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Sample records for angiotensin-receptor blocker telmisartan

  1. Induction of human adiponectin gene transcription by telmisartan, angiotensin receptor blocker, independently on PPAR-{gamma} activation

    SciTech Connect

    Moriuchi, Akie ||. E-mail: f1195@cc.nagasaki-u-ac.jp; Shimamura, Mika; Kita, Atsushi; Kuwahara, Hironaga; Satoh, Tsuyoshi; Satoh, Tsuyoshi; Fujishima, Keiichiro; Fukushima, Keiko |; Hayakawa, Takao; Mizuguchi, Hiroyuki; Nagayama, Yuji; Kawasaki, Eiji

    2007-05-18

    Adiponectin, an adipose tissue-specific plasma protein, has been shown to ameliorate insulin resistance and inhibit the process of atherosclerosis. Recently, several reports have stated that angiotensin type 1 receptor blockers (ARBs), increase adiponectin plasma level, and ameliorate insulin resistance. Telmisartan, a subclass of ARBs, has been shown to be a partial agonist of the peroxisome proliferator-activated receptor (PPAR)-{gamma}, and to increase the plasma adiponectin level. However, the transcriptional regulation of the human adiponectin gene by telmisartan has not been determined yet. To elucidate the effect of telmisartan on adiponectin, the stimulatory regulation of human adiponectin gene by telmisartan was investigated in 3T3-L1 adipocytes, utilizing adenovirus-mediated luciferase reporter gene-transferring technique. This study indicates that telmisartan may stimulate adiponectin transcription independent of PPAR-{gamma}.

  2. Potential of the angiotensin receptor blockers (ARBs) telmisartan, irbesartan, and candesartan for inhibiting the HMGB1/RAGE axis in prevention and acute treatment of stroke.

    PubMed

    Kikuchi, Kiyoshi; Tancharoen, Salunya; Ito, Takashi; Morimoto-Yamashita, Yoko; Miura, Naoki; Kawahara, Ko-ichi; Maruyama, Ikuro; Murai, Yoshinaka; Tanaka, Eiichiro

    2013-09-13

    Stroke is a major cause of mortality and disability worldwide. The main cause of stroke is atherosclerosis, and the most common risk factor for atherosclerosis is hypertension. Therefore, antihypertensive treatments are recommended for the prevention of stroke. Three angiotensin receptor blockers (ARBs), telmisartan, irbesartan and candesartan, inhibit the expression of the receptor for advanced glycation end-products (RAGE), which is one of the pleiotropic effects of these drugs. High mobility group box 1 (HMGB1) is the ligand of RAGE, and has been recently identified as a lethal mediator of severe sepsis. HMGB1 is an intracellular protein, which acts as an inflammatory cytokine when released into the extracellular milieu. Extracellular HMGB1 causes multiple organ failure and contributes to the pathogenesis of hypertension, hyperlipidemia, diabetes mellitus, atherosclerosis, thrombosis, and stroke. This is the first review of the literature evaluating the potential of three ARBs for the HMGB1-RAGE axis on stroke therapy, including prevention and acute treatment. This review covers clinical and experimental studies conducted between 1976 and 2013. We propose that ARBs, which inhibit the HMGB1/RAGE axis, may offer a novel option for prevention and acute treatment of stroke. However, additional clinical studies are necessary to verify the efficacy of ARBs.

  3. Reappraisal of role of angiotensin receptor blockers in cardiovascular protection.

    PubMed

    Ram, C Venkata S

    2011-01-01

    Angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) have shown cardioprotective and renoprotective properties. These agents are recommended as first-line therapy for the treatment of hypertension and the reduction of cardiovascular risk. Early studies pointed to the cardioprotective and renoprotective effects of ARBs in high-risk patients. The ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial (ONTARGET) established the clinical equivalence of the cardioprotective and renoprotective effects of telmisartan and ramipril, but did not find an added benefit of the combination over ramipril alone. Similar findings were observed in the Telmisartan Randomized AssessmeNt Study in aCE INtolerant subjects with cardiovascular Disease (TRANSCEND) trial conducted in ACEI-intolerant patients. In ONTARGET, telmisartan had a better tolerability profile with similar renoprotective properties compared with ramipril, suggesting a potential clinical benefit over ramipril. The recently completed Olmesartan Reducing Incidence of Endstage Renal Disease in Diabetic Nephropathy Trial (ORIENT) and Olmesartan and Calcium Antagonists Randomized (OSCAR) studies will further define the role of ARBs in cardioprotection and renoprotection for high-risk patients.

  4. Angiotensin receptor blockers & endothelial dysfunction: Possible correlation & therapeutic implications

    PubMed Central

    Radenković, Miroslav; Stojanović, Marko; Nešić, Ivana Milićević; Prostran, Milica

    2016-01-01

    The endothelium is one of the most important constituents of vascular homeostasis, which is achieved through continual and balanced production of different relaxing and contractile factors. When there is a pathological disturbance in release of these products, endothelial dysfunction (ED) will probably occur. ED is considered to be the initial step in the development of atherosclerosis. This pathological activation and inadequate functioning of endothelial cells was shown to be to some extent a reversible process, which all together resulted in increased interest in investigation of different beneficial treatment options. To this point, the pharmacological approach, including for example, the use of angiotensin-converting enzyme inhibitors or statins, was clearly shown to be effective in the improvement of ED. One of many critical issues underlying ED represents instability in the balance between nitric oxide and angiotensin II (Ang II) production. Considering that Ang II was confirmed to be important for the development of ED, the aim of this review article was to summarize the findings of up to date clinical studies associated with therapeutic application of angiotensin receptor blockers and improvement in ED. In addition, it was of interest to review the pleiotropic actions of angiotensin receptor blockers linked to the improvement of ED. The prospective, randomized, double-blind, placebo or active-controlled clinical trials were identified and selected for the final evaluation. PMID:27934794

  5. Combination ACE inhibitor and angiotensin receptor blocker therapy - future considerations.

    PubMed

    Sica, Domenic A

    2007-01-01

    Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers are regularly prescribed for the management of hypertension. Each of these drug classes has also been shown to provide survival benefits for patients with heart failure, proteinuric chronic kidney disease, and/or a high cardiac risk profile. The individual gains seen with each of these drug classes have led to speculation that their combination might offer additive if not synergistic outcome benefits. The foundation of this hypothesis, although biologically possible, has thus far not been sufficiently well proven to support the everyday use of these 2 drug classes in combination. Additional outcomes trials, which are currently proceeding to their conclusion, may provide the necessary proof to support an expanded use of these 2 drug classes in combination.

