. Blood volume increase in salt-induced pulmonary hypertension, heart failure and ascites in broiler and White Leghorn chickens.

    PubMed Central

    Mirsalimi, S M; O'Brien, P J; Julian, R J

    1993-01-01

    In this study we tested the hypothesis that excess dietary salt produces an expansion of extracellular fluid volume which may be associated with pulmonary hypertension-induced right ventricular failure in chickens with rapid growth rates. One-week-old broiler and White Leghorn chickens were given 0.5% salt in their drinking water for three weeks. Saline water had a minimal effect on White Leghorns. The hypothesis appears to be correct since salt-treatment in broilers resulted in up to 30% expansion in blood volume and there was 50% mortality from pulmonary hypertension-induced right ventricular failure and ascites. There was marked (up to 88% in some broilers) right ventricular hypertrophy, an indicator of pulmonary hypertension. There was less left ventricular hypertrophy as shown by an increase in the ratio of the right to total ventricle weight. There was up to 32% decrease in growth rate. There was renal hypertrophy in the salt-treated birds as shown by a higher kidney to body weight ratio. PMID:8490804

  19. Increased Clearance of Reactive Aldehydes and Damaged Proteins in Hypertension-Induced Compensated Cardiac Hypertrophy: Impact of Exercise Training

    PubMed Central

    Campos, Juliane Cruz; Fernandes, Tiago; Bechara, Luiz Roberto Grassmann; da Paixão, Nathalie Alves; Brum, Patricia Chakur; de Oliveira, Edilamar Menezes; Ferreira, Julio Cesar Batista

    2015-01-01

    Background. We previously reported that exercise training (ET) facilitates the clearance of damaged proteins in heart failure. Here, we characterized the impact of ET on cardiac protein quality control during compensated ventricular hypertrophy in spontaneously hypertensive rats (SHR). Methods and Results. SHR were randomly assigned into sedentary and swimming-trained groups. Sedentary SHR displayed cardiac hypertrophy with preserved ventricular function compared to normotensive rats, characterizing a compensated cardiac hypertrophy. Hypertensive rats presented signs of cardiac oxidative stress, depicted by increased lipid peroxidation. However, these changes were not followed by accumulation of lipid peroxidation-generated reactive aldehydes and damaged proteins. This scenario was explained, at least in part, by the increased catalytic activity of both aldehyde dehydrogenase 2 (ALDH2) and proteasome. Of interest, ET exacerbated cardiac hypertrophy, improved ventricular function, induced resting bradycardia, and decreased blood pressure in SHR. These changes were accompanied by reduced cardiac oxidative stress and a consequent decrease in ALDH2 and proteasome activities, without affecting small chaperones levels and apoptosis in SHR. Conclusion. Increased cardiac ALDH2 and proteasomal activities counteract the deleterious effect of excessive oxidative stress in hypertension-induced compensated cardiac hypertrophy in rats. ET has a positive effect in reducing cardiac oxidative stress without affecting protein quality control. PMID:25954323

  20. Hypothalamic signaling mechanisms in hypertension.

    PubMed

    Carmichael, Casey Y; Wainford, Richard D

    2015-05-01

    The etiology of hypertension, a critical public health issue affecting one in three US adults, involves the integration of the actions of multiple organ systems, including the central nervous system. Increased activation of the central nervous system, driving enhanced sympathetic outflow and increased blood pressure, has emerged as a major contributor to the pathogenesis of hypertension. The hypothalamus is a key brain site acting to integrate central and peripheral inputs to ultimately impact blood pressure in multiple disease states that evoke hypertension. This review highlights recent advances that have identified novel signal transduction mechanisms within multiple hypothalamic nuclei (e.g., paraventricular nucleus, arcuate nucleus) acting to drive the pathophysiology of hypertension in neurogenic hypertension, angiotensin II hypertension, salt-sensitive hypertension, chronic intermittent hypoxia, and obesity-induced hypertension. Increased understanding of hypothalamic activity in hypertension has the potential to identify novel targets for future therapeutic interventions designed to treat hypertension. PMID:25860531

  1. Exogenous administration of thiosulfate, a donor of hydrogen sulfide, attenuates angiotensin II-induced hypertensive heart disease in rats

    PubMed Central

    Snijder, P M; Frenay, A R; de Boer, R A; Pasch, A; Hillebrands, J L; Leuvenink, H G D; van Goor, H

    2015-01-01

    Background and Purpose Hypertension is an important mediator of cardiac damage and remodelling. Hydrogen sulfide (H2S) is an endogenously produced gasotransmitter with cardioprotective properties. However, it is not yet in clinical use. We, therefore, investigated the protective effects of sodium thiosulfate (STS), a clinically applicable H2S donor substance, in angiotensin II (Ang II)-induced hypertensive cardiac disease in rats. Experimental Approach Male Sprague Dawley rats were infused with Ang II (435 ng kg min−1) or saline (control) for 3 weeks via s.c. placed osmotic minipumps. During these 3 weeks, rats received i.p. injections of either STS, NaHS or vehicle (0.9% NaCl). Key Results Compared with controls, Ang II infusion caused an increase in systolic and diastolic BP with associated cardiac damage as evidenced by cardiac hypertrophy, an increase in atrial natriuretic peptide (ANP) mRNA, cardiac fibrosis and increased oxidative stress. Treatment with NaHS and STS prevented the development of hypertension and the increase in ANP mRNA levels. Furthermore, the degree of cardiac hypertrophy, the extent of histological fibrosis in combination with the expression of profibrotic genes and the levels of oxidative stress were all significantly decreased. Conclusions and Implications Ang II-induced hypertensive cardiac disease can be attenuated by treatment with STS and NaHS. Although BP regulation is the most plausible mechanism of cardiac protection, the antifibrotic and antioxidant properties of released sulfide may also contribute to their effects. Our data show that H2S might be a valuable addition to the already existing antihypertensive and cardioprotective therapies. Linked Articles This article is part of a themed section on Pharmacology of the Gasotransmitters. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2015.172.issue-6 PMID:24962324

  2. Identification of a Novel Mucin Gene HCG22 Associated With Steroid-Induced Ocular Hypertension

    PubMed Central

    Jeong, Shinwu; Patel, Nitin; Edlund, Christopher K.; Hartiala, Jaana; Hazelett, Dennis J.; Itakura, Tatsuo; Wu, Pei-Chang; Avery, Robert L.; Davis, Janet L.; Flynn, Harry W.; Lalwani, Geeta; Puliafito, Carmen A.; Wafapoor, Hussein; Hijikata, Minako; Keicho, Naoto; Gao, Xiaoyi; Argüeso, Pablo; Allayee, Hooman; Coetzee, Gerhard A.; Pletcher, Mathew T.; Conti, David V.; Schwartz, Stephen G.; Eaton, Alexander M.; Fini, M. Elizabeth

    2015-01-01

    Purpose. The pathophysiology of ocular hypertension (OH) leading to primary open-angle glaucoma shares many features with a secondary form of OH caused by treatment with glucocorticoids, but also exhibits distinct differences. In this study, a pharmacogenomics approach was taken to discover candidate genes for this disorder. Methods. A genome-wide association study was performed, followed by an independent candidate gene study, using a cohort enrolled from patients treated with off-label intravitreal triamcinolone, and handling change in IOP as a quantitative trait. Results. An intergenic quantitative trait locus (QTL) was identified at chromosome 6p21.33 near the 5′ end of HCG22 that attained the accepted statistical threshold for genome-level significance. The HCG22 transcript, encoding a novel mucin protein, was expressed in trabecular meshwork cells, and expression was stimulated by IL-1, and inhibited by triamcinolone acetate and TGF-β. Bioinformatic analysis defined the QTL as an approximately 4 kilobase (kb) linkage disequilibrium block containing 10 common single nucleotide polymorphisms (SNPs). Four of these SNPs were identified in the National Center for Biotechnology Information (NCBI) GTEx eQTL browser as modifiers of HCG22 expression. Most are predicted to disrupt or improve motifs for transcription factor binding, the most relevant being disruption of the glucocorticoid receptor binding motif. A second QTL was identified within the predicted signal peptide of the HCG22 encoded protein that could affect its secretion. Translation, O-glycosylation, and secretion of the predicted HCG22 protein was verified in cultured trabecular meshwork cells. Conclusions. Identification of two independent QTLs that could affect expression of the HCG22 mucin gene product via two different mechanisms (transcription or secretion) is highly suggestive of a role in steroid-induced OH. PMID:25813999

  3. Downregulation of vascular soluble guanylate cyclase induced by high salt intake in spontaneously hypertensive rats

    PubMed Central

    Kagota, Satomi; Tamashiro, Akiko; Yamaguchi, Yu; Sugiura, Reiko; Kuno, Takayoshi; Nakamura, Kazuki; Kunitomo, Masaru

    2001-01-01

    Cyclic guanosine monophosphate (cyclic GMP)-mediated mechanism plays an important role in vasodilatation and blood pressure regulation. We investigated the effects of high salt intake on the nitric oxide (NO) – cyclic GMP signal transduction pathway regulating relaxation in aortas of spontaneously hypertensive rats (SHR).Four-week-old SHR and normotensive Wistar-Kyoto rats (WKY) received a normal salt diet (0.3% NaCl) or a high salt diet (8% NaCl) for 4 weeks.In aortic rings from SHR, endothelium-dependent relaxations in response to acetylcholine (ACh), adenosine diphosphate (ADP) and calcium ionophore A23187 were significantly impaired by the high salt intake. The endothelium-independent relaxations in response to sodium nitroprusside (SNP) and nitroglycerin were also impaired, but that to 8-bromo-cyclic GMP remained unchanged. On the other hand, high salt diet had no significant effects on the relaxations of aortic rings from WKY.In aortas from SHR, the release of NO stimulated by ACh was significantly enhanced, whereas the production of cyclic GMP induced by either ACh or SNP was decreased by the high salt intake.Western blot analysis showed that the protein level of endothelial NO synthase (eNOS) was slightly increased, whereas that of soluble guanylate cyclase (sGC) was dramatically reduced by the high salt intake.These results indicate that in SHR, excessive dietary salt can result in downregulation of sGC followed by decreased cyclic GMP production, which leads to impairment of vascular relaxation in responses to NO. It is notable that chronic high salt intake impairs the sGC/cyclic GMP pathway but not the eNOS/NO pathway. PMID:11606313

  4. Impact of interleukin-6 on hypoxia-induced pulmonary hypertension and lung inflammation in mice

    PubMed Central

    Savale, Laurent; Tu, Ly; Rideau, Dominique; Izziki, Mohamed; Maitre, Bernard; Adnot, Serge; Eddahibi, Saadia

    2009-01-01

    Background Inflammation may contribute to the pathogenesis of various forms of pulmonary hypertension (PH). Recent studies in patients with idiopathic PH or PH associated with underlying diseases suggest a role for interleukin-6 (IL-6). Methods To determine whether endogenous IL-6 contributes to mediate hypoxic PH and lung inflammation, we studied IL-6-deficient (IL-6-/-) and wild-type (IL-6+/+) mice exposed to hypoxia for 2 weeks. Results Right ventricular systolic pressure, right ventricle hypertrophy, and the number and media thickness of muscular pulmonary vessels were decreased in IL-6-/- mice compared to wild-type controls after 2 weeks' hypoxia, although the pressure response to acute hypoxia was similar in IL-6+/+ and IL-6-/- mice. Hypoxia exposure of IL-6+/+ mice led to marked increases in IL-6 mRNA and protein levels within the first week, with positive IL-6 immunostaining in the pulmonary vessel walls. Lung IL-6 receptor and gp 130 (the IL-6 signal transducer) mRNA levels increased after 1 and 2 weeks' hypoxia. In vitro studies of cultured human pulmonary-artery smooth-muscle-cells (PA-SMCs) and microvascular endothelial cells revealed prominent synthesis of IL-6 by PA-SMCs, with further stimulation by hypoxia. IL-6 also markedly stimulated PA-SMC migration without affecting proliferation. Hypoxic IL-6-/- mice showed less inflammatory cell recruitment in the lungs, compared to hypoxic wild-type mice, as assessed by lung protein levels and immunostaining for the specific macrophage marker F4/80, with no difference in lung expression of adhesion molecules or cytokines. Conclusion These data suggest that IL-6 may be actively involved in hypoxia-induced lung inflammation and pulmonary vascular remodeling in mice. PMID:19173740

  5. The role of sustained release isosorbide mononitrate on corticosteroid-induced hypertension in healthy human subjects.

    PubMed

    Williamson, P M; Ong, S L H; Whitworth, J A; Kelly, J J

    2015-12-01

    There is evidence implicating abnormalities in the nitric oxide (NO) pathway in the development of glucocorticoid-induced hypertension (GC-HT). In humans, a reduction in NO availability during cortisol treatment has been observed. This study examined whether the NO donation may reverse the elevated blood pressure (BP) observed with cortisol treatment. A randomised double-blind, placebo-controlled, crossover study was undertaken in eight healthy men to address the effect of co-administration of isosorbide mononitrate (ISMN, 60 mg single dose, day 5) with cortisol (200 mg per day, days 1-6) and then compared with placebo (single dose, day 5) with cortisol. After a 2-week washout period, subjects crossed over to the alternate treatment. BP measurements were obtained using a mercury sphygmomanometer. Tonometry was used to estimate central pressures. There was a significant rise in mean arterial pressure with cortisol: 80 ± 3 vs 89 ± 3 mm Hg (day 1 vs day 5, cortisol+ISMN phase, P < 0.001) and 81 ± 3 vs 89 ± 3 mm Hg (day 1 vs day 5, cortisol+placebo phase, P < 0.01). ISMN significantly decreased aortic augmentation index: -17.3 ± 3.2 vs 1.8 ± 3.5%, (differences calculated from day 5-day 1, cortisol/ISMN vs cortisol+placebo, P < 0.001). These results demonstrated that GC-HT can be modified by co-administration of exogenous NO donors, consistent with the hypothesis that GC-HT is accompanied by reduced NO activity in humans. PMID:25810066

  6. New models of pulmonary hypertension based on VEGF receptor blockade-induced endothelial cell apoptosis

    PubMed Central

    Nicolls, Mark R.; Mizuno, Shiro; Taraseviciene-Stewart, Laima; Farkas, Laszlo; Drake, Jennnifer I.; Al Husseini, Aysar; Gomez-Arroyo, Jose G.; Voelkel, Norbert F.; Bogaard, Herman J.

    2012-01-01

    In spite of treatment, severe angioproliferative pulmonary arterial hypertension (PAH) remains a disease characterized by great morbidity and shortened survival. New treatment strategies for patients with PAH are needed, and after drug development, preclinical studies are best conducted in animal models which present with pulmonary angio-obliterative disease and right heart failure. A rat model of severe pulmonary hypertension and right heart failure, described a decade ago, continues to be investigated and provide insight into the nature of the lung vascular lesions and mechanisms of cardiac adaptation to an altered lung circulation. This rat model is based on the combination of VEGF receptor blockade with Su5416 and chronic hypoxia; use of this pulmonary hypertension induction strategy led to developing the concept of apoptosis-dependent compensatory vascular cell growth. Although, often employed in experimental designs, chronic hypoxia is not necessary for the development of angio-obliterative pulmonary hypertension. Left pneumonectomy combined with Su5416 also results in severe pulmonary hypertension in normoxic conditions. Similarly, the immune insufficiency component of severe PAH can be modeled in athymic rats (lacking T-lymphocytes). In these rats housed under normoxic conditions, treatment with the VEGFR receptor blocker results in angioproliferative pulmonary hypertension; cardiopulmonary disease in these animals can be prevented by immune reconstitution of regulatory T-cells (Tregs). Finally, chronic hypoxia can be replaced with another stimulator of HIF-1α: Ovalbumin (Ova). Immunization of rats with Ova increases lung tissue HIF-1α protein expression, and in Su5416-treated rats causes lethal pulmonary hypertension. Finally, we postulate that these models may also be useful for “reverse translation”; that is, the mechanisms of lung vascular cell death and growth and the modifying influences of immune and bone marrow cells that have been identified

  7. Oxidative stress-dependent activation of collagen synthesis is induced in human pulmonary smooth muscle cells by sera from patients with scleroderma-associated pulmonary hypertension

    PubMed Central

    2014-01-01

    Pulmonary arterial hypertension is a major complication of systemic sclerosis. Although oxidative stress, intima hyperplasia and a progressive vessel occlusion appear to be clearly involved, the fine molecular mechanisms underpinning the onset and progression of systemic sclerosis-associated pulmonary arterial hypertension remain largely unknown. Here we shows for the first time that an increase of NADPH-derived reactive oxygen species production induced by sera from systemic sclerosis patients with pulmonary arterial hypertension drives collagen type I promoter activity in primary human pulmonary artery smooth muscle cells, suggesting that antioxidant-based therapies should be considered in the treatment of systemic sclerosis-associated vascular diseases. PMID:25085432

  8. Qingxuan Jiangya Decoction Reverses Vascular Remodeling by Inducing Vascular Smooth Muscle Cell Apoptosis in Spontaneously Hypertensive Rats.

    PubMed

    Xiao, Fei; He, Fei; Chen, Hongwei; Lin, Shan; Shen, Aling; Chen, Youqin; Chu, Jianfeng; Peng, Jun

    2016-01-01

    Qingxuan Jiangya Decoction (QXJYD), a traditional Chinese medicine formula prescribed by academician Ke-ji Chen, has been used in China to clinically treat hypertension for decades of years. However, the molecular mechanisms of its action remain largely unknown. In this study, we examined the therapeutic efficacy of QXJYD against elevated systolic blood pressure in the spontaneously hypertensive rat (SHR) model, and investigated the underlying molecular mechanisms. We found that oral administration of QXJYD significantly reduced the elevation of systolic blood pressure in SHR but had no effect on body weight change. Additionally, QXJYD treatment significantly decreased the media thickness and ratio of media thickness/lumen diameter in the carotid arteries of SHR. Moreover, QXJYD remarkably promoted apoptosis of vascular smooth muscle cells and reduced the expression of anti-apoptotic B-cell leukemia/lymphoma 2. Furthermore, QXJYD significantly decreased the plasma Angiotensin II level in SHR. Collectively, our findings suggest that reversing vascular remodeling via inducing VSMC apoptosis could be one of the mechanisms whereby QXJYD treats hypertension. PMID:27455221

  9. Inhalable delivery of AAV-based MRP4/ABCC4 silencing RNA prevents monocrotaline-induced pulmonary hypertension

    PubMed Central

    Claude, Caroline; Mougenot, Nathalie; Bechaux, Julia; Hadri, Lahouaria; Brockschnieder, Damian; Clergue, Michel; Atassi, Fabrice; Lompré, Anne-Marie; Hulot, Jean-Sébastien

    2015-01-01

    The ATP-binding cassette transporter MRP4 (encoded by ABCC4) regulates membrane cyclic nucleotides concentrations in arterial cells including smooth muscle cells. MRP4/ABCC4 deficient mice display a reduction in smooth muscle cells proliferation and a prevention of pulmonary hypertension in response to hypoxia. We aimed to study gene transfer of a MRP4/ABCC4 silencing RNA via intratracheal delivery of aerosolized adeno-associated virus 1 (AAV1.shMRP4 or AAV1.control) in a monocrotaline-induced model of pulmonary hypertension in rats. Gene transfer was performed at the time of monocrotaline administration and the effect on the development of pulmonary vascular remodeling was assessed 35 days later. AAV1.shMRP4 dose-dependently reduced right ventricular systolic pressure and hypertrophy with a significant reduction with the higher doses (i.e., >1011 DRP/animal) as compared to AAV1.control. The higher dose of AAV1.shMRP4 was also associated with a significant reduction in distal pulmonary arteries remodeling. AAV1.shMRP4 was finally associated with a reduction in the expression of ANF, a marker of cardiac hypertrophy. Collectively, these results support a therapeutic potential for downregulation of MRP4 for the treatment of pulmonary artery hypertension. PMID:26052533

  10. Plasma Cardiotrophin-1 as a Marker of Hypertension and Diabetes-Induced Target Organ Damage and Cardiovascular Risk

    PubMed Central

    Gamella-Pozuelo, Luis; Fuentes-Calvo, Isabel; Gómez-Marcos, Manuel A.; Recio-Rodriguez, José I.; Agudo-Conde, Cristina; Fernández-Martín, José L.; Cannata-Andía, Jorge B.; López-Novoa, José M.; García-Ortiz, Luis; Martínez-Salgado, Carlos

    2015-01-01

    Abstract The search for biomarkers of hypertension and diabetes-induced damage to multiple target organs is a priority. We analyzed the correlation between plasma cardiotrophin-1 (CT-1), a chemokine that participates in cardiovascular remodeling and organ fibrosis, and a wide range of parameters currently used to diagnose morphological and functional progressive injury in left ventricle, arteries, and kidneys of diabetic and hypertensive patients, in order to validate plasma levels of CT-1 as clinical biomarker. This is an observational study with 93 type 2-diabetic patients, 209 hypertensive patients, and 82 healthy controls in which we assessed the following parameters: plasma CT-1, basal glycaemia, systolic blood pressure (SBP), diastolic blood pressure (DBP), pulse pressure (PP), left ventricular hypertrophy (LVH by electrocardiographic indexes), peripheral vascular disease (by pulse wave velocity—PWV, carotid intima-media thickness—C-IMT, and ankle-brachial index—ABI), and renal impairment (by microalbuminuria, albumin/creatinine urinary ratio, plasma creatinine concentrations, and glomerular filtration rate). Hypertensive or diabetic patients have higher plasma CT-1 than control patients. CT-1 positively correlates with basal glycaemia, SBP, DBP, PP, LVH, arterial damage (increased IMT, decreased ABI), and early renal damage (microalbuminuria, elevated albumin/creatinine ratio). CT-1 also correlates with increased 10-year cardiovascular risk. Multiple linear regression analysis confirmed that CT-1 was associated with arterial injury assessed by PWV, IMT, ABI, and cardiac damage evaluated by Cornell voltage duration product. Increases in plasma CT-1 are strongly related to the intensity of several parameters associated to target organ damage supporting further investigation of its diagnostic capacity as single biomarker of cardiovascular injury and risk and, possibly, of subclinical renal damage. PMID:26222851

  11. Up-regulation of renal Na+, K+-ATPase: the possible novel mechanism of leptin-induced hypertension.

    PubMed

    Bełtowski, Jerzy; Jamroz-Wiśniewska, Anna; Borkowska, Ewelina; Wójcicka, Grazyna

    2004-01-01

    Hyperleptinemia may be involved in the pathogenesis of obesity-associated hypertension, however, the mechanism of hypertensive effect of leptin has not been elucidated. We investigated the effect of experimental hyperleptinemia on renal function, renal Na(+), K(+)-ATPase and ouabain-sensitive H(+), K(+)-ATPase activities in the rat. Leptin administered for 7 days (0.25 mg/kg twice daily sc) decreased food intake on 6th and 7th day of treatment but had no effect on body weight. Systolic blood pressure was 30.5% higher in leptin-treated animals. Urinary excretion of sodium decreased by 35.0% following leptin treatment. Leptin had no effect on potassium and phosphate excretion as well as on creatinine clearance. The activity of Na(+), K(+)-ATPase in the renal cortex and medulla was higher in leptin-treated rats by 32.4% and 84.2%, respectively. In contrast, leptin had no effect on either cortical or medullary ouabain-sensitive H(+), K(+)-ATPase. In pair-fed group, in which food intake was reduced to the level observed in leptin-treated group, no changes in sodium metabolism and renal Na(+), K(+)-ATPase were observed. Leptin decreased urinary excretion of nitric oxide metabolites by 55.0% and urinary excretion of cGMP by 26.3%. Plasma concentration of atrial natriuretic peptide tended to be higher and urinary excretion of urodilatin was 64.9% higher in leptin-treated animals. These data suggest that hyperleptinemia decreases natriuresis by up-regulating Na(+), K(+)-ATPase and stimulating tubular sodium reabsorption. This effect is mediated, at least in part, by deficiency of nitric oxide (NO). Abnormal renal sodium retention and vasoconstriction associated with NO deficiency may contribute to leptin-induced hypertension and to blood pressure elevation in hypertensive obese individuals. PMID:15156072

  12. Plasma Cardiotrophin-1 as a Marker of Hypertension and Diabetes-Induced Target Organ Damage and Cardiovascular Risk.

    PubMed

    Gamella-Pozuelo, Luis; Fuentes-Calvo, Isabel; Gómez-Marcos, Manuel A; Recio-Rodriguez, José I; Agudo-Conde, Cristina; Fernández-Martín, José L; Cannata-Andía, Jorge B; López-Novoa, José M; García-Ortiz, Luis; Martínez-Salgado, Carlos

    2015-07-01

    The search for biomarkers of hypertension and diabetes-induced damage to multiple target organs is a priority. We analyzed the correlation between plasma cardiotrophin-1 (CT-1), a chemokine that participates in cardiovascular remodeling and organ fibrosis, and a wide range of parameters currently used to diagnose morphological and functional progressive injury in left ventricle, arteries, and kidneys of diabetic and hypertensive patients, in order to validate plasma levels of CT-1 as clinical biomarker.This is an observational study with 93 type 2-diabetic patients, 209 hypertensive patients, and 82 healthy controls in which we assessed the following parameters: plasma CT-1, basal glycaemia, systolic blood pressure (SBP), diastolic blood pressure (DBP), pulse pressure (PP), left ventricular hypertrophy (LVH by electrocardiographic indexes), peripheral vascular disease (by pulse wave velocity-PWV, carotid intima-media thickness-C-IMT, and ankle-brachial index-ABI), and renal impairment (by microalbuminuria, albumin/creatinine urinary ratio, plasma creatinine concentrations, and glomerular filtration rate).Hypertensive or diabetic patients have higher plasma CT-1 than control patients. CT-1 positively correlates with basal glycaemia, SBP, DBP, PP, LVH, arterial damage (increased IMT, decreased ABI), and early renal damage (microalbuminuria, elevated albumin/creatinine ratio). CT-1 also correlates with increased 10-year cardiovascular risk. Multiple linear regression analysis confirmed that CT-1 was associated with arterial injury assessed by PWV, IMT, ABI, and cardiac damage evaluated by Cornell voltage duration product.Increases in plasma CT-1 are strongly related to the intensity of several parameters associated to target organ damage supporting further investigation of its diagnostic capacity as single biomarker of cardiovascular injury and risk and, possibly, of subclinical renal damage. PMID:26222851

  13. Prolonged Subcutaneous Administration of Oxytocin Accelerates Angiotensin II-Induced Hypertension and Renal Damage in Male Rats

    PubMed Central

    Phie, James; Haleagrahara, Nagaraja; Newton, Patricia; Constantinoiu, Constantin; Sarnyai, Zoltan; Chilton, Lisa; Kinobe, Robert

    2015-01-01

    Oxytocin and its receptor are synthesised in the heart and blood vessels but effects of chronic activation of this peripheral oxytocinergic system on cardiovascular function are not known. In acute studies, systemic administration of low dose oxytocin exerted a protective, preconditioning effect in experimental models of myocardial ischemia and infarction. In this study, we investigated the effects of chronic administration of low dose oxytocin following angiotensin II-induced hypertension, cardiac hypertrophy and renal damage. Angiotensin II (40 μg/Kg/h) only, oxytocin only (20 or 100 ng/Kg/h), or angiotensin II combined with oxytocin (20 or 100 ng/Kg/h) were infused subcutaneously in adult male Sprague-Dawley rats for 28 days. At day 7, oxytocin or angiotensin-II only did not change hemodynamic parameters, but animals that received a combination of oxytocin and angiotensin-II had significantly elevated systolic, diastolic and mean arterial pressure compared to controls (P < 0.01). Hemodynamic changes were accompanied by significant left ventricular cardiac hypertrophy and renal damage at day 28 in animals treated with angiotensin II (P < 0.05) or both oxytocin and angiotensin II, compared to controls (P < 0.01). Prolonged oxytocin administration did not affect plasma concentrations of renin and atrial natriuretic peptide, but was associated with the activation of calcium-dependent protein phosphatase calcineurin, a canonical signalling mechanism in pressure overload-induced cardiovascular disease. These data demonstrate that oxytocin accelerated angiotensin-II induced hypertension and end-organ renal damage, suggesting caution should be exercised in the chronic use of oxytocin in individuals with hypertension. PMID:26393919

  14. Preventive effect of gomisin J from Schisandra chinensis on angiotensin II-induced hypertension via an increased nitric oxide bioavailability.

    PubMed

    Ye, Byeong Hyeok; Lee, Seung Jin; Choi, Young Whan; Park, So Youn; Kim, Chi Dae

    2015-03-01

    Gomisin J (GJ) is a small molecular weight lignan found in Schisandra chinensis and has been demonstrated to have vasodilatory activity. In this study, the authors investigated the effect of GJ on blood pressure (BP) in angiotensin II (Ang II)-induced hypertensive mice. In addition, we determined the relative potencies of gomisin A (GA) and GJ with respect to vasodilatory activity and antihypertensive effects. C57/BL6 mice infused s.c. with Ang II (2 μg kg(-1) min(-1) for 2 weeks) showed an increase in BP and a decrease in plasma nitric oxide (NO) metabolites. In the thoracic aortas of Ang II-induced hypertensive mice, a decrease in vascular NO was accompanied by an increase in reactive oxygen species (ROS) production. Furthermore, these alterations in BP, plasma concentrations of NO metabolites and in the vascular productions of NO and ROS in Ang II-treated mice were reversed by the co-administration of GJ (1 and 3 μg kg(-1) min(-1)). In in vitro studies, Ang II decreased the cellular concentration of NO, which was accompanied by a reduction in phosphorylated endothelial nitric oxide synthase (eNOS) and an increase in ROS production. These eNOS phosphorylation and ROS production changes in Ang II-treated cells were also reversed by GJ pretreatment (0-3 μg ml(-1)). Interestingly, the vasodilatory and antihypertensive effects of GJ were more prominent than those of GA. Collectively, an increase in BP in mice treated with Ang II was markedly attenuated by GJ, which was attributed to the preservations of vascular NO bioavailability and eNOS function, and to the inhibition of ROS production in Ang II-induced hypertensive mice. PMID:25427681

  15. Ameliorative Effect of Hydroethanolic Leaf Extract of Byrsocarpus coccineus in Alcohol- and Sucrose-Induced Hypertension in Rats

    PubMed Central

    Akindele, Abidemi J.; Iyamu, Endurance A.; Dutt, Prabhu; Satti, Naresh K.; Adeyemi, Olufunmilayo O.

    2014-01-01

    Hypertension remains a major health problem worldwide considering the prevalence of morbidity and mortality. Plants remain a reliable source of efficacious and better tolerated drugs and botanicals. This study was designed to investigate the effect of the chemo-profiled hydroethanolic leaf extract of Byrsocarpus coccineus in ethanol- and sucrose-induced hypertension. Groups of rats were treated orally (p.o.) with distilled water (10 ml/kg), ethanol (35%; 3 g/kg), sucrose (5-7%), and B. coccineus (100, 200, and 400 mg/kg), and nifedipine together with ethanol and sucrose separately for 8 weeks. At the end of the treatment period, blood pressure and heart rate of rats were determined. Blood was collected for serum biochemical parameters and lipid profile assessment, and the liver, aorta, kidney, and heart were harvested for estimation of in vivo antioxidants and malondialdehyde (MDA). Results obtained in this study showed that B. coccineus at the various doses administered reduced the systolic, diastolic, and arterial blood pressure elevated by ethanol and sucrose. Also, the extract reversed the reduction in catalase (CAT), reduced glutathione (GSH), glutathione peroxidase (GPx), and superoxide dismutase (SOD) induced by ethanol and sucrose. The level of MDA was reduced compared to the ethanol- and sucrose-induced hypertensive group. With respect to lipid profile, administration of B. coccineus at the various doses reduced the levels of triglycerides, low-density lipoprotein (LDL), cholesterol, and atherogenic indices, compared to the ethanol and sucrose groups. In conclusion the hydroethanolic leaf extract of B. coccineus exerted significant antihypertensive effect and this is probably related to the antioxidant property and improvement of lipid profile observed in this study. PMID:25161923

  16. Ameliorative Effect of Hydroethanolic Leaf Extract of Byrsocarpus coccineus in Alcohol- and Sucrose-Induced Hypertension in Rats.

    PubMed

    Akindele, Abidemi J; Iyamu, Endurance A; Dutt, Prabhu; Satti, Naresh K; Adeyemi, Olufunmilayo O

    2014-07-01

    Hypertension remains a major health problem worldwide considering the prevalence of morbidity and mortality. Plants remain a reliable source of efficacious and better tolerated drugs and botanicals. This study was designed to investigate the effect of the chemo-profiled hydroethanolic leaf extract of Byrsocarpus coccineus in ethanol- and sucrose-induced hypertension. Groups of rats were treated orally (p.o.) with distilled water (10 ml/kg), ethanol (35%; 3 g/kg), sucrose (5-7%), and B. coccineus (100, 200, and 400 mg/kg), and nifedipine together with ethanol and sucrose separately for 8 weeks. At the end of the treatment period, blood pressure and heart rate of rats were determined. Blood was collected for serum biochemical parameters and lipid profile assessment, and the liver, aorta, kidney, and heart were harvested for estimation of in vivo antioxidants and malondialdehyde (MDA). Results obtained in this study showed that B. coccineus at the various doses administered reduced the systolic, diastolic, and arterial blood pressure elevated by ethanol and sucrose. Also, the extract reversed the reduction in catalase (CAT), reduced glutathione (GSH), glutathione peroxidase (GPx), and superoxide dismutase (SOD) induced by ethanol and sucrose. The level of MDA was reduced compared to the ethanol- and sucrose-induced hypertensive group. With respect to lipid profile, administration of B. coccineus at the various doses reduced the levels of triglycerides, low-density lipoprotein (LDL), cholesterol, and atherogenic indices, compared to the ethanol and sucrose groups. In conclusion the hydroethanolic leaf extract of B. coccineus exerted significant antihypertensive effect and this is probably related to the antioxidant property and improvement of lipid profile observed in this study. PMID:25161923

  17. Impaired Nrf2 regulation of mitochondrial biogenesis in rostral ventrolateral medulla on hypertension induced by systemic inflammation.

    PubMed

    Wu, Kay L H; Wu, Chih-Wei; Chao, Yung-Mei; Hung, Chun-Ying; Chan, Julie Y H

    2016-08-01

    Oxidative stress in rostral ventrolateral medulla (RVLM), where sympathetic premotor neurons reside, is involved in the development of hypertension under systemic inflammation. Mitochondrial dysfunction contributes to tissue oxidative stress. In this study, we sought to investigate whether hypertension developed under systemic inflammation is attributable to impaired mitochondrial biogenesis in RVLM. In normotensive Sprague-Dawley rats, intraperitoneal infusion of a low dose Escherichia coli lipopolysaccharide (LPS) for 7 days promoted a pressor response, alongside a decrease in mitochondrial DNA (mtDNA) copy number, reductions in protein expression of nuclear DNA-encoded transcription factors for mitochondrial biogenesis, including mitochondrial transcription factor A (TFAM) and nuclear factor erythroid-derived 2-like 2 (Nrf2), and suppression of nuclear translocation of the phosphorylated Nrf2 (p-Nrf2) in RVLM neurons; all of which were abrogated by treatment with intracisternal infusion of an interleukin-1β (IL-1β) blocker, IL-1Ra, or a mobile mitochondrial electron carrier, coenzyme Q10 (CoQ10). Microinjection into RVLM of IL-1β suppressed the expressions of p-Nrf2 and TFAM, and evoked a pressor response; conversely, the Nrf2 inducer, tert-butylhydroquinone, lessened the LPS-induced suppression of TFAM expression and pressor response. At cellular level, exposure of neuronal N2a cells to IL-1β decreased mtDNA copy number, increased protein interaction of Nrf2 to its negative regulator, kelch-like ECH-associated protein 1 (Keap1), and reduced DNA binding activity of p-Nrf2 to Tfam gene. Together these results indicate that defect mitochondrial biogenesis in RVLM neurons entailing redox-sensitive and IL-1β-dependent suppression of TFAM because of the increase in the formation of Keap1/Nrf2 complex, reductions in nuclear translocation of the activated Nrf2 and its binding to the Tfam gene promoter may underlie hypertension developed under the LPS-induced

  18. A Critical Role of the mTOR/eIF2α Pathway in Hypoxia-Induced Pulmonary Hypertension

    PubMed Central

    Wang, Ai-ping; Li, Xiao-hui; Yang, Yong-mei; Li, Wen-qun; Zhang, Wang; Hu, Chang-ping; Zhang, Zheng; Li, Yuan-jian

    2015-01-01

    Enhanced proliferation of pulmonary arterial vascular smooth muscle cells (PASMCs) is a key pathological component of vascular remodeling in hypoxia-induced pulmonary hypertension (HPH). Mammalian targeting of rapamycin (mTOR) signaling has been shown to play a role in protein translation and participate in the progression of pulmonary hypertension. Eukaryotic translation initiation factor-2α (eIF2α) is a key factor in regulation of cell growth and cell cycle, but its role in mTOR signaling and PASMCs proliferation remains unknown. Pulmonary hypertension (PH) rat model was established by hypoxia. Rapamycin was used to treat rats as an mTOR inhibitor. Proliferation of primarily cultured rat PASMCs was induced by hypoxia, rapamycin and siRNA of mTOR and eIF2α were used in loss-of-function studies. The expression and activation of eIF2α, mTOR and c-myc were analyzed. Results showed that mTOR/eIF2α signaling was significantly activated in pulmonary arteries from hypoxia exposed rats and PASMCs cultured under hypoxia condition. Treatment with mTOR inhibitor for 21 days attenuated vascular remodeling, suppressed mTOR and eIF2α activation, inhibited c-myc expression in HPH rats. In hypoxia-induced PASMCs, rapamycin and knockdown of mTOR and eIF2α by siRNA significantly abolished proliferation and increased c-myc expression. These results suggest a critical role of the mTOR/eIF2αpathway in hypoxic vascular remodeling and PASMCs proliferation of HPH. PMID:26120832

  19. [Secondary hypertension].

    PubMed

    Yoshida, Yuichi; Shibata, Hirotaka

    2015-11-01

    Hypertension is a common disease and a crucial predisposing factor of cardiovascular diseases. Approximately 10% of hypertensive patients are secondary hypertension, a pathogenetic factor of which can be identified. Secondary hypertension consists of endocrine, renal, and other diseases. Primary aldosteronism, Cushing's syndrome, pheochromocytoma, hyperthyroidism, and hypothyroidism result in endocrine hypertension. Renal parenchymal hypertension and renovascular hypertension result in renal hypertension. Other diseases such as obstructive sleep apnea syndrome are also very prevalent in secondary hypertension. It is very crucial to find and treat secondary hypertension at earlier stages since most secondary hypertension is curable or can be dramatically improved by specific treatment. One should keep in mind that screening of secondary hypertension should be done at least once in a daily clinical practice. PMID:26619670

  20. Portal Hypertension

    MedlinePlus

    ... Chronic Hepatitis C Additional Content Medical News Portal Hypertension By Steven K. Herrine, MD NOTE: This is ... Hepatic Encephalopathy Jaundice in Adults Liver Failure Portal Hypertension Portal hypertension is abnormally high blood pressure in ...

  1. Diesel Exhaust-Induced Pulmonary and Cardiovascular Impairment: The Role of Hypertension Intervention

    EPA Science Inventory

    Background–Exposure to diesel exhaust (DE) particles and associated gases is linked to cardiovascular impairments; however the susceptibility of hypertensive individuals is less well understood. Objective–1) To determine cardiopulmonary effects of gas-phase versus whole-DE, and 2...