  6. A retrospective study of the effects of angiotensin receptor blockers and angiotensin converting enzyme inhibitors in diabetic nephropathy

    PubMed Central

    Pathak, Jahnavi V.; Dass, Ervilla E.

    2015-01-01

    Objective: Till date, several studies have compared angiotensin converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) in terms of delaying the progression of diabetic nephropathy. But the superiority of one drug class over the other remains unsettled. This study has retrospectively compared the effects of ACE inhibitors and ARBs in diabetic nephropathy. The study aims to compare ACE inhibitors and ARBs in terms of delaying or preventing the progression of diabetic nephropathy, association between blood pressure (B.P) and urinary albumin and also B.P and serum creatinine with ACE inhibitor and ARB, know the percentage of hyperkalemia in patients of diabetic nephropathy receiving ACE inhibitor or ARB. Settings and Design: A total of 134 patients diagnosed with diabetic nephropathy during the years 2001–2010 and having a complete follow-up were studied, out of which 99 were on ARB (63 patients of Losartan and 36 of Telmisartan) and 35 on ACE inhibitor (Ramipril). Subjects and Methods: There was at least 1-month of interval between each observation made and also between the date of treatment started and the first reading that is, the observation of the 1st month. In total, three readings were taken that is, of the 1st, 2nd and 3rd month after the treatment started. Comparison of the 1st and 3rd month after the treatment started was done. Mean ± standard deviation, Paired t-test, and Chi-square were used for the analysis of the data. Results: The results reflect that ARBs (Losartan and Telmisartan) when compared to ACE inhibitor (Ramipril) are more effective in terms of delaying the progression of diabetic nephropathy and also in providing renoprotection. Also, ARBs have the property of simultaneously decreasing the systolic B.P and albuminuria when compared to ACE inhibitor (Ramipril). Conclusions: Angiotensin receptor blockers are more renoprotective than ACE inhibitors and also provide better cardioprotection. PMID:25878372

  7. Is there any difference between angiotensin converting enzyme inhibitors and angiotensin receptor blockers for heart failure?

    PubMed

    Rain, Carmen; Rada, Gabriel

    2015-07-06

    Angiotensin receptor blockers are usually considered as equivalent to angiotensin converting enzyme inhibitors for patients with heart failure and low-ejection fraction. Some guidelines even recommend the former as first line treatment given their better adverse effects profile. Searching in Epistemonikos database, which is maintained by screening 30 databases, we identified four systematic reviews including eight pertinent randomized controlled trials. We combined the evidence using meta-analysis and generated a summary of findings following the GRADE approach. We concluded angiotensin receptor blockers and angiotensin converting enzyme inhibitors probably have a similar effect on mortality, and they might be equivalent in reducing hospitalization risk too. Treatment withdrawal due to adverse effects is probably lower with angiotensin receptor blockers than with angiotensin converting enzyme inhibitors.

  8. Remission of post-transplant focal segmental glomerulosclerosis with angiotensin receptor blockers

    PubMed Central

    Bansal, S. B.; Sethi, S. K.; Jha, P.; Duggal, R.; Kher, V.

    2017-01-01

    Recurrence of focal segmental glomerulosclerosis (FSGS) is common after kidney transplantation. Plasmapheresis (PP) is considered to be the most effective treatment; however, results are variable and relapse is common after stopping plasmapheresis. Here, we report an unusual case of recurrent FSGS, who achieved complete remission with angiotensin receptor blocker therapy.

  9. Postnatal acute renal failure after fetal exposure to angiotensin receptor blockers.

    PubMed

    Marchetto, Luca; Sordino, Desiree; De Bernardo, Giuseppe; Trevisanuto, Daniele

    2015-07-02

    Maternal hypertensive treatment with angiotensin receptor blockers (ARBs) during the second and third trimester of pregnancy is associated with several fetal and neonatal complications, and potential adverse outcomes. We report a neonate presenting with transient renal acute failure during the first days of life after maternal treatment with ARBs. Women who became pregnant while taking one of these drugs must modify antihypertensive therapy with a different class drug as soon as pregnancy is recognised.

  10. Treating the Host Response to Ebola Virus Disease with Generic Statins and Angiotensin Receptor Blockers

    PubMed Central

    Jacobson, Jeffrey R.; Rordam, Ole Martin; Opal, Steven M.

    2015-01-01

    ABSTRACT Treatments targeting the Ebola virus may eventually be shown to work, but they will not have an impact on overall Ebola mortality in West Africa. Endothelial dysfunction is responsible for the fluid and electrolyte imbalances seen in Ebola patients. Because inexpensive generic statins and angiotensin receptor blockers restore endothelial barrier integrity, they can be used to treat the host response in these patients. In Sierra Leone, approximately 100 Ebola patients were treated with this combination, and reports indicate that survival was greatly improved. PMID:26106080

  11. Angiotensin converting enzyme inhibitors and angiotensin receptor blockers in the treatment of hypertension: should they be used together?

    PubMed

    Verdecchia, Paolo; Angeli, Fabio; Mazzotta, Giovanni; Ambrosio, Giuseppe; Reboldi, Gianpaolo

    2010-11-01

    The combined use of angiotensin converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) poses a dilemma to clinicians. On the one hand, indirect evidence from compelling, but still surrogate outcome measures such as blood pressure and proteinuria suggest some merits of this combination. On the other hand, the outcome benefits of the ACEIs+ARBs combination in morbidity/mortality trials remain confined to patients with severe congestive heart failure (CHF) and reduced ejection fraction. Incidentally, most of the benefit offered by the ACEIs+ARBs combination in these patients was not driven by mortality, but by fewer rehospitalizations for CHF. Even in patients with renal disease and proteinuria, the combined use of ACEIs and ARBs, although highly effective in reducing urinary protein excretion, has not yet been proven to significantly delay end-stage renal disease and the need for dialysis. In the Ongoing Telmisartan Alone and In Combination With Ramipril Global Endpoint Trial (ONTARGET), the dual blockade of the renin angiotensin system did not produce additional outcome benefit over that afforded by ACE inhibition alone. Notably, however, patients with BP >160/100 mmHg at entry were excluded from ONTARGET, thus limiting the applicability of these results to the treatment of hypertension. The European Society of Hypertension guidelines do not suggest large-scale use of the ACEIs+ARBs combination in patients with hypertension. However, patients with resistant hypertension, particularly if proteinuria coexists, could benefit from this combination, which however requires close monitoring for adverse events, including hyperkalemia and worsening renal function.