  2. Phosducin influences sympathetic activity and prevents stress-induced hypertension in humans and mice.

    PubMed

    Beetz, Nadine; Harrison, Michael D; Brede, Marc; Zong, Xiangang; Urbanski, Michal J; Sietmann, Anika; Kaufling, Jennifer; Lorkowski, Stefan; Barrot, Michel; Seeliger, Mathias W; Vieira-Coelho, Maria Augusta; Hamet, Pavel; Gaudet, Daniel; Seda, Ondrej; Tremblay, Johanne; Kotchen, Theodore A; Kaldunski, Mary; Nüsing, Rolf; Szabo, Bela; Jacob, Howard J; Cowley, Allen W; Biel, Martin; Stoll, Monika; Lohse, Martin J; Broeckel, Ulrich; Hein, Lutz

    2009-12-01

    Hypertension and its complications represent leading causes of morbidity and mortality. Although the cause of hypertension is unknown in most patients, genetic factors are recognized as contributing significantly to an individual's lifetime risk of developing the condition. Here, we investigated the role of the G protein regulator phosducin (Pdc) in hypertension. Mice with a targeted deletion of the gene encoding Pdc (Pdc-/- mice) had increased blood pressure despite normal cardiac function and vascular reactivity, and displayed elevated catecholamine turnover in the peripheral sympathetic system. Isolated postganglionic sympathetic neurons from Pdc-/- mice showed prolonged action potential firing after stimulation with acetylcholine and increased firing frequencies during membrane depolarization. Furthermore, Pdc-/- mice displayed exaggerated increases in blood pressure in response to post-operative stress. Candidate gene-based association studies in 2 different human populations revealed several SNPs in the PDC gene to be associated with stress-dependent blood pressure phenotypes. Individuals homozygous for the G allele of an intronic PDC SNP (rs12402521) had 12-15 mmHg higher blood pressure than those carrying the A allele. These findings demonstrate that PDC is an important modulator of sympathetic activity and blood pressure and may thus represent a promising target for treatment of stress-dependent hypertension. PMID:19959875

  3. Structure/Function Analysis of Protein-Protein Interactions Developed by the Yeast Pih1 Platform Protein and Its Partners in Box C/D snoRNP Assembly.

    PubMed

    Quinternet, Marc; Rothé, Benjamin; Barbier, Muriel; Bobo, Claude; Saliou, Jean-Michel; Jacquemin, Clémence; Back, Régis; Chagot, Marie-Eve; Cianférani, Sarah; Meyer, Philippe; Branlant, Christiane; Charpentier, Bruno; Manival, Xavier

    2015-08-28

    In eukaryotes, nucleotide post-transcriptional modifications in RNAs play an essential role in cell proliferation by contributing to pre-ribosomal RNA processing, ribosome assembly and activity. Box C/D small nucleolar ribonucleoparticles catalyze site-specific 2'-O-methylation of riboses, one of the most prevalent RNA modifications. They contain one guide RNA and four core proteins and their in vivo assembly requires numerous factors including (HUMAN/Yeast) BCD1/Bcd1p, NUFIP1/Rsa1p, ZNHIT3/Hit1p, the R2TP complex composed of protein PIH1D1/Pih1p and RPAP3/Tah1p that bridges the R2TP complex to the HSP90/Hsp82 chaperone and two AAA+ ATPases. We show that Tah1p can stabilize Pih1p in the absence of Hsp82 activity during the stationary phase of growth and consequently that the Tah1p:Pih1p interaction is sufficient for Pih1p stability. This prompted us to establish the solution structure of the Tah1p:Pih1p complex by NMR. The C-terminal tail S93-S111 of Tah1p snakes along Pih1p264-344 folded in a CS domain to form two intermolecular β-sheets and one covering loop. However, a thorough inspection of the NMR and crystal structures revealed structural differences that may be of functional importance. In addition, our NMR and isothermal titration calorimetry data revealed the formation of direct contacts between Pih1p257-344 and the Hsp82MC domain in the presence of Tah1p. By co-expression in Escherichia coli, we demonstrate that Pih1p has two other direct partners, the Rsa1p assembly factor and the Nop58p core protein, and in vivo and in vitro experiments mapped the required binding domains. Our data suggest that these two interactions are mutually exclusive. The implication of this finding for box C/D small nucleolar ribonucleoparticle assembly is discussed. PMID:26210662

  4. Role of oxidative stress, inflammation, nitric oxide and transforming growth factor-beta in the protective effect of diosgenin in monocrotaline-induced pulmonary hypertension in rats.

    PubMed

    Ahmed, Lamiaa A; Obaid, Al Arqam Z; Zaki, Hala F; Agha, Azza M

    2014-10-01

    Pulmonary hypertension is a progressive disease of various origins that is associated with right ventricular dysfunction. In the present study, the protective effect of diosgenin was investigated in monocrotaline-induced pulmonary hypertension in rats. Pulmonary hypertension was induced by a single subcutaneous injection of monocrotaline (60 mg/kg). Diosgenin (100 mg/kg) was given by oral administration once daily for 3 weeks. At the end of the experiment, mean arterial blood pressure, electrocardiography and echocardiography were recorded. Rats were then sacrificed and serum was separated for determination of total nitrate/nitrite level. Right ventricles and lungs were isolated for estimation of oxidative stress markers, tumor necrosis factor-alpha, total nitrate/nitrite and transforming growth factor-beta contents. Myeloperoxidase and caspase-3 activities in addition to endothelial and inducible nitric oxide synthase protein expression were also determined. Moreover, histological analysis of pulmonary arteries and cardiomyocyte cross-sectional area was performed. Diosgenin treatment provided a significant improvement toward preserving hemodynamic changes and alleviating oxidative stress, inflammatory and apoptotic markers induced by monocrotaline in rats. Furthermore, diosgenin therapy prevented monocrotaline-induced changes in nitric oxide production, endothelial and inducible nitric oxide synthase protein expression as well as histological analysis. These findings support the beneficial effect of diosgenin in pulmonary hypertension induced by monocrotaline in rats. PMID:25062790

  5. Age and hypertension strongly induce aortic stiffening in rats at basal and matched blood pressure levels.

    PubMed

    Lindesay, George; Ragonnet, Christophe; Chimenti, Stefano; Villeneuve, Nicole; Vayssettes-Courchay, Christine

    2016-05-01

    Age and hypertension are major causes of large artery remodeling and stiffening, a cardiovascular risk factor for heart and kidney damage. The aged spontaneously hypertensive rat (SHR) model is recognized for human cardiovascular pathology, but discrepancies appeared in studies of arterial stiffness. We performed experiments using a robust analysis via echo tracking in 20-week adult (n = 8) and 80-week-old SHR (n = 7), with age-matched normotensive Wistar Kyoto rats (WKY, n = 6;6) at basal and matched levels of blood pressure (BP). After anesthesia with pentobarbital, abdominal aortic diameter and pressure were recorded and BP was decreased by clonidine i.v. At basal BP, aortic pulse distension, compliance, and distensibility (AD) were reduced and stiffness index increased with age and hypertension and further altered with age + hypertension. When BP was adjusted in SHR to that of normotensive rats (130 mmHg), there was no difference between 20-week-old SHR and WKY Importantly, the age effect was maintained in both WKY and SHR and accentuated by hypertension in old rats. At 130 mmHg, with similar pulse pressure in the four groups, AD (kPa(-3)) = 24.2 ± 1 in 20 weeks WKY, 19.7 ± 1.4 in 20 weeks SHR, 12.4 ± 1.3 in 80 weeks WKY and 6.6 ± 0.6 in 80 weeks SHR; distension = 7.6 ± 0.4%, 6.7 ± 0.6%, 3.7 ± 0.3%, and 1.8 ± 0.2% in the same groups. In conclusion, reduced distensibility, that is, stiffening due to age is clearly shown here in both WKY and SHR as well as a synergistic effect of age and hypertension. This technique will allow new studies on the mechanisms responsible and drug intervention. PMID:27233301

  6. Role of excitatory amino acid input in rostral ventrolateral medulla neurons in rats with obesity-induced hypertension.

    PubMed

    Suhaimi, Farah Wahida; Yusoff, Nurul Hasnida Mohammad; Dewa, Aidiahmad; Yusof, Ahmad Pauzi M D

    2010-03-01

    Obesity is intimately associated with hypertension; increases in blood pressure are closely related to the magnitude of weight gain. The present study aims to determine whether the excitatory amino acid input to rostral ventrolateral medulla (RVLM) contributes to elevated blood pressure in rats with diet-induced obesity. Male Sprague-Dawley rats weighing 280 to 300 grams were fed with a low-fat diet (10% kcal from fat) or moderately high-fat diet (32% kcal from fat) for 16 weeks. At week 16, rats on the moderate high-fat diet were segregated into obesity-prone and obesity-resistant rats based on body weight distribution. Baseline mean arterial pressure (MAP) was significantly higher in obesity-prone rats as compared to obesity-resistant and rats on a low-fat diet. Bilateral injection of kynurenic acid (KYN) (40 nM) into the RVLM of the obesity-prone rats reduced MAP to levels significantly different from those observed in rats on a low-fat diet and obesity-resistant rats (no change in MAP). At a lower concentration (4 nM), KYN injection did not produce any change in MAP in any group. The results obtained suggest that excitatory amino acid input to the RVLM does contribute to the development of hypertension in rats with diet-induced obesity. PMID:20514927

  7. Prevalence of systemic arterial hypertension, electrocardiogram abnormalities, and noise-induced hearing loss in agricultural workers.

    PubMed

    Tomei, Gianfranco; Sancini, Angela; Tomei, Francesco; Vitarelli, Antonio; Andreozzi, Giorgia; Rinaldi, Giovanni; Di Giorgio, Valeria; Samperi, Ilaria; Fiaschetti, Maria; Tasciotti, Zaira; Cetica, Carlotta; Capozzella, Assunta; Ciarrocca, Manuela; Caciari, Tiziana

    2013-01-01

    ABSTRACT The literature suggests that farmers nowadays are more likely to contract cardiovascular diseases than in the past. This study involved 79 farmers and 64 controls. The workers completed a questionnaire to identify exclusion factors for audiological and cardiovascular risk factors. The participants underwent medical examination, measurement of blood pressure, electrocardiogram, blood tests, audiometry, and measurement of noise exposure. The farmers were found to have a higher prevalence of systolic and diastolic arterial hypertension as well as electrocardiogram (ECG) abnormalities compared with the controls. A significant prevalence of arterial hypertension was detected in the farmers exposed to noise, when compared with those who were not exposed. These results suggest that farmers are at risk of cardiovascular effects and that noise is a cardiovascular risk factor for farmers. PMID:23697692

  8. Curcumin Induces Nrf2 Nuclear Translocation and Prevents Glomerular Hypertension, Hyperfiltration, Oxidant Stress, and the Decrease in Antioxidant Enzymes in 5/6 Nephrectomized Rats

    PubMed Central

    Tapia, Edilia; Soto, Virgilia; Ortiz-Vega, Karla Mariana; Zarco-Márquez, Guillermo; Molina-Jijón, Eduardo; Cristóbal-García, Magdalena; Santamaría, José; García-Niño, Wylly Ramsés; Correa, Francisco; Zazueta, Cecilia; Pedraza-Chaverri, José

    2012-01-01

    Renal injury resulting from renal ablation induced by 5/6 nephrectomy (5/6NX) is associated with oxidant stress, glomerular hypertension, hyperfiltration, and impaired Nrf2-Keap1 pathway. The purpose of this work was to know if the bifunctional antioxidant curcumin may induce nuclear translocation of Nrf2 and prevents 5/6NX-induced oxidant stress, renal injury, decrease in antioxidant enzymes, and glomerular hypertension and hyperfiltration. Four groups of rats were studied: (1) control, (2) 5/6NX, (3) 5/6NX +CUR, and (4) CUR (n = 8–10). Curcumin was given by gavage to NX5/6 +CUR and CUR groups (60 mg/kg/day) starting seven days before surgery. Rats were studied 30 days after NX5/6 or sham surgery. Curcumin attenuated 5/6NX-induced proteinuria, systemic and glomerular hypertension, hyperfiltration, glomerular sclerosis, interstitial fibrosis, interstitial inflammation, and increase in plasma creatinine and blood urea nitrogen. This protective effect was associated with enhanced nuclear translocation of Nrf2 and with prevention of 5/6NX-induced oxidant stress and decrease in the activity of antioxidant enzymes. It is concluded that the protective effect of curcumin against 5/6NX-induced glomerular and systemic hypertension, hyperfiltration, renal dysfunction, and renal injury was associated with the nuclear translocation of Nrf2 and the prevention of both oxidant stress and the decrease of antioxidant enzymes. PMID:22919438

  9. Cardiac and aortic structural alterations due to surgically-induced menopause associated with renovascular hypertension in rats.

    PubMed

    Mendonça, Leonardo de Souza; Fernandes-Santos, Caroline; Mandarim-de-Lacerda, Carlos Alberto

    2007-08-01

    Menopause and hypertension independently alter cardiovascular remodelling, but little is known about their effect on left ventricular and aortic wall remodelling. Eight-weeks-old Wistar rats were divided into four groups of six animals each: Sham group, OVX group (ovariectomized rats), 2K1C (two-kidneys, one-clip rats) and OVX + 2K1C group and kept until 19 weeks. Blood pressure (BP) increased 12% in OVX group, 35% in 2K1C and OVX + 2K1C groups compared with sham group. Vaginal cytology showed Sham and 2K1C rats cycling normally, whereas OVX and OVX + 2K1C rats were persistently in dioestrus or proestrus. At euthanasia, left ventricle (LV) and thoracic aorta were removed and analysed (immunohistochemistry and stereology). LV mass/tibia length ratio and cross-sectional area of cardiomyocytes increased in all groups except Sham. The intramyocardial vascularization reduced 30% in comparison with Sham group, with no difference among OVX, 2K1C and OVX + 2K1C groups. The cardiac interstitium increased more than 45% in both 2K1C and OVX + 2K1C groups compared with Sham, but there was no significant difference between Sham and OVX groups. Nuclei number of LV cardiomyocyte diminished in OVX group, followed by 2K1C group and OVX + 2K1C group, with no difference between the 2K1C and the OVX + 2K1C groups. There was positive immunostaining for angiotensin II AT1 receptor in smooth muscle cell layer of aortic tunica media in all groups. These results show that both ovariectomy and renovascular hypertension enhance BP as a single stimulus and therefore produce adverse cardiac remodelling. However, renovascular hypertension exerts a far greater influence than surgically-induced menopause in this parameter. PMID:17696911

  10. NADPH oxidases and reactive oxygen species at different stages of chronic hypoxia-induced pulmonary hypertension in newborn piglets

    PubMed Central

    Dennis, Kathleen E.; Aschner, J. L.; Milatovic, D.; Schmidt, J. W.; Aschner, M.; Kaplowitz, M. R.; Zhang, Y.

    2009-01-01

    Recently, we reported that reactive oxygen species (ROS) generated by NADPH oxidase (NOX) contribute to aberrant responses in pulmonary resistance arteries (PRAs) of piglets exposed to 3 days of hypoxia (Am J Physiol Lung Cell Mol Physiol 295: L881–L888, 2008). An objective of the present study was to determine whether NOX-derived ROS also contribute to altered PRA responses at a more advanced stage of pulmonary hypertension, after 10 days of hypoxia. We further wished to advance knowledge about the specific NOX and antioxidant enzymes that are altered at early and later stages of pulmonary hypertension. Piglets were raised in room air (control) or hypoxia for 3 or 10 days. Using a cannulated artery technique, we found that treatments with agents that inhibit NOX (apocynin) or remove ROS [an SOD mimetic (M40403) + polyethylene glycol-catalase] diminished responses to ACh in PRAs from piglets exposed to 10 days of hypoxia. Western blot analysis showed an increase in expression of NOX1 and the membrane fraction of p67phox. Expression of NOX4, SOD2, and catalase were unchanged, whereas expression of SOD1 was reduced, in arteries from piglets raised in hypoxia for 3 or 10 days. Markers of oxidant stress, F2-isoprostanes, measured by gas chromatography-mass spectrometry, were increased in PRAs from piglets raised in hypoxia for 3 days, but not 10 days. We conclude that ROS derived from some, but not all, NOX family members, as well as alterations in the antioxidant enzyme SOD1, contribute to aberrant PRA responses at an early and a more progressive stage of chronic hypoxia-induced pulmonary hypertension in newborn piglets. PMID:19592458

  11. Schistosome-induced cholangiocyte proliferation and osteopontin secretion correlate with fibrosis and portal hypertension in human and murine schistosomiasis mansoni

    PubMed Central

    Pereira, Thiago A.; Syn, Wing-Kin; Machado, Mariana V.; Vidigal, Paula V.; Resende, Vivian; Voieta, Izabela; Xie, Guanhua; Otoni, Alba; Souza, Márcia M.; Santos, Elisângela T.; Chan, Isaac S.; Trindade, Guilherme V.M.; Choi, Steve S.; Witek, Rafal P.; Pereira, Fausto E.; Secor, William E.; Andrade, Zilton A.; Lambertucci, José Roberto

    2015-01-01

    Schistosomiasis is a major cause of portal hypertension worldwide. It associates with portal fibrosis that develops during chronic infection. The mechanisms by which the pathogen evokes these host responses remain unclear. We evaluated the hypothesis that schistosome eggs release factors that directly stimulate liver cells to produce osteopontin (OPN), a pro-fibrogenic protein that stimulates hepatic stellate cells to become myofibroblasts. We also investigated the utility of OPN as a biomarker of fibrosis and/or severity of portal hypertension. Cultured cholangiocytes, Kupffer cells and hepatic stellate cells were treated with soluble egg antigen (SEA); OPN production was quantified by quantitative reverse transcriptase polymerase chain reaction (qRTPCR) and ELISA; cell proliferation was assessed by BrdU (5-bromo-2'-deoxyuridine). Mice were infected with Schistosoma mansoni for 6 or 16 weeks to cause early or advanced fibrosis. Liver OPN was evaluated by qRTPCR and immunohistochemistry (IHC) and correlated with liver fibrosis and serum OPN. Livers from patients with schistosomiasis mansoni (early fibrosis n=15; advanced fibrosis n=72) or healthy adults (n=22) were immunostained for OPN and fibrosis markers. Results were correlated with plasma OPN levels and splenic vein pressures. SEA-induced cholangiocyte proliferation and OPN secretion (P<0.001 compared with controls). Cholangiocytes were OPN (+) in Schistosoma-infected mice and humans. Liver and serum OPN levels correlated with fibrosis stage (mice: r=0.861; human r=0.672, P=0.0001) and myofibroblast accumulation (mice: r=0.800; human: r=0.761, P=0.0001). Numbers of OPN (+) bile ductules strongly correlated with splenic vein pressure (r=0.778; P=0.001). S. mansoni egg antigens stimulate cholangiocyte proliferation and OPN secretion. OPN levels in liver and blood correlate with fibrosis stage and portal hypertension severity. PMID:26201095

  12. Decreased creatine kinase is linked to diastolic dysfunction in rats with right heart failure induced by pulmonary artery hypertension

    PubMed Central

    Fowler, Ewan D.; Benoist, David; Drinkhill, Mark J.; Stones, Rachel; Helmes, Michiel; Wüst, Rob C.I.; Stienen, Ger J.M.; Steele, Derek S.; White, Ed

    2015-01-01

    Our objective was to investigate the role of creatine kinase in the contractile dysfunction of right ventricular failure caused by pulmonary artery hypertension. Pulmonary artery hypertension and right ventricular failure were induced in rats by monocrotaline and compared to saline-injected control animals. In vivo right ventricular diastolic pressure–volume relationships were measured in anesthetized animals; diastolic force–length relationships in single enzymatically dissociated myocytes and myocardial creatine kinase levels by Western blot. We observed diastolic dysfunction in right ventricular failure indicated by significantly steeper diastolic pressure–volume relationships in vivo and diastolic force–length relationships in single myocytes. There was a significant reduction in creatine kinase protein expression in failing right ventricle. Dysfunction also manifested as a shorter diastolic sarcomere length in failing myocytes. This was associated with a Ca2 +-independent mechanism that was sensitive to cross-bridge cycling inhibition. In saponin-skinned failing myocytes, addition of exogenous creatine kinase significantly lengthened sarcomeres, while in intact healthy myocytes, inhibition of creatine kinase significantly shortened sarcomeres. Creatine kinase inhibition also changed the relatively flat contraction amplitude–stimulation frequency relationship of healthy myocytes into a steeply negative, failing phenotype. Decreased creatine kinase expression leads to diastolic dysfunction. We propose that this is via local reduction in ATP:ADP ratio and thus to Ca2 +-independent force production and diastolic sarcomere shortening. Creatine kinase inhibition also mimics a definitive characteristic of heart failure, the inability to respond to increased demand. Novel therapies for pulmonary artery hypertension are needed. Our data suggest that cardiac energetics would be a potential ventricular therapeutic target. PMID:26116865

  13. Hypertension and cognitive function.

    PubMed

    Paglieri, Cristina; Bisbocci, Daniela; Caserta, Mimma; Rabbia, Franco; Bertello, Chiara; Canadè, Antonella; Veglio, Franco

    2008-11-01

    Arterial hypertension, cerebrovascular disease, and dementia are related pathologies. This paper has reviewed comparatively the incidence of arterial hypertension and adult-onset dementia disorders. Hypertension is associated with cerebrovascular disease, which is in turn associated with dementia. It is the most important modifiable risk factor for stroke, which is a recognized cause of vascular dementia. In terms of pathophysiology of hypertensive brain damage, several hypotheses were developed, such as that vascular alterations induced by hypertension can induce lacunar or cortical infarcts and leucoaraiosis, that hypertension is responsible for cerebrovascular disease and acts into the contest of a pre-existing subclinic Alzheimer's disease (AD), that hypertension determines neurobiologic alterations (such as beta-amyloid accumulation) resulting in neuropathologic damage, and that aging and cerebrovascular risk factors act together to cause cerebral capillary degeneration, mitochondrial disruption, reduced glucose oxidation, and reduced ATP synthesis. The consequence of these alterations are neuronal death and dementia. Macroscopic results of these mechanisms are the so-called white matter lesions (WML), the significance of which is analyzed. Increasing clinical evidence suggests a close relationship between the reduction of elevated blood pressure and countering of both vascular dementia and AD. Antihypertensive treatment probably influences cognitive performances and prevents cognitive function alterations and the development of dementia. It is therefore important to evaluate as soon as possible cognitive functions of hypertensive patients. PMID:19021021

  14. Salidroside exerts protective effects against chronic hypoxia-induced pulmonary arterial hypertension via AMPKα1-dependent pathways

    PubMed Central

    Chen, Mayun; Cai, Hui; Yu, Chang; Wu, Peiliang; Fu, Yangyang; Xu, Xiaomei; Fan, Rong; Xu, Cunlai; Chen, Yanfan; Wang, Liangxing; Huang, Xiaoying

    2016-01-01

    Salidroside, an active ingredient isolated from Rhodiola rosea, has shown to exert protective effects against chronic hypoxia-induced pulmonary arterial hypertension (PAH). However, the underlying mechanisms were not well known. Based on our recent reports, we predicted the involvement of adenosine monophosphate-activated protein kinase (AMPK) mediated effects in salidroside regulation of PAH. Firstly, to prove the hypothesis, rats were exposed to chronic hypoxia and treated with increasing concentrations of salidroside or a selective AMPK activator-5’-aminoimidazole-4-carboxamide ribonucleoside (AICAR) for 4 weeks. After salidroside or AICAR treatment, the chronic hypoxia-induced right ventricular hypertrophy and pulmonary artery remodeling were attenuated. Then the effects of salidroside or AICAR on hypoxia-induced excess cellular proliferation and apoptosis resistance of pulmonary arterial smooth muscle cells (PASMCs), which contributed to pulmonary arterial remodeling, were investigated. Our results suggested salidroside, as well as AICAR, reversed hypoxia-induced PASMCs proliferation and apoptosis resistance while AMPK inhibitor Compound C enhanced the effects of hypoxia. To reveal the potential cellular mechanisms, activation of AMPKα1 and expression of the genes related to proliferation and apoptosis were analyzed in PASMCs after salidroside treatment under hypoxia conditions. The results demonstrated salidroside as well as AICAR might inhibit chronic hypoxia-induced PASMCs proliferation via AMPKα1-P53-P27/P21 pathway and reverse apoptosis resistance via AMPKα1-P53-Bax/Bcl-2-caspase 9-caspase 3 pathway. PMID:27069536

  15. Genetic knockdown of estrogen receptor-alpha in the subfornical organ augments ANG II-induced hypertension in female mice.

    PubMed

    Xue, Baojian; Zhang, Zhongming; Beltz, Terry G; Guo, Fang; Hay, Meredith; Johnson, Alan Kim

    2015-03-15

    The present study tested the hypotheses that 1) ERα in the brain plays a key role in the estrogen-protective effects against ANG II-induced hypertension, and 2) that the subfornical organ (SFO) is a key site where ERα mediates these protective actions. In this study, a "floxed" ERα transgenic mouse line (ERα(flox)) was used to create models in which ERα was knocked down in the brain or just in the SFO. Female mice with ERα ablated in the nervous system (Nestin-ERα(-) mice) showed greater increases in blood pressure (BP) in response to ANG II. Furthermore, females with ERα knockdown specifically in the SFO [SFO adenovirus-Cre (Ad-Cre) injected ERα(flox) mice] also showed an enhanced pressor response to ANG II. Immunohistochemical (IHC), RT-PCR, and Western blot analyses revealed a marked reduction in the expression of ERα in nervous tissues and, in particular, in the SFO. These changes were not present in peripheral tissues in Nestin-ERα(-) mice or Ad-Cre-injected ERα(flox) mice. mRNA expression of components of the renin-angiotensin system in the lamina terminalis were upregulated in Nestin-ERα(-) mice. Moreover, ganglionic blockade on day 7 after ANG II infusions resulted in a greater reduction of BP in Nestin-ERα(-) mice or SFO Ad-Cre-injected mice, suggesting that knockdown of ERα in the nervous system or the SFO alone augments central ANG II-induced increase in sympathetic tone. The results indicate that interfering with the action of estrogen on SFO ERα is sufficient to abolish the protective effects of estrogen against ANG II-induced hypertension. PMID:25552661

  16. Acute and chronic antihypertensive effects of Cinnamomum zeylanicum stem bark methanol extract in L-NAME-induced hypertensive rats

    PubMed Central

    2013-01-01

    Background Previous study showed that the aqueous extract of the stem bark of Cinnamomum zeylanicum possesses antihypertensive and vasodilatory properties. The present work investigates the acute and chronic antihypertensive effects of the methanol extract of Cinnamomum zeylanicum stem bark (MECZ) in L-NAME-induced hypertensive rats. Methods The acute antihypertensive effects of MECZ (5, 10 and 20 mg/kg) administered intravenously were evaluated in rats in which acute arterial hypertension has been induced by intravenous administration of L-NAME (20 mg/kg). For chronic antihypertensive effects, animals were treated with L-NAME (40 mg/kg/day) plus the vehicle or L-NAME (40 mg/kg/day) in combination with captopril (20 mg/kg/day) or MECZ (300 mg/kg/day) and compared with control group receiving only distilled water. All drugs were administered per os and at the end of the experiment that lasted for four consecutive weeks, blood pressure was measured by invasive method and blood samples were collected for the determination of the lipid profile. The heart and aorta were collected, weighed and used for both histological analysis and determination of NO tissue content. Results Acute intravenous administration of C. zeylanicum extract (5, 10 and 20 mg/kg) to L-NAME-induced hypertensive rats provoked a long-lasting decrease in blood pressure. Mean arterial blood pressure decreased by 12.5%, 26.6% and 30.6% at the doses of 5, 10 and 20 mg/kg, respectively. In chronic administration, MECZ and captopril significantly prevented the increase in blood pressure and organs’ weights, as well as tissue histological damages and were able to reverse the depletion in NO tissue’s concentration. The MECZ also significantly lower the plasma level of triglycerides (38.1%), total cholesterol (32.1%) and LDL-cholesterol (75.3%) while increasing that of HDL-cholesterol (58.4%) with a significant low atherogenic index (1.4 versus 5.3 for L-NAME group). Conclusion MECZ possesses

  17. Cervical Spondylosis and Hypertension

    PubMed Central

    Peng, Baogan; Pang, Xiaodong; Li, Duanming; Yang, Hong

    2015-01-01

    Abstract Cervical spondylosis and hypertension are all common diseases, but the relationship between them has never been studied. Patients with cervical spondylosis are often accompanied with vertigo. Anterior cervical discectomy and fusion is an effective method of treatment for cervical spondylosis with cervical vertigo that is unresponsive to conservative therapy. We report 2 patients of cervical spondylosis with concomitant cervical vertigo and hypertension who were treated successfully with anterior cervical discectomy and fusion. Stimulation of sympathetic nerve fibers in pathologically degenerative disc could produce sympathetic excitation, and induce a sympathetic reflex to cause cervical vertigo and hypertension. In addition, chronic neck pain could contribute to hypertension development through sympathetic arousal and failure of normal homeostatic pain regulatory mechanisms. Cervical spondylosis may be one of the causes of secondary hypertension. Early treatment for resolution of symptoms of cervical spondylosis may have a beneficial impact on cardiovascular disease risk in patients with cervical spondylosis. PMID:25761188

  18. Clinical study on the influence of phloroglucinol on plasma angiotensin II and D-Dimer index in patients with severe pregnancy-induced hypertension.

    PubMed

    Ai, Liang; Lan, Xinzhi; Wang, Limin; Xu, Yanjie; Zhang, Bin

    2016-07-01

    To observe the effect of phloroglucinol on plasma angiotensin II and D-dimer index when it was applied to patients with severe pregnancy-induced hypertension. 212 cases of severe pregnancy-induced hypertension patients diagnosed clinically were selected to be randomly divided into the research group and the control group. The research groups were given phloroglucinol, while the control groups were given magnesium sulfate. The plasma angiotensin II and D-dimer index in patients were detected before treatment and after 7 days respectively with statistical analysis of results. The diffidence after treatment was statistically significant (P<0.05). Compared within the same group, the difference of each index before and after treatment in the research group was statistically significant (P<0.05), while the control group was not statistically significant (P>0.05). It showed that the research group could reduce the plasma D-dimer and angiotensin II index in severe pregnancy-induced hypertension patients, and its effect was significantly better than the control group according to the plasma D-dimer and angiotensin II index changes in patients, it indicated that it was effective of phloroglucinol treatment for patients with pregnancy-induced hypertension disease and superior to the western medicine conventional treatment, worth clinical promotion. PMID:27592487

  19. Cytochrome P4501A1 is Required for Vascular Dysfunction and Hypertension Induced by 2,3,7,8-Tetrachlorodibenzo-p-dioxin

    Technology Transfer Automated Retrieval System (TEKTRAN)

    National Health and Nutrition Examination Survey data show an association between hypertension and exposure to dioxin-like halogenated aromatic hydrocarbons (HAH). Further, chronic exposure of mice to the prototypical HAH, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), induces reactive oxygen species (...

  20. Cimicifuga racemosa impairs fatty acid β-oxidation and induces oxidative stress in livers of ovariectomized rats with renovascular hypertension.

    PubMed

    Campos, Lilian Brites; Gilglioni, Eduardo Hideo; Garcia, Rosângela Fernandes; Brito, Márcia do Nascimento; Natali, Maria Raquel Marçal; Ishii-Iwamoto, Emy Luiza; Salgueiro-Pagadigorria, Clairce Luzia

    2012-08-15

    The aim of this work was to evaluate the effects of therapeutic doses of Cimicifuga racemosa on cardiovascular parameters and on liver lipid metabolism and redox status in an animal model of estrogen deficiency associated with hypertension, a condition that could make the liver more vulnerable to drug-induced injuries. Female Wistar rats were subjected to the surgical procedures of bilateral ovariectomy (OVX) and induction of renovascular hypertension (two-kidneys, one-clip; 2K1C). These animals (OVX + 2K1C) were treated with daily doses of a C. racemosa extract, using a dose that is similar to that recommended to postmenopausal women (0.6 mg/kg), over a period of 15 days. The results were compared to those of untreated OVX + 2K1C, OVX, and control rats. The treatment with C. racemosa caused a significant reduction in blood pressure. In the liver, treatment did not prevent the development of steatosis, and it reduced the mitochondrial and peroxisomal capacity to oxidize octanoyl-CoA compared to the untreated animals. In addition, C. racemosa caused numerous undesirable effects on the liver redox status: it increased the mitochondrial reactive oxygen species generation, an event that was not accompanied by an increase in the activity of superoxide dismutase, and it induced a decrease in peroxisomal catalase activity. Although the reduced glutathione content had not been affected, a phenomenon that probably reflected the restoration of glucose-6-phosphate dehydrogenase activity by C. racemosa, oxidative damage was evidenced by the elevated level of thiobarbituric acid-reactive substances found in the liver of treated animals. PMID:22684021

  1. Naringenin adds to the protective effect of L-arginine in monocrotaline-induced pulmonary hypertension in rats: favorable modulation of oxidative stress, inflammation and nitric oxide.

    PubMed

    Ahmed, Lamiaa A; Obaid, Al Arqam Z; Zaki, Hala F; Agha, Azza M

    2014-10-01

    The present study was directed to investigate the possible modulatory effect of naringenin when co-administered with L-arginine in monocrotaline-induced pulmonary hypertension in rats. Pulmonary hypertension was induced by a single subcutaneous injection of monocrotaline (60 mg/kg). L-arginine (500 mg/kg) and naringenin (50 mg/kg) were orally administered daily, alone and in combination, for 3 weeks. Mean arterial blood pressure, electrocardiography and echocardiography were then recorded and rats were sacrificed and serum was separated for determination of total nitrate/nitrite level. Right ventricles and lungs were isolated for estimation of oxidative stress markers, tumor necrosis factor-alpha, total nitrate/nitrite and transforming growth factor-beta. Myeloperoxidase and caspase-3 activities in addition to endothelial and inducible nitric oxide synthase protein expression were also determined. Moreover, histological analysis of pulmonary arteries and cardiomyocyte cross-sectional area was performed. Combined therapy provided a significant improvement in L-arginine protective effect toward preserving hemodynamic changes and alleviating oxidative stress, inflammatory and apoptotic markers induced by monocrotaline treatment. Furthermore, combined therapy prevented monocrotaline-induced changes in endothelial and inducible nitric oxide synthase protein expression as well as histological analysis compared with either treatment alone. In conclusion, naringenin significantly adds to the protective effect of L-arginine in pulmonary hypertension induced by monocrotaline in rats. PMID:24878387

  2. Development of nonfibrotic left ventricular hypertrophy in an ANG II-induced chronic ovine hypertension model.

    PubMed

    Klatt, Niklas; Scherschel, Katharina; Schad, Claudia; Lau, Denise; Reitmeier, Aline; Kuklik, Pawel; Muellerleile, Kai; Yamamura, Jin; Zeller, Tanja; Steven, Daniel; Baldus, Stephan; Schäffer, Benjamin; Jungen, Christiane; Eickholt, Christian; Wassilew, Katharina; Schwedhelm, Edzard; Willems, Stephan; Meyer, Christian

    2016-09-01

    Hypertension is a major risk factor for many cardiovascular diseases and leads to subsequent concomitant pathologies such as left ventricular hypertrophy (LVH). Translational approaches using large animals get more important as they allow the use of standard clinical procedures in an experimental setting. Therefore, the aim of this study was to establish a minimally invasive ovine hypertension model using chronic angiotensin II (ANG II) treatment and to characterize its effects on cardiac remodeling after 8 weeks. Sheep were implanted with osmotic minipumps filled with either vehicle control (n = 7) or ANG II (n = 9) for 8 weeks. Mean arterial blood pressure in the ANG II-treated group increased from 87.4 ± 5.3 to 111.8 ± 6.9 mmHg (P = 0.00013). Cardiovascular magnetic resonance imaging showed an increase in left ventricular mass from 112 ± 12.6 g to 131 ± 18.7 g after 7 weeks (P = 0.0017). This was confirmed by postmortem measurement of left ventricular wall thickness which was higher in ANG II-treated animals compared to the control group (18 ± 4 mm vs. 13 ± 2 mm, respectively, P = 0.002). However, ANG II-treated sheep did not reveal any signs of fibrosis or inflammatory infiltrates as defined by picrosirius red and H&E staining on myocardial full thickness paraffin sections of both atria and ventricles. Measurements of plasma high-sensitivity C-reactive protein and urinary 8-iso-prostaglandin F2α were inconspicuous in all animals. Furthermore, multielectrode surface mapping of the heart did not show any differences in epicardial conduction velocity and heterogeneity. These data demonstrate that chronic ANG II treatment using osmotic minipumps presents a reliable, minimally invasive approach to establish hypertension and nonfibrotic LVH in sheep. PMID:27613823

  3. Renovascular hypertension

    MedlinePlus

    Renal hypertension; Hypertension - renovascular; Renal artery occlusion; Stenosis - renal artery; Renal artery stenosis ... Renal artery stenosis is a narrowing or blockage of the arteries that supply blood to the kidneys. The most ...

  4. Hypertension - overview

    MedlinePlus Videos and Cool Tools

    If left untreated, hypertension can lead to the thickening of arterial walls causing its lumen, or blood passage way, to narrow in diameter. ... the narrowed arterial openings. In addition, people with hypertension may be more susceptible to stroke.

  5. Renovascular hypertension

    MedlinePlus

    Renal hypertension; Hypertension - renovascular; Renal artery occlusion; Stenosis - renal artery; Renal artery stenosis ... blood pressure to rise. Risk factors for atherosclerosis: High blood pressure Smoking Diabetes High cholesterol Heavy alcohol use Cocaine ...

  6. Disulfiram-Induced Reversible Hypertension: A Prospective Case Series and Review of The Literature

    PubMed Central

    Kulkarni, Ranganath R.; Ramdurg, Santosh I.; Bairy, Bhavya K.

    2014-01-01

    Disulfiram (DSF) is one of the recommended aids in the management of selected patients with alcohol dependence. Hypertension (HTN) as an adverse effect of DSF therapy is less understood. In our prospective case series of 7 subjects with co-morbid alcohol and nicotine dependence, a temporal, dose-dependent, and reversible grade 1-3 HTN within 1-6 weeks of initiation of DSF therapy (125-500 mg/day) with no other detectable causes of HTN was noted. Challenges and strategies surrounding diagnosis and treatment along with mean change and percentage rise in blood pressure are described. Literature review and clinical description of case series may suggest neurobiological role in its causation. HTN may be a clinically significant, dose-dependent, and reversible adverse effect of DSF therapy, especially in co-morbid alcohol and nicotine-dependent patients. Awareness amongst clinicians may render better health care delivery to subjects with alcohol dependence. PMID:25336781

  7. Effect of angiotensin-induced hypertension on rat coronary arteries and myocardium.

    PubMed Central

    Giacomelli, F.; Anversa, P.; Wiener, J.

    1976-01-01

    Acute hypertension has been produced in rats by the intravenous infusion of angiotensin amide for 4 hours. Both control and hypertensive animals were injected intravenously prior to sacrifice with either horseradish peroxidase (HRP) or colloidal carbon. Epicardial arteries and blocks of ventricular myocardium containing intramyocardial arteries and arterioles have been processed for electron microscopy. HRP appears to penetrate the endoethelium of epicardial arteries from control animals within vesicles that bypass endothelial junctions and empty into interendoethelial clefts. Peroxidase does not traverse the endothelium of intramural arteries and arterioles of controls over the 10-minute period of observation. There is acceleration of lateral vesicular transport in the endothelium of epicardial arteries after angiotensin infusion and direct permeation of interendothelial clefts of intramural arterial vessels. Medial fragmentation and more extensive necrosis are observed in intramyocardial but not in epicardial arterial vessels. Foci of myocardial damage resembling irreversible ischemic or anoxic injury followed by reflow are described. It is suggested that the increased permeability of epicardial arteries may be due to elevated pressure, while the altered permeability and vascular lesions of intramural arteries and arterioles are more readily attributable to the vasoconstriction produced by angiotension. The vascular and myocardial lesions are also discussed in relation to the regional actions of angiotensin on the coronary circulation and known effects of this vasoactive peptide on myocardium. Images Figure 19 Figure 26 Figure 27 Figure 28 Figure 1 Figure 2 Figures 20 and 21 Figure 29 Figure 30 Figure 3 Figure 4 Figures 5-8 Figure 9 Figure 22 Figure 10 Figure 11 Figure 12 Figure 13 Figure 14 Figure 15 Figure 23 Figure 24 Figure 25 Figure 16 Figure 17 Figure 18 PMID:937512

  8. Fucoidan from Undaria pinnatifida prevents vascular dysfunction through PI3K/Akt/eNOS-dependent mechanisms in the l-NAME-induced hypertensive rat model.