  12. [Analysis of the Cochrane Review: Angiotensin Converging Enzyme Inhibitors Versus Angiotensin Receptor Blockers for Primary Hypertension. Cochrane Database Syst Rev. 2014,8: CD009096].

    PubMed

    Nogueira-Silva, Luís; Fonseca, João A

    2015-01-01

    Angiotensin converting enzyme inhibitors and angiotensin receptor blockers are first line drugs in the treatment of hypertension. The aim of this review was to assess if there are differences between these drug classes regarding the prevention of total mortality, occurrence of cardiovascular events and of adverse effects. A systematic review and metanalysis was performed, searching for studies that compare angiotensin converting enzyme inhibitors and angiotensin receptor blockers face-to-face, in several databases until July 2014. The study selection and data extraction were performed by 2 independent researchers. Nine studies were included, with a total of 10 963 participants, 9 398 of which participated in the same study and had high cardiovascular risk. No differences were observed regarding total mortality, cardiovascular mortality or total cardiovascular events. A slightly smaller risk was observed with angiotensin receptor blockers regarding withdrawal due to adverse effects (55 people were needed to be treated with angiotensin receptor blockers for 4.1 years to avoid one withdrawal due to adverse effect), mainly due to the occurrence of dry cough with angiotensin converting enzyme inhibitors. Thus, no differences were observed between angiotensin converting enzyme inhibitors and angiotensin receptor blockers in the prevention of total mortality and cardiovascular events, and angiotensin receptor blockers were better tolerated. Given the large proportion of participants with a high cardiovascular risk, the generalization of these results to other populations is limited.

  13. Moderation of dietary sodium potentiates the renal and cardiovascular protective effects of angiotensin receptor blockers.

    PubMed

    Lambers Heerspink, Hiddo J; Holtkamp, Frank A; Parving, Hans-Henrik; Navis, Gerjan J; Lewis, Julia B; Ritz, Eberhard; de Graeff, Pieter A; de Zeeuw, Dick

    2012-08-01

    Dietary sodium restriction has been shown to enhance the short-term response of blood pressure and albuminuria to angiotensin receptor blockers (ARBs). Whether this also enhances the long-term renal and cardiovascular protective effects of ARBs is unknown. Here we conducted a post-hoc analysis of the RENAAL and IDNT trials to test this in patients with type 2 diabetic nephropathy randomized to ARB or non-renin-angiotensin-aldosterone system (non-RAASi)-based antihypertensive therapy. Treatment effects on renal and cardiovascular outcomes were compared in subgroups based on dietary sodium intake during treatment, measured as the 24-h urinary sodium/creatinine ratio of 1177 patients with available 24-h urinary sodium measurements. ARB compared to non-RAASi-based therapy produced the greatest long-term effects on renal and cardiovascular events in the lowest tertile of sodium intake. Compared to non-RAASi, the trend in risk for renal events was significantly reduced by 43%, not changed, or increased by 37% for each tertile of increased sodium intake, respectively. The trend for cardiovascular events was significantly reduced by 37%, increased by 2% and 25%, respectively. Thus, treatment effects of ARB compared with non-RAASi-based therapy on renal and cardiovascular outcomes were greater in patients with type 2 diabetic nephropathy with lower than higher dietary sodium intake. This underscores the avoidance of excessive sodium intake, particularly in type 2 diabetic patients receiving ARB therapy.

  14. Angiotensin-Receptor Blocker, Angiotensin-Converting Enzyme Inhibitor, and Risks of Atrial Fibrillation

    PubMed Central

    Hsieh, Yu-Cheng; Hung, Chen-Ying; Li, Cheng-Hung; Liao, Ying-Chieh; Huang, Jin-Long; Lin, Ching-Heng; Wu, Tsu-Juey

    2016-01-01

    Abstract Both angiotensin-receptor blockers (ARB) and angiotensin-converting enzyme inhibitors (ACEI) have protective effects against atrial fibrillation (AF). The differences between ARB and ACEI in their effects on the primary prevention of AF remain unclear. This study compared ARB and ACEI in combined antihypertensive medications for reducing the risk of AF in patients with hypertension, and determined which was better for AF prevention in a nationwide cohort study. Patients aged ≥55 years and with a history of hypertension were identified from Taiwan National Health Insurance Research Database. Medical records of 25,075 patients were obtained, and included 6205 who used ARB, 8034 who used ACEI, and 10,836 nonusers (no ARB or ACEI) in their antihypertensive regimen. Cox regression models were applied to estimate the hazard ratio (HR) for new-onset AF. During an average of 7.7 years’ follow-up, 1619 patients developed new-onset AF. Both ARB (adjusted HR: 0.51, 95% CI 0.44–0.58, P < 0.001) and ACEI (adjusted HR: 0.53, 95% CI 0.47–0.59, P < 0.001) reduced the risk of AF compared to nonusers. Subgroup analysis showed that ARB and ACEI were equally effective in preventing new-onset AF regardless of age, gender, the presence of heart failure, diabetes, and vascular disease, except for those with prior stroke or transient ischemic attack (TIA). ARB prevents new-onset AF better than ACEI in patients with a history of stroke or TIA (log-rank P = 0.012). Both ARB and ACEI reduce new-onset AF in patients with hypertension. ARB prevents AF better than ACEI in patients with a history of prior stroke or TIA. PMID:27196491

  15. ACE Inhibitor and Angiotensin Receptor Blocker Use and Mortality in Patients with Chronic Kidney Disease

    PubMed Central

    Molnar, Miklos Z; Kalantar-Zadeh, Kamyar; Lott, Evan H; Lu, Jun Ling; Malakauskas, Sandra M; Ma, Jennie Z; Quarles, Darryl L; Kovesdy, Csaba P

    2014-01-01

    Objective To assess the association between ACEI/ARB use and mortality in CKD patients. Background There is insufficient evidence about the association of angiotensin converting enzyme inhibitors (ACEI) or angiotensin receptor blockers (ARBs) with mortality in chronic kidney disease (CKD) patients. Methods A logistic regression analysis was used to calculate the propensity of ACEI/ARB initiation in 141,413 US veterans with non-dialysis CKD previously unexposed to ACEI/ARB treatment. We examined the association of ACEI/ARB administration with all-cause mortality in patients matched by propensity scores, using the Kaplan-Meier method and Cox models in “intention-to-treat” analyses, and in generalized linear models with binary outcomes and inverse probability treatment weighing (IPTW) in “as-treated” analyses. Results The mean±SD age of the patients at baseline was 75±10 years, 8% of patients were black, and 22% were diabetic. ACEI/ARB administration was associated with significantly lower risk of mortality both in the intention-to-treat analysis (HR=0.81; 95%CI: 0.78-0.84, p<0.001) and in the as-treated analysis with IPTW (OR=0.37; 95%CI: 0.34-0.41, p<0.001). The association of ACEI/ARB treatment with lower risk of mortality was present in all examined subgroups. Conclusions In this large contemporary cohort of non-dialysis dependent CKD patients, ACEI/ARB administration was associated with greater survival. PMID:24269363

  16. The comparative efficacy and safety of the angiotensin receptor blockers in the management of hypertension and other cardiovascular diseases.