    PubMed

    Li, Xiaofei; Li, Jian; Li, Zhike; Sang, Ying; Niu, Yunhui; Zhang, Qianying; Ding, Hong; Yin, Shanye

    2016-05-18

    Despite major scientific advances in its prevention, treatment and care, hypertension remains a serious condition that might lead to long-term complications such as heart disease and stroke. The great majority of forms of hypertension eventually result from an increased vasomotor tone activity that is regulated by endothelial NOS (eNOS) in vascular endothelium. Here, we examined the effect of fucoidan on eNOS activation in human umbilical vein endothelial cells (HUVECs). We also examined the effects of functional components of Undaria pinnatifida fucoidan on blood pressure and vascular function in eNOS inhibition-induced hypertensive rats in vivo. Our results suggest that fucoidan increased nitric oxide production by activating eNOS and Akt phosphorylation, which could be impaired by Akt or eNOS inhibitors. In the hypertensive rat model, treatment of fucoidan resulted in potent and persistent reduction of high blood pressure (BP) even after drug withdrawal. Our results showed that the mechanisms might involve protection against vascular structure damage, enhanced endothelium-independent vascular function and inhibition of abnormal proliferation of smooth muscle cells, which are mediated by the Akt-eNOS signaling pathway. Moreover, fucoidan treatment reduced the vascular inflammation and oxidative stress control caused by iNOS expression. Together, these results support a putative role of fucoidan in hypertension prevention and treatment. PMID:27153123

  9. Deletion of interleukin-6 prevents cardiac inflammation, fibrosis and dysfunction without affecting blood pressure in angiotensin II-high salt-induced hypertension

    PubMed Central

    González, Germán E.; Rhaleb, Nour-Eddine; D’ambrosio, Martin A.; Nakagawa, Pablo; Liu, Yunhe; Leung, Pablo; Dai, Xiangguo; Yang, Xiao-Ping; Peterson, Edward L.; Carretero, Oscar A.

    2014-01-01

    Objective Inflammation has been proposed as a key component in the development of hypertension and cardiac remodeling associated with different cardiovascular diseases. However, the role of the proinflammatory cytokine interleukin-6 in the chronic stage of hypertension is not well defined. Here, we tested the hypothesis that deletion of interleukin-6 protects against the development of hypertension, cardiac inflammation, fibrosis, remodeling and dysfunction induced by high salt diet and angiotensin II (Ang II). Methods Male C57BL/6J and interleukin-6-knock out (KO) mice were implanted with telemetry devices for blood pressure (BP) measurements, fed a 4% NaCl diet, and infused with either vehicle or Ang II (90 ng/min per mouse subcutaneously) for 8 weeks. We studied BP and cardiac function by echocardiography at baseline, 4 and 8 weeks. Results Myocyte cross-sectional area (MCSA), macrophage infiltration, and myocardial fibrosis were also assessed. BP increased similarly in both strains when treated with Ang II and high salt (Ang II-high salt); however, C57BL/6J mice developed a more severe decrease in left ventricle ejection fraction, fibrosis, and macrophage infiltration compared with interleukin-6-KO mice. No differences between strains were observed in MCSA, capillary density and MCSA to capillary density ratio. Conclusion In conclusion, absence of interleukin -6 did not alter the development of Ang II-high salt-induced hypertension and cardiac hypertrophy, but it prevented the development of cardiac dysfunction, myocardial inflammation, and fibrosis. This indicates that interleukin-6 plays an important role in hypertensive heart damage but not in the development of hypertension. PMID:25304471

  10. MATERNAL DIET DURING GESTATION AND LACTATION MODIFIES THE SEVERITY OF SALT-INDUCED HYPERTENSION AND RENAL INJURY IN DAHL SALT-SENSITIVE RATS

    PubMed Central

    Geurts, Aron M.; Mattson, David L.; Liu, Pengyuan; Cabacungan, Erwin; Skelton, Meredith M.; Kurth, Theresa M.; Yang, Chun; Endres, Bradley T.; Klotz, Jason; Liang, Mingyu; Cowley, Allen W.

    2014-01-01

    Environmental exposure of parents or early in life may affect disease development in adults. We found that hypertension and renal injury induced by a high-salt diet were substantially attenuated in Dahl SS/JrHsdMcwiCrl (SS/Crl) rats that had been maintained for many generations on the grain-based 5L2F diet compared to SS/JrHsdMcwi rats (SS/Mcw) maintained on the casein-based AIN-76A diet (mean arterial pressure 116±9 vs. 154±25 mmHg; urinary albumin excretion 23±12 vs. 170±80 mg/day). RNA-seq analysis of the renal outer medulla identified 129 and 82 genes responding to a high-salt diet uniquely in SS/Mcw and SS/Crl rats, respectively, along with minor genetic differences between the SS substrains. The 129 genes responding to salt in the SS/Mcw strain included numerous genes with homologs associated with hypertension, cardiovascular disease, or renal disease in human. To narrow the critical window of exposure, we performed embryo transfer experiments in which single-cell embryos from one colony (SS/Mcw or SS/Crl) were transferred to surrogate mothers from the other colony, with parents and surrogate mothers maintained on their respective original diet. All offspring were fed the AIN-76A diet after weaning. Salt-induced hypertension and renal injury were substantially exacerbated in rats developed from SS/Crl embryos transferred to SS/Mcw surrogate mothers. Conversely, salt-induced hypertension and renal injury were significantly attenuated in rats developed from SS/Mcw embryos transferred to SS/Crl surrogate mothers. Together, the data suggests that maternal diet during the gestational-lactational period has substantial effects on the development of salt-induced hypertension and renal injury in adult SS rats. PMID:25452472

  11. The effect of hydroalcoholic extract of Ferula foetida stems on blood pressure and oxidative stress in dexamethasone-induced hypertensive rats

    PubMed Central

    Safaeian, Leila; Ghannadi, Alireza; Javanmard, Shaghayegh Haghjoo; Vahidian, Mohammad Hadi

    2015-01-01

    Ferula foetida (Bunge) Regel. is one of the most widespread and important Ferula species with nutritional and medicinal applications. Some phytochemicals with helpful cardiovascular effects have been isolated from Ferula species. The present study was designed to evaluate the effects of hydroalcoholic extract of the stems of F. foetida in dexamethasone (Dex)-induced hypertension in rats. Hypertension was induced by subcutaneous injection of Dex (30 µg/kg) for 14 days. In a prevention study, rats received oral F. foetida extract (200, 400 and 800 mg/kg) for 4 days prior to Dex administration and during the test period (Days 1-18). In a treatment study, F. foetida extract was administered from day 8 to 14. Systolic blood pressure (SBP) was evaluated using tail-cuff method. The thymus weight was measured as an indicator of glucocorticoid activity. The hydrogen peroxide (H2O2) concentration and ferric reducing antioxidant power (FRAP) were measured in plasma samples. Dex-induced hypertensive rats showed significant increases in SBP and in plasma H2O2 and decreases in the body and thymus weights and in FRAP value (P<0.001). Administration of F. foetida extract significantly prevented and reversed hypertension at all doses. It also increased plasma FRAP value (P<0.001) but failed to decrease plasma H2O2 concentration. These results suggest antihypertensive and antioxidant effects of F. foetida stem extract in Dex-induced hypertension. More investigations are needed to elucidate the exact mechanism of antihypertensive effect of this traditional phytomedicine. PMID:26600859

  12. Maternal diet during gestation and lactation modifies the severity of salt-induced hypertension and renal injury in Dahl salt-sensitive rats.

    PubMed

    Geurts, Aron M; Mattson, David L; Liu, Pengyuan; Cabacungan, Erwin; Skelton, Meredith M; Kurth, Theresa M; Yang, Chun; Endres, Bradley T; Klotz, Jason; Liang, Mingyu; Cowley, Allen W

    2015-02-01

    Environmental exposure of parents or early in life may affect disease development in adults. We found that hypertension and renal injury induced by a high-salt diet were substantially attenuated in Dahl SS/JrHsdMcwiCrl (SS/Crl) rats that had been maintained for many generations on the grain-based 5L2F diet compared with SS/JrHsdMcwi rats (SS/Mcw) maintained on the casein-based AIN-76A diet (mean arterial pressure, 116±9 versus 154±25 mm Hg; urinary albumin excretion, 23±12 versus 170±80 mg/d). RNAseq analysis of the renal outer medulla identified 129 and 82 genes responding to a high-salt diet uniquely in SS/Mcw and SS/Crl rats, respectively, along with minor genetic differences between the SS substrains. The 129 genes responding to salt in the SS/Mcw strain included numerous genes with homologs associated with hypertension, cardiovascular disease, or renal disease in human. To narrow the critical window of exposure, we performed embryo-transfer experiments in which single-cell embryos from 1 colony (SS/Mcw or SS/Crl) were transferred to surrogate mothers from the other colony, with parents and surrogate mothers maintained on their respective original diet. All offspring were fed the AIN-76A diet after weaning. Salt-induced hypertension and renal injury were substantially exacerbated in rats developed from SS/Crl embryos transferred to SS/Mcw surrogate mothers. Conversely, salt-induced hypertension and renal injury were significantly attenuated in rats developed from SS/Mcw embryos transferred to SS/Crl surrogate mothers. Together, the data suggest that maternal diet during the gestational-lactational period has substantial effects on the development of salt-induced hypertension and renal injury in adult SS rats. PMID:25452472

  13. Cytochrome P4501A1 Is Required for Vascular Dysfunction and Hypertension Induced by 2,3,7,8-Tetrachlorodibenzo-p-Dioxin

    PubMed Central

    Kopf, Phillip G.; Scott, Jason A.; Agbor, Larry N.; Boberg, Jason R.; Elased, Khalid M.; Huwe, Janice K.; Walker, Mary K.

    2010-01-01

    National Health and Nutrition Examination Survey data show an association between hypertension and exposure to dioxin-like halogenated aromatic hydrocarbons (HAHs). Furthermore, chronic exposure of mice to the prototypical HAH, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), induces reactive oxygen species (ROS), endothelial dysfunction, and hypertension. Because TCDD induces cytochrome P4501A1 (CYP1A1) and CYP1A1 can increase ROS, we tested the hypothesis that TCDD-induced endothelial dysfunction and hypertension are mediated by CYP1A1. CYP1A1 wild-type (WT) and knockout (KO) mice were fed one control or TCDD-containing pill (180 ng TCDD/kg, 5 days/week) for 35 days (n = 10–14/genotype/treatment). Blood pressure was monitored by radiotelemetry, and liver TCDD concentration, CYP1A1 induction, ROS, and aortic reactivity were measured at 35 days. TCDD accumulated to similar levels in livers of both genotypes. TCDD induced CYP1A1 in endothelium of aorta and mesentery without detectable expression in the vessel wall. TCDD also induced superoxide anion production, measured by NADPH-dependent lucigenin luminescence, in aorta, heart, and kidney of CYP1A1 WT mice but not KO mice. In contrast, TCDD induced hydrogen peroxide, measured by amplex red assay, to similar levels in aorta of CYP1A1 WT and KO mice but not in heart or kidney. TCDD reduced acetylcholine-dependent vasorelaxation in aortic rings of CYP1A1 WT mice but not in KO mice. Finally, TCDD steadily increased blood pressure after 15 days, which plateaued after 25 days (+20 mmHg) in CYP1A1 WT mice but failed to alter blood pressure in KO mice. These results demonstrate that CYP1A1 is required for TCDD-induced cardiovascular superoxide anion production, endothelial dysfunction, and hypertension. PMID:20634294

  14. Vascular endothelial-cadherin downregulation as a feature of endothelial transdifferentiation in monocrotaline-induced pulmonary hypertension.

    PubMed

    Nikitopoulou, Ioanna; Orfanos, Stylianos E; Kotanidou, Anastasia; Maltabe, Violetta; Manitsopoulos, Nikolaos; Karras, Panagiotis; Kouklis, Panos; Armaganidis, Apostolos; Maniatis, Nikolaos A

    2016-08-01

    Increased pulmonary vascular resistance in pulmonary hypertension (PH) is caused by vasoconstriction and obstruction of small pulmonary arteries by proliferating vascular cells. In analogy to cancer, subsets of proliferating cells may be derived from endothelial cells transitioning into a mesenchymal phenotype. To understand phenotypic shifts transpiring within endothelial cells in PH, we injected rats with alkaloid monocrotaline to induce PH and measured lung tissue levels of endothelial-specific protein and critical differentiation marker vascular endothelial (VE)-cadherin. VE-cadherin expression by immonoblotting declined significantly 24 h and 15 days postinjection to rebound to baseline at 30 days. There was a concomitant increase in transcriptional repressors Snail and Slug, along with a reduction in VE-cadherin mRNA. Mesenchymal markers α-smooth muscle actin and vimentin were upregulated by immunohistochemistry and immunoblotting, and α-smooth muscle actin was colocalized with endothelial marker platelet endothelial cell adhesion molecule-1 by confocal microscopy. Apoptosis was limited in this model, especially in the 24-h time point. In addition, monocrotaline resulted in activation of protein kinase B/Akt, endothelial nitric oxide synthase (eNOS), nuclear factor (NF)-κB, and increased lung tissue nitrotyrosine staining. To understand the etiological relationship between nitrosative stress and VE-cadherin suppression, we incubated cultured rat lung endothelial cells with endothelin-1, a vasoconstrictor and pro-proliferative agent in pulmonary arterial hypertension. This resulted in activation of eNOS, NF-κB, and Akt, in addition to induction of Snail, downregulation of VE-cadherin, and synthesis of vimentin. These effects were blocked by eNOS inhibitor N(ω)-nitro-l-arginine methyl ester. We propose that transcriptional repression of VE-cadherin by nitrosative stress is involved in endothelial-mesenchymal transdifferentiation in experimental PH. PMID

  15. N-acetylcysteine improves established monocrotaline-induced pulmonary hypertension in rats

    PubMed Central

    2014-01-01

    Background The outcome of patients suffering from pulmonary arterial hypertension (PAH) are predominantly determined by the response of the right ventricle to the increase afterload secondary to high vascular pulmonary resistance. However, little is known about the effects of the current available or experimental PAH treatments on the heart. Recently, inflammation has been implicated in the pathophysiology of PAH. N-acetylcysteine (NAC), a well-known safe anti-oxidant drug, has immuno-modulatory and cardioprotective properties. We therefore hypothesized that NAC could reduce the severity of pulmonary hypertension (PH) in rats exposed to monocrotaline (MCT), lowering inflammation and preserving pulmonary vascular system and right heart function. Methods Saline-treated control, MCT-exposed, MCT-exposed and NAC treated rats (day 14–28) were evaluated at day 28 following MCT for hemodynamic parameters (right ventricular systolic pressure, mean pulmonary arterial pressure and cardiac output), right ventricular hypertrophy, pulmonary vascular morphometry, lung inflammatory cells immunohistochemistry (monocyte/macrophages and dendritic cells), IL-6 expression, cardiomyocyte hypertrophy and cardiac fibrosis. Results The treatment with NAC significantly decreased pulmonary vascular remodeling, lung inflammation, and improved total pulmonary resistance (from 0.71 ± 0.05 for MCT group to 0.50 ± 0.06 for MCT + NAC group, p < 0.05). Right ventricular function was also improved with NAC treatment associated with a significant decrease in cardiomyocyte hypertrophy (625 ± 69 vs. 439 ± 21 μm2 for MCT and MCT + NAC group respectively, p < 0.001) and heart fibrosis (14.1 ± 0.8 vs. 8.8 ± 0.1% for MCT and MCT + NAC group respectively, p < 0.001). Conclusions Through its immuno-modulatory and cardioprotective properties, NAC has beneficial effect on pulmonary vascular and right heart function in experimental PH. PMID:24929652

  16. Involvement of mast cells in monocrotaline-induced pulmonary hypertension in rats

    PubMed Central

    2011-01-01

    Background Mast cells (MCs) are implicated in inflammation and tissue remodeling. Accumulation of lung MCs is described in pulmonary hypertension (PH); however, whether MC degranulation and c-kit, a tyrosine kinase receptor critically involved in MC biology, contribute to the pathogenesis and progression of PH has not been fully explored. Methods Pulmonary MCs of idiopathic pulmonary arterial hypertension (IPAH) patients and monocrotaline-injected rats (MCT-rats) were examined by histochemistry and morphometry. Effects of the specific c-kit inhibitor PLX and MC stabilizer cromolyn sodium salt (CSS) were investigated in MCT-rats both by the preventive and therapeutic approaches. Hemodynamic and right ventricular hypertrophy measurements, pulmonary vascular morphometry and analysis of pulmonary MC localization/counts/activation were performed in animal model studies. Results There was a prevalence of pulmonary MCs in IPAH patients and MCT-rats as compared to the donors and healthy rats, respectively. Notably, the perivascular MCs were increased and a majority of them were degranulated in lungs of IPAH patients and MCT-rats (p < 0.05 versus donor and control, respectively). In MCT-rats, the pharmacological inhibitions of MC degranulation and c-kit with CSS and PLX, respectively by a preventive approach (treatment from day 1 to 21 of MCT-injection) significantly attenuated right ventricular systolic pressure (RVSP) and right ventricular hypertrophy (RVH). Moreover, vascular remodeling, as evident from the significantly decreased muscularization and medial wall thickness of distal pulmonary vessels, was improved. However, treatments with CSS and PLX by a therapeutic approach (from day 21 to 35 of MCT-injection) neither improved hemodynamics and RVH nor vascular remodeling. Conclusions The accumulation and activation of perivascular MCs in the lungs are the histopathological features present in clinical (IPAH patients) and experimental (MCT-rats) PH. Moreover, the

  17. Key Role of ROS in the Process of 15-Lipoxygenase/15-Hydroxyeicosatetraenoiccid-Induced Pulmonary Vascular Remodeling in Hypoxia Pulmonary Hypertension

    PubMed Central

    Qiu, Yanli; Liu, Gaofeng; Sheng, Tingting; Yu, Xiufeng; Wang, Shuang; Zhu, Daling

    2016-01-01

    We previously reported that 15-lipoxygenase (15-LO) and its metabolite 15-hydroxyeicosatetraenoic acid (15-HETE) were up-regulated in pulmonary arterial cells from both pulmonary artery hypertension patients and hypoxic rats and that these factors mediated the progression of pulmonary hypertension (PH) by affecting the proliferation and apoptosis of pulmonary arterial (PA) cells. However, the underlying mechanisms of the remodeling induced by 15-HETE have remained unclear. As reactive oxygen species (ROS) and 15-LO are both induced by hypoxia, it is possible that ROS are involved in the events of hypoxia-induced 15-LO expression that lead to PH. We employed immunohistochemistry, tube formation assays, bromodeoxyuridine (BrdU) incorporation assays, and cell cycle analyses to explore the role of ROS in the process of 15-HETE-mediated hypoxic pulmonary hypertension (HPH). We found that exogenous 15-HETE facilitated the generation of ROS and that this effect was mainly localized to mitochondria. In particular, the mitochondrial electron transport chain and nicotinamide-adenine dinucleotide phosphate oxidase 4 (Nox4) were responsible for the significant 15-HETE-stimulated increase in ROS production. Moreover, ROS induced by 15-HETE stimulated endothelial cell (EC) migration and promoted pulmonary artery smooth muscle cell (PASMC) proliferation under hypoxia via the p38 MAPK pathway. These results indicated that 15-HETE-regulated ROS mediated hypoxia-induced pulmonary vascular remodeling (PVR) via the p38 MAPK pathway. PMID:26871724

  18. [Childhood hypertension].

    PubMed

    Takemura, Tsukasa

    2015-11-01

    For accurate diagnosis of childhood hypertension, selection of appropriate manchette size according to the child age and the circumstantial size of upper limb is essentially important. In addition, except for the emergency case of hypertension, repeated measurement of blood pressure would be desirable in several weeks interval. Recently, childhood hypertension might be closely related to the abnormality of maternal gestational period caused by the strict diet and the maternal smoking. Developmental Origins of Health and Disease(DOHaD) theory is now highlighted in the pathogenesis of adulthood hypertension. To prevent hypertension of small-for-date baby in later phase of life, maternal education for child nursing should be conducted. In children, secondary hypertension caused by renal, endocrinologic, or malignant disease is predominant rather than idiopathic hypertension. PMID:26619664

  19. Central Infusion of Angiotensin II Type 2 Receptor Agonist Compound 21 Attenuates DOCA/NaCl-Induced Hypertension in Female Rats

    PubMed Central

    Dai, Shu-Yan; Zhang, Yu-Ping; Peng, Wei; Shen, Ying; He, Jing-Jing

    2016-01-01

    The present study investigated whether central activation of angiotensin II type 2 receptor (AT2-R) attenuates deoxycorticosterone acetate (DOCA)/NaCl-induced hypertension in intact and ovariectomized (OVX) female rats and whether female sex hormone status has influence on the effects of AT2-R activation. DOCA/NaCl elicited a greater increase in blood pressure in OVX females than that in intact females. Central infusion of compound 21, a specific AT2-R agonist, abolished DOCA/NaCl pressor effect in intact females, whereas same treatment in OVX females produced an inhibitory effect. Real-time RT-PCR analysis revealed that DOCA/NaCl enhanced the mRNA expression of hypertensive components including AT1-R, ACE-1, and TNF-α in the paraventricular nucleus of hypothalamus in both intact and OVX females. However, the mRNA expressions of antihypertensive components such as AT2-R, ACE-2, and IL-10 were increased only in intact females. Central AT2-R agonist reversed the changes in the hypertensive components in all females, while this agonist further upregulated the expression of ACE2 and IL-10 in intact females, but only IL-10 in OVX females. These results indicate that brain AT2-R activation plays an inhibitory role in the development of DOCA/NaCl-induced hypertension in females. This beneficial effect of AT2-R activation involves regulation of renin-angiotensin system and proinflammatory cytokines. PMID:26783414

  20. The effects of chronic lead treatment and hypertension on the severity of cardiac arrhythmias induced by coronary artery occlusion or by noradrenaline in anaesthetised rats.

    PubMed

    Evis, M J; Dhaliwal, K; Kane, K A; Moore, M R; Parratt, J R

    1987-02-01

    The aim of this study was to investigate whether chronic (3 months) lead (250 or 1000 ppm), administered as lead acetate in the drinking water, commencing either after weaning (in normotensive or spontaneously hypertensive male rats) or from conception (normotensive rats only) altered the susceptibility of the heart to arrhythmias induced either by coronary artery occlusion or by noradrenaline. Treatment with lead alone had no marked effect on the arrhythmias elicited by either method. Spontaneously hypertensive rats treated with either dose of lead exhibited more ectopic beats following coronary artery occlusion than normotensive rats but not more than those observed in control spontaneously hypertensive rats. An enhanced arrhythmogenic effect of noradrenaline was observed only in hypertensive rats administered 250 ppm lead. Both doses of lead accelerated the development of high blood pressure and in normotensive rats the higher dose also resulted in an elevated pressure. Following administration of lead, blood lead concentrations were elevated to 0.96 and 2.11 mumol l-1 after 250 and 1000 ppm, respectively. Accumulation of lead in heart and bone was also observed. We conclude that chronic exposure to these concentrations of lead, when combined with high blood pressure, slightly enhances the susceptibility of the heart to arrhythmias induced by myocardial ischaemia. PMID:3579598

  1. Adipose-derived stromal cell autologous transplantation ameliorates pulmonary arterial hypertension induced by shunt flow in rat models.

    PubMed

    Liu, Kai; Liu, Ruifang; Cao, Guangqing; Sun, Hourong; Wang, Xuping; Wu, Shuming

    2011-06-01

    Hyperkinetic pulmonary arterial hypertension (PAH) severely influences the success of operation for congenital heart disease and deteriorates the prognosis of disease. Adipose-derived stromal cell (ADSC) is a good alternative multipotent stem cell for regeneration medicine. PAH rat models were established by arteriovenous shunt and ADSCs were isolated, cultured, and labeled in vitro. Twelve weeks after shunt operation, rats received an injection of 5 × 10(7) ADSCs. Two weeks after transplantation, hemodynamic abnormality induced by the shunt flow and the hypertrophy of right ventricle were reversed, which was confirmed by invasive measurement and echocardiography examination. The PAH rats receiving cell transplantation demonstrated decreased remodeling of small arteries in the lung; immunohistochemistry analysis showed augmented expression of hepatocyte growth factor (HGF) and increased number of pulmonary small arteries. Western blot and real-time reverse transcriptase-polymerase chain reaction indicated that the protein and mRNA levels of HGF and endothelial nitric oxide synthase increased, respectively, in the lung after cell transplantation. Our results suggested that ADSC transplantation can ameliorate PAH induced by shunt flow by enhancing the expression of HGF and subsequently promoting angiogenesis in the injured lung tissue. PMID:20828291

  2. Excessive Adventitial Remodeling Leads to Early Aortic Maladaptation in Angiotensin-Induced Hypertension.

    PubMed

    Bersi, Matthew R; Bellini, Chiara; Wu, Jing; Montaniel, Kim R C; Harrison, David G; Humphrey, Jay D

    2016-05-01

    The primary function of central arteries is to store elastic energy during systole and to use it to sustain blood flow during diastole. Arterial stiffening compromises this normal mechanical function and adversely affects end organs, such as the brain, heart, and kidneys. Using an angiotensin II infusion model of hypertension in wild-type mice, we show that the thoracic aorta exhibits a dramatic loss of energy storage within 2 weeks that persists for at least 4 weeks. This diminished mechanical functionality results from increased structural stiffening as a result of an excessive accumulation of adventitial collagen, not a change in the intrinsic stiffness of the wall. A detailed analysis of the transmural biaxial wall stress suggests that the exuberant production of collagen results more from an inflammatory response than from a mechano-adaptation, hence reinforcing the need to control inflammation, not just blood pressure. Although most clinical assessments of arterial stiffening focus on intimal-medial thickening, these results suggest a need to measure and control the highly active and important adventitia. PMID:27001298

  3. Development and Characterization of an Inducible Rat Model of Chronic Thromboembolic Pulmonary Hypertension.

    PubMed

    Arias-Loza, Paula-Anahi; Jung, Pius; Abeßer, Marco; Umbenhauer, Sandra; Williams, Tatjana; Frantz, Stefan; Schuh, Kai; Pelzer, Theo

    2016-05-01

    Chronic thromboembolic pulmonary hypertension (CTEPH) is an entity of PH that not only limits patients quality of life but also causes significant morbidity and mortality. The treatment of choice is pulmonary endarterectomy. However numerous patients do not qualify for pulmonary endarterectomy or present with residual vasculopathy post pulmonary endarterectomy and require specific vasodilator treatment. Currently, there is no available specific small animal model of CTEPH that could serve as tool to identify targetable molecular pathways and to test new treatment options. Thus, we generated and standardized a rat model that not only resembles functional and histological features of CTEPH but also emulates thrombi fibrosis. The pulmonary embolism protocol consisted of 3 sequential tail vein injections of fibrinogen/collagen-covered polystyrene microspheres combined with thrombin and administered to 10-week-old male Wistar rats. After the third embolism, rats developed characteristic features of CTEPH including elevated right ventricular systolic pressure, right ventricular cardiomyocyte hypertrophy, pulmonary artery remodeling, increased serum brain natriuretic peptide levels, thrombi fibrosis, and formation of pulmonary cellular-fibrotic lesions. The current animal model seems suitable for detailed study of CTEPH pathophysiology and permits preclinical testing of new pharmacological therapies against CTEPH. PMID:27045032

  4. Activation of autophagy induces retinal ganglion cell death in a chronic hypertensive glaucoma model

    PubMed Central

    Park, H-Y Lopilly; Kim, J H; Park, C K

    2012-01-01

    Autophagy is reported to have important roles in relation to regulated cell death pathways and neurodegeneration. This study used chronic hypertensive glaucoma rat model to investigate whether the autophagy pathway has a role in the apoptosis of retinal ganglion cells (RGCs) after chronic intraocular pressure (IOP) elevation. Under electron microscopy, autophagosomes were markedly accumulated in the dendrites and cytoplasm of RGCs after IOP elevation. Western blot analysis showed that LC3-II/LC3-I and beclin-1 were upregulated throughout the 8-weeks period after IOP elevation. The pattern of LC3 immunostaining showed autophagy activation in the cytoplasm of RGCs to increase and peak at 4 weeks after IOP elevation. Most of these LC3B-positive RGCs underwent apoptosis by terminal deoxynucleotidyltransferase-mediated biotinylated UTP nick end labeling, and inhibition of autophagy with 3-methyladenine decreased RGC apoptosis. The activated pattern shows that autophagy is initially activated in the dendrites of the RGCs, but, thereafter autophagy is mainly activated in the cytoplasm of RGCs. This may show that autophagy is differently regulated in different compartments of the neuron. This present study showed that autophgy is activated in RGCs and has a role in autophagic cell death after chronic IOP elevation. PMID:22476098

  5. Murine prolylcarboxypeptidase depletion induces vascular dysfunction with hypertension and faster arterial thrombosis

    PubMed Central

    Adams, Gregory N.; LaRusch, Gretchen A.; Stavrou, Evi; Zhou, Yihua; Nieman, Marvin T.; Jacobs, Gretta H.; Cui, Yingjie; Lu, Yuan; Jain, Mukesh K.; Mahdi, Fakhri; Shariat-Madar, Zia; Okada, Yoshio; D'Alecy, Louis G.

    2011-01-01

    Prolylcarboxypeptidase (PRCP) activates prekallikrein to plasma kallikrein, leading to bradykinin liberation, and degrades angiotensin II. We now identify PRCP as a regulator of blood vessel homeostasis. β-Galactosidase staining in PRCPgt/gt mice reveals expression in kidney and vasculature. Invasive telemetric monitorings show that PRCPgt/gt mice have significantly elevated blood pressure. PRCPgt/gt mice demonstrate shorter carotid artery occlusion times in 2 models, and their plasmas have increased thrombin generation times. Pharmacologic inhibition of PRCP with Z-Pro-Prolinal or plasma kallikrein with soybean trypsin inhibitor, Pro-Phe-Arg-chloromethylketone or PKSI 527 also shortens carotid artery occlusion times. Aortic and renal tissues have uncoupled eNOS and increased reactive oxygen species (ROS) in PRCPgt/gt mice as detected by dihydroethidium or Amplex Red fluorescence or lucigenin luminescence. The importance of ROS is evidenced by the fact that treatment of PRCPgt/gt mice with antioxidants (mitoTEMPO, apocynin, Tempol) abrogates the hypertensive, prothrombotic phenotype. Mechanistically, our studies reveal that PRCPgt/gt aortas express reduced levels of Kruppel-like factors 2 and 4, thrombomodulin, and eNOS mRNA, suggesting endothelial cell dysfunction. Further, PRCP siRNA treatment of endothelial cells shows increased ROS and uncoupled eNOS and decreased protein C activation because of thrombomodulin inactivation. Collectively, our studies identify PRCP as a novel regulator of vascular ROS and homeostasis. PMID:21297000

  6. Multiple esophageal variceal ruptures with massive ascites due to myelofibrosis-induced portal hypertension

    PubMed Central

    Tokai, Koichi; Miyatani, Hiroyuki; Yoshida, Yukio; Yamada, Shigeki

    2012-01-01

    A 75-year old man had been diagnosed at 42 years of age as having polycythemia vera and had been monitored at another hospital. Progression of anemia had been recognized at about age 70, and the patient was thus referred to our center in 2008 where secondary myelofibrosis was diagnosed based on bone marrow biopsy findings. Hematemesis due to rupture of esophageal varices occurred in January and February of 2011. The bleeding was stopped by endoscopic variceal ligation. Furthermore, in March of the same year, hematemesis recurred and the patient was transported to our center. He was in irreversible hemorrhagic shock and died. The autopsy showed severe bone marrow fibrosis with mainly argyrophilic fibers, an observation consistent with myelofibrosis. The liver weighed 1856 g the spleen 1572 g, indicating marked hepatosplenomegaly. The liver and spleen both showed extramedullary hemopoiesis. Myelofibrosis is often complicated by portal hypertension and is occasionally associated with gastrointestinal hemorrhage due to esophageal varices. A patient diagnosed as having myelofibrosis needs to be screened for esophageal/gastric varices. Myelofibrosis has a poor prognosis. Therefore, it is necessary to carefully decide the therapeutic strategy in consideration of the patient’s concomitant conditions, treatment invasiveness and quality of life. PMID:22851873

  7. Antihypertensive and antioxidant effects of hydroalcoholic extract from the aerial parts of Kelussia odoratissima Mozaff. in dexamethasone-induced hypertensive rats

    PubMed Central

    Safaeian, Leila; Sajjadi, Seyed Ebrahim; Javanmard, Shaghayegh Haghjoo; Gholamzadeh, Hadi

    2016-01-01

    Background: Kelussia odoratissima Mozaff. is a monotypic endemic plant of Apiaceae growing wild in Iran. The aerial parts of this plant are used for treatment of hypertension, ulcer, and inflammatory conditions in folk medicine. In this study, the effects of hydroalcoholic extract of the aerial parts of K. odoratissima were evaluated in dexamethasone (Dex)-induced hypertension in male Wistar rats. Materials and Methods: For induction of hypertension, Dex (30 μg/kg/day) was administered subcutaneously for 14 days. In a prevention study, rats received oral K. odoratissima extract (100, 200, and 400 mg/kg) from 4 days before Dex administration and during the test period (days 1–18). In a reversal study, K. odoratissima extract was administered orally from day 8 to 14. Systolic blood pressure (SBP) was evaluated using tail-cuff method. The hydrogen peroxide (H2O2) concentration and ferric-reducing antioxidant power (FRAP) were measured in plasma samples. Results: Administrations of Dex significantly induced an increase in SBP and in plasma H2O2 and a decrease in body and thymus weights, and in FRAP value (P < 0.001). K. odoratissima extract dose-dependently prevented and reversed hypertension (P < 0.001). It also prevented and reduced the plasma H2O2 concentration and prevented the body weight loss upon Dex administration at all doses (100–400 mg/kg, P < 0.001) but failed to improve FRAP value. Conclusions: These results suggest antihypertensive and antioxidant effects of K. odoratissima extract in Dex-induced hypertension. Further studies are needed to elucidate the exact mechanism of the antihypertensive effect of this herbal medicine. PMID:27014652

  8. Exposure to stimulatory CpG oligonucleotides during gestation induces maternal hypertension and excess vasoconstriction in pregnant rats.

    PubMed

    Goulopoulou, Styliani; Wenceslau, Camilla F; McCarthy, Cameron G; Matsumoto, Takayuki; Webb, R Clinton

    2016-04-15

    Bacterial infections increase risk for pregnancy complications, such as preeclampsia and preterm birth. Unmethylated CpG DNA sequences are present in bacterial DNA and have immunostimulatory effects. Maternal exposure to CpG DNA induces fetal demise and craniofacial malformations; however, the effects of CpG DNA on maternal cardiovascular health have not been examined. We tested the hypothesis that exposure to synthetic CpG oligonucleotides (ODNs) during gestation would increase blood pressure and cause vascular dysfunction in pregnant rats. Pregnant and nonpregnant female rats were treated with CpG ODN (ODN 2395) or saline (Veh) starting on gestationalday 14or corresponding day for the nonpregnant groups. Exposure to CpG ODN increased systolic blood pressure in pregnant (Veh: 121 ± 2 mmHg vs. ODN 2395: 134 ± 2 mmHg,P< 0.05) but not in nonpregnant rats (Veh: 111 ± 2 mmHg vs. ODN 2395: 108 ± 5 mmHg,P> 0.05). Mesenteric resistance arteries from pregnant CpG ODN-treated rats had increased contractile responses to U46619 [thromboxane A2(TxA2) mimetic] compared with arteries from vehicle-treated rats [Emax(%KCl), Veh: 87 ± 4 vs. ODN 2395: 104 ± 4,P< 0.05]. Nitric oxide synthase (NOS) inhibition increased contractile responses to U46619, and CpG ODN treatment abolished this effect in arteries from pregnant ODN 2395-treated rats. CpG ODN potentiated the involvement of cyclooxygenase (COX) to U46619-induced contractions. In conclusion, exposure to CpG ODN during gestation induces maternal hypertension, augments resistance artery contraction, increases the involvement of COX-dependent mechanisms and reduces the contribution of NOS-dependent mechanisms to TxA2-induced contractions in mesenteric resistance arteries. PMID:26873968

  9. Cigarette Smoke-Induced Emphysema and Pulmonary Hypertension Can Be Prevented by Phosphodiesterase 4 and 5 Inhibition in Mice

    PubMed Central

    Pichl, Alexandra; Bednorz, Mariola; Ghofrani, Hossein Ardeschir; Schermuly, Ralph Theo; Seeger, Werner; Grimminger, Friedrich; Weissmann, Norbert

    2015-01-01

    Rationale Chronic obstructive pulmonary disease (COPD) is a widespread disease, with no curative therapies available. Recent findings suggest a key role of NO and sGC-cGMP signaling for the pathogenesis of the disease. Previous data suggest a downregulation/inactivation of the cGMP producing soluble guanylate cyclase, and sGC stimulation prevented cigarette smoke-induced emphysema and pulmonary hypertension (PH) in mice. We thus aimed to investigate if the inhibition of the cGMP degrading phosphodiesterase (PDE)5 has similar effects. Results were compared to the effects of a PDE 4 inhibitor (cAMP elevating) and a combination of both. Methods C57BL6/J mice were chronically exposed to cigarette smoke and in parallel either treated with Tadalafil (PDE5 inhibitor), Piclamilast (PDE4 inhibitor) or both. Functional measurements (lung compliance, hemodynamics) and structural investigations (alveolar and vascular morphometry) as well as the heart ratio were determined after 6 months of tobacco smoke exposure. In addition, the number of alveolar macrophages in the respective lungs was counted. Results Preventive treatment with Tadalafil, Piclamilast or a combination of both almost completely prevented the development of emphysema, the increase in lung compliance, tidal volume, structural remodeling of the lung vasculature, right ventricular systolic pressure, and right ventricular hypertrophy induced by cigarette smoke exposure. Single, but not combination treatment prevented or reduced smoke-induced increase in alveolar macrophages. Conclusion Cigarette smoke-induced emphysema and PH could be prevented by inhibition of the phosphodiesterases 4 and 5 in mice. PMID:26058042

  10. Resistant Hypertension.

    PubMed

    Doroszko, Adrian; Janus, Agnieszka; Szahidewicz-Krupska, Ewa; Mazur, Grzegorz; Derkacz, Arkadiusz

    2016-01-01

    Resistant hypertension is a severe medical condition which is estimated to appear in 9-18% of hypertensive patients. Due to higher cardiovascular risk, this disorder requires special diagnosis and treatment. The heterogeneous etiology, risk factors and comorbidities of resistant hypertension stand in need of sophisticated evaluation to confirm the diagnosis and select the best therapeutic options, which should consider lifestyle modifications as well as pharmacological and interventional treatment. After having excluded pseudohypertension, inappropriate blood pressure measurement and control as well as the white coat effect, suspicion of resistant hypertension requires an analysis of drugs which the hypertensive patient is treated with. According to one definition - ineffective treatment with 3 or more antihypertensive drugs including diuretics makes it possible to diagnose resistant hypertension. A multidrug therapy including angiotensin - converting enzyme inhibitors, angiotensin II receptor blockers, beta blockers, diuretics, long-acting calcium channel blockers and mineralocorticoid receptor antagonists has been demonstrated to be effective in resistant hypertension treatment. Nevertheless, optional, innovative therapies, e.g. a renal denervation or baroreflex activation, may create a novel pathway of blood pressure lowering procedures. The right diagnosis of this disease needs to eliminate the secondary causes of resistant hypertension e.g. obstructive sleep apnea, atherosclerosis and renal or hormonal disorders. This paper briefly summarizes the identification of the causes of resistant hypertension and therapeutic strategies, which may contribute to the proper diagnosis and an improvement of the long term management of resistant hypertension. PMID:26935512

  11. Long-term exposure to high-altitude chronic hypoxia during gestation induces neonatal pulmonary hypertension at sea level

    PubMed Central

    Herrera, Emilio A.; Riquelme, Raquel A.; Ebensperger, Germán; Reyes, Roberto V.; Ulloa, César E.; Cabello, Gertrudis; Krause, Bernardo J.; Parer, Julian T.; Giussani, Dino A.