    PubMed

    Abraham, Hazel Mae A; White, C Michael; White, William B

    2015-01-01

    All national guidelines for the management of hypertension recommend angiotensin receptor blockers (ARBs) as an initial or add-on antihypertensive therapy. The eight available ARBs have variable clinical efficacy when used for control of hypertension. Additive blood pressure-lowering effects have been demonstrated when ARBs are combined with thiazide diuretics or dihydropyridine calcium channel blockers, augmenting hypertension control. Furthermore, therapeutic use of ARBs goes beyond their antihypertensive effects, with evidence-based benefits in heart failure and diabetic renal disease particularly among angiotensin-converting enzyme inhibitor-intolerant patients. On the other hand, combining renin-angiotensin system blocking agents, a formerly common practice among medical subspecialists focusing on the management of hypertension, has ceased, as there is not only no evidence of cardiovascular benefit but also modest evidence of harm, particularly with regard to renal dysfunction. ARBs are very well tolerated as monotherapy, as well as in combination with other antihypertensive medications, which improve adherence to therapy and have become a mainstay in the treatment of stage 1 and stage 2 hypertension.

  17. Clinic and Home Blood Pressure Lowering Effect of an Angiotensin Receptor Blocker, Fimasartan, in Postmenopausal Women with Hypertension

    PubMed Central

    Kim, Song-Yi; Joo, Seung-Jae; Shin, Mi-Seung; Kim, Changsoo; Cho, Eun Joo; Sung, Ki-Chul; Kang, Seok-Min; Kim, Dong-Soo; Lee, Seung Hwan; Hwang, Kyung-Kuk; Park, Jeong Bae

    2016-01-01

    Abstract Angiotensin receptor blockers may be an appropriate first-line agent for postmenopausal women with hypertension because the activation of renin–angiotensin–aldosterone system is suggested as one possible mechanism of postmenopausal hypertension. However, there are few studies substantiating this effect. This study aimed to investigate clinic and home blood pressure (BP) lowering effect of fimasartan, a new angiotensin receptor blocker, in postmenopausal women with hypertension. Among patients with hypertension enrolled in K-Mets Study, 1373 women with fimasartan as a first antihypertensive drug and 3-months follow-up data were selected. They were divided into 2 groups; premenopausal women (pre-MPW; n = 382, 45.3 ± 4.6 years) and postmenopausal women (post-MPW; n = 991, 60.9 ± 8.2 years). Baseline clinic systolic BP was not different (pre-MPW; 152.9 ± 15.2 vs. post-MPW; 152.8 ± 13.5 mm Hg), but diastolic BP was lower in post-MPW (pre-MPW; 95.7 ± 9.4 vs. post-MPW; 91.9 ± 9.4 mm Hg, P <0.001). After 3-month treatment, clinic BP declined effectively without significant differences between 2 groups (Δsystolic/diastolic BP: pre-MPW; −25.7 ± 17.7/−14.2 ± 11.3 vs. post-MPW; −25.7 ± 16.3/−13.1 ± 10.9 mm Hg). Home morning and evening systolic BP decreased similarly in both groups (Δmorning/evening systolic BP: pre-MPW; −21.3 ± 17.9/−23.1 ± 15.8 vs. post-MPW; −20.4 ± 17.3/−20.2 ± 19.2 mm Hg). Fimasartan also significantly decreased the standard deviations of home morning and evening systolic BP of pre-MPW and post-MPW. Fimasartan was a similarly effective BP lowering agent in both post-MPW and pre-MPW with hypertension, and it also decreased day-to-day BP variability. PMID:27258507

  18. Influence of initial angiotensin receptor blockers on treatment persistence in uncomplicated hypertension: A nation-wide population-based study.

    PubMed

    Ah, Young-Mi; Lee, Ju-Yeun; Choi, Yun-Jung; Kong, Jisun; Kim, Baegeum; Choi, Kyung Hee; Han, Nayoung; Yu, Yun Mi; Oh, Jung Mi; Shin, Wan Gyoon; Lee, Hae-Young

    2016-01-01

    We identified 55 504 uncomplicated, treatment-naïve hypertensive patients who started angiotensin II receptor blockers (ARBs) in 2012 from national claims data. The proportion of patients remaining on any hypertension treatment at 12 months and the adherence rate were similar between the losartan cohort (66.82% and 68.25%) and the nonlosartan ARB cohort (67.48% and 69.01%). After adjusting for confounding factors, there was no difference in persistence (aHR 0.98, 95% confidence interval (CI) 0.95-1.01) on hypertension treatment between losartan and nonlosartan ARB cohort. Post hoc analysis showed that patients initially prescribed eprosartan, irbesartan (both, aHR 1.33), and telmisartan (aHR 1.11) were more likely to discontinue the initial drug, whereas valsartan initiators (aHR 0.96) were less likely compared with losartan initiators.

  19. Cardiovascular risk reduction in hypertension: angiotensin-converting enzyme inhibitors, angiotensin receptor blockers. Where are we up to?