    2010-01-01

    We determined whether postnatal pulmonary hypertension induced by 70% of pregnancy at high altitude (HA) persists once the offspring return to sea level and investigated pulmonary vascular mechanisms operating under these circumstances. Pregnant ewes were divided into two groups: conception, pregnancy, and delivery at low altitude (580 m, LLL) and conception at low altitude, pregnancy at HA (3,600 m) from 30% of gestation until delivery, and return to lowland (LHL). Pulmonary arterial pressure (PAP) was measured in vivo. Vascular reactivity and morphometry were assessed in small pulmonary arteries (SPA). Protein expression of vascular mediators was determined. LHL lambs had higher basal PAP and a greater increment in PAP after NG-nitro-l-arginine methyl ester (20.9 ± 1.1 vs. 13.7 ± 0.5 mmHg; 39.9 ± 5.0 vs. 18.3 ± 1.3 mmHg, respectively). SPA from LHL had a greater maximal contraction to K+ (1.34 ± 0.05 vs. 1.16 ± 0.05 N/m), higher sensitivity to endothelin-1 and nitroprusside, and persistence of dilatation following blockade of soluble guanylate cyclase. The heart ratio of the right ventricle-to-left ventricle plus septum was higher in the LHL relative to LLL. The muscle area of SPA (29.3 ± 2.9 vs. 21.1 ± 1.7%) and the protein expression of endothelial nitric oxide synthase (1.7 ± 0.1 vs. 1.1 ± 0.2), phosphodiesterase (1.4 ± 0.1 vs. 0.7 ± 0.1), and Ca2+-activated K+ channel (0.76 ± 0.16 vs. 0.30 ± 0.01) were greater in LHL compared with LLL lambs. In contrast, LHL had decreased heme oxygenase-1 expression (0.82 ± 0.26 vs. 2.22 ± 0.44) and carbon monoxide production (all P < 0.05). Postnatal pulmonary hypertension induced by 70% of pregnancy at HA promotes cardiopulmonary remodeling that persists at sea level. PMID:20881096

  12. Broiler pulmonary hypertensive responses during lipopolysaccharide-induced tolerance and cyclooxygenase inhibition.

    PubMed

    Wideman, R F; Bowen, O T; Erf, G F

    2009-01-01

    Bacterial lipopolysaccharide (LPS, endotoxin) triggers pulmonary hypertension (PH) characterized by an increase in pulmonary arterial pressure (PAP) that reaches a peak value within 20 to 25 min and then gradually subsides within 60 min. As the PAP subsides PH cannot be reinitiated, signifying the onset of a period of tolerance (refractoriness) to repeated LPS exposure. The present study was conducted to determine the duration of this tolerance, and to evaluate key mediators thought to contribute to LPS-mediated PH in broilers. Tolerance was shown to persist for 4 to 5 d after the initial exposure to LPS. In tolerant broilers supramaximal i.v. injections of LPS did not reinitiate PH, nor was a significant modulatory role for nitric oxide demonstrated. The pulmonary vasculature of tolerant broilers remains responsive to the thromboxane A(2) (TxA(2)) mimetic U44069, 5-hydroxytryptamine (5-HT, serotonin), and constitutive nitric oxide. Meclofenamate successfully blocked the conversion of arachidonic acid to vasoconstrictive eicosanoids such as TxA(2); nevertheless, meclofenamate failed to inhibit PH in response to LPS. Therefore, TxA(2) does not appear to be the primary vasoconstrictor involved in the PH response to LPS and neither does 5-HT. Broilers emerging from tolerance 5 d after the initial exposure to LPS exhibited interindividual variation in their PH responsiveness to a second LPS injection, ranging from zero response (individuals that remain fully tolerant) to large increases in PAP (post-tolerant individuals). Tolerance might be an important compensatory or protective mechanism for broilers whose pulmonary vascular capacity is marginally adequate under optimal conditions, and whose respiratory systems are chronically challenged with LPS in commercial production facilities. The key vasoconstrictors responsible for the PH elicited by LPS remain to be determined. PMID:19096060

  13. Mechanisms of the antihypertensive effects of Nigella sativa oil in L-NAME-induced hypertensive rats

    PubMed Central

    Jaarin, Kamsiah; Foong, Wai Dic; Yeoh, Min Hui; Kamarul, Zaman Yusoff Nik; Qodriyah, Haji Mohd Saad; Azman, Abdullah; Zuhair, Japar Sidik Fadhlullah; Juliana, Abdul Hamid; Kamisah, Yusof

    2015-01-01

    OBJECTIVES This study was conducted to determine whether the blood pressure-lowering effect of Nigella sativa might be mediated by its effects on nitric oxide, angiotensin-converting enzyme, heme oxygenase and oxidative stress markers. METHODS: Twenty-four adult male Sprague-Dawley rats were divided equally into 4 groups. One group served as the control (group 1), whereas the other three groups (groups 2-4) were administered L-NAME (25 mg/kg, intraperitoneally). Groups 3 and 4 were given oral nicardipine daily at a dose of 3 mg/kg and Nigella sativa oil at a dose of 2.5 mg/kg for 8 weeks, respectively, concomitantly with L-NAME administration. RESULTS Nigella sativa oil prevented the increase in systolic blood pressure in the L-NAME-treated rats. The blood pressure reduction was associated with a reduction in cardiac lipid peroxidation product, NADPH oxidase, angiotensin-converting enzyme activity and plasma nitric oxide, as well as with an increase in heme oxygenase-1 activity in the heart. The effects of Nigella sativa on blood pressure, lipid peroxidation product, nicotinamide adenine dinucleotide phosphate oxidase and angiotensin-converting enzyme were similar to those of nicardipine. In contrast, L-NAME had opposite effects on lipid peroxidation, angiotensin-converting enzyme and NO. CONCLUSION: The antihypertensive effect of Nigella sativa oil appears to be mediated by a reduction in cardiac oxidative stress and angiotensin-converting enzyme activity, an increase in cardiac heme oxygenase-1 activity and a prevention of plasma nitric oxide loss. Thus, Nigella sativa oil might be beneficial for controlling hypertension. PMID:26602523

  14. NF kappa B and Matrix Metalloproteinase induced Receptor Cleavage in the Spontaneously Hypertensive Rat

    PubMed Central

    Wu, Kwan-I Sharon; Schmid-Schönbein, Geert W.

    2011-01-01

    Recent evidence suggests that inflammation in the spontaneously hypertensive rat (SHR) is associated with an uncontrolled matrix metalloproteinase (MMP) activity. We hypothesize that the transcription factor nuclear factor kappa B (NF–κB) is overexpressed in the SHR, enhancing its MMP activity and enzymatic cleavage of the beta-2 adrenergic receptor (β2AR), thereby diminishing catecholamine-mediated arteriolar vasodilation. NF-κB expression level and translocation were compared between Wistar Kyoto rat (WKY) and SHR kidney, heart and brain. The animals were treated with a NF-κB inhibitor, pyrrolidine dithiocarbamate (PDTC), for ten weeks and correlations between NF-κB and MMP activity were determined. Immunohistochemistry showed that NF-κB expression is increased in untreated SHR kidney (~ 14%) and brain hypothalamus (~ 22%) compared to that in WKY (p <0.05), but not in myocardium and cerebral cortex. After PDTC treatment, the SHR systolic blood pressure was reduced close to WKY levels. NF-κB expression level in treated-SHR was also decreased in kidney and hypothalamus compared to non-treated animals (p <0.05). Furthermore, MMP-2 and -9 activities in SHR plasma were significantly reduced (~41%) by PDTC treatment. Additionally, zymographic analyses and in situ zymography showed decreased MMP-2 activity in kidney homogenates and decreased MMP-1,-9 activities in brain. The level of the β2AR extracellular, but not intracellular, domain density was found reduced in kidney showing a receptor cleavage process that can be blocked by PDTC treatment. These results suggest NF-κB is an important transcription factor in the SHR and may be involved in the enhanced MMP activity and consequently receptor cleavage. PMID:21220710

  15. A study on the involvement of GABA-transaminase in MCT induced pulmonary hypertension.

    PubMed

    Lingeshwar, Poorella; Kaur, Gurpreet; Singh, Neetu; Singh, Seema; Mishra, Akanksha; Shukla, Shubha; Ramakrishna, Rachumallu; Laxman, Tulsankar Sachin; Bhatta, Rabi Sankar; Siddiqui, Hefazat H; Hanif, Kashif

    2016-02-01

    Increased sympathetic nervous system (SNS) activity is associated with cardiovascular diseases but its role has not been completely explored in pulmonary hypertension (PH). Increased SNS activity is distinguished by elevated level of norepinephrine (NE) and activity of γ-Amino butyric acid Transminase (GABA-T) which degrades GABA, an inhibitory neurotransmitter within the central and peripheral nervous system. Therefore, we hypothesized that GABA-T may contribute in pathophysiology of PH by modulating level of GABA and NE. The effect of daily oral administration of GABA-T inhibitor, Vigabatrin (GVG, 50 and 75 mg/kg/day, 35 days) was studied following a single subcutaneous administration of monocrotaline (MCT, 60 mg/kg) in male SD rats. The pressure and hypertrophy of right ventricle (RV), oxidative stress, inflammation, pulmonary vascular remodelling were assessed after 35 days in MCT treated rats. The expression of GABA-T and HIF-1α was studied in lung tissue. The levels of plasma NE (by High performance liquid chromatography coupled with electrochemical detector; HPLC-ECD) and lung GABA (by liquid chromatography-mass spectrometry) were also estimated. GVG at both doses significantly attenuated increased in pressure (35.82 ± 4.80 mm Hg, p < 0.001; 28.37 ± 3.32 mm Hg, p < 0.001 respectively) and hypertrophy of RV, pulmonary vascular remodelling, oxidative stress and inflammation in lungs of MCT exposed rats. GVG also reduced the expression of GABA-T and HIF-1α in MCT treated rats. Increased NE level and decreased GABA level was also reversed by GVG in MCT exposed rats. GABA-T plays an important role in PH by modulating SNS activity and may be considered as a therapeutic target in PH. PMID:26608704

  16. Folic Acid Promotes Recycling of Tetrahydrobiopterin and Protects Against Hypoxia-Induced Pulmonary Hypertension by Recoupling Endothelial Nitric Oxide Synthase

    PubMed Central

    Chalupsky, Karel; Kračun, Damir; Kanchev, Ivan; Bertram, Katharina

    2015-01-01

    Abstract Aims: Nitric oxide (NO) derived from endothelial NO synthase (eNOS) has been implicated in the adaptive response to hypoxia. An imbalance between 5,6,7,8-tetrahydrobiopterin (BH4) and 7,8-dihydrobiopterin (BH2) can result in eNOS uncoupling and the generation of superoxide instead of NO. Dihydrofolate reductase (DHFR) can recycle BH2 to BH4, leading to eNOS recoupling. However, the role of DHFR and eNOS recoupling in the response to hypoxia is not well understood. We hypothesized that increasing the capacity to recycle BH4 from BH2 would improve NO bioavailability as well as pulmonary vascular remodeling (PVR) and right ventricular hypertrophy (RVH) as indicators of pulmonary hypertension (PH) under hypoxic conditions. Results: In human pulmonary artery endothelial cells and murine pulmonary arteries exposed to hypoxia, eNOS was uncoupled as indicated by reduced superoxide production in the presence of the nitric oxide synthase inhibitor, L-(G)-nitro-L-arginine methyl ester (L-NAME). Concomitantly, NO levels, BH4 availability, and expression of DHFR were diminished under hypoxia. Application of folic acid (FA) restored DHFR levels, NO bioavailability, and BH4 levels under hypoxia. Importantly, FA prevented the development of hypoxia-induced PVR, right ventricular pressure increase, and RVH. Innovation: FA-induced upregulation of DHFR recouples eNOS under hypoxia by improving BH4 recycling, thus preventing hypoxia-induced PH. Conclusion: FA might serve as a novel therapeutic option combating PH. Antioxid. Redox Signal. 23, 1076–1091. PMID:26414244

  17. Inactivated Pseudomonas aeruginosa inhibits hypoxia-induced pulmonary hypertension by preventing TGF-β1/Smad signaling

    PubMed Central

    Chai, S.D.; Liu, T.; Dong, M.F.; Li, Z.K.; Tang, P.Z.; Wang, J.T.; Ma, S.J.

    2016-01-01

    Pseudomonas aeruginosa is one of the common colonizing bacteria of the human body and is an opportunistic pathogen frequently associated with respiratory infections. Inactivated P. aeruginosa (IPA) have a variety of biological effects against inflammation and allergy. Transforming growth factor-β (TGF-β) signaling plays a critical role in the regulation of cell growth, differentiation, and development in a wide range of biological systems. The present study was designed to investigate the effects of IPA on TGF-β/Smad signaling in vivo, using a hypoxia-induced pulmonary hypertension (PH) rat model. Sprague Dawley rats (n=40) were exposed to 10% oxygen for 21 days to induce PH. At the same time, IPA was administered intravenously from day 1 to day 14. Mean pulmonary artery pressure (mPAP) and the right ventricle (RV) to left ventricle plus the interventricular septum (LV+S) mass ratio were used to evaluate the development of PH. Vessel thickness and density were measured using immunohistochemistry. Primary arterial smooth muscle cells (PASMCs) were isolated and the proliferation of PASMCs was assayed by flow cytometry. The production of TGF-β1 in cultured supernatant of PASMCs was assayed by ELISA. The expression levels of α-smooth muscle actin (α-SMA), TGF-β1 and phospho-Smad 2/3 in PASMCs were assayed by western blot. Our data indicated that IPA attenuated PH, RV hypertrophy and pulmonary vascular remodeling in rats, which was probably mediated by restraining the hypoxia-induced overactive TGF-β1/Smad signaling. In conclusion, IPA is a promising protective treatment in PH due to the inhibiting effects on TGF-β1/Smad 2/3 signaling. PMID:27580007

  18. Inactivated Pseudomonas aeruginosa inhibits hypoxia-induced pulmonary hypertension by preventing TGF-β1/Smad signaling.

    PubMed

    Chai, S D; Liu, T; Dong, M F; Li, Z K; Tang, P Z; Wang, J T; Ma, S J

    2016-01-01

    Pseudomonas aeruginosa is one of the common colonizing bacteria of the human body and is an opportunistic pathogen frequently associated with respiratory infections. Inactivated P. aeruginosa (IPA) have a variety of biological effects against inflammation and allergy. Transforming growth factor-β (TGF-β) signaling plays a critical role in the regulation of cell growth, differentiation, and development in a wide range of biological systems. The present study was designed to investigate the effects of IPA on TGF-β/Smad signaling in vivo, using a hypoxia-induced pulmonary hypertension (PH) rat model. Sprague Dawley rats (n=40) were exposed to 10% oxygen for 21 days to induce PH. At the same time, IPA was administered intravenously from day 1 to day 14. Mean pulmonary artery pressure (mPAP) and the right ventricle (RV) to left ventricle plus the interventricular septum (LV+S) mass ratio were used to evaluate the development of PH. Vessel thickness and density were measured using immunohistochemistry. Primary arterial smooth muscle cells (PASMCs) were isolated and the proliferation of PASMCs was assayed by flow cytometry. The production of TGF-β1 in cultured supernatant of PASMCs was assayed by ELISA. The expression levels of α-smooth muscle actin (α-SMA), TGF-β1 and phospho-Smad 2/3 in PASMCs were assayed by western blot. Our data indicated that IPA attenuated PH, RV hypertrophy and pulmonary vascular remodeling in rats, which was probably mediated by restraining the hypoxia-induced overactive TGF-β1/Smad signaling. In conclusion, IPA is a promising protective treatment in PH due to the inhibiting effects on TGF-β1/Smad 2/3 signaling. PMID:27580007

  19. Early Macrophage Recruitment and Alternative Activation Are Critical for the Later Development of Hypoxia-induced Pulmonary Hypertension

    PubMed Central

    Vergadi, Eleni; Chang, Mun Seog; Lee, Changjin; Liang, Olin; Liu, Xianlan; Fernandez-Gonzalez, Angeles; Mitsialis, S. Alex; Kourembanas, Stella

    2011-01-01

    Background Lung inflammation precedes the development of hypoxia-induced pulmonary hypertension (HPH); however its role in the pathogenesis of HPH is poorly understood. We sought to characterize the hypoxic inflammatory response and elucidate its role in the development of HPH. We also aimed to investigate the mechanisms by which heme oxygenase-1 (HO-1), an anti-inflammatory enzyme, is protective in HPH. Methods and Results We generated bitransgenic mice that overexpress human HO-1 under doxycycline (dox) control in an inducible, lung-specific manner. Hypoxic exposure of mice in the absence of dox resulted in early transient accumulation of monocytes/macrophages in the bronchoalveolar lavage. Alveolar macrophages acquired an alternatively activated phenotype (M2) in response to hypoxia, characterized by the expression of Found in Inflammatory Zone-1, Arginase-1 and Chitinase-3-like-3. A brief, two-day pulse of dox delayed but did not prevent the peak of hypoxic inflammation, and could not protect from HPH. In contrast, a seven-day dox treatment sustained high HO-1 levels during the entire period of hypoxic inflammation, inhibited macrophage accumulation and activation, induced macrophage IL-10 expression, and prevented the development of HPH. Supernatants from hypoxic M2 macrophages promoted proliferation of pulmonary artery smooth muscle cells while treatment with carbon monoxide, a HO-1 enzymatic product, abrogated this effect. Conclusions Early recruitment and alternative activation of macrophages in hypoxic lungs is critical for the later development of HPH. HO-1 may confer protection from HPH by effectively modifing macrophage activation state in hypoxia. PMID:21518986

  20. Selective Serotonin-norepinephrine Re-uptake Inhibition Limits Renovas-cular-hypertension Induced Cognitive Impairment, Endothelial Dysfunction, and Oxidative Stress Injury.

    PubMed

    Singh, Prabhat; Sharma, Bhupesh

    2016-01-01

    Hypertension has been reported to induce cognitive decline and dementia of vascular origin. Serotonin- norepinephrine reuptake transporters take part in the control of inflammation, cognitive functions, motivational acts and deterioration of neurons. This study was carried out to examine the effect of venlafaxine; a specific serotonin-norepinephrine reuptake inhibitor (SNRI), in two-kidney-one-clip-2K1C (renovascular hypertension) provoked vascular dementia (VaD) in albino rats. 2K1C technique was performed to provoke renovascular-hypertension in adult male albino Wistar rats. Learning and memory were assessed by using the elevated plus maze and Morris water maze. Mean arterial blood pressure- MABP, as well as endothelial function, were assessed by means of BIOPAC system. Serum nitrosative stress (nitrite/ nitrate), aortic superoxide anion, brain oxidative stress, inflammation, cholinergic dysfunction and brain damage (2,3,5-triphenylterazolium chloride staining) were also assessed. 2K1C has increased MABP, endothelial dysfunction as well as learning and memory impairments. 2K1C method has increased serum nitrosative stress (reduced nitrite/nitrate level), oxidative stress (increased brain thiobarbituric acid reactive species and aortic superoxide anion content along with decreased levels of brain superoxide dismutase, glutathione, and catalase), brain inflammation (increased myeloperoxidase), cholinergic dysfunction (increased acetylcholinesterase activity) and brain damage. Treatment with venlafaxine considerably attenuated renovascular-hypertension induced cognition impairment, endothelial dysfunction, serum nitrosative stress, brain and aortic oxidative stress, cholinergic function, inflammation as well as cerebral damage. The finding of this study indicates that specific modulation of the serotonin-norepinephrine transporter perhaps regarded as potential interventions for the management of renovascular hypertension provoked VaD. PMID:26915517

  1. Chronic N(G)-nitro-L-arginine methyl ester-induced hypertension : novel molecular adaptation to systolic load in absence of hypertrophy

    NASA Technical Reports Server (NTRS)

    Bartunek, J.; Weinberg, E. O.; Tajima, M.; Rohrbach, S.; Katz, S. E.; Douglas, P. S.; Lorell, B. H.; Schneider, M. (Principal Investigator)

    2000-01-01

    BACKGROUND: Chronic N(G)-nitro-L-arginine methyl ester (L-NAME), which inhibits nitric oxide synthesis, causes hypertension and would therefore be expected to induce robust cardiac hypertrophy. However, L-NAME has negative metabolic effects on protein synthesis that suppress the increase in left ventricular (LV) mass in response to sustained pressure overload. In the present study, we used L-NAME-induced hypertension to test the hypothesis that adaptation to pressure overload occurs even when hypertrophy is suppressed. METHODS AND RESULTS: Male rats received L-NAME (50 mg. kg(-1). d(-1)) or no drug for 6 weeks. Rats with L-NAME-induced hypertension had levels of systolic wall stress similar to those of rats with aortic stenosis (85+/-19 versus 92+/-16 kdyne/cm). Rats with aortic stenosis developed a nearly 2-fold increase in LV mass compared with controls. In contrast, in the L-NAME rats, no increase in LV mass (1. 00+/-0.03 versus 1.04+/-0.04 g) or hypertrophy of isolated myocytes occurred (3586+/-129 versus 3756+/-135 microm(2)) compared with controls. Nevertheless, chronic pressure overload was not accompanied by the development of heart failure. LV systolic performance was maintained by mechanisms of concentric remodeling (decrease of in vivo LV chamber dimension relative to wall thickness) and augmented myocardial calcium-dependent contractile reserve associated with preserved expression of alpha- and beta-myosin heavy chain isoforms and sarcoplasmic reticulum Ca(2+) ATPase (SERCA-2). CONCLUSIONS: When the expected compensatory hypertrophic response is suppressed during L-NAME-induced hypertension, severe chronic pressure overload is associated with a successful adaptation to maintain systolic performance; this adaptation depends on both LV remodeling and enhanced contractility in response to calcium.

  2. Oral CoQ10 attenuates high salt-induced hypertension by restoring neurotransmitters and cytokines in the hypothalamic paraventricular nucleus.

    PubMed

    Gao, Hong-Li; Yu, Xiao-Jing; Qi, Jie; Yi, Qiu-Yue; Jing, Wang-Hui; Sun, Wen-Yan; Cui, Wei; Mu, Jian-Jun; Yuan, Zu-Yi; Zhao, Xiu-Fang; Liu, Kai-Li; Zhu, Guo-Qing; Shi, Xiao-Lian; Liu, Jin-Jun; Kang, Yu-Ming

    2016-01-01

    High salt intake leads to an increase in some proinflammatory cytokines and neurotransmitters involved in the pathogenesis of hypertension. The purpose of this work was to know if oral administration of anti-oxidant and free-radical scavenger CoQ10 may attenuate high salt-induced hypertension via regulating neurotransmitters and cytokines in the hypothalamic paraventricular nucleus (PVN). Adult male Sprague-Dawley (SD) rats were fed with a normal salt diet (NS, 0.3% NaCl) or a high salt diet (HS, 8% NaCl) for 15 weeks to induce hypertension. These rats received CoQ10 (10 mg/kg/day) dissolved in olive oil was given by gavage (10 mg/kg/day) for 15 weeks. HS resulted in higher mean arterial pressure (MAP) and the sympathetic nerve activity (RSNA). These HS rats had higher PVN levels of norepinephrine (NE), tyrosine hydroxylase (TH), interleukin (IL)-1β, NOX2 and NOX4, lower PVN levels of gamma-aminobutyric acid (GABA), IL-10, copper/zinc superoxide dismutase (Cu/Zn-SOD) and the 67-kDa isoform of glutamate decarboxylase (GAD67), as compared with NS group. CoQ10 supplementation reduced NE, TH, IL-1β, NOX2 and NOX4 in the PVN, and induced IL-10, Cu/Zn-SOD and GAD67 in the PVN. These findings suggest that CoQ10 supplementation restores neurotransmitters and cytokines in the PVN, thereby attenuating high salt-induced hypertension. PMID:27452860

  3. Angiotensin II-Induced Hypertension Is Attenuated by Reduction of Sympathetic Output in NO-Sensitive Guanylyl Cyclase 1 Knockout Mice.

    PubMed

    Broekmans, Kathrin; Stegbauer, Johannes; Potthoff, Sebastian A; Russwurm, Michael; Koesling, Doris; Mergia, Evanthia

    2016-01-01

    In the regulation of vascular tone, the dilatory nitric oxide (NO)/cGMP pathway balances vasoconstriction induced by the renin-angiotensin and sympathetic nervous systems. NO-induced cGMP formation is catalyzed by two guanylyl cyclases (GC), NO-sensitive guanylyl cyclase 1 (NO-GC1) and NO-GC2, with indistinguishable enzymatic properties. In vascular smooth muscle cells, NO-GC1 is the major isoform and is responsible for more than 90% of cGMP formation. Despite reduced vasorelaxation, NO-GC1-deficient mice are not hypertensive. Here, the role of NO-GC1 in hypertension provoked by contractile agonists angiotensin II (Ang II) and norepinephrine (NE) was evaluated in NO-GC1-deficient mice. Hypertension induced by chronic Ang II treatment did not differ between wild-type (WT) and NO-GC1 knockout mice (KO). Also, attenuation of NO-dependent aortic relaxation induced by the Ang II treatment was similar in both genotypes and was most probably attributable to an increase of phosphodiesterase 1 expression. Analysis of plasma NE content-known to be influenced by Ang II-revealed lower NE in the NO-GC1 KO under Ang II-treated- and nontreated conditions. The finding indicates reduced sympathetic output and is underlined by the lower heart rate in the NO-GC1 KO. To find out whether the lack of higher blood pressure in the NO-GC1 KO is a result of reduced sympathetic activity counterbalancing the reduced vascular relaxation, mice were challenged with chronic NE application. As the resulting blood pressure was higher in the NO-GC1 KO than in WT, we conclude that the reduced sympathetic activity in the NO-GC1 KO prevents hypertension and postulate a possible sympatho-excitatory action of NO-GC1 counteracting NO-GC1's dilatory effect in the vasculature. PMID:26559126

  4. Oral CoQ10 attenuates high salt-induced hypertension by restoring neurotransmitters and cytokines in the hypothalamic paraventricular nucleus

    PubMed Central

    Gao, Hong-Li; Yu, Xiao-Jing; Qi, Jie; Yi, Qiu-Yue; Jing, Wang-Hui; Sun, Wen-Yan; Cui, Wei; Mu, Jian-Jun; Yuan, Zu-Yi; Zhao, Xiu-Fang; Liu, Kai-Li; Zhu, Guo-Qing; Shi, Xiao-Lian; Liu, Jin-Jun; Kang, Yu-Ming

    2016-01-01

    High salt intake leads to an increase in some proinflammatory cytokines and neurotransmitters involved in the pathogenesis of hypertension. The purpose of this work was to know if oral administration of anti-oxidant and free-radical scavenger CoQ10 may attenuate high salt-induced hypertension via regulating neurotransmitters and cytokines in the hypothalamic paraventricular nucleus (PVN). Adult male Sprague-Dawley (SD) rats were fed with a normal salt diet (NS, 0.3% NaCl) or a high salt diet (HS, 8% NaCl) for 15 weeks to induce hypertension. These rats received CoQ10 (10 mg/kg/day) dissolved in olive oil was given by gavage (10 mg/kg/day) for 15 weeks. HS resulted in higher mean arterial pressure (MAP) and the sympathetic nerve activity (RSNA). These HS rats had higher PVN levels of norepinephrine (NE), tyrosine hydroxylase (TH), interleukin (IL)-1β, NOX2 and NOX4, lower PVN levels of gamma-aminobutyric acid (GABA), IL-10, copper/zinc superoxide dismutase (Cu/Zn-SOD) and the 67-kDa isoform of glutamate decarboxylase (GAD67), as compared with NS group. CoQ10 supplementation reduced NE, TH, IL-1β, NOX2 and NOX4 in the PVN, and induced IL-10, Cu/Zn-SOD and GAD67 in the PVN. These findings suggest that CoQ10 supplementation restores neurotransmitters and cytokines in the PVN, thereby attenuating high salt-induced hypertension. PMID:27452860

  5. Malignant hypertension

    MedlinePlus

    ... Lippincott Williams & Wilkins; 2009:chap 89. Read More Acute kidney failure Alertness - decreased Angina Heart attack Preeclampsia Pulmonary edema Renovascular hypertension Seizures Stroke Update ...

  6. Mineralocorticoid hypertension

    PubMed Central

    Gupta, Vishal

    2011-01-01

    Hypertension affects about 10 – 25% of the population and is an important risk factor for cardiovascular and renal disease. The renin-angiotensin system is frequently implicated in the pathophysiology of hypertension, be it primary or secondary. The prevalence of primary aldosteronism increases with the severity of hypertension, from 2% in patients with grade 1 hypertension to 20% among resistant hypertensives. Mineralcorticoid hypertension includes a spectrum of disorders ranging from renin-producing pathologies (renin-secreting tumors, malignant hypertension, coarctation of aorta), aldosterone-producing pathologies (primary aldosteronism – Conns syndrome, familial hyperaldosteronism 1, 2, and 3), non-aldosterone mineralocorticoid producing pathologies (apparent mineralocorticoid excess syndrome, Liddle syndrome, deoxycorticosterone-secreting tumors, ectopic adrenocorticotropic hormones (ACTH) syndrome, congenitalvadrenal hyperplasia), and drugs with mineraocorticoid activity (locorice, carbenoxole therapy) to glucocorticoid receptor resistance syndromes. Clinical presentation includes hypertension with varying severity, hypokalemia, and alkalosis. Ratio of plasma aldosterone concentraion to plasma renin activity remains the best screening tool. Bilateral adrenal venous sampling is the best diagnostic test coupled with a CT scan. Treatment is either surgical (adrenelectomy) for unilateral adrenal disease versus medical therapy for idiopathic, ambiguous, or bilateral disease. Medical therapy focuses on blood pressure control and correction of hypokalemia using a combination of anti-hypertensives (calcium channel blockers, angiotensin converting enzyme inhibitors, or angiotensin receptor blockers) and potassium-raising therapies (mineralcorticoid receptor antagonist or potassium sparing diuretics). Direct aldosterone synthetase antagonists represent a promising future therapy. PMID:22145132

  7. Candidate genes in quantitative trait loci associated with absolute and relative kidney weight in rats with Inherited Stress Induced Arterial Hypertension

    PubMed Central

    2015-01-01

    Background The kidney mass is significantly increased in hypertensive ISIAH rats with Inherited Stress Induced Arterial Hypertension as compared with normotensive WAG rats. The QTL/microarray approach was carried out to determine the positional candidate genes in the QTL for absolute and relative kidney weight. Results Several known and predicted genes differentially expressed in ISIAH and WAG kidney were mapped to genetic loci associated with the absolute and relative kidney weight in 6-month old F2 hybrid (ISIAHxWAG) males. The knowledge-driven filtering of the list of candidates helped to suggest several positional candidate genes, which may be related to the structural and mass changes in hypertensive ISIAH kidney. In the current study, we showed that all loci found for absolute and relative kidney weight didn't overlap with significant or suggestive loci for arterial blood pressure level. So, the genes differentially expressed in ISIAH and WAG kidneys and located in these QTL regions associated with absolute and relative kidney weight shouldn't substantially influence the BP level in the 6 month-old ISIAH rats. However, in some cases, small effects may be suggested. Conclusions The further experimental validation of causative genes and detection of polymorphisms will provide opportunities to advance our understanding of the underlying nature of structural and mass changes in hypertensive ISIAH kidney. PMID:25707311

  8. [Socioeconomic pathology as a cause of regional differences in the prevalence of metabolic syndrome and pregnancy-induced hypertension].

    PubMed

    López-Jaramillo, Patricio; Pradilla, Lina P; Castillo, Víctor R; Lahera, Vicente

    2007-02-01

    The epidemic of cardiovascular disease being experienced by developing countries has resulted in a debate about the possible existence of regional differences in etiology and pathophysiology that could be associated with socio-economic factors. Clear demonstration of these differences is important because there may be a need for different approaches to prevention, diagnosis and treatment. There is some evidence that there are differences between populations in developed and developing countries in the pathophysiologic mechanisms underlying pregnancy-induced hypertension and metabolic syndrome, just as there are in the relative weightings of risk factors that predict the appearance of these conditions. Observations in our country suggest that increasing exposure to changes in lifestyle brought about by the consumer society (e.g., a lack of exercise, and a high-fat, high-calorie diet) results in a natural biological response (e.g., obesity, metabolic syndrome, and diabetes) that increases the risk of cardiovascular disease. We propose that the term socioeconomic pathology should be used to describe these changes associated with modern society so that they can be differentiated and considered in isolation from socioeconomic factors and other risk factors. We regard the interaction between these various factors as the most important cause of the rapidly increasing incidence of cardiovascular disease observed in developing countries in recent years. PMID:17338881

  9. The Stop-Bang Questionnaire as a Screening Tool for Obstructive Sleep Apnea-Induced Hypertension in Asian Population

    PubMed Central

    Pavarangkul, Tanut; Jungtrakul, Thipphailin; Chaobangprom, Pichsinee; Nitiwatthana, Luxanawadee; Jongkumchok, Wisit; Morrakotkhiew, Weerachat; Kachenchart, Sitthan; Chindaprasirt, Jarin; Limpawattana, Panita; Srisaenpang, Sompong; Pinitsoontorn, Somdej; Sawanyawisuth, Kittisak

    2016-01-01

    Obstructive sleep apnea (OSA) is a common public health issue. If left untreated, OSA may cause a large health economic burden from cardiovascular complications particularly stroke. The diagnosis of OSA can be made by polysomnography, but its availability is limited in the developing countries in Asia. STOP-BANG questionnaire is a good screening tool but may need some adjustment for Asian population. STOP-BANG stands for: Snoring history, Tired during the day, Observed stop breathing while sleep, High blood pressure, body mass index (BMI) more than 35 kg/m2, Age more than 50 years, Neck circumference more than 40 cm and male Gender. We compared clinical features in STOP-BANG questionnaire between 42 OSA induced hypertension patients and 82 healthy control subjects in the Faculty of Medicine, Khon Kaen University, Thailand. The best cutoff point for the BMI and the neck circumference were 24.5 kg/m2 and 36 cm, respectively. The sensitivity and specificity of the BMI cutoff point were 97.2% and 91.40, while those of the neck circumference were 94.7% and 82.9%. In conclusion, the appropriate cutoff points of BMI and neck circumference for Thai STOP-BANG questionnaire were 25 kg/m2 and 36 cm. PMID:27127598

  10. The Stop-Bang Questionnaire as a Screening Tool for Obstructive Sleep Apnea-Induced Hypertension in Asian Population.

    PubMed

    Pavarangkul, Tanut; Jungtrakul, Thipphailin; Chaobangprom, Pichsinee; Nitiwatthana, Luxanawadee; Jongkumchok, Wisit; Morrakotkhiew, Weerachat; Kachenchart, Sitthan; Chindaprasirt, Jarin; Limpawattana, Panita; Srisaenpang, Sompong; Pinitsoontorn, Somdej; Sawanyawisuth, Kittisak

    2016-04-01

    Obstructive sleep apnea (OSA) is a common public health issue. If left untreated, OSA may cause a large health economic burden from cardiovascular complications particularly stroke. The diagnosis of OSA can be made by polysomnography, but its availability is limited in the developing countries in Asia. STOP-BANG questionnaire is a good screening tool but may need some adjustment for Asian population. STOP-BANG stands for: Snoring history, Tired during the day, Observed stop breathing while sleep, High blood pressure, body mass index (BMI) more than 35 kg/m(2), Age more than 50 years, Neck circumference more than 40 cm and male Gender. We compared clinical features in STOP-BANG questionnaire between 42 OSA induced hypertension patients and 82 healthy control subjects in the Faculty of Medicine, Khon Kaen University, Thailand. The best cutoff point for the BMI and the neck circumference were 24.5 kg/m(2) and 36 cm, respectively. The sensitivity and specificity of the BMI cutoff point were 97.2% and 91.40, while those of the neck circumference were 94.7% and 82.9%. In conclusion, the appropriate cutoff points of BMI and neck circumference for Thai STOP-BANG questionnaire were 25 kg/m(2) and 36 cm. PMID:27127598

  11. Induced hypertension for the treatment of cerebral ischemia after subarachnoid hemorrhage. Direct effect on cerebral blood flow

    SciTech Connect

    Muizelaar, J.P.; Becker, D.P.

    1986-04-01

    The best treatment for symptomatic cerebral ischemia from presumed vasospasm after aneurysmal subarachnoid hemorrhage remains a matter of controversy. A direct effect of any treatment modality on regional cerebral blood flow has never been documented. In a series of 43 patients operated on for ruptured anterior circulation aneurysms, five patients (11.6%) developed clinical signs of cerebral ischemia postoperatively. In four of those patients, the diagnosis of vasospasm was made with measurements of cerebral blood flow (133Xe inhalation or intravenous injection, 10-16 detectors, cerebral blood flow infinity). Treatment with induced arterial hypertension with phenylephrine was instituted. Hemodilution was instituted in one patient; the other three patients already had hematocrits in the range of 33. Within 1 hour, the cerebral blood flow measurement was repeated to document the effect of treatment. The average pretreatment hemispherical blood flow on the operated side was 18.8 mL/100 g per minute, on the contralateral side 21.0 mL/100 g per minute. With treatment these flows increased to 30.8 and 35.8 mL/100 g per minute, respectively. There was also an immediate and obvious positive clinical effect in all patients. The role of measurement of cerebral blood flow in the clinical management of vasospasm is discussed. We stress the theoretical and practical advances of measurements of cerebral blood flow over cerebral angiography, especially in comatose patients.

  12. SPONTANEOUSLY HYPERTENSIVE RATS ARE SUSCEPTIBLE TO AIRWAY DISEASE INDUCED BY SULFUR DIOXIDE

    EPA Science Inventory

    Rodent models of chronic pulmonary diseases induced by sulfur dioxide (SO2), elastase or tobacco smoke have limited utility because of their lack of chronicity of inflammation, and they demonstrate limited sensitivity to a given experimental manipulation. We hypothesized that dis...

  13. Synergistic Antihypertensive Effect of Carthamus tinctorius L. Extract and Captopril in L-NAME-Induced Hypertensive Rats via Restoration of eNOS and AT₁R Expression.

    PubMed

    Maneesai, Putcharawipa; Prasarttong, Patoomporn; Bunbupha, Sarawoot; Kukongviriyapan, Upa; Kukongviriyapan, Veerapol; Tangsucharit, Panot; Prachaney, Parichat; Pakdeechote, Poungrat

    2016-03-01

    This study examined the effect of Carthamus tinctorius (CT) extract plus captopril treatment on blood pressure, vascular function, nitric oxide (NO) bioavailability, oxidative stress and renin-angiotensin system (RAS) in N(ω)-Nitro-l-arginine methyl ester (l-NAME)-induced hypertension. Rats were treated with l-NAME (40 mg/kg/day) for five weeks and given CT extract (75 or 150 or 300 or 500 mg/kg/day): captopril (5 mg/kg/day) or CT extract (300 mg/kg/day) plus captopril (5 mg/kg/day) for two consecutive weeks. CT extract reduced blood pressure dose-dependently, and the most effective dose was 300 mg/kg/day. l-NAME-induced hypertensive rats showed abnormalities including high blood pressure, high vascular resistance, impairment of acetylcholine-induced vasorelaxation in isolated aortic rings and mesenteric vascular beds, increased vascular superoxide production and plasma malondialdehyde levels, downregulation of eNOS, low level of plasma nitric oxide metabolites, upregulation of angiotensin II type 1 receptor and increased plasma angiotensin II. These abnormalities were alleviated by treatment with either CT extract or captopril. Combination treatment of CT extract and captopril normalized all the abnormalities found in hypertensive rats except endothelial dysfunction. These data indicate that there are synergistic antihypertensive effects of CT extract and captopril. These effects are likely mediated by their anti-oxidative properties and their inhibition of RAS. PMID:26938552

  14. Synergistic Antihypertensive Effect of Carthamus tinctorius L. Extract and Captopril in l-NAME-Induced Hypertensive Rats via Restoration of eNOS and AT1R Expression

    PubMed Central

    Maneesai, Putcharawipa; Prasarttong, Patoomporn; Bunbupha, Sarawoot; Kukongviriyapan, Upa; Kukongviriyapan, Veerapol; Tangsucharit, Panot; Prachaney, Parichat; Pakdeechote, Poungrat

    2016-01-01

    This study examined the effect of Carthamus tinctorius (CT) extract plus captopril treatment on blood pressure, vascular function, nitric oxide (NO) bioavailability, oxidative stress and renin-angiotensin system (RAS) in Nω-Nitro-l-arginine methyl ester (l-NAME)-induced hypertension. Rats were treated with l-NAME (40 mg/kg/day) for five weeks and given CT extract (75 or 150 or 300 or 500 mg/kg/day): captopril (5 mg/kg/day) or CT extract (300 mg/kg/day) plus captopril (5 mg/kg/day) for two consecutive weeks. CT extract reduced blood pressure dose-dependently, and the most effective dose was 300 mg/kg/day. l-NAME-induced hypertensive rats showed abnormalities including high blood pressure, high vascular resistance, impairment of acetylcholine-induced vasorelaxation in isolated aortic rings and mesenteric vascular beds, increased vascular superoxide production and plasma malondialdehyde levels, downregulation of eNOS, low level of plasma nitric oxide metabolites, upregulation of angiotensin II type 1 receptor and increased plasma angiotensin II. These abnormalities were alleviated by treatment with either CT extract or captopril. Combination treatment of CT extract and captopril normalized all the abnormalities found in hypertensive rats except endothelial dysfunction. These data indicate that there are synergistic antihypertensive effects of CT extract and captopril. These effects are likely mediated by their anti-oxidative properties and their inhibition of RAS. PMID:26938552

  15. Leukotriene B4 mediates macrophage influx and pulmonary hypertension in bleomycin-induced chronic neonatal lung injury.

    PubMed

    Ee, Mong Tieng; Kantores, Crystal; Ivanovska, Julijana; Wong, Mathew J; Jain, Amish; Jankov, Robert P

    2016-08-01

    Systemically-administered bleomycin causes inflammation, arrested lung growth, and pulmonary hypertension (PHT) in the neonatal rat, similar to human infants with severe bronchopulmonary dysplasia (BPD). Leukotrienes (LTs) are inflammatory lipid mediators produced by multiple cell types in the lung. The major LTs, LTB4 and cysteinyl LTs, are suggested to contribute to BPD, but their specific roles remain largely unexplored in experimental models. We hypothesized that LTs are increased in bleomycin-induced BPD-like injury, and that inhibition of LT production would prevent inflammatory cell influx and thereby ameliorate lung injury. Rat pups were exposed to bleomycin (1 mg·kg(-1)·day(-1) ip) or vehicle (control) from postnatal days 1-14 and were treated with either zileuton (5-lipoxygenase inhibitor), montelukast (cysteinyl LT1 receptor antagonist), or SC57461A (LTA4 hydrolase inhibitor) 10 mg·kg(-1)·day(-1) ip. Bleomycin led to increased lung content of LTB4, but not cysteinyl LTs. Bleomycin-induced increases in tissue neutrophils and macrophages and lung contents of LTB4 and tumor necrosis factor-α were all prevented by treatment with zileuton. Treatment with zileuton or SC57461A also prevented the hemodynamic and structural markers of chronic PHT, including raised pulmonary vascular resistance, increased Fulton index, and arterial wall remodeling. However, neither treatment prevented impaired alveolarization or vascular hypoplasia secondary to bleomycin. Treatment with montelukast had no effect on macrophage influx, PHT, or on abnormal lung structure. We conclude that LTB4 plays a crucial role in lung inflammation and PHT in experimental BPD. Agents targeting LTB4 or LTB4-mediated signaling may have utility in infants at risk of developing BPD-associated PHT. PMID:27317685

  16. Ruscogenin exerts beneficial effects on monocrotaline-induced pulmonary hypertension by inhibiting NF-κB expression

    PubMed Central

    Zhu, Rong; Bi, Liqing; Kong, Hui; Xie, Weiping; Hong, Yongqing; Wang, Hong

    2015-01-01

    This study aims to examine the effect of ruscogenin on pulmonary arterial hypertension (PAH) and to determine the mechanism underlying this effect. We isolated pulmonary vascular smooth muscle cells (PVSMCs) from the pulmonary artery of the rats; the PVSMCs were cultured in vitro and then were treated with platelet-derived growth factor (PDGF), PDGF + ruscogenin, or PDGF + ruscogenin + parthenolide. We randomized Sprague-Dawley rats into five groups as follows: control group, PAH group, low-dose group, medium-dose group, and high-dose group; the rats in the low-, medium-, and high-dose groups received the vehicle and ruscogenin 0.1, 0.4, and 0.7 mg/kg, respectively, from day 1 to day 21 after injection of monocrotaline (MCT). We measured the mean pulmonary arterial pressure (mPAP), right ventricular systolic pressure (RVSP), and medial wall thickness of the pulmonary artery (PAWT). We examined the levels of the nuclear factor kappa B (NF-κB) protein by using immunohistochemistry and western blot analysis, and the mRNA levels of NF-κB in PVSMCs were evaluated using real-time polymerase chain reaction (PCR). The mPAP, RVSP, and PAWT and the protein and mRNA levels of NF-κB were significantly higher in the PAH model group than in the control group (P < 0.05). Ruscogenin induced a significant dose-dependent decrease in the mPAP, RVSP, and PAWT and in the NF-κB expression in the PAH group (P < 0.05), which suggests that ruscogenin will also exert dose-dependent effects on MCT-induced PAH through the inhibition of NF-κB. PMID:26722401

  17. Icariin Inhibits Pulmonary Hypertension Induced by Monocrotaline through Enhancement of NO/cGMP Signaling Pathway in Rats

    PubMed Central

    Li, Li-sheng; Luo, Yun-mei; Liu, Juan; Zhang, Yu; Fu, Xiao-xia; Yang, Dan-li

    2016-01-01

    It has been reported that icariin (ICA) increased contents of nitric oxide (NO) and cyclic guanosine monophosphate (cGMP) by improving expression of endothelial nitric oxide synthase (eNOS) and inhibition of phosphodiesterase type 5 (PDE5). In addition, dysfunction of the NO/cGMP pathway may play a crucial role in the pathogenesis of pulmonary hypertension (PH). In this study, the potential protective effects of ICA on PH induced by monocrotaline (MCT, 50 mg/kg) singly subcutaneous injection were investigated and the possible mechanisms involved in NO/cGMP pathway were explored in male Sprague Dawley rats. The results showed that ICA (20, 40, and 80 mg/kg/d) treatment by intragastric administration could significantly ameliorate PH and upregulate the expression of eNOS gene and downregulate the expression of PDE5 gene in MCT-treated rats. Both ICA (40 mg/kg/d) and L-arginine (200 mg/kg/d), a precursor of NO as positive control, notably increased the contents of NO and cGMP in lung tissue homogenate, which were inversed by treatment with NG-nitro-L-arginine-methyl ester (L-NAME), a NOS inhibitor, and L-NAME-treatment could also inhibit the protective effects of ICA (40 mg/kg/d) on mean pulmonary artery pressure and artery remodeling and tends to inhibit right ventricle hypertrophy index. In summary, ICA is effective in protecting against MCT-induced PH in rats through enhancement of NO/cGMP signaling pathway in rats. PMID:27366192

  18. Diosmin, a bioflavonoid reverses alterations in blood pressure, nitric oxide, lipid peroxides and antioxidant status in DOCA-salt induced hypertensive rats.

    PubMed

    Silambarasan, Thangarasu; Raja, Boobalan

    2012-03-15

    The present study was aimed to evaluate the antihypertensive effect of diosmin in deoxycorticosterone acetate (DOCA)-salt induced hypertension in male Wistar rats. Hypertension was induced in uninephrectomized rats by weekly twice subcutaneous injection of DOCA (25 mg/kg body weight) and 1% NaCl in the drinking water for six consecutive weeks. The important pathological events that occurred in DOCA-salt treated rats were significant increase in systolic, diastolic blood pressure, sodium and chloride in serum and lipid peroxidation products (thiobarbituric acid reactive substances, lipid hydroperoxides and conjugated dienes) in plasma and tissues (liver, kidney, heart and aorta) and significant decrease in serum potassium, total nitrite and nitrate levels in plasma. The activities of hepatic aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, and gamma-glutamyl transpeptidase and the levels of renal urea, uric acid, creatinine in serum, water intake, and organ weight (kidney and heart) were significantly increased in DOCA-salt hypertensive rats. DOCA-salt treated rats also showed a significant decrease in body weight, activities of superoxide dismutase, catalase and glutathione peroxidase in erythrocyte and tissues and the levels of reduced glutathione, vitamin C and vitamin E in plasma and tissues. Treatment with diosmin (25, 50 and 100 mg/kg body weight) brings back all the above parameters to near normal level, in which 50 mg/kg body weight showed the highest effect than that of other two doses. Histopathology of heart and kidney also confirmed the protective effect of diosmin. Thus the experiment clearly showed that diosmin acts as an antihypertensive agent against DOCA-salt induced hypertension. PMID:22266490

  19. Effects of a novel ACE inhibitor, 3-(3-thienyl)-l-alanyl-ornithyl-proline, on endothelial vasodilation and hepatotoxicity in l-NAME-induced hypertensive rats

    PubMed Central

    Seth, Mahesh Kumar; Hussain, M Ejaz; Pasha, Santosh; Fahim, Mohammad

    2016-01-01

    Nitric oxide (NO) is a widespread biological mediator involved in many physiological and pathological processes, eg, in the regulation of vascular tone and hypertension. Chronic inhibition of NO synthase by NG-nitro-l-arginine methyl ester (l-NAME) hydrochloride results in the development of hypertension accompanied by an increase in vascular responsiveness to adrenergic stimuli. Recently, we developed a novel sulfur-containing angiotensin-converting enzyme inhibitor: 3-(3-thienyl)-l-alanyl-ornithyl-proline (TOP). Our previous studies indicated a superior nature of the molecule as an antihypertensive agent in spontaneously hypertensive rats (showing the involvement of renin–angiotensin–aldosterone system) in comparison to captopril. The aim of the present study was to investigate the effect of TOP on NO pathway in l-NAME-induced hypertensive rats, and captopril was included as the standard treatment group. Treatment with both TOP (20 mg/kg) and captopril (40 mg/kg) prevented the development of hypertension in l-NAME model, but TOP showed better restoration of NO and normal levels of angiotensin-converting enzyme. In addition, in vitro vasorelaxation assay showed an improvement in endothelium-dependent vasodilation in both the cases. Further, the biochemical (malondialdehyde, alanine aminotransferase, and aspartate aminotransferase) and the histopathological effects of TOP on rat liver tissues revealed a protective nature of TOP in comparison to captopril in the l-NAME model. In conclusion, TOP at 50% lesser dose than captopril was found to be better in the l-NAME model. PMID:27143859

  20. [Resistant hypertension].

    PubMed

    Feldstein, Carlos A

    2008-04-01

    Resistant hypertension, defined as a persistent blood pressure over 140/90 mmHg despite the use of three antihypertensive drugs including a diuretic, is unusual. The diagnosis requires ruling out initially pseudoresistance and a lack of compliance with treatment. Ambulatory blood pressure recording allow the recognition of white coat hypertension. When there is a clinical or laboratory suspicion, secondary causes of hypertension should be discarded. Excessive salt intake, the presence of concomitant diseases such as diabetes mellitus, chronic renal disease, obesity, and psychiatric conditions such as panic attacks, anxiety and depression, should also be sought. The presence of target organ damage requires a more aggressive treatment of hypertension. Recent clinical studies indicate that the administration of aldosterone antagonists as a fourth therapeutic line provides significant additional blood pressure reduction, when added to previous antihypertensive regimens in subjects with resistant hypertension. The possible blood pressure lowering effects of prolonged electrical activation of carotid baroreceptors is under investigation. PMID:18769797

  1. Chronic infusion of enalaprilat into hypothalamic paraventricular nucleus attenuates angiotensin II-induced hypertension and cardiac hypertrophy by restoring neurotransmitters and cytokines

    SciTech Connect

    Kang, Yu-Ming; Zhang, Dong-Mei; Yu, Xiao-Jing; Yang, Qing; Qi, Jie; Su, Qing; Suo, Yu-Ping; Yue, Li-Ying; Zhu, Guo-Qing; Qin, Da-Nian

    2014-02-01

    The renin–angiotensin system (RAS) in the brain is involved in the pathogenesis of hypertension. We hypothesized that inhibition of angiotensin-converting enzyme (ACE) in the hypothalamic paraventricular nucleus (PVN) attenuates angiotensin II (ANG II)-induced hypertension via restoring neurotransmitters and cytokines. Rats underwent subcutaneous infusions of ANG II or saline and bilateral PVN infusions of ACE inhibitor enalaprilat (ENL, 2.5 μg/h) or vehicle for 4 weeks. ANG II infusion resulted in higher mean arterial pressure and cardiac hypertrophy as indicated by increased whole heart weight/body weight ratio, whole heart weight/tibia length ratio, left ventricular weight/tibia length ratio, and mRNA expressions of cardiac atrial natriuretic peptide and beta-myosin heavy chain. These ANG II-infused rats had higher PVN levels of glutamate, norepinephrine, tyrosine hydroxylase, pro-inflammatory cytokines (PICs) and the chemokine monocyte chemoattractant protein-1, and lower PVN levels of gamma-aminobutyric acid, interleukin (IL)-10 and the 67-kDa isoform of glutamate decarboxylase (GAD67), and higher plasma levels of PICs, norepinephrine and aldosterone, and lower plasma IL-10, and higher renal sympathetic nerve activity. However, PVN treatment with ENL attenuated these changes. PVN microinjection of ANG II induced increases in IL-1β and IL-6, and a decrease in IL-10 in the PVN, and pretreatment with angiotensin II type 1 receptor (AT1-R) antagonist losartan attenuated these changes. These findings suggest that ANG II infusion induces an imbalance between excitatory and inhibitory neurotransmitters and an imbalance between pro- and anti-inflammatory cytokines in the PVN, and PVN inhibition of the RAS restores neurotransmitters and cytokines in the PVN, thereby attenuating ANG II-induced hypertension and cardiac hypertrophy. - Highlights: • Chronic ANG II infusion results in sympathetic hyperactivity and cardiac hypertrophy. • PVN inhibition of ACE

  2. Blood Pressure Interventions Affect Acute and Four-Week Diesel Exhaust Induced Pulmonary Injury in Healthy and Hypertensive Rats

    EPA Science Inventory

    Rationale: We recently showed that inhalation exposure of normotensive Wistar Kyoto (WKY) rats to whole diesel exhaust (DE) elicits changes in cardiac gene expression that broadly mimics expression in spontaneously hypertensive (SH) rats without DE. We hypothesized that pharmacol...

  3. Role of renin-angiotensin-aldosterone system gene polymorphisms and hypertension-induced end-stage renal disease in autosomal dominant polycystic kidney disease.

    PubMed

    Ramanathan, Gnanasambandan; Elumalai, Ramprasad; Periyasamy, Soundararajan; Lakkakula, Bhaskar

    2014-07-01

    Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited disease of the kidneys and is marked by progressive cyst growth and decline in kidney function, resulting in end-stage renal disease (ESRD). Hypertension is thought to be a significant modifying factor in the progression of renal failure in ADPKD. A number of genetic variations involved in renin-angiotensin-aldosterone system (RAAS) pathway genes have clinical or physiological impacts on pathogenesis of hypertension-induced ESRD in ADPKD. Information on RAAS pathway gene polymorphisms and their association with ESRD and ADPKD, published till March 2013, was collected using MEDLINE search. The present review deals with RAAS gene polymorphisms focused on hypertension-induced ESRD in ADPKD in different populations. The results were inconclusive and limited by heterogeneity in the study designs and the population stratification. In lieu of applying next generation sequencing technologies to study complex diseases, it is also possible to apply the same to unravel the complexity of ESRD in ADPKD. PMID:25001132

  4. A pivotal role of the vascular endothelial growth factor signaling pathway in the formation of venous hypertension-induced dural arteriovenous fistulas

    PubMed Central

    LI, QIANG; ZHANG, QI; HUANG, QING-HAI; FANG, YI-BIN; ZHANG, ZHAO-LONG; XU, YI; LIU, JIAN-MIN

    2014-01-01

    Dural arteriovenous fistulas (DAVFs) are associated with venous hypertension. Numerous studies have revealed high expression levels of vascular endothelial growth factor (VEGF) in human DAVF specimens, as well as in animal models of experimental venous hypertension. The objective of the present study was to clarify whether the VEGF signaling pathway is important in the development of DAVFs. Rats (n=216) were randomly divided into six groups. In the rats from five groups (groups A and C-E, n=45 in each group; group B, n=12), experimental venous hypertension was induced by right common carotid artery (CCA)-external jugular vein (EJV) anastomosis, superior sinus occlusion and left transver sinus occlusion, while the remaining group (group F, n=24) underwent sham surgery. The rats in group A received a VEGF recombinant adenovirus injection into the distal section of the right EJV 30 min prior to anastomosis of the CCA and EJV. An equivalent control adenovirus was injected into the right EJV of group B rats prior to anastomosis. The rats in group C received no virus prior to anastomosis and no medicine subsequent to surgery. The group D rats were lavaged with Vatalanib, a VEGF receptor (VEGFR) inhibitor, and the group E rats were lavaged with an equal quantity of saline weekly following surgery. Six rats from groups A-E and one rat from group F were sacrificed in the first, second, fourth and twelfth weeks after surgery for immunohistochemical analysis of VEGF expression and analysis of microvessel density. Cerebral angiography was performed on the remaining rats in each group on the twelfth week after surgery. The results revealed that following transfection with VEGF recombinant adenovirus, angiogenesis in the dura mater of venous hypertensive rats was increased subsequent to the increase in the VEGF expression levels of the brain and dura mater. The rate of DAVF induction by venous hypertension was significantly reduced by the VEGFR antagonist due to reduced

  5. The complement receptor C5aR1 contributes to renal damage but protects the heart in angiotensin II-induced hypertension.

    PubMed

    Weiss, Sebastian; Rosendahl, Alva; Czesla, Daniel; Meyer-Schwesinger, Catherine; Stahl, Rolf A K; Ehmke, Heimo; Kurts, Christian; Zipfel, Peter F; Köhl, Jörg; Wenzel, Ulrich O

    2016-06-01

    Adaptive and innate immune responses contribute to hypertension and hypertensive end-organ damage. Here, we determined the role of anaphylatoxin C5a, a major inflammatory effector of the innate immune system that is generated in response to complement activation, in hypertensive end-organ damage. For this purpose, we assessed the phenotype of C5a receptor 1 (C5aR1)-deficient mice in ANG II-induced renal and cardiac injury. Expression of C5aR1 on infiltrating and resident renal as well as cardiac cells was determined using a green fluorescent protein (GFP)-C5aR1 reporter knockin mouse. Flow cytometric analysis of leukocytes isolated from the kidney of GFP-C5aR1 reporter mice showed that 28% of CD45-positive cells expressed C5aR1. Dendritic cells were identified as the major C5aR1-expressing population (88.5%) followed by macrophages and neutrophils. Using confocal microscopy, we detected C5aR1 in the kidney mainly on infiltrating cells. In the heart, only infiltrating cells stained C5aR1 positive. To evaluate the role of C5aR1 deficiency in hypertensive injury, an aggravated model of hypertension was used. Unilateral nephrectomy was performed followed by infusion of ANG II (1.5 ng·g(-1)·min(-1)) and salt in wild-type (n = 34) and C5aR1-deficient mice (n = 32). C5aR1-deficient mice exhibited less renal injury, as evidenced by significantly reduced albuminuria. In contrast, cardiac injury was accelerated with significantly increased cardiac fibrosis and heart weight in C5aR1-deficient mice after ANG II infusion. No effect was found on blood pressure. In summary, the C5a:C5aR1 axis drives end-organ damage in the kidney but protects from the development of cardiac fibrosis and hypertrophy in experimental ANG II-induced hypertension. PMID:27053686

  6. A pivotal role of the vascular endothelial growth factor signaling pathway in the formation of venous hypertension-induced dural arteriovenous fistulas.

    PubMed

    Li, Qiang; Zhang, Qi; Huang, Qing-Hai; Fang, Yi-Bin; Zhang, Zhao-Long; Xu, Yi; Liu, Jian-Min

    2014-05-01

    Dural arteriovenous fistulas (DAVFs) are associated with venous hypertension. Numerous studies have revealed high expression levels of vascular endothelial growth factor (VEGF) in human DAVF specimens, as well as in animal models of experimental venous hypertension. The objective of the present study was to clarify whether the VEGF signaling pathway is important in the development of DAVFs. Rats (n=216) were randomly divided into six groups. In the rats from five groups (groups A and C-E, n=45 in each group; group B, n=12), experimental venous hypertension was induced by right common carotid artery (CCA)‑external jugular vein (EJV) anastomosis, superior sinus occlusion and left transver sinus occlusion, while the remaining group (group F, n=24) underwent sham surgery. The rats in group A received a VEGF recombinant adenovirus injection into the distal section of the right EJV 30 min prior to anastomosis of the CCA and EJV. An equivalent control adenovirus was injected into the right EJV of group B rats prior to anastomosis. The rats in group C received no virus prior to anastomosis and no medicine subsequent to surgery. The group D rats were lavaged with Vatalanib, a VEGF receptor (VEGFR) inhibitor, and the group E rats were lavaged with an equal quantity of saline weekly following surgery. Six rats from groups A-E and one rat from group F were sacrificed in the first, second, fourth and twelfth weeks after surgery for immunohistochemical analysis of VEGF expression and analysis of microvessel density. Cerebral angiography was performed on the remaining rats in each group on the twelfth week after surgery. The results revealed that following transfection with VEGF recombinant adenovirus, angiogenesis in the dura mater of venous hypertensive rats was increased subsequent to the increase in the VEGF expression levels of the brain and dura mater. The rate of DAVF induction by venous hypertension was significantly reduced by the VEGFR antagonist due to reduced

  7. Resveratrol Inhibition of Rac1-Derived Reactive Oxygen Species by AMPK Decreases Blood Pressure in a Fructose-Induced Rat Model of Hypertension.

    PubMed

    Cheng, Pei-Wen; Lee, Hui-Chieh; Lu, Pei-Jung; Chen, Hsin-Hung; Lai, Chi-Cheng; Sun, Gwo-Ching; Yeh, Tung-Chen; Hsiao, Michael; Lin, Yu-Te; Liu, Chun-Peng; Tseng, Ching-Jiunn

    2016-01-01

    Recent studies have reported that the activation of AMP-activated protein kinase (AMPK) suppressed oxidative stress. The aim of this study was to examine whether the activation of AMPK in the brain decreased Rac1-induced ROS generation, thereby reducing blood pressure (BP) in rats with fructose-induced hypertension. The inhibition of ROS by treatment with an AMPK activator (oral resveratrol, 10 mg/kg/day) for 1 week decreased the BP and increased the NO production in the rostral ventrolateral medulla (RVLM) of fructose-fed rats but not in control Wistar-Kyoto (WKY) rats. In addition, resveratrol treatment abolished the Rac1-induced increases in the activity of the NADPH oxidase subunits p22-phox and reduced the activity of SOD2, while treatment with an AMPK inhibitor (compound C, 40 μM/day) had the opposite effect, in the fructose-fed rats. Interestingly, the activation of AMPK abolished Rac1 activation and decreased BP by inducing the activities of extracellular signal-regulated kinases 1 and 2 (ERK1/2) and ribosomal protein S6 kinase (RSK) and nNOS phosphorylation in the fructose-fed rats. We conclude that the activation of AMPK decreased BP, abolished ROS generation, and enhanced ERK1/2-RSK-nNOS pathway activity by negatively regulating Racl-induced NADPH oxidase levels in the RVLM during oxidative stress-associated hypertension. PMID:27138844

  8. Resveratrol Inhibition of Rac1-Derived Reactive Oxygen Species by AMPK Decreases Blood Pressure in a Fructose-Induced Rat Model of Hypertension

    PubMed Central

    Cheng, Pei-Wen; Lee, Hui-Chieh; Lu, Pei-Jung; Chen, Hsin-Hung; Lai, Chi-Cheng; Sun, Gwo-Ching; Yeh, Tung-Chen; Hsiao, Michael; Lin, Yu-Te; Liu, Chun-Peng; Tseng, Ching-Jiunn

    2016-01-01

    Recent studies have reported that the activation of AMP-activated protein kinase (AMPK) suppressed oxidative stress. The aim of this study was to examine whether the activation of AMPK in the brain decreased Rac1-induced ROS generation, thereby reducing blood pressure (BP) in rats with fructose-induced hypertension. The inhibition of ROS by treatment with an AMPK activator (oral resveratrol, 10 mg/kg/day) for 1 week decreased the BP and increased the NO production in the rostral ventrolateral medulla (RVLM) of fructose-fed rats but not in control Wistar-Kyoto (WKY) rats. In addition, resveratrol treatment abolished the Rac1-induced increases in the activity of the NADPH oxidase subunits p22-phox and reduced the activity of SOD2, while treatment with an AMPK inhibitor (compound C, 40 μM/day) had the opposite effect, in the fructose-fed rats. Interestingly, the activation of AMPK abolished Rac1 activation and decreased BP by inducing the activities of extracellular signal-regulated kinases 1 and 2 (ERK1/2) and ribosomal protein S6 kinase (RSK) and nNOS phosphorylation in the fructose-fed rats. We conclude that the activation of AMPK decreased BP, abolished ROS generation, and enhanced ERK1/2-RSK-nNOS pathway activity by negatively regulating Racl-induced NADPH oxidase levels in the RVLM during oxidative stress–associated hypertension. PMID:27138844

  9. Endothelin-1 critically contribute to EPC reduction and dysfunction via an ETA/NADPH oxidase pathway-induced oxidative stress in salt-sensitive hypertension

    PubMed Central

    Chen, Dan-Dan; Dong, Yu-Gang; Chen, Alex F.

    2012-01-01

    Circulating endothelial progenitor cells (EPCs) are reduced in hypertension, which inversely correlates with its mortality. DOCA–salt hypertension features elevated ET-1 and oxidative stress. We tested the hypothesis that ET-1 induces EPC dysfunction by elevating oxidative stress through the ETA/NADPH oxidase pathway in salt-sensitive hypertension. Both ETA and ETB receptors were expressed in EPCs, but only ETA receptors were significantly increased in EPCs of DOCA-salt rats. EPC number and function were reduced in DOCA-salt rats compared with Sham controls, both were reversed by in vivo blockade of ETA receptors or NADPH oxidase. The enzymatic activity of NAPDH oxidase and its subunits gp91phox, p22phox and Rac1 were augmented in EPCs of DOCA-salt rats, with concomitantly decreased antioxidant enzymes MnSOD, CuZnSOD, and GPx-1. ROS level was elevated in EPCs from DOCA-salt rats, accompanied by increased EPC telomerase inactivation, senescence and apoptosis, which were rescued by ETA or NADPH oxidase blockade. Cell therapy of normal or treated DOCA EPCs, but not untreated DOCA EPCs, significantly increased capillary density and blood perfusion in ischemic hindlimbs of DOCA-salt rats. p53 and Bax/Bcl-2 ratios were increased in EPCs of DOCA-salt rats, which were reversed by ETA antagonist or NADPH oxidase inhibitor or superoxide scavenger (PEG-SOD). Finally, in ETB-deficient rats, plasma ET-1 was elevated and EPC number and telomerase activity were diminished. These results demonstrate, for the first time, that ET-1 contributes to EPC reduction and dysfunction via an ETA/NADPH oxidase pathway-induced oxidative stress in salt-sensitive hypertension. PMID:22431579

  10. Hypertensive crisis.

    PubMed

    Rubenstein, E B; Escalante, C

    1989-07-01

    Hypertensive crisis is an acute emergency requiring aggressive management. Its incidence has decreased in recent years but still is prevalent in the medical community. From review of past and present treatment regimens, the following recommendations can be considered. (1) In the treatment of malignant hypertension with associated CHF, sodium nitroprusside is still an excellent agent. It has a rapid onset of action and blood pressure can be easily titrated. Nitroglycerin is also another agent that can be used in this situation. (2) In the treatment of malignant hypertension with associated aortic dissection, trimethophan camsylate is the preferred agent. An alternative choice is the combination of nitroprusside and labetalol. (3) In the treatment of malignant hypertension with associated myocardial ischemia, an excellent choice is nitroglycerin. Labetalol also should be considered in this situation. (4) In the treatment of hypertension during pregnancy, hydralazine is still a good choice. Labetalol has also been shown to be efficacious. (5) In the treatment of malignant hypertension with associated cerebral ischemia, the following drugs should be considered: nitroprusside, nitroglycerin, and labetalol. The most important attribute of these agents is that they are nonsedating and rapid in onset. (6) In the treatment of postoperative hypertension the choices best suited are labetalol, enalapril, nitroprusside, and nitroglycerin. These agents are rapid in onset and all can be administered intravenously. PMID:2670090

  11. Role of estrogen receptor β selective agonist in ameliorating portal hypertension in rats with CCl4-induced liver cirrhosis

    PubMed Central

    Zhang, Cheng-Gang; Zhang, Bin; Deng, Wen-Sheng; Duan, Ming; Chen, Wei; Wu, Zhi-Yong

    2016-01-01

    AIM: To investigate the role of diarylpropionitrile (DPN), a selective agonist of estrogen receptor β (ERβ), in liver cirrhosis with portal hypertension (PHT) and isolated hepatic stellate cells (HSCs). METHODS: Female Sprague-Dawley rats were ovariectomized (OVX), and liver cirrhosis with PHT was induced by CCl4 injection. DPN and PHTPP, the selective ERβ agonist and antagonist, were used as drug interventions. Liver fibrosis was assessed by hematoxylin and eosin (HE) and Masson’s trichrome staining and by analyzing smooth muscle actin expression. Hemodynamic parameters were determined in vivo using colored microspheres technique. Protein expression and phosphorylation were determined by immunohistochemical staining and Western blot analysis. Messenger RNA levels were analyzed by quantitative real-time polymerase chain reaction (qRT-PCR). Collagen gel contraction assay was performed using gel lattices containing HSCs treated with DPN, PHTPP, or Y-27632 prior to ET-1 addition. RESULTS: Treatment with DPN in vivo greatly lowered portal pressure and improved hemodynamic parameters without affecting mean arterial pressure, which was associated with the attenuation of liver fibrosis and intrahepatic vascular resistance (IHVR). In CCl4-treated rat livers, DPN significantly decreased the expression of RhoA and ROCK II, and even suppressed ROCK II activity. Moreover, DPN remarkedly increased the levels of endothelial nitric oxide synthase (eNOS) and phosphorylated eNOS, and promoted the activities of protein kinase G (PKG), which is an NO effector in the liver. Furthermore, DPN reduced the contractility of activated HSCs in the 3-dimensional stress-relaxed collagen lattices, and decreased the ROCK II activity in activated HSCs. Finally, in vivo/in vitro experiments demonstrated that MLC activity was inhibited by DPN. CONCLUSION: For OVX rats with liver cirrhosis, DPN suppressed liver RhoA/ROCK signal, facilitated NO/PKG pathways, and decreased IHVR, giving rise to

  12. Diet-induced antisecretory factor prevents intracranial hypertension in a dosage-dependent manner.

    PubMed

    Johansson, Ewa; Al-Olama, Mohamed; Hansson, Hans-Arne; Lange, Stefan; Jennische, Eva

    2013-06-28

    Intake of specially processed cereal (SPC) stimulates endogenous antisecretory factor (AF) activity, and SPC intake has proven to be beneficial for a number of clinical conditions. The aim of the present study was to investigate the dosage relationship between SPC intake and plasma AF activity and to further correlate achieved AF levels to a biological effect. SPC was fed to rats in concentrations of 5, 10 or 15% for 2 weeks. A further group was fed 5% SPC for 4 weeks. AF activity and the complement factors C3c and factor H were analysed in plasma after the feeding period. Groups of rats fed the various SPC concentrations were subjected to a standardised freezing brain injury, known to induce increases in intracranial pressure (ICP). The AF activity in plasma increased after intake of SPC, in a dosage- and time-dependent manner. The complement factors C3c and factor H increased in a time-dependent manner. Measurements of ICP in animals fed with SPC prior to the brain injury showed that the ICP was significantly lower, compared with that of injured rats fed with a standard feed, and that the change was dose and time dependent. AF activity increases, in a dosage- and time-dependent manner, after intake of SPC. The inverse relationship between ICP after a head injury and the percentage of SPC in the feed indicate that the protective effect is, to a large extent, due to AF. PMID:23153478

  13. Administration of antioxidant peptide SS-31 attenuates transverse aortic constriction-induced pulmonary arterial hypertension in mice

    PubMed Central

    Lu, Hung-i; Huang, Tien-hung; Sung, Pei-hsun; Chen, Yung-lung; Chua, Sarah; Chai, Han-yan; Chung, Sheng-ying; Liu, Chu-feng; Sun, Cheuk-kwan; Chang, Hsueh-wen; Zhen, Yen-yi; Lee, Fan-yen; Yip, Hon-kan

    2016-01-01

    Aim: Antioxidant peptide SS-31 is a class of cell-permeable small peptides, which selectively resides on the inner mitochondrial membrane and possesses intrinsic mitochondrial protective capacities. In this study we investigated the therapeutic effects of antioxidant peptide SS-31 on transverse aortic constriction (TAC)-induced pulmonary arterial hypertension (PAH) in a murine model. Methods: Adult male mice were divided into 3 groups: sham-operated mice, TAC mice, and TAC+SS-31 mice that underwent TAC surgery and received SS-31 (2 mg/d, ip) for 60 d. The right ventricular systolic blood pressure (RVSBP) was measured on d 60 prior to sacrificing the mice; then their right heart and lung tissues were collected for histological and biochemical examinations. Lung injury scores were defined by the increased crowded area and decreased number of alveolar sacs. Results: TAC mice showed significantly higher RVSBP compared with sham-operated mice, the elevation was substantially suppressed in TAC+SS-31 mice. The same pattern of changes was found in pulmonary levels of oxidative stress proteins (NOX-1/NOX-2/oxidized proteins), cytosolic cytochrome c, biomarkers related to inflammation (MMP-9/TNF-α/iNOS), calcium overload index (TRPC1, 2, 4, 6), apoptosis (mitochondrial BAX, cleaved caspase 3/PARP), fibrosis (Smad3/TGF-β), hypoxic (HIF-1α), DNA damage (γ-H2AX) and endothelial function (eNOS/ET-1R), as well as in lung injury score, number of muscularized vessels in lungs, number of TRPC1+ and HIF-1α+ cells in pulmonary artery, and number of γ-H2AX+ and Ki-67+ cells in lung parenchyma. An opposite pattern of changes was observed in pulmonary anti-fibrotic markers (Smad1/5, BMP-2), number of small vessels, and number of alveolar sacs. In contrast, the levels of antioxidant proteins (HO-1/NQO-1/GR/GPx) in lung parenchyma were progressively and significantly increased from sham-operated mice, TAC mice to TAC+SS-31 mice. Conclusion: Antioxidant peptide SS-31 administration

  14. Pulmonary Hypertension

    MedlinePlus

    Pulmonary hypertension (PH) is high blood pressure in the arteries to your lungs. It is a serious condition. If you have ... and you can develop heart failure. Symptoms of PH include Shortness of breath during routine activity, such ...

  15. Hypertension screening

    NASA Technical Reports Server (NTRS)

    Foulke, J. M.

    1975-01-01

    An attempt was made to measure the response to an announcement of hypertension screening at the Goddard Space Center, to compare the results to those of previous statistics. Education and patient awareness of the problem were stressed.

  16. [Hypertensive retinopathy].

    PubMed

    Genevois, Olivier; Paques, Michel

    2010-01-20

    Acute hypertensive retinopathy should be distinguished from retinal arteriolosclerosis. The presence of microvascular abnormalities in the ocular fundus increases the risk of heart and/or brain attack. At the clinical level, the current classification of chronic hypertensive retinopathy is based on the long-term risk of stroke. In research, a great number of studies are focused on the predictive value of retinal vascular diameters related to the general micro- and macrovascular disease. PMID:20222306

  17. Tranexamic Acid Diminishes Laser-Induced Melanogenesis

    PubMed Central

    Kim, Myoung Shin; Bang, Seung Hyun; Kim, Jeong-Hwan; Shin, Hong-Ju; Choi, Jee-Ho

    2015-01-01

    Background The treatment of post-inflammatory hyperpigmentation (PIH) remains challenging. Tranexamic acid, a well-known anti-fibrinolytic drug, has recently demonstrated a curative effect towards melasma and ultraviolet-induced PIH in Asian countries. However, the precise mechanism of its inhibitory effect on melanogenesis is not fully understood. Objective In order to clarify the inhibitory effect of tranexamic acid on PIH, we investigated its effects on mouse melanocytes (i.e., melan-a cells) and human melanocytes. Methods Melan-a cells and human melanocytes were cultured with fractional CO2 laser-treated keratinocyte-conditioned media. Melanin content and tyrosinase activity were evaluated in cells treated with or without tranexamic acid. Protein levels of tyrosinase, tyrosinase-related protein (TRP)-1, and TRP-2 were evaluated in melan-a cells. Signaling pathway molecules involved in melanogenesis in melanoma cells were also investigated. Results Tranexamic acid-treated melanocytes exhibited reduced melanin content and tyrosinase activity. Tranexamic acid also decreased tyrosinase, TRP-1, and TRP-2 protein levels. This inhibitory effect on melanogenesis was considered to be involved in extracellular signal-regulated kinase signaling pathways and subsequently microphthalmia-associated transcription factor degradation. Conclusion Tranexamic acid may be an attractive candidate for the treatment of PIH. PMID:26082580

  18. Systemic hypertension.

    PubMed

    Elliott, William J

    2007-04-01

    Hypertension is a growing public health problem worldwide. Only 37% of American hypertensives currently have their blood pressures controlled. Hypertension is traditionally diagnosed in the medical office, but both home and ambulatory blood pressure monitoring can help. Lifestyle modifications are recommended for everyone who has higher than "normal" blood pressure (<120/80 mm Hg). Voluminous clinical trial data support beginning drug therapy with low-dose chlorthalidone, unless the patient has a specific indication for a different drug. Additional drugs (typically in the sequence, angiotensin converting-enzyme inhibitor or angiotensin receptor blocker, calcium antagonist, beta-blocker, alpha-blocker, aldosterone antagonist, direct vasodilator, and centrally acting alpha(2)-agonist) can be added to achieve the blood pressure goal (usually <140/90 mm Hg, but <130/80 mm Hg for diabetics and those with chronic kidney disease). Special circumstances exist for treatment of hypertension in pregnancy, in childhood, in the elderly, and in both extremes of blood pressure (pre-hypertension or hypertensive emergencies). PMID:17398315

  19. Prenatal inflammation-induced NF-κB dyshomeostasis contributes to renin-angiotensin system over-activity resulting in prenatally programmed hypertension in offspring

    PubMed Central

    Deng, Youcai; Deng, Yafei; He, Xiaoyan; Chu, Jianhong; Zhou, Jianzhi; Zhang, Qi; Guo, Wei; Huang, Pei; Guan, Xiao; Tang, Yuan; Wei, Yanling; Zhao, Shanyu; Zhang, Xingxing; Wei, Chiming; Namaka, Michael; Yi, Ping; Yu, Jianhua; Li, Xiaohui

    2016-01-01

    Studies involving the use of prenatally programmed hypertension have been shown to potentially contribute to prevention of essential hypertension (EH). Our previous research has demonstrated that prenatal inflammatory stimulation leads to offspring’s aortic dysfunction and hypertension in pregnant Sprague-Dawley rats challenged with lipopolysaccharide (LPS). The present study found that prenatal LPS exposure led to NF-κB dyshomeostasis from fetus to adult, which was characterized by PI3K-Akt activation mediated degradation of IκBα protein and impaired NF-κB self-negative feedback loop mediated less newly synthesis of IκBα mRNA in thoracic aortas (gestational day 20, postnatal week 7 and 16). Prenatal or postnatal exposure of the IκBα degradation inhibitor, pyrollidine dithiocarbamate, effectively blocked NF-κB activation, endothelium dysfunction, and renin-angiotensin system (RAS) over-activity in thoracic aortas, resulting in reduced blood pressure in offspring that received prenatal exposure to LPS. Surprisingly, NF-κB dyshomeostasis and RAS over-activity were only found in thoracic aortas but not in superior mesenteric arteries. Collectively, our data demonstrate that the early life NF-κB dyshomeostasis induced by prenatal inflammatory exposure plays an essential role in the development of EH through triggering RAS over-activity. We conclude that early life NF-κB dyshomeostasis is a key predictor of EH, and thus, NF-κB inhibition represents an effective interventional strategy for EH prevention. PMID:26877256

  20. Over-expression of copper/zinc superoxide dismutase in the median preoptic nucleus attenuates chronic angiotensin II-induced hypertension in the rat.