    PubMed

    Sindone, A; Erlich, J; Lee, C; Newman, H; Suranyi, M; Roger, S D

    2016-03-01

    Previously, management of hypertension has concentrated on lowering elevated blood pressure. However, the target has shifted to reducing absolute cardiovascular (CV) risk. It is estimated that two in three Australian adults have three or more CV risk factors at the same time. Moderate reductions in several risk factors can, therefore, be more effective than major reductions in one. When managing hypertension, therapy should be focused on medications with the strongest evidence for CV event reduction, substituting alternatives only when a primary choice is not appropriate. Hypertension management guidelines categorise angiotensin-converting enzyme inhibitors (ACEI) and angiotensin receptor blockers (ARB) interchangeably as first-line treatments in uncomplicated hypertension. These medications have different mechanisms of action and quite different evidence bases. They are not interchangeable and their prescription should be based on clinical evidence. Despite this, currently ARB prescriptions are increasing at a higher rate than those for ACEI and other antihypertensive classes. Evidence that ACEI therapy prevents CV events and death, in patients with coronary artery disease or multiple CV risk factors, emerged from the European trial on reduction of cardiac events with perindopril in stable coronary artery disease (EUROPA) and Heart Outcomes Prevention Evaluation (HOPE) trials respectively. The consistent benefit has been demonstrated in meta-analyses. The clinical trial data for ARB are less consistent, particularly regarding CV outcomes and mortality benefit. The evidence supports the use of ACEI (Class 1a) compared with ARB despite current prescribing trends.

  20. Angiotensin receptor blocker drugs and inhibition of adrenal beta-arrestin-1-dependent aldosterone production: Implications for heart failure therapy

    PubMed Central

    Lymperopoulos, Anastasios; Aukszi, Beatrix

    2017-01-01

    Aldosterone mediates many of the physiological and pathophysiological/cardio-toxic effects of angiotensin II (AngII). Its synthesis and secretion from the zona glomerulosa cells of the adrenal cortex, elevated in chronic heart failure (HF), is induced by AngII type 1 receptors (AT1Rs). The AT1R is a G protein-coupled receptor, mainly coupling to Gq/11 proteins. However, it can also signal through β-arrestin-1 (βarr1) or -2 (βarr2), both of which mediate G protein-independent signaling. Over the past decade, a second, Gq/11 protein-independent but βarr1-dependent signaling pathway emanating from the adrenocortical AT1R and leading to aldosterone production has become appreciated. Thus, it became apparent that AT1R antagonists that block both pathways equally well are warranted for fully effective aldosterone suppression in HF. This spurred the comparison of all of the currently marketed angiotensin receptor blockers (ARBs, AT1R antagonists or sartans) at blocking activation of the two signaling modes (G protein-, and βarr1-dependent) at the AngII-activated AT1R and hence, at suppression of aldosterone in vitro and in vivo. Although all agents are very potent inhibitors of G protein activation at the AT1R, candesartan and valsartan were uncovered to be the most potent ARBs at blocking βarr activation by AngII and at suppressing aldosterone in vitro and in vivo in post-myocardial infarction HF animals. In contrast, irbesartan and losartan are virtually G protein-“biased” blockers at the human AT1R, with very low efficacy for βarr inhibition and aldosterone suppression. Therefore, candesartan and valsartan (and other, structurally similar compounds) may be the most preferred ARB agents for HF pharmacotherapy, as well as for treatment of other conditions characterized by elevated aldosterone.

  1. Differences in the clinical effects of angiotensin-converting enzyme inhibitors and Angiotensin receptor blockers: a critical review of the evidence.

    PubMed

    Dézsi, Csaba András

    2014-06-01

    The renin-angiotensin-aldosterone system plays a major role in the pathophysiology of hypertension and closely related cardio- and cerebrovascular events. Although both angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor antagonists (angiotensin receptor blockers; ARBs) are equally important in the treatment of hypertension, according to the results of recent years, there might be substantial differences in their cardiovascular protective effects, and these differences might be explained by our increasing knowledge of their non-overlapping mechanisms of action. The number of studies investigating how ACE inhibitors and ARB agents differ will certainly be increasing in the future. ACE inhibitors are the safe therapeutic opportunity for hypertensive patients at high risk, with a cardiological comorbidity.

  2. Aliskiren in Patients Failing to Achieve Blood Pressure Targets With Angiotensin Converting Enzyme Inhibitors or Angiotensin Receptor Blockers

    PubMed Central

    Hawkins, Elizabeth B.; Ling, Hua; Burns, Tammy L.; Mooss, Aryan N.; Hilleman, Daniel E.

    2012-01-01

    Background To assess the efficacy of aliskiren in patients failing to reach blood pressure (BP) goals with angiotensin converting enzyme inhibitor (ACEI) or angiotensin receptor blocker (ARB). Methods A total of 107 patients who failed to reach BP goals on ACEI or ARB were switched to aliskiren. Changes in BP were determined during maximal ACEI, ARB, or aliskiren therapy. Results Mean reduction in sBP and dBP with ACEI was 8.5 ± 6.3 mmHg and 6.0 ± 4.7 mmHg, respectively. Mean reduction in sBP and dBP with ARB was 8.3 ± 6.7 mmHg and 5.0 ± 5.2 mmHg, respectively. Mean reduction in sBP and dBP with aliskiren 150 mg/d was 6.7 ± 5.4 mmHg and 5.4 ± 4.8 mmHg, respectively. Mean reduction in sBP and dBP with aliskiren 300 mg/d was 8.6 ± 6.3 mmHg and 6.0 ± 4.9 mmHg, respectively. BP reductions between ACEI, ARB, and aliskiren were not significantly different. Conclusions Aliskiren is ineffective in patients failing ACEI or ARB therapy. Given the label changes restricting the use of aliskiren in combination with ACEI and ARB, excess cost compared to ACEI and ARB, and a paucity of outcome data, there is a limited role for aliskiren in practice.

  3. Initial reduction of oxidative stress by angiotensin receptor blocker contributes long term outcomes after percutaneous coronary intervention

    PubMed Central

    Noro, Tadanori; Takehara, Naofumi; Sumitomo, Kazuhiro; Takeuchi, Toshiharu; Ishii, Yoshinao; Kato, Jun-ichi; Kawabe, Jun-ichi; Hasebe, Naoyuki