    PubMed

    Collister, John P; Bellrichard, Mitch; Drebes, Donna; Nahey, David; Tian, Jun; Zimmerman, Matthew C

    2014-01-01

    The brain senses circulating levels of angiotensin II (AngII) via circumventricular organs, such as the subfornical organ (SFO), and is thought to adjust sympathetic nervous system output accordingly via this neuro-hormonal communication. However, the cellular signaling mechanisms involved in these communications remain to be fully understood. Previous lesion studies of either the SFO, or the downstream median preoptic nucleus (MnPO) have shown a diminution of the hypertensive effects of chronic AngII, without providing a clear explanation as to the intracellular signaling pathway(s) involved. Additional studies have reported that over-expressing copper/zinc superoxide dismutase (CuZnSOD), an intracellular superoxide (O2·-) scavenging enzyme, in the SFO attenuates chronic AngII-induced hypertension. Herein, we tested the hypothesis that overproduction of O2·- in the MnPO is an underlying mechanism in the long-term hypertensive effects of chronic AngII. Adenoviral vectors encoding human CuZnSOD (AdCuZnSOD) or control vector (AdEmpty) were injected directly into the MnPO of rats implanted with aortic telemetric transmitters for recording of arterial pressure. After a 3 day control period of saline infusion, rats were intravenously infused with AngII (10 ng/kg/min) for ten days. Rats over-expressing CuZnSOD (n = 7) in the MnPO had a blood pressure increase of only 6 ± 2 mmHg after ten days of AngII infusion while blood pressure increased 21 ± 4 mmHg in AdEmpty-infected rats (n = 9). These results support the hypothesis that production of O2·- in the MnPO contributes to the development of chronic AngII-dependent hypertension. PMID:25474089

  1. Gene expression of cyclin-dependent kinase inhibitors and effect of heparin on their expression in mice with hypoxia-induced pulmonary hypertension

    SciTech Connect

    Yu Lunyin; Quinn, Deborah A.; Garg, Hari G.; Hales, Charles A. . E-mail: chales@partners.org

    2006-07-14

    The balance between cell proliferation and cell quiescence is regulated delicately by a variety of mediators, in which cyclin-dependent kinases (CDK) and CDK inhibitors (CDKI) play a very important role. Heparin which inhibits pulmonary artery smooth muscle cell (PASMC) proliferation increases the levels of two CDKIs, p21 and p27, although only p27 is important in inhibition of PASMC growth in vitro and in vivo. In the present study we investigated the expression profile of all the cell cycle regulating genes, including all seven CDKIs (p21, p27, p57, p15, p16, p18, and p19), in the lungs of mice with hypoxia-induced pulmonary hypertension. A cell cycle pathway specific gene microarray was used to profile the 96 genes involved in cell cycle regulation. We also observed the effect of heparin on gene expression. We found that (a) hypoxic exposure for two weeks significantly inhibited p27 expression and stimulated p18 activity, showing a 98% decrease in p27 and 81% increase in p18; (b) other CDKIs, p21, p57, p15, p16, and p19 were not affected significantly in response to hypoxia; (c) heparin treatment restored p27 expression, but did not influence p18; (d) ERK1/2 and p38 were mediators in heparin upregulation of p27. This study provides an expression profile of cell cycle regulating genes under hypoxia in mice with hypoxia-induced pulmonary hypertension and strengthens the previous finding that p27 is the only CDKI involved in heparin regulation of PASMC proliferation and hypoxia-induced pulmonary hypertension.

  2. The effect of hydroalcoholic extract from the leaves of Moringa peregrina (Forssk.) Fiori. on blood pressure and oxidative status in dexamethasone-induced hypertensive rats

    PubMed Central

    Safaeian, Leila; Asghari, Gholamreza; Javanmard, Shaghayegh Haghjoo; Heidarinejad, Arman

    2015-01-01

    Background: Moringa peregrina (Forssk.) Fiori. is a tropical tree growing in southeast of Iran. All parts of this plant have nutritional uses and pharmacological activities. The present study was designed to evaluate the effect of hydroalcoholic extract from the leaves of M. peregrina in dexamethasone (Dex)-induced hypertension in rats. Materials and Methods: Male Wistar rats received Dex (30 μg/kg, subcutaneously; s.c.) or saline (as vehicle, 1 ml/kg, s.c.) for 14 days. In a prevention study, the rats received M. peregrina extract (100, 200 and 400 mg/kg, orally) for 4 days, followed by Dex for 14 days. In a reversal study, the animals received M. peregrina extract orally from day 8 to 14. The systolic blood pressure (SBP) was measured using tail-cuff method. The hydrogen peroxide (H2O2) concentration and ferric reducing antioxidant power (FRAP) were assessed in plasma samples. Results: Dex significantly increased the SBP and the plasma H2O2 and decreased the plasma FRAP value (P < 0.001). M. peregrina extract at a dose of 400 mg/kg prevented (P < 0.01) but did not reverse Dex-induced hypertension in rats. It also dose-dependently reduced the plasma H2O2 concentration and improved the FRAP value upon Dex administration. Conclusions: The findings of the present study indicated the antioxidant and partially antihypertensive effects of the hydroalcoholic extract from the leaves of M. peregrina in Dex-induced hypertension. Further experiments on other fractions of the leaves and also other parts of this plant are suggested for better evaluation of its antihypertensive effect and finding its mechanisms of action. PMID:26015927

  3. Hypertensive emergencies.

    PubMed

    Murphy, C

    1995-11-01

    Hypertensive emergencies are uncommon and physiologically diverse. Consequently, it is difficult for most physicians to develop a familiarity with all the different hypertensive crises and with all drugs available for treating them (Table 4). Clinicians should not agonize over which is the perfect therapeutic agent for a particular emergency, but instead, they should focus on scrupulous monitoring and familiarize themselves with a few agents that will serve in most situations. Generally, these agents will be sodium nitroprusside and nitroglycerin. Vigilant neurologic monitoring is mandatory in all hypertensive emergencies. The early symptoms and signs of cerebral hypoperfusion can be vague and subtle, but if recognized, serious complications of therapy can be avoided. Remember, the patient may still be hypertensive. Avoid acute (during the first hour) reductions in MAP of more than 20% whenever possible; subsequent reductions should be gradual. In patients known to have markedly elevated ICP and who need acute reductions in their BP, serious consideration should be given to direct monitoring of the ICP so that CPP can be maintained within safe limits. In general, oral agents should not be used for the treatment of hypertensive emergencies. Intravenous Labetalol and intravenous nicardipine are not suitable for general use in hypertensive emergencies. In special situations (e.g., perioperative hypertension and subarachnoid hemorrhage), however, they may be employed. Their role may expand with further study. Trimethaphan may be superior to nitroprusside for hypertension complicated by elevated ICP or cerebral dysfunction. Realistically, most physicians will continue to use nitroprusside. Intense neurologic monitoring is more important than the specific agent used. Nitroglycerin is the agent of choice for acute ischemic heart disease complicated by severe hypertension; if it fails, use nitroprusside. For aortic dissection, the combination of nitroprusside and IV

  4. 2-(1-Hexyn-1-yl)adenosine-induced intraocular hypertension is mediated via K+ channel opening through adenosine A2A receptor in rabbits.

    PubMed

    Konno, Takashi; Uchibori, Takehiro; Nagai, Akihiko; Kogi, Kentaro; Nakahata, Norimichi

    2005-08-22

    The present study was performed to clarify the mechanism of change in intraocular pressure by 2-(1-hexyn-1-yl)adenosine (2-H-Ado), a selective adenosine A2 receptor agonist, in rabbits. 2-H-Ado (0.1%, 50 microl)-induced ocular hypertension (E(max): 7.7 mm Hg) was inhibited by an adenosine A2A receptor antagonist 1,3,7-trimethyl-8-(3-chlorostyryl)xanthine, ATP-sensitive K+ channel blocker glibenclamide or 5-hydroxydecanoic acid, but not by an adenosine A1 receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine, an adenosine A2B receptor antagonist alloxazine or a cyclooxygenase inhibitor indomethacin. The outflow facility induced by 2-H-Ado seems to be independent of increase in intraocular pressure or ATP-sensitive K+ channel. In contrast, the recovery rate in intraocular pressure decreased by hypertonic saline was accelerated by 2-H-Ado, and this response was dependent on ATP-sensitive K+ channel. These results suggest that 2-H-Ado-induced ocular hypertension is mediated via K+ channel opening through adenosine A2A receptor, and this is probably due to aqueous formation, but independent of change in outflow facility or prostaglandin production. PMID:16023100

  5. The Soluble Guanylate Cyclase Stimulator Riociguat Ameliorates Pulmonary Hypertension Induced by Hypoxia and SU5416 in Rats

    PubMed Central

    Tian, Xia; Kalymbetov, Anuar; Weissmann, Norbert; Grimminger, Friedrich; Kretschmer, Axel; Stasch, Johannes-Peter; Seeger, Werner; Ghofrani, Hossein Ardeschir; Schermuly, Ralph Theo

    2012-01-01

    Background The nitric oxide (NO)–soluble guanylate cyclase (sGC)–cyclic guanosine monophosphate (cGMP) signal-transduction pathway is impaired in many cardiovascular diseases, including pulmonary arterial hypertension (PAH). Riociguat (BAY 63–2521) is a stimulator of sGC that works both in synergy with and independently of NO to increase levels of cGMP. The aims of this study were to investigate the role of NO–sGC–cGMP signaling in a model of severe PAH and to evaluate the effects of sGC stimulation by riociguat and PDE5 inhibition by sildenafil on pulmonary hemodynamics and vascular remodeling in severe experimental PAH. Methods and Results Severe angioproliferative PAH was induced in rats by combined exposure to the vascular endothelial growth factor receptor antagonist SU5416 and hypoxia (SUHx). Twenty-one days thereafter rats were randomized to receive either riociguat (10 mg/kg/day), sildenafil (50 mg/kg/day) or vehicle by oral gavage, for 14 days until the day of the terminal hemodynamic measurements. Administration of riociguat or sildenafil significantly decreased right ventricular systolic pressure (RVSP). Riociguat significantly decreased RV hypertrophy (RVH) (0.55±0.02, p<0.05), increased cardiac output (60.8±.8 mL/minute, p<0.05) and decreased total pulmonary resistance (4.03±0.3 mmHg min−1 ml−1 100 g BW, p<0.05), compared with sildenafil and vehicle. Both compounds significantly decreased the RV collagen content and improved RV function, but the effects of riociguat on tricuspid annular plane systolic excursion and RV myocardial performance were significantly better than those of sildenafil (p<0.05). The proportion of occluded arteries was significantly lower in animals receiving riociguat than in those receiving vehicle (p<0.05); furthermore, the neointima/media ratio was significantly lower in those receiving riociguat than in those receiving sildenafil or vehicle (p<0.05). Conclusion Riociguat and sildenafil significantly reduced

  6. Mild Renal Artery Stenosis Can Induce Renovascular Hypertension and is Associated with Elevated Renal Vein Renin Secretion.

    PubMed

    Balamuthusamy, Saravanan; Kannan, Arun; Thajudeen, Bijin; Ottley, Dean; Jalandhara, Nishant

    2015-01-01

    Renovascular hypertension is a syndrome which encompasses the physiological response of the kidney to changes in renal blood flow and renal perfusion pressure. Such physiological changes can occur with renal artery occlusion irrespective of the severity of the lesion. We have analyzed hypertensive patients with mild renal artery stenosis and compared them to patients with no stenosis. Renal vein renin sampling from catheterization of the renal vein was performed in all these patients. Patients with mild stenosis had higher renal vein renin ratio (3.01 ± 1.5) than the patients with no stenosis (1.10 ± 0.29; p = 0.002). Patients with mild stenosis were also found to have higher diastolic blood pressure and renal artery resistive indices when compared to patients with no stenosis. We therefore conclude that mild stenosis can precipitate renin-mediated hypertension in renovascular stenosis and also emphasis that parameters pertinent to renal physiology need to be evaluated before considering treatment options in patients with renal artery stenosis and medical management with RAAS blockade is the preferred modality of therapy for patients with renin-mediated hypertension. PMID:24943669

  7. Beneficial effects of a novel agonist of the adenosine A2A receptor on monocrotaline-induced pulmonary hypertension in rats

    PubMed Central

    Alencar, Allan K N; Pereira, Sharlene L; Montagnoli, Tadeu L; Maia, Rodolfo C; Kümmerle, Arthur E; Landgraf, Sharon S; Caruso-Neves, Celso; Ferraz, Emanuelle B; Tesch, Roberta; Nascimento, José H M; de Sant'Anna, Carlos M R; Fraga, Carlos A M; Barreiro, Eliezer J; Sudo, Roberto T; Zapata-Sudo, Gisele

    2013-01-01

    Background and Purpose Pulmonary arterial hypertension (PAH) is characterized by enhanced pulmonary vascular resistance, right ventricular hypertrophy and increased right ventricular systolic pressure. Here, we investigated the effects of a N-acylhydrazone derivative, 3,4-dimethoxyphenyl-N-methyl-benzoylhydrazide (LASSBio-1359), on monocrotaline (MCT)-induced pulmonary hypertension in rats. Experimental Approach PAH was induced in male Wistar rats by a single i.p. injection of MCT (60 mg·kg−1) and 2 weeks later, oral LASSBio-1359 (50 mg·kg−1) or vehicle was given once daily for 14 days. Echocardiography was used to measure cardiac function and pulmonary artery dimensions, with histological assay of vascular collagen. Studies of binding to human recombinant adenosine receptors (A1, A2A, A3) and of docking with A2A receptors were also performed. Key Results MCT administration induced changes in vascular and ventricular structure and function, characteristic of PAH. These changes were reversed by treatment with LASSBio-1359. MCT also induced endothelial dysfunction in pulmonary artery, as measured by diminished relaxation of pre-contracted arterial rings, and this dysfunction was reversed by LASSBio-1359. In pulmonary artery rings from normal Wistar rats, LASSBio-1359 induced relaxation, which was decreased by the adenosine A2A receptor antagonist, ZM 241385. In adenosine receptor binding studies, LASSBio-1359 showed most affinity for the A2A receptor and in the docking analyses, binding modes of LASSBio-1359 and the A2A receptor agonist, CGS21680, were very similar. Conclusion and Implications In rats with MCT-induced PAH, structural and functional changes in heart and pulmonary artery were reversed by treatment with oral LASSBio-1359, most probably through the activation of adenosine A2A receptors. PMID:23530610

  8. Drug-induced hypertension

    MedlinePlus

    ... Genetics Foods eaten, weight, and other body-related variables Levels of various hormones in the body Volume ... www.urac.org). URAC's accreditation program is an independent audit to verify that A.D.A.M. ...

  9. Types of Pulmonary Hypertension

    MedlinePlus

    ... from the NHLBI on Twitter. Types of Pulmonary Hypertension The World Health Organization divides pulmonary hypertension (PH) ... are called pulmonary hypertension.) Group 1 Pulmonary Arterial Hypertension Group 1 PAH includes: PAH that has no ...

  10. Diagnosing hypertension

    PubMed Central

    Gelfer, Mark; Dawes, Martin; Kaczorowski, Janusz; Padwal, Raj; Cloutier, Lyne

    2015-01-01

    Abstract Objective To highlight the 2015 Canadian Hypertension Education Program (CHEP) recommendations for the diagnosis and assessment of hypertension. Quality of evidence A systematic search was performed current to August 2014 by a Cochrane Collaboration librarian using the MEDLINE and PubMed databases. The search results were critically appraised by the CHEP subcommittee on blood pressure (BP) measurement and diagnosis, and evidence-based recommendations were presented to the CHEP Central Review Committee for independent review and grading. Finally, the findings and recommendations were presented to the Recommendations Task Force for discussion, debate, approval, and voting. The main recommendations are based on level II evidence. Main message Based on the most recent evidence, CHEP has made 4 recommendations in 2 broad categories for 2015 to improve BP measurement and the way hypertension is diagnosed. A strong recommendation is made to use electronic BP measurement in the office setting to replace auscultatory BP measurement. For patients with elevated office readings, CHEP is recommending early use of out-of-office BP measurement, preferably ambulatory BP measurement, in order to identify early in the process those patients with white-coat hypertension. Conclusion Improvements in diagnostic accuracy are critical to optimizing hypertension management in Canada. The annual updates provided by CHEP ensure that practitioners have up-to-date evidence-based information to inform practice. PMID:26564654

  11. [Portopulmonary hypertension].

    PubMed

    Halank, M; Miehlke, S; Kolditz, M; Hoeffken, G

    2005-07-01

    Patients with portal hypertension may develop pulmonary complications such as hepatopulmonary syndrome (HPS) or portopulmonary hypertension (PPHT). PPHT is defined as elevated pulmonary pressure, elevated pulmonary vascular resistance, a normal pulmonary capillary wedge pressure, and portal hypertension in the absence of other known causes pulmonary hypertension. Various factors such as hyperdynamic circulation, volume overload, and circulating vasoactive mediators are suspected to be involved in the pathogenesis of PPHT. The prognosis of patients with severe PPHT is significantly reduced due to the risk of right heart failure. In patients with moderate to severe PPHT liver transplantation is associated with a significantly increased mortality. The chief symptom of PPHT may be dyspnoe in the presence of typical histomorphological alterations comparable with idiopathic pulmonary hypertension. Continuous intravenous application of prostacyclin is currently regarded as the treatment of choice for patients with severe PPHT. Inhaled prostacyclin or its analogue iloprost or oral treatment with the endothelin-receptor antagonist bosentan may be promising alternatives which should be further investigated in randomized controlled trials. PMID:16001350

  12. Critical role of renal dipeptidyl peptidase-4 in ameliorating kidney injury induced by saxagliptin in Dahl salt-sensitive hypertensive rats.

    PubMed

    Sakai, Mariko; Uchii, Masako; Myojo, Kensuke; Kitayama, Tetsuya; Kunori, Shunji

    2015-08-15

    Saxagliptin, a potent dipeptidyl peptidase-4 (DPP-4) inhibitor, is currently used to treat type 2 diabetes mellitus, and it has been reported to exhibit a slower rate of dissociation from DPP-4 compared with another DPP-4 inhibitor, sitagliptin. In this study, we compared the effects of saxagliptin and sitagliptin on hypertension-related renal injury and the plasma and renal DPP-4 activity levels in Dahl salt-sensitive hypertensive (Dahl-S) rats. The high-salt diet (8% NaCl) significantly increased the blood pressure and quantity of urinary albumin excretion and induced renal glomerular injury in the Dahl-S rats. Treatment with saxagliptin (14mg/kg/day via drinking water) for 4 weeks significantly suppressed the increase in urinary albumin excretion and tended to ameliorate glomerular injury without altering the blood glucose levels and systolic blood pressure. On the other hand, the administration of sitagliptin (140mg/kg/day via drinking water) did not affect urinary albumin excretion and glomerular injury in the Dahl-S rats. Meanwhile, the high-salt diet increased the renal DPP-4 activity but did not affect the plasma DPP-4 activity in the Dahl-S rats. Both saxagliptin and sitagliptin suppressed the plasma DPP-4 activity by 95% or more. Although the renal DPP-4 activity was also inhibited by both drugs, the inhibitory effect of saxagliptin was more potent than that of sitagliptin. These results indicate that saxagliptin has a potent renoprotective effect in the Dahl-S rats, independent of its glucose-lowering actions. The inhibition of the renal DPP-4 activity induced by saxagliptin may contribute to ameliorating renal injury in hypertension-related renal injury. PMID:25936515

  13. The effect of hydro-alcoholic celery (Apiumgraveolens) leaf extract on cardiovascular parameters and lipid profile in animal model of hypertension induced by fructose

    PubMed Central

    Dianat, Mahin; Veisi, Ali; Ahangarpour, Akram; Fathi Moghaddam, Hadi

    2015-01-01

    Objectives: Hypertension is one of the most common diseases of the modern era. This study evaluates the effect of hydro-alcoholic celery leaf extract onsystolic blood pressure (SBP), heart rate (HR) and lipid profile in animals’ model of hypertension induced by fructose. Materials and Methods: Sprague Dawley rats were divided into five groups: 1) control group (free access to tap drinking water), 2) group receiving 200mg/kg celery leaf extract, 3) group receiving fructose 10%, and 4,5) receiving fructose and 100mg/kg or 200mg/kg of extract (n=8). In all groups, before and during the test period, SBP and HR were measured by Power lab system. Lipid profiles were determined by auto analysis. Repeated measurement and one way ANOVA were used for data analysis. P<0.05 was considered statistically significant. Results: The SBP in the fructose group significantly increased compared to control group (P<0.01). SBP, in groups receiving fructose+100mg/kg extract, fructose and receiving 200mg/kg extract, and receiving 200mg/kg of extract, compared to fructose group significantly decreased. Heart rate in any of these groups showed no significant difference. Cholesterol, triglyceride, LDL and VLDL in the fructose group significantly increased; however, these effects significantly decreased in the recipient extract groups. HDL levels in the fructose group showed no difference while in the groups receiving the extract they significantly increased. Conclusions: Celery leaf extract reduces SBP, cholesterol, triglyceride, LDL and VLDL in animal model of fructose-induced hypertension. In conclusion, celery leaf extract with its blood pressure and lipid lowering effects, can be considered as an antihypertensive agent in chronic treatment of elevated SBP. PMID:26101753

  14. Mechanism of IFN-γ in regulating OPN/Th17 pathway during vascular collagen remodeling of hypertension induced by ANG II

    PubMed Central

    Jiang, Lei; He, Pengcheng; Liu, Yong; Chen, Jiyan; Wei, Xuebiao; Tan, Ning

    2015-01-01

    More and more researches show that hypertensive vascular remodeling is closely related to the imbalance of immune system in recent years. IFN-γ is natural protein with the function of immune regulation and has resistance effect on vascular remodeling. However, the mechanism of IFN-γ is to be defined. This paper is to explore the mechanism of IFN-γ in regulating OPN/Th17 pathway. In this research, animal models of vascular collagen remodeling were established by inducing hypertensive mice with ANG II. There was no statistical significance when the systolic blood pressures and the percentages of wall thickness/lumen diameter in both groups of WT + AngII + IFN-γ and WT + PBS were compared (P=0.219>0.05, P=0.118>0.05). The concentration of serum precollagen-type I and III and their ratio in WT + AngII + IFN-γ group were decreased after the IFN-γ being given (P<0.01). Expression of OPN within tissue in WT + Ang II group was relatively high, but lowered after treated by IFN-γ. Th17 cell ratio was decreased in WT + AngII + IFN-γ group (P<0.01). Expressions of RORα and RORγt mRNA within Th17 cell were decreased (P<0.01). The content of IL-23 in WT + AngII + IFN-γ group was increased, while IL-10 and TGF-β decreased. It has proved that IFN-γ can regulate the hypertensive vascular collagen remodeling induced by ANG II, lower the systolic pressure and reduce the pathological damage of vascular collagen remodeling and the collagen synthesis. The mechanism may that the differentiation of Th17 is inhibited by suppressing the OPN expression and regulating the secretion of inflammatory cytokines. PMID:26823760

  15. Augmented Endothelial-Specific L-Arginine Transport Blunts the Contribution of the Sympathetic Nervous System to Obesity Induced Hypertension in Mice

    PubMed Central

    Rajapakse, Niwanthi W.; Karim, Florian; Evans, Roger G.

    2015-01-01

    Augmenting endothelial specific transport of the nitric oxide precursor L-arginine via cationic amino acid transporter-1 (CAT1) can prevent obesity related hypertension. We tested the hypotheses that CAT1 overexpression prevents obesity-induced hypertension by buffering the influence of the sympathetic nervous system (SNS) on the maintenance of arterial pressure and by buffering pressor responses to stress. Wild type (WT; n=13) and CAT1 overexpressing mice (CAT+; n=13) were fed a normal or a high fat diet for 20 weeks. Mice fed a high fat diet were returned to the control diet before experiments commenced. Baseline mean arterial pressure (MAP) and effects of restraint-, shaker- and almond feeding-stress and ganglionic blockade (pentolinium; 5 mg/kg; i.p.) on MAP were determined in conscious mice. Fat feeding increased body weight to a similar extent in WT and CAT+ but MAP was greater only in WT compared to appropriate controls (by 29%). The depressor response to pentolinium was 65% greater in obese WT than lean WT (P < 0.001), but was similar in obese and lean CAT+ (P = 0.65). In lean WT and CAT+, pressor responses to shaker and feeding stress, but not restraint stress, were less in the latter genotype compared to the former (P ≤ 0.001). Pressor responses to shaker and feeding stress were less in obese WT than lean WT (P ≤ 0.001), but similar in obese and lean CAT+. The increase in MAP in response to restraint stress was less in obese WT (22 ± 2%), but greater in obese CAT+ (37 ± 2%), when compared to respective lean WT (31 ± 3%) and lean CAT+ controls (27 ± 2%; P ≤ 0.02). We conclude that CAT1 overexpression prevents obesity-induced hypertension by reducing the influence of the SNS on the maintenance of arterial pressure but not by buffering pressor responses to stress. PMID:26186712

  16. PARP-inhibitor treatment prevents hypertension induced cardiac remodeling by favorable modulation of heat shock proteins, Akt-1/GSK-3β and several PKC isoforms.

    PubMed

    Deres, Laszlo; Bartha, Eva; Palfi, Anita; Eros, Krisztian; Riba, Adam; Lantos, Janos; Kalai, Tamas; Hideg, Kalman; Sumegi, Balazs; Gallyas, Ferenc; Toth, Kalman; Halmosi, Robert

    2014-01-01

    Spontaneously hypertensive rat (SHR) is a suitable model for studies of the complications of hypertension. It is known that activation of poly(ADP-ribose) polymerase enzyme (PARP) plays an important role in the development of postinfarction as well as long-term hypertension induced heart failure. In this study, we examined whether PARP-inhibitor (L-2286) treatment could prevent the development of hypertensive cardiopathy in SHRs. 6-week-old SHR animals were treated with L-2286 (SHR-L group) or placebo (SHR-C group) for 24 weeks. Wistar-Kyoto rats were used as aged-matched, normotensive controls (WKY group). Echocardiography was performed, brain-derived natriuretic peptide (BNP) activity and blood pressure were determined at the end of the study. We detected the extent of fibrotic areas. The amount of heat-shock proteins (Hsps) and the phosphorylation state of Akt-1(Ser473), glycogen synthase kinase (GSK)-3β(Ser9), forkhead transcription factor (FKHR)(Ser256), mitogen activated protein kinases (MAPKs), and protein kinase C (PKC) isoenzymes were monitored. The elevated blood pressure in SHRs was not influenced by PARP-inhibitor treatment. Systolic left ventricular function and BNP activity did not differ among the three groups. L-2286 treatment decreased the marked left ventricular (LV) hypertrophy which was developed in SHRs. Interstitial collagen deposition was also decreased by L-2286 treatment. The phosphorylation of extracellular signal-regulated kinase (ERK)1/2(Thr183-Tyr185), Akt-1(Ser473), GSK-3β(Ser9), FKHR(Ser256), and PKC ε(Ser729) and the level of Hsp90 were increased, while the activity of PKC α/βII(Thr638/641), ζ/λ(410/403) were mitigated by L-2286 administration. We could detect signs of LV hypertrophy without congestive heart failure in SHR groups. This alteration was prevented by PARP inhibition. Our results suggest that PARP-inhibitor treatment has protective effect already in the early stage of hypertensive myocardial remodeling. PMID

  17. Functional and morphological effects of laser-induced ocular hypertension in retinas of adult albino Swiss mice

    PubMed Central

    Salinas-Navarro, Manuel; Alarcón-Martínez, Luis; Valiente-Soriano, Francisco Javier; Ortín-Martínez, Arturo; Jiménez-López, Manuel; Avilés-Trigueros, Marcelino; Villegas-Pérez, María Paz; de la Villa, Pedro

    2009-01-01

    Purpose To investigate the effects of laser photocoagulation (LP)-induced ocular hypertension (OHT) on the survival and retrograde axonal transport of retinal ganglion cells (RGC), as well as on the function of retinal layers. Methods Adult albino Swiss mice (35–45 g) received laser photocoagulation of limbal and episcleral veins in the left eye. Mice were sacrificed at 8, 17, 35, and 63 days. Intraocular pressure (IOP) in both eyes was measured with a Tono-Lab before LP and at various days after LP. Flash electroretinogram (ERG) scotopic threshold response (STR) and a- and b-wave amplitudes were recorded before LP and at various times after LP. RGCs were labeled with 10% hydroxystilbamidine methanesulfonate (OHSt) applied to both superior colliculi before sacrifice and in some mice, with dextran tetramethylrhodamine (DTMR) applied to the ocular stump of the intraorbitally transected optic nerve. Retinas were immunostained for RT97 or Brn3a. Retinas were prepared as whole-mounts and photographed under a fluorescence microscope. Labeled RGCs were counted using image analysis software, and an isodensity contour plot was generated for each retina. Results IOP increased to twice its basal values by 24 h and was maintained until day 5, after which IOP gradually declined to reach basal values by 1 wk. Similar IOP increases were observed in all groups. The mean total number of OHSt+ RGCs was 13,428±6,295 (n=12), 10,456±14,301 (n=13), 12,622±14,174 (n=21), and 10,451±13,949 (n=13) for groups I, II, III, and IV, respectively; these values represented 28%, 23%, 26%, and 22% of the values found in their contralateral fellow retinas. The mean total population of Brn3a+ RGCs was 24,343±5,739 (n=12) and 10,219±8,887 (n=9), respectively, for groups I and III; these values represented 49% and 20%, respectively, of the values found in their fellow eyes. OHT retinas showed an absence of OHSt+ and DTMR+ RGCs in both focal wedge-shaped and diffuse regions of the retina. By 1

  18. Grape seed proanthocyanidins prevent DOCA-salt hypertension-induced renal injury and its mechanisms in rats.

    PubMed

    Lan, Chao-Zong; Ding, Ling; Su, Yi-Lin; Guo, Kun; Wang, Li; Kan, Hong-Wei; Ou, Yu-Rong; Gao, Shan

    2015-07-01

    Renal dysfunction is one of the major effects of DOCA (deoxycorticosterone acetate)-salt hypertension and there is an increasing amount of evidence that oxidative stress damages the function of the kidney. Grape seed proanthocyanidins (GSPE) have been reported to be potent anti-oxidants and free radical scavengers. The present study sought to investigate the ability of GSPE to prevent renal injury in DOCA-salt hypertensive rats and to explore the molecular mechanisms underlying its protective effects. A total of 54 Sprague Dawley (SD) rats were randomly divided into 7 groups: Sham group (n = 7), UnX-sham group (n = 8), DOCA-salt group (n = 8), GSPE150 group (150 mg kg(-1), n = 7), GSPE240 group (240 mg kg(-1), n = 8), GSPE384 group (384 mg kg(-1), n = 8) and ALM (amlodipine besylate tablets) group (5 mg kg(-1), n = 8), and treated for 4 weeks. Compared to sham group rats, renal injury was observed in DOCA-salt hypertensive group rats as the urine protein, KW/BW (kidney weight/body weight), degree of renal fibrosis, renal MDA (malondialdehyde) and Hyp (hydroxyproline) contents significantly increased (P < 0.01). Moreover, SOD (Superoxide Dismutase) activities decreased in the model group (P < 0.01). In contrast, DOCA-salt hypertensive rats treated with different dose of GSPE or ALM showed a significant improvement of renal injury with decreased urine protein, KW/BW, degree of renal fibrosis, renal total MDA and Hyp contents compared to the untreated group. In addition, SOD activities increased in the treatment group. Since the experimental modeling time was short, kidney damage occurs to a lesser extent. BUN (Blood Urea Nitrogen), Scr (Serum Creatinine) and UA (Uric Acid) contents did not appear significantly changed in all groups. Finally, the activation of JNK and p38 kinases in the kidney was suppressed in rats treated with GSPEs or ALM compared to the untreated group, suggesting that the inhibition of these kinase pathways by GSPE contributes to the improvement

  19. Ellagic Acid Prevents L-NAME-Induced Hypertension via Restoration of eNOS and p47phox Expression in Rats

    PubMed Central

    Berkban, Thewarid; Boonprom, Pattanapong; Bunbupha, Sarawoot; Umka Welbat, Jariya; Kukongviriyapan, Upa; Kukongviriyapan, Veerapol; Pakdeechote, Poungrat; Prachaney, Parichat

    2015-01-01

    The effect of ellagic acid on oxidative stress and hypertension induced by Nω-Nitro-l-arginine methyl ester hydrochloride (L-NAME) was investigated. Male Sprague-Dawley rats were administrated with L-NAME (40 mg/kg/day) for five weeks. L-NAME induced high systolic blood pressure (SBP) and increased heart rate (HR), hindlimb vascular resistance (HVR) and oxidative stress. Concurrent treatment with ellagic acid (7.5 or 15 mg/kg) prevented these alterations. Co-treatment with ellagic acid was associated with up-regulation of endothelial nitric oxide synthase (eNOS) protein production and alleviation of oxidative stress as indicated by decreased superoxide production in the vascular tissue, reduced plasma malondialdehyde levels, reduced NADPH oxidase subunit p47phox expression and increased plasma nitrate/nitrite levels. Our results indicate that ellagic acid attenuates hypertension by reducing NADPH oxidase subunit p47phox expression, which prevents oxidative stress and restores NO bioavailability. PMID:26133972

  20. A case of lithium intoxication induced by an antihypertensive angiotensin 1 subtype-specific angiotensin II receptor blocker in an elderly patient with bipolar disorder and hypertension.

    PubMed

    Hayashi, Yuichi; Nishida, Shohei; Takekoshi, Akira; Murakami, Muneharu; Yamada, Megumi; Kimura, Akio; Suzuki, Akio; Inuzuka, Takashi

    2016-01-01

    Lithium carbonate is considered to be a first-line treatment for bipolar disorder; however, this drug has a narrow therapeutic window, and lithium intoxication is commonly induced by various drugs interaction and situations. We herein report a case of lithium intoxication induced by the administration of an antihypertensive agent targeting the angiotensin 1 (AT1) subtype of the angiotensin II receptor in a 65-year-old woman with a 40-year history of bipolar disorder type 1, and 1-year history of essential hypertension. Her bipolar disorder had been well-controlled with 600 mg/day of lithium carbonate for more than 10 years. She was later diagnosed with hypertension and the AT1 receptor blocker, azilsartan was thereafter administrated on a daily basis. After 3 weeks of azilsartan administration, she presented with progressive action tremor and showed a gradual deterioration of her physical state. Four months after the start of azilsartan administration, she presented with alternating episodes of diarrhea and constipation. Two weeks before admission to our hospital, she presented with mild consciousness disturbances, myoclonus, truncal ataxia, and appetite loss. She was diagnosed to have lithium intoxication based on an elevated serum lithium concentration of 3.28 mEq/l.It is therefore important to evaluate the serum lithium concentration after the administration of antihypertensive agents, and consider lithium-antihypertensive agent interactions when selecting antihypertensive agents in elderly patients receiving long-term lithium carbonate treatment. PMID:27535187

  1. Differential Responses to Blood Pressure and Oxidative Stress in Streptozotocin-Induced Diabetic Wistar-Kyoto Rats and Spontaneously Hypertensive Rats: Effects of Antioxidant (Honey) Treatment

    PubMed Central

    Erejuwa, Omotayo O.; Sulaiman, Siti A.; Wahab, Mohd Suhaimi Ab; Sirajudeen, Kuttulebbai N. S.; Salleh, Md Salzihan Md; Gurtu, Sunil

    2011-01-01

    Oxidative stress is implicated in the pathogenesis and/or complications of hypertension and/or diabetes mellitus. A combination of these disorders increases the risk of developing cardiovascular events. This study investigated the effects of streptozotocin (60 mg/kg; ip)-induced diabetes on blood pressure, oxidative stress and effects of honey on these parameters in the kidneys of streptozotocin-induced diabetic Wistar-Kyoto (WKY) and spontaneously hypertensive rats (SHR). Diabetic WKY and SHR were randomized into four groups and received distilled water (0.5 mL) and honey (1.0 g/kg) orally once daily for three weeks. Control SHR had reduced malondialdehyde (MDA) and increased systolic blood pressure (SBP), catalase (CAT) activity, and total antioxidant status (TAS). SBP, activities of glutathione peroxidase (GPx) and glutathione reductase (GR) were elevated while TAS was reduced in diabetic WKY. In contrast, SBP, TAS, activities of GPx and GR were reduced in diabetic SHR. Antioxidant (honey) treatment further reduced SBP in diabetic SHR but not in diabetic WKY. It also increased TAS, GSH, reduced glutathione (GSH)/oxidized glutathione (GSSG) ratio, activities of GPx and GR in diabetic SHR. These data suggest that differences in types, severity, and complications of diseases as well as strains may influence responses to blood pressure and oxidative stress. PMID:21673929

  2. Calorie restriction improves cognitive decline via up-regulation of brain-derived neurotrophic factor: tropomyosin-related kinase B in hippocampus ofobesity-induced hypertensive rats.

    PubMed

    Kishi, Takuya; Hirooka, Yoshitaka; Nagayama, Tomomi; Isegawa, Kengo; Katsuki, Masato; Takesue, Ko; Sunagawa, Kenji

    2015-01-01

    In metabolic syndrome (MetS), previous studies have suggested that cognitive decline is worsened. Among the factors associated with cognition, decreased brain-derived neurotrophic factor (BDNF) in the hippocampus causes cognitive decline. We previously reported that exercise training with calorie restriction yielded protection against cognitive decline via BDNF in the hippocampus of hypertensive rats. The aim of the present study was to determine whether or not calorie restriction results in protection against cognitive decline via BDNF and its receptor tropomyosin-related kinase B (TrkB) in the hippocampus of MetS model rats. We divided dietary-induced obesity-prone and hypertensive rats (OP), as metabolic syndrome model rats, into three groups, fed with a high fat diet (HF), treated with calorie restriction (CR) plus vehicle, and treated with CR and ANA-12 (a TrkB antagonist) (CR+A). After treatment for 28 days, body weight, insulin, fasting blood glucose, adiponectin, systolic blood pressure, and oxidative stress in the hippocampus were significantly lower, and BDNF expression in the hippocampus was significantly higher in CR and CR+A than in HF. Cognitive performance determined by the Morris water maze test was significantly higher in CR than in HF, whereas the benefit was attenuated in CR+A. In conclusion, calorie restriction protects against cognitive decline via up-regulation of BDNF/TrkB through an antioxidant effect in the hippocampus of dietary-induced obesity rats. PMID:25503654

  3. Portal hypertension induced by congenital hepatic arterioportal fistula: Report of four clinical cases and review of the literature

    PubMed Central

    Zhang, Dan-Ying; Weng, Shu-Qiang; Dong, Ling; Shen, Xi-Zhong; Qu, Xu-Dong

    2015-01-01

    Intrahepatic arterioportal fistula (IAPF) can be caused by many secondary factors. We report four cases of portal hypertension that were eventually determined to be caused by congenital hepatic arterioportal fistula. The clinical manifestations included ascites, variceal hemorrhage and hepatic encephalopathy. Computed tomography scans from all of the patients revealed the early enhancement of the portal branches in the hepatic arterial phase. All patients were diagnosed using digital subtraction angiography (DSA). DSA before embolization revealed an arteriovenous fistula with immediate filling of the portal venous radicles. All four patients were treated with interventional embolization. The four patients remained in good condition throughout follow-up and at the time of publication. IAPF is frequently misdiagnosed due to its rarity; therefore, clinicians should consider IAPF as a potential cause of non-cirrhotic portal hypertension. PMID:25717263

  4. Renal injury in angiotensin II+l-NAME-induced hypertensive rats is independent of elevated blood pressure

    PubMed Central

    Polichnowski, Aaron J.; Lu, Limin

    2011-01-01

    The balance between angiotensin II (ANG II) and nitric oxide plays an important role in renal function and is thought to contribute to the progression of renal injury in experimental hypertension. In the present study, we investigated the extent of blood pressure (BP)-dependent and BP-independent pathways of renal injury following 2 wk of hypertension produced by intravenous infusion of ANG II (5 ng·kg−1·min−1)+Nω-nitro-l-arginine methyl ester (l-NAME; 1.4 μg·kg−1·min−1) in male Sprague-Dawley rats. An aortic balloon occluder was positioned between the renal arteries to maintain (24 h/day) BP to the left kidney (servo-controlled) at baseline levels, whereas the right kidney (uncontrolled) was chronically exposed to elevated BP. Over the 14-day experimental protocol, the average BP to uncontrolled kidneys (152.7 ± 1.8 mmHg) was significantly elevated compared with servo-controlled (113.0 ± 0.2 mmHg) kidneys and kidneys from sham rats (108.3 ± 0.1 mmHg). ANG II+l-NAME infusion led to renal injury that was focal in nature and mainly confined to the outer medulla. Despite the differences in BP between servo-controlled and uncontrolled kidneys, there was a similar ∼3.5-fold increase in renal outer medullary tubular injury, ∼2-fold increase in outer medullary interstitial fibrosis, ∼2-fold increase in outer medullary macrophage infiltration, and a significant increase in renal oxidative stress, all of which are indicative of BP-independent mediated pathways. The results of this study have important implications regarding the pathogenesis of renal injury in various experimental models of hypertension and provide novel insights regarding the variable association observed between hypertension and renal injury in some human populations. PMID:21270093

  5. Pulmonary Hypertension

    MedlinePlus

    Pulmonary hypertension (PH) is high blood pressure in the arteries to your lungs. It is a serious condition. If you have it, the blood ... heart has to work harder to pump the blood through. Over time, your heart weakens and ... of PH include Shortness of breath during routine activity, such ...

  6. Portopulmonary hypertension.

    PubMed

    Lv, Yong; Han, Guohong; Fan, Daiming

    2016-07-01

    Portopulmonary hypertension (PoPH) refers to the condition that pulmonary arterial hypertension (PAH) occur in the stetting of portal hypertension. The development of PoPH is thought to be independent of the severity of portal hypertension or the etiology or severity of liver disease. PoPH results from excessive vasoconstriction, vascular remodeling, and proliferative and thrombotic events within the pulmonary circulation that lead to progressive right ventricular failure and ultimately to death. Untreated PoPH is associated with a poor prognosis. As PoPH is frequently asymptomatic or symptoms are generally non-specific, patients should be actively screened for the presence of PoPH. Two-dimensional transthoracic echocardiography is a useful non-invasive screening tool, but a definitive diagnosis requires invasive hemodynamic confirmation by right heart catheterization. Despite a dearth of randomized, prospective data, an ever-expanding clinical experience shows that patients with PoPH benefit from therapy with PAH-specific medications including with endothelin receptor antagonists, phosphodiesterase-5 inhibitors, and/or prostanoids. Due to high perioperative mortality, transplantation should be avoided in those patients who have severe PoPH that is refractory to medical therapy. PMID:27002212

  7. Pulmonary Hypertension

    MedlinePlus

    ... Anticoagulants (blood-thinning medicine) Calcium channel blockers Diuretics (water pills) Digoxin Your doctor will decide what type of medicine is right for you. In some cases, people who have pulmonary hypertension need surgical treatment. Surgical treatment options include a lung transplant and ...

  8. Tert-butylhydroquinone lowers blood pressure in AngII-induced hypertension in mice via proteasome-PTEN-Akt-eNOS pathway.

    PubMed

    Xu, Bing-Can; Long, Hui-Bao; Luo, Ke-Qin

    2016-01-01

    Tert-butylhydroquinone (tBHQ), as an antioxidant, has been widely used for many years to prevent oxidization of food products. The aim of this study was to investigate whether tBHQ activates endothelial nitric oxide synthase (eNOS) to prevent endothelial dysfunction and lower blood pressure. The role of Akt in tBHQ-induced eNOS phosphorylation was examined in human umbilical vein endothelial cells (HUVEC) or in mice. tBHQ treatment of HUVEC increased both Akt-Ser473 phosphorylation, accompanied with increased eNOS-Ser1177 phosphorylation and NO release. Mechanically, pharmacologic or genetic inhibition of Akt abolished tBHQ-enhanced NO release and eNOS phosphorylation in HUVEC. Gain-function of PTEN or inhibition of 26S proteasome abolished tBHQ-enhanced Akt phosphorylation in HUVEC. Ex vivo analysis indicated that tBHQ improved Ach-induced endothelium-dependent relaxation in LPC-treated mice aortic arteries, which were abolished by inhibition of Akt or eNOS. In animal study, administration of tBHQ significantly increased eNOS-Ser1177 phosphorylation and acetylcholine-induced vasorelaxation, and lowered AngII-induced hypertension in wildtype mice, but not in mice deficient of Akt or eNOS. In conclusion, tBHQ via proteasome-dependent degradation of PTEN increases Akt phosphorylation, resulting in upregulation of eNOS-derived NO production and consequent improvement of endothelial function in vivo. In this way, tBHQ lowers blood pressure in hypertensive mice. PMID:27435826

  9. Mineralocorticoid and angiotensin II type 1 receptors in the subfornical organ mediate angiotensin II - induced hypothalamic reactive oxygen species and hypertension.

    PubMed

    Wang, Hong-Wei; Huang, Bing S; White, Roselyn A; Chen, Aidong; Ahmad, Monir; Leenen, Frans H H

    2016-08-01

    Activation of angiotensinergic pathways by central aldosterone (Aldo)-mineralocorticoid receptor (MR) pathway plays a critical role in angiotensin II (Ang II)-induced hypertension. The subfornical organ (SFO) contains both MR and angiotensin II type 1 receptors (AT1R) and can relay the signals of circulating Ang II to downstream nuclei such as the paraventricular nucleus (PVN), supraoptic nucleus (SON) and rostral ventrolateral medulla (RVLM). In Wistar rats, subcutaneous (sc) infusion of Ang II at 500ng/min/kg for 1 or 2weeks increased reactive oxygen species (ROS) as measured by dihydroethidium (DHE) staining in a nucleus - specific pattern. Intra-SFO infusion of AAV-MR- or AT1aR-siRNA prevented the Ang II-induced increase in AT1R mRNA expression in the SFO and decreased MR mRNA. Both MR- and AT1aR-siRNA prevented increases in ROS in the PVN and RVLM. MR- but not AT1aR-siRNA in the SFO prevented the Ang II-induced ROS in the SON. Both MR- and AT1aR-siRNA in the SFO prevented most of the Ang II-induced hypertension as assessed by telemetry. These results indicate that Aldo-MR signaling in the SFO is needed for the activation of Ang II-AT1R-ROS signaling from the SFO to the PVN and RVLM. Activation of Aldo-MR signaling from the SFO to the SON may enhance AT1R dependent activation of pre-sympathetic neurons in the PVN. PMID:27163380

  10. Interleukin 13– and interleukin 17A–induced pulmonary hypertension phenotype due to inhalation of antigen and fine particles from air pollution

    PubMed Central

    Park, Sung-Hyun; Chen, Wen-Chi; Esmaeil, Nafiseh; Lucas, Benjamin; Marsh, Leigh M.; Reibman, Joan

    2014-01-01

    Abstract Pulmonary hypertension has a marked detrimental effect on quality of life and life expectancy. In a mouse model of antigen-induced pulmonary arterial remodeling, we have recently shown that coexposure to urban ambient particulate matter (PM) significantly increased the thickening of the pulmonary arteries and also resulted in significantly increased right ventricular systolic pressures. Here we interrogate the mechanism and show that combined neutralization of interleukin 13 (IL-13) and IL-17A significantly ameliorated the increase in right ventricular systolic pressure, the circumferential muscularization of pulmonary arteries, and the molecular change in the right ventricle. Surprisingly, our data revealed a protective role of IL-17A for the antigen- and PM-induced severe thickening of pulmonary arteries. This protection was due to the inhibition of the effects of IL-13, which drove this response, and the expression of metalloelastase and resistin-like molecule α. However, the latter was redundant for the arterial thickening response. Anti-IL-13 exacerbated airway neutrophilia, which was due to a resulting excess effect of IL-17A, confirming concurrent cross inhibition of IL-13- and IL-17A-dependent responses in the lungs of animals exposed to antigen and PM. Our experiments also identified IL-13/IL-17A-independent molecular reprogramming in the lungs induced by exposure to antigen and PM, which indicates a risk for arterial remodeling and protection from arterial constriction. Our study points to IL-13- and IL-17A-coinduced inflammation as a new template for biomarkers and therapeutic targeting for the management of immune response–induced pulmonary hypertension. PMID:25610601

  11. Tert-butylhydroquinone lowers blood pressure in AngII-induced hypertension in mice via proteasome-PTEN-Akt-eNOS pathway

    PubMed Central

    Xu, Bing-Can; Long, Hui-Bao; Luo, Ke-Qin

    2016-01-01

    Tert-butylhydroquinone (tBHQ), as an antioxidant, has been widely used for many years to prevent oxidization of food products. The aim of this study was to investigate whether tBHQ activates endothelial nitric oxide synthase (eNOS) to prevent endothelial dysfunction and lower blood pressure. The role of Akt in tBHQ-induced eNOS phosphorylation was examined in human umbilical vein endothelial cells (HUVEC) or in mice. tBHQ treatment of HUVEC increased both Akt-Ser473 phosphorylation, accompanied with increased eNOS-Ser1177 phosphorylation and NO release. Mechanically, pharmacologic or genetic inhibition of Akt abolished tBHQ-enhanced NO release and eNOS phosphorylation in HUVEC. Gain-function of PTEN or inhibition of 26S proteasome abolished tBHQ-enhanced Akt phosphorylation in HUVEC. Ex vivo analysis indicated that tBHQ improved Ach-induced endothelium-dependent relaxation in LPC-treated mice aortic arteries, which were abolished by inhibition of Akt or eNOS. In animal study, administration of tBHQ significantly increased eNOS-Ser1177 phosphorylation and acetylcholine-induced vasorelaxation, and lowered AngII-induced hypertension in wildtype mice, but not in mice deficient of Akt or eNOS. In conclusion, tBHQ via proteasome-dependent degradation of PTEN increases Akt phosphorylation, resulting in upregulation of eNOS-derived NO production and consequent improvement of endothelial function in vivo. In this way, tBHQ lowers blood pressure in hypertensive mice. PMID:27435826

  12. The Effect of Amlodipine and Sildenafil on the NT-ProBNP Level of Patients with COPD-Induced Pulmonary Hypertension.

    PubMed

    Sharif-Kashani, Babak; Hamraghani, Ali; Salamzadeh, Jamshid; Abbasi Nazari, Mohammad; Malekmohammad, Majid; Behzadnia, Neda; Fahimi, Fanak

    2014-01-01

    Pulmonary hypertension (PH) is an important cause of heart failure in chronic obstructive pulmonary disease (COPD). The pro brain natriuretic peptide N-terminal (NT-proBNP) has been suggested as a noninvasive marker to evaluate ventricular function. However, there is no evidence to support the use of NT-proBNP in monitoring the benefits of vasodilators in COPD induced PH. Thus, we used NT-proBNP as a biomarker to evaluate the effect of oral vasodilators on cardiac function in COPD-induced PH. Forty clinically-stable PH patients were enrolled with history of COPD, normal left ventricular ejection-fraction (LVEF), right ventricular systolic pressure (RVSP) > 45 mmHg and baseline blood NT-proBNP levels >100 pg/mL. Patients were randomized into two groups, one group received sildenafil and second group were given amlodipine for two weeks. NT-proBNP and systolic pulmonary arterial pressure (systolic PA-pressure) were measured at the beginning and the end of study. Mean NT-proBNP level in the first group was 1297 ± 912 pg/mL before therapy and 554 ± 5 pg/mL after two weeks drug therapy, respectively. Similarly, in second group NT-proBNP level was 1657 ± 989 pg/mL and 646 ± 5 pg/mL before and after treatment. Amlodipine or sildenafil significantly reduced NT-proBNP levels in COPD-induced PH patients (p < 0.05). Our study shows that amlodipine and sildenafil have a similar effect on NT-proBNP levels. In both groups NT- proBNP levels were significantly reduced after treatment. Therefore, our findings support the potential benefits of treatment with vasodilators in COPD induced PH. Pulmonary hypertension, Chronic obstructive pulmonary disease, NT-proBNP, Amlodipine, Sildenafil. PMID:24711842

  13. Hypertensive leucocytosis.

    PubMed

    Rajkumari, Rolinda; Laishram, Deben; Thiyam, Joshna; Javan, Ng

    2013-04-01

    There are studies showing association of high WBC count with the higher incidence of hypertension though a few are done in the Indian population. The present study was conducted with the view to find any significant increase in total leucocyte count and differential leucocyte count in hypertensive patient Twenty-seven hypertensives with 12 males and 15 females and 27 age and sex matched control subjects (normotensive) were studied. Hypertension was defined when the systolic BP > or = 140 mmHg or diastolic BP > or = 90 mmHg or history of taking antihypertensive medicine. Three blood pressure recordings at an interval of 2 minutes were taken after the patient was made to sit for 30 minutes with a standard mercury sphygmomanometer in the left arm. The disappearance of sound was used for diastolic blood pressure. Blood was drawn into EDTA containing vials. Two separate counts were performed: First for total leucocyte count (TLC) and second for determination of percentage of polymorphonuclear cells. For the TLC, 0.5 part of blood mixed with 10 part of Turk's fluid followed by counting of leucocyte in a counting chamber under light microscope. The percentage of polymorphonuclear leucocyte was performed on a slide after making the slide and staining it with Leishman's stain. The erythrocyte sedimentation rate (ESR) was performed using Wintrobe's methods. The first 1 hour reading on the Wintrobe's tube was taken for analysis. The total leucocyte count (TLC) for the study group as compared to the controls were 7413.70 +/- 735.45 cells/cmm and 5236.30 +/- 528.77 cells/ cmm which was statistically significant. The mean percentage neutrophils were 62.04 +/- 4.99 for study group and 53.00 +/- 3.44 for the controls; the mean percentage lymphocytes for the study group and the controls were 34.37 +/- 4.55 and 39.11 +/- 4.40 respectively. Both the mean percentage neutrophils and lymphocytes showed significant differences. The mean erythrocyte sedimentation rate (ESR) also showed

  14. Inhibition of Nitric Oxide Synthase 1 Induces Salt-Sensitive Hypertension in Nitric Oxide Synthase 1α Knockout and Wild-Type Mice.

    PubMed

    Wang, Ximing; Chandrashekar, Kiran; Wang, Lei; Lai, En Yin; Wei, Jin; Zhang, Gensheng; Wang, Shaohui; Zhang, Jie; Juncos, Luis A; Liu, Ruisheng

    2016-04-01

    We recently showed that α, β, and γ splice variants of neuronal nitric oxide synthase (NOS1) expressed in the macula densa and NOS1β accounts for most of the NO generation. We have also demonstrated that the mice with deletion of NOS1 specifically from the macula densa developed salt-sensitive hypertension. However, the global NOS1 knockout (NOS1KO) strain is neither hypertensive nor salt sensitive. This global NOS1KO strain is actually an NOS1αKO model. Consequently, we hypothesized that inhibition of NOS1β in NOS1αKO mice induces salt-sensitive hypertension. NOS1αKO and C57BL/6 wild-type (WT) mice were implanted with telemetry transmitters and divided into 7-nitroindazole (10 mg/kg/d)-treated and nontreated groups. All of the mice were fed a normal salt (0.4% NaCl) diet for 5 days, followed by a high-salt diet (4% NaCl). NO generation by the macula densa was inhibited by >90% in WT and NOS1αKO mice treated with 7-nitroindazole. Glomerular filtration rate in conscious mice was increased by ≈40% after a high-salt diet in both NOS1αKO and WT mice. In response to acute volume expansion, glomerular filtration rate, diuretic and natriuretic response were significantly blunted in the WT and knockout mice treated with 7-nitroindazole. Mean arterial pressure had no significant changes in mice fed a high-salt diet, but increased ≈15 mm Hg similarly in NOS1αKO and WT mice treated with 7-nitroindazole. We conclude that NOS1β, but not NOS1α, plays an important role in control of sodium excretion and hemodynamics in response to either an acute or a chronic salt loading. PMID:26883268

  15. Immunization with an ApoB-100 Related Peptide Vaccine Attenuates Angiotensin-II Induced Hypertension and Renal Fibrosis in Mice

    PubMed Central

    Honjo, Tomoyuki; Chyu, Kuang-Yuh; Dimayuga, Paul C.; Lio, Wai Man; Yano, Juliana; Trinidad, Portia; Zhao, Xiaoning; Zhou, Jianchang; Cercek, Bojan; Shah, Prediman K.

    2015-01-01

    Recent studies suggest the potential involvement of CD8+ T cells in the pathogenesis of murine hypertension. We recently reported that immunization with apoB-100 related peptide, p210, modified CD8+ T cell function in angiotensin II (AngII)-infused apoE (-/-) mice. In this study, we hypothesized that p210 vaccine modulates blood pressure in AngII-infused apoE (-/-) mice. Male apoE (-/-) mice were immunized with p210 vaccine and compared to unimmunized controls. At 10 weeks of age, mice were subcutaneously implanted with an osmotic pump which released AngII for 4 weeks. At 13 weeks of age, p210 immunized mice showed significantly lower blood pressure response to AngII compared to controls. CD8+ T cells from p210 immunized mice displayed a different phenotype compared to CD8+ T cells from unimmunized controls. Serum creatinine and urine albumin to creatinine ratio were significantly decreased in p210 immunized mice suggesting that p210 vaccine had renal protective effect. At euthanasia, inflammatory genes IL-6, TNF-α, and MCP-1 in renal tissue were down-regulated by p210 vaccine. Renal fibrosis and pro-fibrotic gene expression were also significantly reduced in p210 immunized mice. To assess the role of CD8+ T cells in these beneficial effects of p210 vaccine, CD8+ T cells were depleted by CD8 depleting antibody in p210 immunized mice. p210 immunized mice with CD8+ T cell depletion developed higher blood pressure compared to mice receiving isotype control. Depletion of CD8+ T cells also increased renal fibrotic gene expression compared to controls. We conclude that immunization with p210 vaccine attenuated AngII-induced hypertension and renal fibrosis. CD8+ T cells modulated by p210 vaccine could play an important role in the anti-hypertensive, anti-fibrotic and renal-protective effect of p210 vaccine. PMID:26121471

  16. CS-3150, a Novel Nonsteroidal Mineralocorticoid Receptor Antagonist, Shows Preventive and Therapeutic Effects On Renal Injury in Deoxycorticosterone Acetate/Salt-Induced Hypertensive Rats.

    PubMed

    Arai, Kiyoshi; Morikawa, Yuka; Ubukata, Naoko; Tsuruoka, Hiroyuki; Homma, Tsuyoshi

    2016-09-01

    The present study was designed to assess both preventive and therapeutic effects of (S)-1-(2-Hydroxyethyl)-4-methyl-N-[4-(methylsulfonyl) phenyl]-5-[2-(trifluoromethyl) phenyl]-1H-pyrrole-3-carboxamide (CS-3150), a novel nonsteroidal mineralocorticoid receptor antagonist, on renal injury in deoxycorticosterone acetate (DOCA)/salt-induced hypertensive rats (DOCA rats). From 7 weeks of age, DOCA was subcutaneously administered once a week for 4 weeks to uninephrectomized rats fed a high-salt diet. In experiment 1, CS-3150 (0.3-3 mg/kg) was orally administered once a day for 4 weeks coincident with DOCA administration. In experiment 2, after establishment of renal injury by 4 weeks of DOCA/salt loading, CS-3150 (3 mg/kg) was orally administered once a day for 4 weeks with or without continuous DOCA administration. In experiment 1, DOCA/salt loading significantly increased systolic blood pressure (SBP), which was prevented by CS-3150 in a dose-dependent manner. Development of renal injury (proteinuria, renal hypertrophy, and histopathological changes in glomeruli and tubule) was also suppressed by CS-3150 with inhibition of mRNA expression of fibrosis, inflammation, and oxidative stress markers. In experiment 2, under continuous DOCA treatment, CS-3150 clearly ameliorated existing renal injury without lowering SBP, indicating that CS-3150 regressed renal injury independent of its antihypertensive action. Moreover, CS-3150 treatment in combination with withdrawal of DOCA showed further therapeutic effect on renal injury accompanied by reduction in SBP. These results demonstrate that CS-3150 not only prevents but also ameliorates hypertension and renal injury in DOCA rats. Therefore, CS-3150 could be a promising agent for the treatment of hypertension and renal disorders, and may have potential to promote regression of renal injury. PMID:27384074

  17. Effect of a nitric oxide-releasing naproxen derivative on hypertension and gastric damage induced by chronic nitric oxide inhibition in the rat.

    PubMed

    Muscará, M N; McKnight, W; Del Soldato, P; Wallace, J L

    1998-01-01

    NSAIDs can elevate blood pressure through mechanisms such as renal vasoconstriction and sodium retention. These effects are particularly evident in hypertensive individuals. Nitric oxide-releasing NSAID derivatives have been shown to have greatly reduced toxicity in the gastrointestinal tract and kidney. We therefore evaluated the effects of a 4 week treatment with either naproxen or its nitric oxide-releasing derivative (NO-naproxen) on systemic arterial blood pressure and gastric damage in rats in which hypertension was induced by L-NAME. Rats received either L-NAME dissolved in the drinking water (400 mg/L) or tap water (control). Vehicle, naproxen (10 mg/kg) or an equimolar dose of NO-naproxen (14.5 mg/kg) were administered orally each day. After 4 weeks, blood pressure was measured, blood samples were taken for measurement of thromboxane synthesis, and gastric damage was evaluated by blind, macroscopic scoring. Both naproxen and NO-naproxen inhibited systemic cyclooxygenase activity by >90%. NO-naproxen-treated rats exhibited no significant gastric damage. The gastric damage produced by L-NAME alone was potentiated by naproxen but prevented by NO-naproxen. L-NAME treatment significantly increased blood pressure. In the absence of L-NAME, the naproxen group had significantly higher blood pressure than both the control and NO-naproxen groups. In rats receiving L-NAME, the same conclusions apply, but the concomitant administration of NO-naproxen was able to significantly reduce the blood pressure compared to L-NAME alone. Based on these results, we conclude that NO-naproxen may represent a safer alternative to standard NSAIDs in the treatment of inflammatory conditions in hypertensive patients. PMID:9566780

  18. Common Secondary Causes of Resistant Hypertension and Rational for Treatment

    PubMed Central

    Faselis, Charles; Doumas, Michael; Papademetriou, Vasilios

    2011-01-01

    Resistant hypertension is defined as uncontrolled blood pressure despite the use of three antihypertensive drugs, including a diuretic, in optimal doses. Treatment resistance can be attributed to poor adherence to antihypertensive drugs, excessive salt intake, physician inertia, inappropriate or inadequate medication, and secondary hypertension. Drug-induced hypertension, obstructive sleep apnoea, primary aldosteronism, and chronic kidney disease represent the most common secondary causes of resistant hypertension. Several drugs can induce or exacerbate pre-existing hypertension, with non-steroidal anti-inflammatory drugs being the most common due to their wide use. Obstructive sleep apnoea and primary aldosteronism are frequently encountered in patients with resistant hypertension and require expert management. Hypertension is commonly found in patients with chronic kidney disease and is frequently resistant to treatment, while the management of renovascular hypertension remains controversial. A step-by-step approach of patients with resistant hypertension is proposed at the end of this review paper. PMID:21423678

  19. [Rare forms of hypertension : From pheochromocytoma to vasculitis].

    PubMed

    Haller, H; Limbourg, F; Schmidt, B M; Menne, J

    2015-03-01

    Secondary hypertension affects only 5-10 % of hypertensive patients. Screening is expensive and time-consuming and should be performed only in patients for whom there is a high clinical suspicion of secondary hypertension. Clinical signs of secondary forms of hypertension are new-onset hypertension in patients without other risk factors (i.e., family history, obesity, etc.), sudden increase of blood pressure (BP) in a previously stable patient, increased BP in prepubertal children, resistant hypertension, and severe hypertension or hypertensive emergencies. In adults, renal parenchymal and vascular diseases as well as obstructive sleep apnea are the most common causes of secondary hypertension. Medication-induced hypertension and non-adherence to medication have to be ruled out. Of the endocrine causes associated with hypertension, primary aldosteronism is the most common. Other endocrine causes of hypertension such as thyroid disease (hypo- or hyperthyroidism), hypercortisolism (Cushing's syndrome), hyperparathyroidism, and pheochromocytoma are rare. Monogenetic forms of hypertension are mostly of tubular origin and associated with alterations in mineralocorticoid handling or signaling. Rare causes of hypertension also include inflammatory vascular disease. Acute forms of vasculitis may present as "malignant" hypertension with associated thrombotic microangiopathy and organ damage/failure. It is important to diagnose these rare forms of hypertension in order to prevent acute organ damage in these patients or unnecessary invasive treatment strategies. PMID:25700646

  20. Suppression of endothelial PGC-1α is associated with hypoxia-induced endothelial dysfunction and provides a new therapeutic target in pulmonary arterial hypertension.

    PubMed

    Ye, Jia-Xin; Wang, Shan-Shan; Ge, Min; Wang, Dong-Jin

    2016-06-01

    Endothelial dysfunction plays a principal role in the pathogenesis of pulmonary arterial hypertension (PAH), which is a fatal disease with limited effective clinical treatments. Mitochondrial dysregulation and oxidative stress are involved in endothelial dysfunction. Peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) is a key regulator of cellular energy metabolism and a master regulator of mitochondrial biogenesis. However, the roles of PGC-1α in hypoxia-induced endothelial dysfunction are not completely understood. We hypothesized that hypoxia reduces PGC-1α expression and leads to endothelial dysfunction in hypoxia-induced PAH. We confirmed that hypoxia has a negative impact on endothelial PGC-1α in experimental PAH in vitro and in vivo. Hypoxia-induced PGC-1α inhibited the oxidative metabolism and mitochondrial function, whereas sustained PGC-1α decreased reactive oxygen species (ROS) formation, mitochondrial swelling, and NF-κB activation and increased ATP formation and endothelial nitric oxide synthase (eNOS) phosphorylation. Furthermore, hypoxia-induced changes in the mean pulmonary arterial pressure and right heart hypertrophy were nearly normal after intervention. These results suggest that PGC-1α is associated with endothelial function in hypoxia-induced PAH and that improved endothelial function is associated with improved cellular mitochondrial respiration, reduced inflammation and oxygen stress, and increased PGC-1α expression. Taken together, these findings indicate that PGC-1α may be a new therapeutic target in PAH. PMID:27084848

  1. Effect of endurance training on seizure susceptibility, behavioral changes and neuronal damage after kainate-induced status epilepticus in spontaneously hypertensive rats.

    PubMed

    Tchekalarova, J; Shishmanova, M; Atanasova, D; Stefanova, M; Alova, L; Lazarov, N; Georgieva, K

    2015-11-01

    The therapeutic efficacy of regular physical exercises in an animal model of epilepsy and depression comorbidity has been confirmed previously. In the present study, we examined the effects of endurance training on susceptibility to kainate (KA)-induced status epilepticus (SE), behavioral changes and neuronal damage in spontaneously hypertensive rats (SHRs). Male SHRs were randomly divided into two groups. One group was exercised on a treadmill with submaximal loading for four weeks and the other group was sedentary. Immediately after the training period, SE was evoked in half of the sedentary and trained rats by KA, while the other half of the two groups received saline. Basal systolic (SP), diastolic (DP) and mean arterial pressure (MAP) of all rats were measured at the beginning and at the end of the training period. Anxiety, memory and depression-like behaviour were evaluated a month after SE. The release of 5-HT in the hippocampus was measured using a liquid scintillation method and neuronal damage was analyzed by hematoxylin and eosin staining. SP and MAP of exercised SHRs decreased in comparison with the initial values. The increased resistance of SHRs to KA-induced SE was accompanied by an elongated latent seizure-free period, improved object recognition memory and antidepressant effect after the training program. While the anticonvulsant and positive behavioral effects of endurance training were accompanied by an increase of 5-HT release in the hippocampus, it did not exert neuroprotective activity. Our results indicate that prior exercise is an effective means to attenuate KA-induced seizures and comorbid behavioral changes in a model of hypertension and epilepsy suggesting a potential influence of hippocampal 5-HT on a comorbid depression. However, this beneficial impact does not prevent the development of epilepsy and concomitant brain damage. PMID:26319691

  2. Intratracheal Administration of Prostacyclin Analogue–incorporated Nanoparticles Ameliorates the Development of Monocrotaline and Sugen-Hypoxia-induced Pulmonary Arterial Hypertension

    PubMed Central

    Matsubara, Hiromi; Kondo, Megumi; Miura, Daiji; Matoba, Tetsuya; Egashira, Kensuke; Ito, Hiroshi

    2016-01-01

    Abstract: Nanoparticles (NPs) have been used as novel drug delivery systems. Drug-incorporated NPs for local delivery might optimize the efficacy and minimize the side effects of drugs. Intravenous prostacyclin improves long-term survival in patients with pulmonary arterial hypertension (PAH), but it causes serious side effects such as catheter-related infections. We investigated the efficacy and safety of intratracheal administration of a prostacyclin analogue, beraprost (BPS), incorporated NPs in Sugen-hypoxia-normoxia and monocrotaline rat models of PAH and in human PAH pulmonary arterial smooth muscle cells (PASMCs). After a single administration, BPS NPs significantly decreased right ventricular pressure, right ventricular hypertrophy, and pulmonary artery muscularization in the 2 rat models. BPS NPs significantly improved the survival rate in the monocrotaline rat model. No infiltration of inflammatory cells, hemorrhage, or fibrosis was found in the liver, kidney, spleen, and heart after the administration of BPS NPs. No liver or kidney dysfunction was found in the blood examinations. BPS and BPS NPs significantly inhibited the proliferation of human PAH PASMCs after 24 hours of treatment. BPS NPs significantly continued to inhibit the proliferation of human PAH PASMCs at 24 hours after the removal of BPS NPs. BPS NPs significantly induced apoptosis in PAH PASMCs compared to that in non-PAH PASMCs. Intratracheal administration of BPS NPs ameliorates pulmonary hypertension in PAH rat models by a sustained antiproliferative effect and a proapoptotic effect on PAH PASMCs. PMID:26745002

  3. Effects of Single Drug and Combined Short-term Administration of Sildenafil, Pimobendan, and Nicorandil on Right Ventricular Function in Rats With Monocrotaline-induced Pulmonary Hypertension.

    PubMed

    Nakata, Telma M; Tanaka, Ryou; Yoshiyuki, Rieko; Fukayama, Toshiharu; Goya, Seijiro; Fukushima, Ryuji

    2015-06-01

    This study was designed to assess the progression of pulmonary arterial hypertension (PAH) and the effectiveness of therapy using recently investigated echocardiographic parameters. PAH is characterized by the progressive elevation of pulmonary artery pressure and right ventricular hypertrophy and dysfunction, which ultimately results in right-sided heart failure and death. Echocardiography results and invasive measurements of right and left ventricular systolic pressures were compared after 3-week administrations of sildenafil (S group), pimobendan (P group), nicorandil (N group), and their combinations (SP and SPN groups) in male rats with monocrotaline (MCT)-induced pulmonary hypertension (M group) and without this condition (C group). The groups that received pimobendan alone and in combinations (SP and SPN groups) showed improvement in their echocardiographic parameters of systolic function. A significant improvement of diastolic function was achieved in the SPN group. Invasive measurements showed the most significant decreases of right ventricular systolic pressure in the N and SPN groups, and the use of pimobendan resulted in a comparatively low risk of adverse hemodynamic effects (left ventricular systolic pressure). Although our results suggested the attenuation of PAH severity in all treatment groups, PAH could not be reversed. PMID:25806612

  4. Effects of Single Drug and Combined Short-term Administration of Sildenafil, Pimobendan, and Nicorandil on Right Ventricular Function in Rats With Monocrotaline-induced Pulmonary Hypertension

    PubMed Central

    Tanaka, Ryou; Yoshiyuki, Rieko; Fukayama, Toshiharu; Goya, Seijiro; Fukushima, Ryuji

    2015-01-01

    Abstract: This study was designed to assess the progression of pulmonary arterial hypertension (PAH) and the effectiveness of therapy using recently investigated echocardiographic parameters. PAH is characterized by the progressive elevation of pulmonary artery pressure and right ventricular hypertrophy and dysfunction, which ultimately results in right-sided heart failure and death. Echocardiography results and invasive measurements of right and left ventricular systolic pressures were compared after 3-week administrations of sildenafil (S group), pimobendan (P group), nicorandil (N group), and their combinations (SP and SPN groups) in male rats with monocrotaline (MCT)-induced pulmonary hypertension (M group) and without this condition (C group). The groups that received pimobendan alone and in combinations (SP and SPN groups) showed improvement in their echocardiographic parameters of systolic function. A significant improvement of diastolic function was achieved in the SPN group. Invasive measurements showed the most significant decreases of right ventricular systolic pressure in the N and SPN groups, and the use of pimobendan resulted in a comparatively low risk of adverse hemodynamic effects (left ventricular systolic pressure). Although our results suggested the attenuation of PAH severity in all treatment groups, PAH could not be reversed. PMID:25806612

  5. Comparison of. beta. -adrenergic receptors between different strains of rat with different susceptibility to hypertension: a survey of binding characteristics, responsiveness and corticosteroid induced modulation

    SciTech Connect

    Jazayeri, A.

    1987-01-01

    The objective of this research was two fold: the first objective was to measure ..beta..-adrenergic receptor characteristics (Bmax and Kd) and responsiveness (isoproterenol induced c-AMP production) between different strains of rat with different susceptibility to hypertension. The second objective of this research was to determine if ..beta..-adrenergic receptors of arterial smooth muscle cells (ASMC) can be modulated by corticosteroids. These studies were done under controlled conditions using ASMC grown in culture from the rat aorta. (/sup 3/H)-dihydroalprenolol (DHA) was used to measure ..beta..-adrenergic receptor binding characteristics (Kd and Bmax). Scatchard analysis of (/sup 3/H)-DHA binding revealed one class of binding sites with affinity in the range of 100 pM. (/sup 3/H)-DHA binding comparison between Wistar-Kyoto (WKY) and spontaneously hypertensive rats (SHR) revealed that the Bmax for SHR was significantly lower than WKY. However, isoproterenol stimulated c-AMP production by SHR, is significantly higher than WKY. Fischer 344 rats, showed similar Bmax, Kd, and responsiveness as WKY rats. Dahl-sensitive and Dahl-resistant rats had equal Bmax and Kd measured by (/sup 3/H)-DHA binding.

  6. Chronic vagal nerve stimulation prevents high-salt diet-induced endothelial dysfunction and aortic stiffening in stroke-prone spontaneously hypertensive rats.

    PubMed

    Chapleau, Mark W; Rotella, Diane L; Reho, John J; Rahmouni, Kamal; Stauss, Harald M

    2016-07-01

    Parasympathetic activity is often reduced in hypertension and can elicit anti-inflammatory mechanisms. Thus we hypothesized that chronic vagal nerve stimulation (VNS) may alleviate cardiovascular end-organ damage in stroke-prone spontaneously hypertensive rats. Vagal nerve stimulators were implanted, a high-salt diet initiated, and the stimulators turned on (VNS, n = 10) or left off (sham, n = 14) for 4 wk. Arterial pressure increased equally in both groups. After 4 wk, endothelial function, assessed by in vivo imaging of the long posterior ciliary artery (LPCA) after stimulation (pilocarpine) and inhibition (N(ω)-nitro-l-arginine methyl ester) of endothelial nitric oxide synthase (eNOS), had significantly declined (-2.3 ± 1.2 μm, P < 0.05) in sham, but was maintained (-0.7 ± 0.8 μm, nonsignificant) in VNS. Furthermore, aortic eNOS activation (phosphorylated to total eNOS protein content ratio) was greater in VNS (0.83 ± 0.07) than in sham (0.47 ± 0.08, P < 0.05). After only 3 wk, ultrasound imaging of the aorta demonstrated decreased aortic strain (-9.7 ± 2.2%, P < 0.05) and distensibility (-2.39 ± 0.49 1,000/mmHg, P < 0.05) and increased pulse-wave velocity (+2.4 ± 0.7 m/s, P < 0.05) in sham but not in VNS (-3.8 ± 3.8%, -0.70 ± 1.4 1,000/mmHg, and +0.1 ± 0.7 m/s, all nonsignificant). Interleukin (IL)-6 serum concentrations tended to be higher in VNS than in sham (34.3 ± 8.3 vs. 16.1 ± 4.6 pg/ml, P = 0.06), and positive correlations were found between NO-dependent relaxation of the LPCA and serum levels of IL-6 (r = +0.70, P < 0.05) and IL-10 (r = +0.56, P < 0.05) and between aortic eNOS activation and IL-10 (r = +0.48, P < 0.05). In conclusion, chronic VNS prevents hypertension-induced endothelial dysfunction and aortic stiffening in an animal model of severe hypertension. We speculate that anti-inflammatory mechanisms may contribute to these effects. PMID:27208157

  7. Hypertension Subtypes among Hypertensive Patients in Ibadan

    PubMed Central

    Salako, Babatunde L.; Ogunniyi, Adesola; Cooper, Richard S.

    2014-01-01

    Background. Certain hypertension subtypes have been shown to increase the risk for cardiovascular morbidity and mortality and may be related to specific underlying genetic determinants. Inappropriate characterization of subtypes of hypertension makes efforts at elucidating the genetic contributions to the etiology of hypertension largely vapid. We report the hypertension subtypes among patients with hypertension from South-Western Nigeria. Methods. A total of 1858 subjects comprising 76% female, hypertensive, aged 18 and above were recruited into the study from two centers in Ibadan, Nigeria. Hypertension was identified using JNCVII definition and was further grouped into four subtypes: controlled hypertension (CH), isolated systolic hypertension (ISH), isolated diastolic hypertension (IDH), and systolic-diastolic hypertension (SDH). Results. Systolic-diastolic hypertension was the most prevalent. Whereas SDH (77.6% versus 73.5%) and IDH (4.9% versus 4.7%) were more prevalent among females, ISH (10.1% versus 6.2%) was higher among males (P = 0.048). Female subjects were more obese (P < 0.0001) and SDH was prevalent among the obese group. Conclusion. Gender and obesity significantly influenced the distribution of the hypertension subtypes. Characterization of hypertension by subtypes in genetic association studies could lead to identification of previously unknown genetic variants involved in the etiology of hypertension. Large-scale studies among various ethnic groups may be needed to confirm these observations. PMID:25389499

  8. Disruption of the cytochrome P-450 1B1 gene exacerbates renal dysfunction and damage associated with angiotensin II-induced hypertension in female mice

    PubMed Central

    Jennings, Brett L.; Moore, Joseph A.; Pingili, Ajeeth K.; Estes, Anne M.; Fang, Xiao R.; Kanu, Alie; Gonzalez, Frank J.