    2014-01-01

    Background: It remains unclear whether administration of ARB with reactive oxygen species (ROS) scavenging effects improves the prognosis of patients undergoing PCI. Objectives: This study investigated whether the pre-intervention antioxidant effect of angiotensin receptor blocker (ARB) affects long-term outcomes in patients after successful percutaneous coronary intervention (PCI) without early adverse events. Methods: Fifty-two patients who underwent elective PCI were randomly assigned for treatment with or without ARB, which was administered within 48 hours before PCI. ROS levels in mononuclear cells (MNCs) and serum superoxide dismutase (SOD) activity were measured pre-PCI and 6 months post-PCI. After exclusion of unexpected early adverse events during angiographic follow-up period, the long-term outcome (major adverse cerebro-cardiovascular event; MACCE) was assessed in eligible patients. Results: Forty-three patients (non-ARB n = 22, ARB n = 21) were followed up in this study. During angiographic follow-up period, ROS formation in MNCs was significantly increased in the non-ARB group (from 29.4 [21.6-35.2] to 37.2 [30.7-45.1] arbitrary units; p = 0.031) compared to that in the ARB group. Meanwhile, SOD activity was significantly impaired in the non-ARB group alone (from 24.0 ± 17.0 to 16.3 ± 13.8%, p = 0.004). During the follow-up period (median, 63.3 months), MACCEs were observed in 6 patients. The cumulative event ratio of MACCE was significantly higher in the non-ARB group than in the ARB group (p = 0.018). Conclusions: Concomitant administration of ARB effectively reduced ROS production of PCI patients during angiographic follow-up period. Initial ROS inhibition following ARB administration may contribute to improvement of worse outcomes in patients who have undergone successful PCI. PMID:25628957

  4. The renal protective effect of angiotensin receptor blockers depends on intra-individual response variation in multiple risk markers

    PubMed Central

    Schievink, Bauke; de Zeeuw, Dick; Parving, Hans-Henrik; Rossing, Peter; Lambers Heerspink, Hiddo Jan

    2015-01-01

    Aims Angiotensin receptor blockers (ARBs) are renoprotective and targeted to blood pressure. However, ARBs have multiple other (off-target) effects which may affect renal outcome. It is unknown whether on-target and off-target effects are congruent within individuals. If not, this variation in short term effects may have important implications for the prediction of individual long term renal outcomes. Our aim was to assess intra-individual variability in multiple parameters in response to ARBs in type 2 diabetes. Methods Changes in systolic blood pressure (SBP), albuminuria, potassium, haemoglobin, cholesterol and uric acid after 6 months of losartan treatment were assessed in the RENAAL database. Improvement in predictive performance of renal outcomes (ESRD or doubling serum creatinine) for each individual using ARB-induced changes in all risk markers was assessed by the relative integrative discrimination index (RIDI). Results SBP response showed high variability (mean –5.7 mmHg, 5th to 95th percentile –36.5 to +24.0 mmHg) between individuals. Changes in off-target parameters also showed high variability between individuals. No congruency was observed between responses to losartan in multiple parameters within individuals. Using individual responses in all risk markers significantly improved renal risk prediction (RIDI 30.4%, P < 0.01) compared with using only SBP changes. Results were successfully replicated in two independent trials with irbesartan, IDNT and IRMA-2. Conclusions In this post hoc analysis we showed that ARBs have multiple off-target effects which vary between and within individuals. Combining all ARB-induced responses beyond SBP provides a more accurate prediction of who will benefit from ARB therapy. Prospective trials are required to validate these findings. PMID:25872610

  5. The angiotensin receptor blocker losartan reduces coronary arteriole remodeling in type 2 diabetic mice.

    PubMed

    Husarek, Kathryn E; Katz, Paige S; Trask, Aaron J; Galantowicz, Maarten L; Cismowski, Mary J; Lucchesi, Pamela A

    2016-01-01

    Cardiovascular complications are a leading cause of morbidity and mortality in type 2 diabetes mellitus (T2DM) and are associated with alterations of blood vessel structure and function. Although endothelial dysfunction and aortic stiffness have been documented, little is known about the effects of T2DM on coronary microvascular structural remodeling. The renin-angiotensin-aldosterone system plays an important role in large artery stiffness and mesenteric vessel remodeling in hypertension and T2DM. The goal of this study was to determine whether the blockade of AT1R signaling dictates vascular smooth muscle growth that partially underlies coronary arteriole remodeling in T2DM. Control and db/db mice were given AT1R blocker losartan via drinking water for 4 weeks. Using pressure myography, we found that coronary arterioles from 16-week db/db mice undergo inward hypertrophic remodeling due to increased wall thickness and wall-to-lumen ratio with a decreased lumen diameter. This remodeling was accompanied by decreased elastic modulus (decreased stiffness). Losartan treatment decreased wall thickness, wall-to-lumen ratio, and coronary arteriole cell number in db/db mice. Losartan treatment did not affect incremental elastic modulus. However, losartan improved coronary flow reserve. Our data suggest that Ang II-AT1R signaling mediates, at least in part, coronary arteriole inward hypertrophic remodeling in T2DM without affecting vascular mechanics, further suggesting that targeting the coronary microvasculature in T2DM may help reduce cardiac ischemic events.

  6. Renin-angiotensin-aldosterone system inhibition: overview of the therapeutic use of angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, mineralocorticoid receptor antagonists, and direct renin inhibitors.

    PubMed

    Mercier, Kelly; Smith, Holly; Biederman, Jason

    2014-12-01

    Angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) therapy in hypertensive diabetic patients with macroalbuminuria, microalbuminuria, or normoalbuminuria has been repeatedly shown to improve cardiovascular mortality and reduce the decline in glomerular filtration rate. Renin-angiotensin-aldosterone system (RAAS) blockade in normotensive diabetic patients with normoalbuminuria or microalbuminuria cannot be advocated at present. Dual RAAS inhibition with ACE inhibitors plus ARBs or ACE inhibitors plus direct renin inhibitors has failed to improve cardiovascular or renal outcomes but has predisposed patients to serious adverse events.

  7. Renoprotective effect and cost-effectiveness of using benidipine, a calcium channel blocker, to lower the dose of angiotensin receptor blocker in hypertensive patients with albuminuria.

    PubMed

    Saito, Fumio; Fujita, Hirotaka; Takahashi, Atsuhiko; Ichiyama, Izumi; Harasawa, Shinsuke; Oiwa, Kouji; Takahashi, Naoyuki; Otsuka, Yuji; Uchiyama, Takashi; Kanmatsuse, Katsuo; Kushiro, Toshio

    2007-01-01

    In hypertensive patients with chronic renal disease, angiotensin receptor blockers (ARBs) are among the first-line drugs, and calcium channel blockers (CCBs) are recommended as a second line. We examined the effects of two therapeutic strategies using ARBs and benidipine, a CCB, on blood pressure (BP), urinary albumin excretion (UAE), and cost-effectiveness in hypertensive patients with albuminuria. Patients whose BP was 140/90 mmHg or higher despite treatment with low- or medium-dose ARBs were assigned randomly to two groups. In Group A (n=14), the ARB dose was maximized and then benidipine was added until BP targets were reached (<130/85 mmHg). In Group B (n=18), benidipine was administered first and then the ARB dose was increased until BP targets were reached. The BP targets were achieved by ARB alone in 36% of Group A patients and by the addition of benidipine in 83% of Group B patients. Finally, BP decreased in each group, reaching the targets in 93% of Group A patients and 94% of Group B patients after a 4-month therapeutic period. UAE was decreased in both groups after a 4-month therapeutic period compared to the allocation period (-33+/-6% in Group A, -31+/-6% in Group B; p<0.001, respectively). The monthly drug cost was higher (11,426+/-880 vs. 8,955+/-410 yen, p=0.012) and the cost-effectiveness of antihypertensive treatment was lower (p=0.003) in Group A than in Group B. We conclude that the addition of benidipine to low- or medium-dose ARB is, in light of the renal protection and the cost-effectiveness of this approach, a useful therapeutic strategy for controlling BP in hypertensive patients with albuminuria.

  8. Angiotensin Converting-Enzyme Inhibitors, Angiotensin Receptor Blockers, and Calcium Channel Blockers Are Associated with Prolonged Vascular Access Patency in Uremic Patients Undergoing Hemodialysis

    PubMed Central

    Chen, Yu-Wei; Wu, Yu-Te; Lin, Chih-Ching

    2016-01-01

    Background Vascular access failure is a huge burden for patients undergoing hemodialysis. Many efforts have been made to maintain vascular access patency, including pharmacotherapy. Angiotensin converting enzyme inhibitor (ACE-I), angiotensin receptor blocker (ARB), and calcium channel blocker (CCB) are known for their antihypertensive and cardio-protective effects, however, their effects on long-term vascular access patency are still inconclusive. Design, setting, participants and measurements We retrospectively enrolled patients commencing maintenance hemodialysis between January 1, 2000, and December 31, 2006 by using National Health Insurance Research Database in Taiwan. Primary patency was defined as the date of first arteriovenous fistula (AVF) or arteriovenous graft (AVG) creation to the time of access thrombosis or any intervention aimed to maintain or re-establish vascular access patency. Cox proportional hazards models were used to adjust the influences of patient characteristics, co-morbidities and medications. Results Total 42244 patients were enrolled in this study, 37771 (89.4%) used AVF, 4473 (10.6%) used AVG as their first long term dialysis access. ACE-I, ARB, and CCB use were all associated with prolonged primary patency of AVF [hazard ratio (HR) 0.586, 95% confidence interval (CI) 0.557–0.616 for ACE-I use; HR 0.532, CI 0.508–0.556 for ARB use; HR 0.485, CI 0.470–0.501 for CCB use] and AVG (HR 0.557, CI 0.482–0.643 for ACE-I use, HR 0.536, CI 0.467–0.614 for ARB use, HR 0.482, CI 0.442–0.526 for CCB use). Conclusions In our analysis, ACE-I, ARB, and CCB were strongly associated with prolonged primary patency of both AVF and AVG. Further prospective randomized studies are still warranted to prove the causality. PMID:27832203

  9. Rationale and study design of the Prospective comparison of Angiotensin Receptor neprilysin inhibitor with Angiotensin receptor blocker MEasuring arterial sTiffness in the eldERly (PARAMETER) study

    PubMed Central

    Williams, Bryan; Cockcroft, John R; Kario, Kazuomi; Zappe, Dion H; Cardenas, Pamela; Hester, Allen; Brunel, Patrick; Zhang, Jack

    2014-01-01

    Introduction Hypertension in elderly people is characterised by elevated systolic blood pressure (SBP) and increased pulse pressure (PP), which indicate large artery ageing and stiffness. LCZ696, a first-in-class angiotensin receptor neprilysin inhibitor (ARNI), is being developed to treat hypertension and heart failure. The Prospective comparison of Angiotensin Receptor neprilysin inhibitor with Angiotensin receptor blocker MEasuring arterial sTiffness in the eldERly (PARAMETER) study will assess the efficacy of LCZ696 versus olmesartan on aortic stiffness and central aortic haemodynamics. Methods and analysis In this 52-week multicentre study, patients with hypertension aged ≥60 years with a mean sitting (ms) SBP ≥150 to <180 and a PP>60 mm Hg will be randomised to once daily LCZ696 200 mg or olmesartan 20 mg for 4 weeks, followed by a forced-titration to double the initial doses for the next 8 weeks. At 12–24 weeks, if the BP target has not been attained (msSBP <140  and ms diastolic BP <90 mm Hg), amlodipine (2.5–5 mg) and subsequently hydrochlorothiazide (6.25–25 mg) can be added. The primary and secondary endpoints are changes from baseline in central aortic systolic pressure (CASP) and central aortic PP (CAPP) at week 12, respectively. Other secondary endpoints are the changes in CASP and CAPP at week 52. A sample size of 432 randomised patients is estimated to ensure a power of 90% to assess the superiority of LCZ696 over olmesartan at week 12 in the change from baseline of mean CASP, assuming an SD of 19 mm Hg, the difference of 6.5 mm Hg and a 15% dropout rate. The primary variable will be analysed using a two-way analysis of covariance. Ethics and dissemination The study was initiated in December 2012 and final results are expected in 2015. The results of this study will impact the design of future phase III studies assessing cardiovascular protection. Clinical trials identifier EUDract number 2012

  10. Meta-analysis of the efficacy and safety of adding an angiotensin receptor blocker (ARB) to a calcium channel blocker (CCB) following ineffective CCB monotherapy