    2015-01-01

    Recently, we demonstrated in female mice that protection against ANG II-induced hypertension and associated cardiovascular changes depend on cytochrome P-450 (CYP)1B1. The present study was conducted to determine if Cyp1b1 gene disruption ameliorates renal dysfunction and organ damage associated with ANG II-induced hypertension in female mice. ANG II (700 ng·kg−1·min−1) infused by miniosmotic pumps for 2 wk in female Cyp1b1+/+ mice did not alter water consumption, urine output, Na+ excretion, osmolality, or protein excretion. However, in Cyp1b1−/− mice, ANG II infusion significantly increased (P < 0.05) water intake (5.50 ± 0.42 ml/24 h with vehicle vs. 8.80 ± 0.60 ml/24 h with ANG II), urine output (1.44 ± 0.37 ml/24 h with vehicle vs. 4.30 ± 0.37 ml/24 h with ANG II), and urinary Na+ excretion (0.031 ± 0.016 mmol/24 h with vehicle vs. 0.099 ± 0.010 mmol/24 h with ANG II), decreased osmolality (2,630 ± 79 mosM/kg with vehicle vs. 1,280 ± 205 mosM/kg with ANG II), and caused proteinuria (2.60 ± 0.30 mg/24 h with vehicle vs. 6.96 ± 0.55 mg/24 h with ANG II). Infusion of ANG II caused renal fibrosis, as indicated by an accumulation of renal interstitial α-smooth muscle actin, collagen, and transforming growth factor-β in Cyp1b1−/− but not Cyp1b1+/+ mice. ANG II also increased renal production of ROS and urinary excretion of thiobarburic acid-reactive substances and reduced the activity of antioxidants and urinary excretion of nitrite/nitrate and the 17β-estradiol metabolite 2-methoxyestradiol in Cyp1b1−/− but not Cyp1b1+/+ mice. These data suggest that Cyp1b1 plays a critical role in female mice in protecting against renal dysfunction and end-organ damage associated with ANG II-induced hypertension, in preventing oxidative stress, and in increasing activity of antioxidant systems, most likely via generation of 2-methoxyestradiol from 17β-estradiol. PMID:25694484

  9. [PHYSICAL EXERCISE TRAINING CAN- CELS CONSTITUTIVE NOS UNCOUPLING AND INDUCED VIOLATIONS OF CARDIAC HEMODYNAMICS IN HYPERTENSION (PART III)].

    PubMed

    Dorofeyeva, N A; Kotsuruba, A V; Kopjak, B S; Sagach, V F

    2015-01-01

    In the heart and heart mitochondria spontaneously hypertensive rats investigated the effect of physical exercise training (swimming in a moderate and excessive training mode) on the physiological indicators of cardiac hemodynamics and biochemical parameters that characterize the level of oxidative and nitrosative stress. The index of coupling Ca(2+)-dependent constitutive NO-synthases (cNOS = eNOS + nNOS) and biochemical index of dysfunction were calculated. It turned out that both modes of training is completely restored, and even exceed the reference values in untrained rats Wistar conjugate cNOS state and Ca(2+)-dependent synthesis of nitric oxide (NO). Intensity regime of exercise on the border of functionality have been ineffective for improving the functional state of the cardiovascular system and hypertension can provoke it further. Moderate physical training regime, on the contrary, improves the diastolic function of the heart due to an increase dP/dtmin, reducing end-diastolic pressure and a significant reduction in end-diastolic stiffness. Moderate exercise decreased peripheral resistance and cardiac afterload, as indicated by the decrease in end-systolic pressure and arterial stiffness, which contributed to more efficient and energy-saving of heart work. Improve physiological indicators of cardiac hemodynamics and functional state of the heart in moderate mode of training correlated with changes in both the calculated indices. Moderate mode of training is recommended as a simple physiological preconditioning method for the prevention of cardiac dysfunction, hypertension as a result of state uncoupling cNOS and the resulting excessive generation of superoxide and, conversely, inhibition of Ca(2+)-dependent synthesis of NO. PMID:26552300

  10. Low-Salt Diet and Circadian Dysfunction Synergize to Induce Angiotensin II-Dependent Hypertension in Mice.

    PubMed

    Pati, Paramita; Fulton, David J R; Bagi, Zsolt; Chen, Feng; Wang, Yusi; Kitchens, Julia; Cassis, Lisa A; Stepp, David W; Rudic, R Daniel

    2016-03-01

    Blood pressure exhibits a robust circadian rhythm in health. In hypertension, sleep apnea, and even shift work, this balanced rhythm is perturbed via elevations in night-time blood pressure, inflicting silent damage to the vasculature and body organs. Herein, we examined the influence of circadian dysfunction during experimental hypertension in mice. Using radiotelemetry to measure ambulatory blood pressure and activity, the effects of angiotensin II administration were studied in wild-type (WT) and period isoform knockout (KO) mice (Per2-KO, Per2, 3-KO, and Per1, 2, 3-KO/Per triple KO [TKO] mice). On a normal diet, administration of angiotensin II caused nondipping blood pressure and exacerbated vascular hypertrophy in the Period isoform KO mice relative to WT mice. To study the endogenous effects of angiotensin II stimulation, we then administered a low-salt diet to the mice, which does stimulate endogenous angiotensin II in addition to lowering blood pressure. A low-salt diet decreased blood pressure in wild-type mice. In contrast, Period isoform KO mice lost their circadian rhythm in blood pressure on a low-salt diet, because of an increase in resting blood pressure, which was restorable to rhythmicity by the angiotensin receptor blocker losartan. Chronic administration of low salt caused vascular hypertrophy in Period isoform KO mice, which also exhibited increased renin levels and altered angiotensin 1 receptor expression. These data suggest that circadian clock genes may act to inhibit or control renin/angiotensin signaling. Moreover, circadian disorders such as sleep apnea and shift work may alter the homeostatic responses to sodium restriction to potentially influence nocturnal hypertension. PMID:26781276

  11. Sex differences in primary hypertension

    PubMed Central

    2012-01-01

    Men have higher blood pressure than women through much of life regardless of race and ethnicity. This is a robust and highly conserved sex difference that it is also observed across species including dogs, rats, mice and chickens and it is found in induced, genetic and transgenic animal models of hypertension. Not only do the differences between the ovarian and testicular hormonal milieu contribute to this sexual dimorphism in blood pressure, the sex chromosomes also play a role in and of themselves. This review primarily focuses on epidemiological studies of blood pressure in men and women and experimental models of hypertension in both sexes. Gaps in current knowledge regarding what underlie male-female differences in blood pressure control are discussed. Elucidating the mechanisms underlying sex differences in hypertension may lead to the development of anti-hypertensives tailored to one's sex and ultimately to improved therapeutic strategies for treating this disease and preventing its devastating consequences. PMID:22417477

  12. Liraglutide prevents and reverses monocrotaline-induced pulmonary arterial hypertension by suppressing ET-1 and enhancing eNOS/sGC/PKG pathways

    PubMed Central

    Lee, Mei-Yueh; Tsai, Kun-Bow; Hsu, Jong-Hau; Shin, Shyi-Jang; Wu, Jiunn-Ren; Yeh, Jwu-Lai

    2016-01-01

    Liraglutide, a glucagon-like peptide-1 receptor (GLP-1R) agonist, is widely used to treat diabetes. However, its effect on pulmonary arterial hypertension (PAH) is unknown. In this study, we investigated its effects on rats with monocrotaline (MCT)-induced PAH and mechanisms on rat pulmonary artery smooth muscle cells (PASMCs). Liraglutide was investigated for both prevention and treatment of MCT-induced PAH. The hemodynamic and body weight changes, right heart hypertrophy, lung morphology, immune-reactivity of endothelial nitric oxide synthase (eNOS), endothelin-1 and cyclic guanosine monophosphate (cGMP) levels, protein expressions of eNOS, soluble guanylyl cyclase (sGCα), protein kinase G (PKG) and Rho kinase (ROCK) II pathway were measured in both in vivo and in vitro. Cell migration and cell cycle were also determined. Liraglutide both prevented and reversed MCT-induced PAH, right ventricle hypertrophy and pulmonary vascular wall remodeling. Protein expression of ROCK II was increased while eNOS, sGC and PKG were decreased. Pretreatment with liraglutide inhibited platelet-derived growth factor (PDGF)-BB stimulated PASMCs migration, which were associated with cell-cycle arrest at G0/G1 phase. Liraglutide may have both preventive and therapeutic effects on MCT-induced PAH, through the eNOS/sGC/PKG and Rho kinase pathways. Thus, liraglutide may have a therapeutic role in pulmonary vascular remodelling. PMID:27581840

  13. Liraglutide prevents and reverses monocrotaline-induced pulmonary arterial hypertension by suppressing ET-1 and enhancing eNOS/sGC/PKG pathways.

    PubMed

    Lee, Mei-Yueh; Tsai, Kun-Bow; Hsu, Jong-Hau; Shin, Shyi-Jang; Wu, Jiunn-Ren; Yeh, Jwu-Lai

    2016-01-01

    Liraglutide, a glucagon-like peptide-1 receptor (GLP-1R) agonist, is widely used to treat diabetes. However, its effect on pulmonary arterial hypertension (PAH) is unknown. In this study, we investigated its effects on rats with monocrotaline (MCT)-induced PAH and mechanisms on rat pulmonary artery smooth muscle cells (PASMCs). Liraglutide was investigated for both prevention and treatment of MCT-induced PAH. The hemodynamic and body weight changes, right heart hypertrophy, lung morphology, immune-reactivity of endothelial nitric oxide synthase (eNOS), endothelin-1 and cyclic guanosine monophosphate (cGMP) levels, protein expressions of eNOS, soluble guanylyl cyclase (sGCα), protein kinase G (PKG) and Rho kinase (ROCK) II pathway were measured in both in vivo and in vitro. Cell migration and cell cycle were also determined. Liraglutide both prevented and reversed MCT-induced PAH, right ventricle hypertrophy and pulmonary vascular wall remodeling. Protein expression of ROCK II was increased while eNOS, sGC and PKG were decreased. Pretreatment with liraglutide inhibited platelet-derived growth factor (PDGF)-BB stimulated PASMCs migration, which were associated with cell-cycle arrest at G0/G1 phase. Liraglutide may have both preventive and therapeutic effects on MCT-induced PAH, through the eNOS/sGC/PKG and Rho kinase pathways. Thus, liraglutide may have a therapeutic role in pulmonary vascular remodelling. PMID:27581840

  14. Pharmacologic analysis of 7-O-ethyl-fangchinoline-induced vasodilation properties in isolated perfused common carotid arteries of Wistar Kyoto rats and spontaneously hypertensive rats.

    PubMed

    Matsuura, M; Zenda, H; Chiba, S

    1991-10-01

    Using the cannula insertion method, we investigated vascular effects of 7-O-ethyl-fangchinoline (TJN-220) derived from tetrandrine in isolated and perfused common carotid arteries of Wistar Kyoto rats (WKY) and spontaneously hypertensive rats (SHR). A single dose of TJN-220 caused a vasodilation in a dose-related manner in arteries preconstricted by phenylephrine. The vasodilation was not inhibited by propranolol, a potent beta-adrenoceptor antagonist. A potent alpha-antagonist bunazosin inhibited the vasoconstriction to norepinephrine while TJN-220 did not modify the norepinephrine-induced constriction, indicating TJN-220 had no alpha-blocking activity. A potent calcium entry blocker, diltiazem, markedly attenuated the KCl-induced vasoconstriction, and TJN-220 slightly but significantly attenuated the KCl-induced one in large doses. The vasodilation of TJN-220 was not abolished after removing the endothelium by an intraluminal administration of saponin, although the ACh-induced dilation was completely abolished by it. A comparison of vascular responses in WKY and SHR revealed no significant differences. From these results, it is concluded that 1) a new tetrandrine derivative, TJN-220 has relatively long-lasting vasorelaxant properties, 2) the dilatory effects might not be related to adrenergic, muscarinic or endothelium-dependent mechanisms, and 3) the effects might partially be due to calcium entry antagonistic properties. PMID:1806292

  15. Assessment of antioxidant enzyme activities in erythrocytes of pre-hypertensive and hypertensive women

    PubMed Central

    Amirkhizi, Farshad; Siassi, Fereydoun; Djalali, Mahmoud; Foroushani, Abbas Rahimi

    2010-01-01

    BACKGROUND: Few studies that have investigated hypertension have considered a state of oxidative stress that can contribute to the development of atherosclerosis and other hypertension induced organ damage. The aim of this study was to investigate whether pre-hypertension and hypertension status is associated with activities of erythrocyte antioxidant enzymes in a random sample of cardiovascular disease-free women. METHODS: In this case-control study, 53 pre-hypertensive women, 32 hypertensive women and 75 healthy controls were included. General information was gathered using questionnaires and face-to-face interviews. Blood pressure and anthropometric measurements were measured for each subject. Venous blood samples were drawn from subjects and plasma was separated. Activities of erythrocyte antioxidant enzymes were also evaluated by measuring activities of copper zinc-superoxide dismutase (CuZn-SOD), glutathione peroxidase (GPX) and catalase (CAT) in selected subjects. RESULTS: Fifty-three (33.1%) and 32 (20%) participants were pre-hypertensive and hypertensive, respectively. The hypertensive and pre-hypertensive women had lower CuZn-SOD (p < 0.001) and GPX (p < 0.01) activities compared to normotensives. Furthermore, hypertensive women had lower CAT activity compared to pre-hypertensive and normotensive women (p < 0.001). Moreover, significant differences were also observed between hypertensive and pre-hypertensive women in erythrocyte CAT activity (p < 0.01). CONCLUSIONS: The present findings show that activities of erythrocyte antioxidant enzymes decrease in pre-hypertensive and hypertensive women, which may eventually lead to atherosclerosis and other high blood pressure related health problems. PMID:21526095

  16. Des-aspartate angiotensin I (DAA-I) reduces endothelial dysfunction in the aorta of the spontaneously hypertensive rat through inhibition of angiotensin II-induced oxidative stress.

    PubMed

    Loh, Wei Mee; Ling, Wei Chih; Murugan, Dharmani D; Lau, Yeh Siang; Achike, Francis I; Vanhoutte, Paul M; Mustafa, Mohd Rais

    2015-08-01

    Des-aspartate angiotensin I (DAA-I), an endogenous nonapeptide, counteracts several effects of angiotensin II on vascular tone. The aim of this study was to investigate the acute protective effect of DAA-I on endothelial function in the spontaneously hypertensive rat (SHR) as well as its effect on angiotensin II-induced contractions and oxidative stress. Aortic rings were incubated with DAA-I (0.1μM) for 30min prior to the assessment of angiotensin II-induced contractions (0.1nM-10μM) in WKY and SHR aortas. Total nitrate and nitrite levels were assessed using a colorimetric method and reactive oxygen species (ROS) were measured by dihydroethidium (DHE) fluorescence and lucigenin-enhanced chemiluminescence. The effect of DAA-I was also assessed against endothelium-dependent and -independent relaxations to acetylcholine and sodium nitroprusside, respectively. Angiotensin II-induced contractions were significantly reduced by DAA-I, losartan and tempol. Incubation with ODQ (soluble guanylyl cyclase inhibitor) and removal of the endothelium prevented the reduction of angiotensin II-induced contractions by DAA-I. Total nitrate and nitrite levels were increased in DAA-I, losartan and tempol treated-SHR tissues while ROS level was reduced by DAA-I and the latter inhibitors. In addition, DAA-I significantly improved the impaired acetylcholine-induced relaxation in SHR aortas whilst sodium nitroprusside-induced endothelium-independent relaxation remained unaffected. The present findings indicate that improvement of endothelial function by DAA-I in the SHR aorta is mediated through endothelium-dependent release of nitric oxide and inhibition of angiotensin II-induced oxidative stress. PMID:25869508

  17. Impaired renal endothelial nitric oxide synthase and reticulocyte production as modulators of hypertension induced by rHuEPO in the rat.

    PubMed

    Ribeiro, Sandra; Garrido, Patrícia; Fernandes, João; Vala, Helena; Rocha-Pereira, Petronila; Costa, Elísio; Belo, Luís; Reis, Flávio; Santos-Silva, Alice

    2016-04-15

    Our aim was to study the effect of a broad range of recombinant human erythropoietin (rHuEPO) doses on hematological and biochemical parameters, blood pressure (BP), renal function and damage in the rat, focusing on endothelial nitric oxide synthase (eNOS) and hypoxia-inducible factors (HIFs). Male Wistar rats were divided in 5 groups receiving different doses of rHuEPO (100, 200, 400 and 600IU/kg body weight (BW)/week) and saline solution (control), during 3weeks. Blood and 24h urine were collected to perform hematological and biochemical analysis. BP was measured by the tail-cuff method. Kidney tissue was collected to mRNA and protein expression assays and to characterize renal lesions. A dose-dependent increase in red blood cells count, hematocrit and hemoglobin levels was found with rHuEPO therapy, in rHuEPO200, rHuEPO400 and rHuEPO600 groups. Increased reticulocyte count was found in rHuEPO400 and rHuEPO600 groups. BP raised in all groups receiving rHuEPO. The rHuEPO200 and rHuEPO600 groups presented increased kidney protein levels of HIF2α, a reduction in kidney protein levels of eNOS, and the highest grade of vascular and tubular renal lesions. Our study showed that rHuEPO-induced hypertension is present before significant hematological changes occur and, therefore, might involve direct (renal) and indirect (hematological) effects, which varies according to the dose used. The presence of renal hypoxia reduces eNOS activity. Excessive erythrocytosis increases blood hyperviscosity, which can be modulated by an increase in reticulocytes. Hypertension leads to early renal damage without alterations in traditional markers of renal function, thus underestimating the serious adverse effects and risks. PMID:26924494

  18. Role of the Na+/H+ exchanger 3 in angiotensin II-induced hypertension in NHE3-deficient mice with transgenic rescue of NHE3 in small intestines

    PubMed Central

    Li, Xiao C; Shull, Gary E; Miguel-Qin, Elisa; Chen, Fang; Zhuo, Jia L

    2015-01-01

    The role of Na+/H+ exchanger 3 (NHE3) in the kidney in angiotensin II (ANG II)-induced hypertension remains unknown. The present study used global NHE3-deficient mice with transgenic rescue of the Nhe3 gene in small intestines (tgNhe3−/−) to test the hypothesis that genetic deletion of NHE3 selectively in the kidney attenuates ANG II-induced hypertension. Six groups of wild-type (tgNhe3+/+) and tgNhe3−/− mice were infused with either vehicle or ANG II (1.5 mg/kg/day, i.p., 2 weeks, or 10 nmol/min, i.v., 30 min), treated with or without losartan (20 mg/kg/day, p.o.) for 2 weeks. Basal systolic blood pressure (SBP) and mean intra-arterial blood pressure (MAP) were significantly lower in tgNhe3−/− mice (P < 0.01). Basal glomerular filtration rate, 24 h urine excretion, urinary Na+ excretion, urinary K+ excretion, and urinary Cl− excretion were significantly lower in tgNhe3−/− mice (P < 0.01). These responses were associated with significantly elevated plasma ANG II and aldosterone levels, and marked upregulation in aquaporin 1, the Na+/HCO3 cotransporter, the α1 subunit isoform of Na+/K+-ATPase, protein kinase Cα, MAP kinases ERK1/2, and glycogen synthase kinase 3 α/β in the renal cortex of tgNhe3−/− mice (P < 0.01). ANG II infusion markedly increased SBP and MAP and renal cortical transporter and signaling proteins in tgNhe3+/+, as expected, but all of these responses to ANG II were attenuated in tgNhe3−/− mice (P < 0.01). These results suggest that NHE3 in the kidney is necessary for maintaining normal blood pressure and fully developing ANG II-dependent hypertension. PMID:26564064

  19. Pulmonary Arterial Hypertension

    MedlinePlus

    ... What Is Pulmonary Hypertension? To understand pulmonary hypertension (PH) it helps to understand how blood ows throughout ... is too high, it is called pulmonary hypertension (PH). How the pressure in the right side of ...

  20. Hypertension and Spina Bifida

    MedlinePlus

    SBA National Resource Center: 800-621-3141 Hypertension A disease that often goes undetected. What is hypertension? Hypertension, also called high blood pressure , is a condition in which the arteries of ...

  1. What Causes Pulmonary Hypertension?

    MedlinePlus

    ... from the NHLBI on Twitter. What Causes Pulmonary Hypertension? Pulmonary hypertension (PH) begins with inflammation and changes in the ... different types of PH. Group 1 pulmonary arterial hypertension (PAH) may have no known cause, or the ...

  2. Hormones and Hypertension

    MedlinePlus

    Fact Sheet Hormones and Hypertension What is hypertension? Hypertension, or chronic (long-term) high blood pressure, is a main cause of ... tobacco, alcohol, and certain medications play a part. Hormones made in the kidneys and in blood vessels ...

  3. Enhanced Ca(2+)-induced Ca(2+) release from intracellular stores contributes to catecholamine hypersecretion in adrenal chromaffin cells from spontaneously hypertensive rats.

    PubMed

    Segura-Chama, Pedro; López-Bistrain, Patricia; Pérez-Armendáriz, Elia Martha; Jiménez-Pérez, Nicolás; Millán-Aldaco, Diana; Hernández-Cruz, Arturo

    2015-11-01

    Adrenal chromaffin cells (CCs) from spontaneously hypertensive rats (SHRs) secrete more catecholamine (CA) upon stimulation than CCs from normotensive Wistar Kyoto rats (WKY). Unitary CA exocytosis events, both spontaneous and stimulated, were amperometrically recorded from cultured WKY and SHR CCs. Both strains display spontaneous amperometric spikes but SHR CCs produce more spikes and of higher mean amplitude. After a brief stimulation with high K(+) or caffeine which produces voltage-gated Ca(2+) influx or intracellular Ca(2+) release, respectively, more spikes and of greater mean amplitude and unitary charge were recorded in SHR CCs. Consequently, peak cumulative charge was ~2-fold higher in SHR CCs. Ryanodine (10 μM), a specific blocker of the ryanodine receptors reduced depolarization-induced peak cumulative charge by ~10 % in WKY and ~77 % in SHR CCs, suggesting, a larger contribution of Ca(2+)-induced Ca(2+) release to CA exocytosis in SHR CCs. Accordingly, Ca(2+) imaging showed larger [Ca(2+)]i signals induced both by depolarization and caffeine in SHR CCs. Distribution amplitude histograms showed that small amperometric spikes (0-50 pA) are more frequent in WKY than in SHR CCs. Conversely, medium (50-190 pA) and large (190-290 pA) spikes are more numerous in SHR than in WKY CCs. This study reveals that the enhanced CA secretion in SHR CCs results from a combination of (1) larger depolarization-induced Ca(2+) transients, due to a greater Ca(2+)-induced intracellular Ca(2+) release, (2) more exocytosis events per time unit, and (3) a greater proportion of medium and large amperometric spikes probably due to a higher mean CA content per granule. Enhanced CA release by excessive amplification by Ca(2+) induced Ca(2+) release and larger granule catecholamine content contributes to the increased CA plasma levels and vasomotor tone in SHRs. PMID:25791627

  4. The role of collagen in extralobar pulmonary artery stiffening in response to hypoxia-induced pulmonary hypertension.

    PubMed

    Ooi, Chen Yen; Wang, Zhijie; Tabima, Diana M; Eickhoff, Jens C; Chesler, Naomi C

    2010-12-01

    Hypoxic pulmonary hypertension (HPH) causes extralobar pulmonary artery (PA) stiffening, which potentially impairs right ventricular systolic function. Changes in the extracellular matrix proteins collagen and elastin have been suggested to contribute to this arterial stiffening. We hypothesized that vascular collagen accumulation is a major cause of extralobar PA stiffening in HPH and tested our hypothesis with transgenic mice that synthesize collagen type I resistant to collagenase degradation (Col1a1(R/R)). These mice and littermate controls that have normal collagen degradation (Col1a1(+/+)) were exposed to hypoxia for 10 days; some were allowed to recover for 32 days. In vivo PA pressure and isolated PA mechanical properties and collagen and elastin content were measured for all groups. Vasoactive studies were also performed with U-46619, Y-27632, or calcium- and magnesium-free medium. Pulmonary hypertension occurred in both mouse strains due to chronic hypoxia and resolved with recovery. HPH caused significant PA mechanical changes in both mouse strains: circumferential stretch decreased, and mid-to-high-strain circumferential elastic modulus increased (P < 0.05 for both). Impaired collagen type I degradation prevented a return to baseline mechanical properties with recovery and, in fact, led to an increase in the low and mid-to-high-strain moduli compared with hypoxia (P < 0.05 for both). Significant changes in collagen content were found, which tended to follow changes in mid-to-high-strain elastic modulus. No significant changes in elastin content or vasoactivity were observed. Our results demonstrate that collagen content is important to extralobar PA stiffening caused by chronic hypoxia. PMID:20852040

  5. Hypertension, Cardiac Hypertrophy, and Impaired Vascular Relaxation Induced by 2,3,7,8-Tetrachlorodibenzo-p-Dioxin are Associated with Increased Superoxide

    PubMed Central

    Kopf, Phillip G.; Huwe, Janice K.

    2009-01-01

    The mechanisms by which 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) increases the incidence of human cardiovascular disease are not known. We investigated the degree to which cardiovascular disease develops in mice following subchronic TCDD exposure. Adult male C57BL/6 mice were dosed with vehicle or 300 ng TCDD/kg by oral gavage three times per week for 60 days. Blood pressure was recorded by radiotelemetry and aortic endothelial function was assessed by acetylcholine-induced vasorelaxation. Mean arterial pressure of TCDD-exposed mice was increased significantly by day 4 and between days 7–10, 25–35, and 45–60 with two periods of normalization on days 11–24 and days 36–39. Consistent with a prolonged period of systemic hypertension, heart weight was increased and was associated with concentric left ventricular hypertrophy. Significant increases in superoxide production also were observed in the kidney, heart, and aorta of TCDD-exposed mice. Furthermore, increased aortic superoxide resulted in endothelial dysfunction as demonstrated by significant impairment of acetylcholine-induced vasorelaxation in TCDD-exposed mice, which was restored by tempol, a superoxide dismutase (SOD) mimetic. Our model is the first to definitely demonstrate that sustained AhR activation by TCDD increases blood pressure and induces cardiac hypertrophy, which may be mediated, in part, by increased superoxide. PMID:18850075

  6. Hypertension in the elderly.

    PubMed

    Coope, J

    1987-08-01

    Hypertension is a common finding in patients aged over 60 years, but the following questions need answering. How dangerous is it? Will lowering the blood pressure reduce the attendant risks? What is the 'cost' of such treatment in terms of side effects, drug-induced disease and health service finance? Two recently completed trials throw light on these problems: EWPHE (European Working Party on Hypertension in the Elderly), a European study based on hospital-clinic attenders, using a diuretic backed up with methyldopa; and HEP (randomized trial of treatment of Hypertension in Elderly Patients in Primary Care), based on general-practice screening in England and Wales using atenolol and bendrofluazide. The results of these trials were compared and the findings were broadly similar in the two studies. Some of the differences may be due to the different selection of patients. It is concluded that elderly patients with sustained blood pressures greater or equal to 170/90 mmHg would benefit from treatment by substantial reduction of stroke. Diuretics or beta-blockers, alone or together, are acceptable treatments in elderly subjects. PMID:3312529

  7. Managing hypertension by polyphenols.

    PubMed

    Fernández-Arroyo, Salvador; Camps, Jordi; Menendez, Javier A; Joven, Jorge

    2015-06-01

    Some polyphenols, obtained from plants of broad use, induce a favorable endothelial response in hypertension and beneficial effects in the management of other metabolic cardiovascular risks. Previous studies in our laboratories using the calyces of Hibiscus sabdariffa as a source of polyphenols show that significant effects on hypertension are noticeable in humans only when provided in high amounts. Available data are suggestive in animal models and ex vivo experiments, but data in humans are difficult to acquire. Additionally, and despite the low bioavailability of polyphenols, intervention studies provide evidence for the protective effects of secondary plant metabolites. Assumptions on public health benefits are limited by the lack of scientific knowledge, robust data derived from large randomized clinical trials, and an accurate assessment of the bioactive components provided by common foodstuff. Because it is likely that clinical effects are the result of multiple interactions among different polyphenols rather than the isolated action of unique compounds, to provide polyphenol-rich botanical extracts as dietary supplements is a suggestive option. Unfortunately, the lack of patent perspectives for the pharmaceutical industries and the high cost of production and release for alimentary industries will hamper the performance of the necessary clinical trials. Here we briefly discuss whether and how such limitations may complicate the extensive use of plant-derived products in the management of hypertension and which steps are the necessary to deal with the predictable complexity in a possible clinical practice. PMID:25714729

  8. Effects of AT1 receptor antagonism on kainate-induced seizures and concomitant changes in hippocampal extracellular noradrenaline, serotonin, and dopamine levels in Wistar-Kyoto and spontaneously hypertensive rats.

    PubMed

    Tchekalarova, Jana; Loyens, Ellen; Smolders, Ilse

    2015-05-01

    In the management of epilepsy, AT1 receptor antagonists have been suggested as an additional treatment strategy. A hyperactive brain angiotensin (Ang) II system and upregulated AT1 receptors are implicated in the cerebrovascular alterations in a genetic form of hypertension. Uncontrolled hypertension could also, in turn, be a risk factor for a seizure threshold decrease and development of epileptogenesis. The present study aimed to assess the effects of the selective AT1 receptor antagonist ZD7155 on kainic acid (KA)-induced status epilepticus (SE) development and accompanying changes in the hippocampal extracellular (EC) neurotransmitter levels of noradrenaline (NAD), serotonin (5-HT), and dopamine (DA) in spontaneously hypertensive rats (SHRs) and their parent strain Wistar-Kyoto (WKY) rats, since monoamines are well-known neurotransmitters involved in mechanisms of both epilepsy and hypertension. Status epilepticus was evoked in freely moving rats by a repetitive intraperitoneal (i.p.) administration of KA in subconvulsant doses. In the treatment group, ZD7155 (5mg/kg i.p.) was coadministered with the first KA injection. Spontaneously hypertensive rats exhibited higher susceptibility to SE than WKY rats, but the AT1 receptor antagonist did not alter the development of SE in SHRs or in WKY rats. In vivo microdialysis demonstrated significant KA-induced increases of the hippocampal NAD and DA levels in SHRs and of NAD, 5-HT, and DA in WKY rats. Although SHRs developed more severe seizures while receiving a lower dose of KA compared to WKY rats, AT1 receptor antagonism completely prevented all KA-induced increases of hippocampal monoamine levels in both rat strains without affecting seizure development per se. These results suggest a lack of direct relationship between KA-induced seizure susceptibility and adaptive changes of hippocampal NAD, 5-HT, and DA levels in the effects of ZD7155 in WKY rats and SHRs. PMID:25922088

  9. Essential Hypertension vs. Secondary Hypertension Among Children

    PubMed Central

    Banker, Ashish; Shete, Sanjay; Hashmi, Syed Sharukh; Tyson, John E.; Barratt, Michelle S.; Hecht, Jacqueline T.; Milewicz, Diane M.; Boerwinkle, Eric

    2015-01-01

    BACKGROUND The aim was to determine the proportions and correlates of essential hypertension among children in a tertiary pediatric hypertension clinic. METHODS We evaluated 423 consecutive children and collected demographic and clinical history by retrospective chart review. RESULTS We identified 275 (65%) hypertensive children (blood pressure >95th percentile per the “Fourth Report on the Diagnosis, Evaluation, and Treatment of High Blood Pressure in Children and Adolescents”) from 423 children referred to the clinic for history of elevated blood pressure. The remainder of the patients had normotension (11%), white coat hypertension (11%), prehypertension (10%), and pending diagnosis (3%). Among the 275 hypertensive children, 43% (n = 119; boys = 56%; median age = 12 years; range = 3–17 years) had essential hypertension and 57% (n = 156; boys = 66%; median age = 9 years; range = 0.08–19 years) had secondary hypertension. When compared with those with secondary hypertension, those with essential hypertension had a significantly older age at diagnosis (P = 0.0002), stronger family history of hypertension (94% vs. 68%; P < 0.0001), and lower prevalence of preterm birth (20% vs. 46%; P < 0.001). There was a bimodal distribution of age of diagnosis in those with secondary hypertension. CONCLUSIONS The phenotype of essential hypertension can present as early as 3 years of age and is the predominant form of hypertension in children after age of 6 years. Among children with hypertension, those with essential hypertension present at an older age, have a stronger family history of hypertension, and have lower prevalence of preterm birth. PMID:24842390

  10. Losartan attenuates chronic cigarette smoke exposure-induced pulmonary arterial hypertension in rats: Possible involvement of angiotensin-converting enzyme-2

    SciTech Connect

    Han Suxia; He Guangming; Wang Tao; Chen Lei; Ning Yunye; Luo Feng; An Jin; Yang Ting; Dong Jiajia; Liao Zenglin; Xu Dan; Wen Fuqiang

    2010-05-15

    Chronic cigarette smoking induces pulmonary arterial hypertension (PAH) by largely unknown mechanisms. Renin-angiotensin system (RAS) is known to function in the development of PAH. Losartan, a specific angiotensin II receptor antagonist, is a well-known antihypertensive drug with a potential role in regulating angiotensin-converting enzyme-2 (ACE2), a recently found regulator of RAS. To determine the effect of losartan on smoke-induced PAH and its possible mechanism, rats were daily exposed to cigarette smoke for 6 months in the absence and in the presence of losartan. Elevated right ventricular systolic pressure (RVSP), thickened wall of pulmonary arteries with apparent medial hypertrophy along with increased angiotensin II (Ang II) and decreased ACE2 levels were observed in smoke-exposed-only rats. Losartan administration ameliorated pulmonary vascular remodeling, inhibited the smoke-induced RVSP and Ang II elevation and partially reversed the ACE2 decrease in rat lungs. In cultured primary pulmonary artery smooth muscle cells (PASMCs) from 3- and 6-month smoke-exposed rats, ACE2 levels were significantly lower than in those from the control rats. Moreover, PASMCs from 6-month exposed rats proliferated more rapidly than those from 3-month exposed or control rats, and cells grew even more rapidly in the presence of DX600, an ACE2 inhibitor. Consistent with the in vivo study, in vitro losartan pretreatment also inhibited cigarette smoke extract (CSE)-induced cell proliferation and ACE2 reduction in rat PASMCs. The results suggest that losartan may be therapeutically useful in the chronic smoking-induced pulmonary vascular remodeling and PAH and ACE2 may be involved as part of its mechanism. Our study might provide insight into the development of new therapeutic interventions for PAH smokers.

  11. [Effect of chrysin on expression of NOX4 and NF-κB in right ventricle of monocrotaline-induced pulmonary arterial hypertension of rats].

    PubMed

    Li, Xian-wei; Guo, Bo; Shen, Yuan-yuan; Yang, Jie-ren

    2015-09-01

    The aim of the present study is to investigate the protective effect of chrysin (5,7-dihydroxyflavone) on right ventricular remodeling in a rat model of monocrotaline-induced pulmonary arterial hypertension (PAH). PAH rats were induced by a single injection of monocrotaline (60 mg x kg(-1), sc) and were administered with chrysin (50 or 100 mg x kg(-1) x d(-1)) for 4 weeks. At the end of experiment, the right ventricular systolic pressure (RVSP) and mean pulmonary artery pressure (mPAP) were monitored via the right jugular vein catheterization into the right ventricle. Right ventricle (RV) to left ventricle (LV) + septum (S) and RV to tibial length were calculated. Right ventricular morphological change was observed by HE staining. Masson's trichrome stain was used to demonstrate collagen deposition. The total antioxidative capacity (T-AOC) and malondialdehyde (MDA) levels in right ventricle were determined according to the manufacturer's instructions. The expressions of collagen I, collagen III, NADPH oxidase 4 (NOX4) and nuclear factor-kappa B (NF-κB) were analyzed by immunohistochemisty, qPCR and (or) Western blot. The results showed that chrysin treatment for 4 weeks attenuated RVSP, mPAP and right ventricular remodeling index (RV/LV+S and RV/Tibial length) of PAH rats induced by monocrotaline. Furthermore, monocrotaline-induced right ventricular collagen accumulation and collagen I and collagen III expression were both significantly suppressed by chrysin. The expressions of NOX4, NF-κB and MDA contents were obviously decreased, while the T-AOC was significantly increased in right ventricule from PAH rats with chrysin treatment. These results suggest that chrysin ameliorates right ventricular remodeling of PAH induced by monocrotaline in rats through its down-regulating of NOX4 expression and antioxidant activity, and inhibiting NF-κB expression and collagen accumulation. PMID:26757549

  12. Increase in caveolae and caveolin-1 expression modulates agonist-induced contraction and store- and receptor-operated Ca(2+) entry in pulmonary arteries of pulmonary hypertensive rats.

    PubMed

    Jiao, Hai-Xia; Mu, Yun-Ping; Gui, Long-Xin; Yan, Fu-Rong; Lin, Da-Cen; Sham, James S K; Lin, Mo-Jun

    2016-09-01

    Caveolin-1 (Cav-1) is a major component protein associated with caveolae in the plasma membrane and has been identified as a regulator of store-operated Ca(2+) entry (SOCE) and receptor-operated Ca(2+) entry (ROCE). However, the contributions of caveolae/Cav-1 of pulmonary arterial smooth muscle cells (PASMCs) to the altered Ca(2+) signaling pathways in pulmonary arteries (PAs) during pulmonary hypertension (PH) have not been fully characterized. The present study quantified caveolae number and Cav-1 expression, and determined the effects of caveolae disruption on ET-1, cyclopiazonic acid (CPA) and 1-Oleoyl-2-acetyl-glycerol (OAG)-induced contraction in PAs and Ca(2+) influx in PASMCs of chronic hypoxia (CH)- and monocrotaline (MCT)-induced PH rats. We found that the number of caveolae, and the Cav-1 mRNA and protein levels were increased significantly in PASMCs in both PH models. Disruption of caveolae by cholesterol depletion with methyl-β-cyclodextrin (MβCD) significantly inhibited the contractile response to ET-1, CPA and OAG in PAs of control rats. ET-1, SOCE and ROCE-mediated contractile responses were enhanced, and their susceptibility to MβCD suppression was potentiated in the two PH models. MβCD-induced inhibition was reversed by cholesterol repletion. Introduction of Cav-1 scaffolding domain peptide to mimic Cav-1 upregulation caused significant increase in CPA- and OAG-induced Ca(2+) entry in PASMCs of control, CH and MCT-treated groups. Our results suggest that the increase in caveolae and Cav-1 expression in PH contributes to the enhanced agonist-induced contraction of PA via modulation of SOCE and ROCE; and targeting caveolae/Cav-1 in PASMCs may provide a novel therapeutic strategy for the treatment of PH. PMID:27311393

  13. [Hypertensive emergencies and urgencies].

    PubMed

    Reingardiene, Dagmara

    2005-01-01

    Hypertension is one of the most common medical problems affecting approximately 1 billion individuals worldwide. Severe hypertension that is a potentially life-threatening condition refers to a hypertensive crisis. Severe hypertension is further classified into hypertensive emergencies or hypertensive urgencies. Hypertensive emergency refers to a severe hypertension that is associated with new or progressive end-organ damage. In these clinical situations, blood pressure should be reduced immediately to prevent or minimize organ dysfunction. Hypertensive urgency refers to severe hypertension without evidence of new or worsening end-organ injury. Blood pressure can be lowered less rapidly in this condition. In this review article it is discussed about clinical assessment of patients under these conditions, evaluating neurological, cardiovascular, renal end-organ damage; how much blood pressure should be lowered, which medication should be used to lower blood pressure, treating hypertensive emergencies and urgencies; and management of specific conditions (acute intracranial events, acute left ventricular dysfunction etc). PMID:15998994

  14. Early Training-Induced Reduction of Angiotensinogen in Autonomic Areas—The Main Effect of Exercise on Brain Renin-Angiotensin System in Hypertensive Rats

    PubMed Central

    Chaar, Laiali Jurdi; Alves, Tatiana Pereira; Batista Junior, Alvaro Martins; Michelini, Lisete Compagno

    2015-01-01

    Background Exercise training (T) blunts functional deficits and renin-angiotensin system (RAS) hyperactivity in hypertensive individuals. There is no information on T-induced temporal changes of brain RAS. We evaluate now the simultaneous effects of T on functional responses and time course changes in the expression/activity of brain RAS components in autonomic cardiovascular-controlling areas. Methods and Results Spontaneously hypertensive rats (SHR) and age-matched normotensive controls (WKY) were trained for 0, 1, 2, 4, 8 and 12 weeks. Sedent