    PubMed Central

    Ma, Jin; Wang, Xiao-Yan; Hu, Zhi-De; Zhou, Zhi-Rui; Schoenhagen, Paul

    2015-01-01

    Background We conducted this meta-analysis to systematically review and analyze the clinical benefits of angiotensin receptor blocker (ARB) combined with calcium channel blocker (CCB) following ineffective CCB monotherapy. Methods PubMed was searched for articles published until August 2015. Randomized controlled trials (RCTs) evaluating the clinical benefits of ARB combined with CCB following ineffective CCB monotherapy were included. The primary efficacy endpoint of the studies was normal rate of blood pressure, the secondary efficacy endpoints were the response rate and change in blood pressure from baseline. The safety endpoint of the studies was incidence of adverse events. Differences are expressed as relative risks (RRs) with 95% confidence intervals (CIs) for dichotomous outcomes and weighted mean differences (WMDs) with 95% CIs for continuous outcomes. Heterogeneity across studies was tested by using the I2 statistic. Results Seven RCTs were included and had sample sizes ranging from 185 to 1,183 subjects (total: 3,909 subjects). The pooled analysis showed that the on-target rate of hypertension treatment was significantly higher in the amlodipine + ARB group than in the amlodipine monotherapy group (RR =1.59; 95% CI, 1.31–1.91; P<0.01). The response rate of systolic blood pressure (SBP) (RR =1.28; 95% CI, 1.04–1.58; P<0.01) and diastolic blood pressure (DBP) (RR =1.27; 95% CI, 1.12–1.44; P=0.04) were significantly higher in the amlodipine + ARB group than in the amlodipine monotherapy group. The change in SBP (RR =−3.56; 95% CI, −7.76–0.63; P=0.10) and DBP (RR =−3.03; 95% CI, −6.51–0.45; P=0.09) were higher in hypertensive patients receiving amlodipine + ARB but the difference did not reach statistical significance. ARB + amlodipine treatment carried a lower risk of adverse events relative to amlodipine monotherapy (RR =0.88; 95% CI, 0.80-0.96; P<0.01). Conclusions The results of our meta-analysis demonstrate that adding an ARB to CCB

  11. Angiotensin II receptor blocker telmisartan attenuates aortic stiffening and remodelling in STZ-diabetic rats

    PubMed Central

    2014-01-01

    Background Prevention or attenuation of diabetic vascular complications includes anti-hypertensive treatment with renin-angiotensin system inhibitors on account of their protective effects beyond blood pressure reduction. The present study aimed to investigate the effects of telmisartan, an angiotensin II type 1 receptor blocker (ARB), on blood pressure, aortic stiffening, and aortic remodelling in experimental type 1 diabetes in rats. Methods Diabetes was induced by streptozotocin (STZ) (65 mg/kg) in male Wistar rats. One diabetic group was treated for 10 weeks with telmisartan (10 mg/kg/day p/o). Pressure-independent aortic pulse wave velocity (PWV) was measured under anaesthesia after intravenous infusion of phenylephrine and nitroglycerine. Aortic wall samples were collected for histomorphometrical analysis. Results Untreated diabetes imposed differential effects on aortic stiffening, as demonstrated by increased isobaric PWV over a range of high blood pressures, but not at lower blood pressures. This was associated with loss and disruption of elastin fibres and an increase in collagen fibres in the aortic media. Treatment with telmisartan decreased resting blood pressure, reduced aortic stiffness, and partially prevented the degradation of elastin network within the aortic wall. Conclusions Telmisartan improved the structural and functional indices of aortic stiffening induced by untreated STZ-diabetes, demonstrating the importance of ARBs in the therapeutic approach to diabetic vascular complications. PMID:24920962

  12. Telmisartan protects against diabetic vascular complications in a mouse model of obesity and type 2 diabetes, partially through peroxisome proliferator activated receptor-{gamma}-dependent activity

    SciTech Connect

    Toyama, Kensuke; Nakamura, Taishi; Kataoka, Keiichiro; Yasuda, Osamu; Fukuda, Masaya; Tokutomi, Yoshiko; Dong, Yi-Fei; Ogawa, Hisao; Kim-Mitsuyama, Shokei

    2011-07-08

    Highlights: {yields} Telmisartan, an angiotensin receptor blocker, acts as a partial PPAR{gamma} agonist. {yields} The protective effects of telmisartan against diabetic vascular injury were associated with attenuation of vascular NF{kappa}B activation and TNF {alpha}. {yields} PPAR{gamma} activity of telmisartan was involved in the normalization of vascular PPAR{gamma} downregulation in diabetic mice. {yields} We provided the first evidence indicating that PPAR{gamma} activity of telmisartan contributed to the protective effects of telmisartan against diabetic vascular complication. -- Abstract: Experimental and clinical data support the notion that peroxisome proliferator-activated receptor {gamma} (PPAR{gamma}) activation is associated with anti-atherosclerosis as well as anti-diabetic effect. Telmisartan, an angiotensin receptor blocker (ARB), acts as a partial PPAR{gamma} agonist. We hypothesized that telmisartan protects against diabetic vascular complications, through PPAR{gamma} activation. We compared the effects of telmisartan, telmisartan combined with GW9662 (a PPAR{gamma} antagonist), and losartan with no PPAR{gamma} activity on vascular injury in obese type 2 diabetic db/db mice. Compared to losartan, telmisartan significantly ameliorated vascular endothelial dysfunction, downregulation of phospho-eNOS, and coronary arterial remodeling in db/db mice. More vascular protective effects of telmisartan than losartan were associated with greater anti-inflammatory effects of telmisartan, as shown by attenuation of vascular nuclear factor kappa B (NF{kappa}B) activation and tumor necrosis factor {alpha}. Coadministration of GW9662 with telmisartan abolished the above mentioned greater protective effects of telmisartan against vascular injury than losartan in db/db mice. Thus, PPAR{gamma} activity appears to be involved in the vascular protective effects of telmisartan in db/db mice. Moreover, telmisartan, but not losartan, prevented the downregulation of

  13. Telmisartan, an angiotensin II type 1 receptor blocker, prevents the development of diabetes in male Spontaneously Diabetic Torii rats.

    PubMed

    Hasegawa, Goji; Fukui, Michiaki; Hosoda, Hiroko; Asano, Mai; Harusato, Ichiko; Tanaka, Muhei; Shiraishi, Emi; Senmaru, Takashi; Sakabe, Kazumi; Yamasaki, Masahiro; Kitawaki, Jo; Fujinami, Aya; Ohta, Mitsuhiro; Obayashi, Hiroshi; Nakamura, Naoto

    2009-03-01

    To assess the beneficial effects of the angiotensin II type 1 receptor blocker telmisartan on a non-obese animal model of reduced function and mass of islet beta-cells prior to the development of diabetes, Spontaneously Diabetic Torii (SDT) rats were treated with telmisartan at 8 weeks of age. At 24 weeks of age, the treatment with telmisartan dose-dependently ameliorated hyperglycemia and hypoinsulinemia, and high-dose (5 mg/kg/day) treated SDT rats did not developed diabetes. Real-time RT-PCR analysis revealed that treatment with high-dose telmisartan reduced mRNA expression of local renin-angiotensin system (RAS) components, components of NAD(P)H oxidase, transforming growth factor-beta1 and vascular endothelial growth factor in the pancreas of male SDT rats. Immunohistochemical and Western blot analyses revealed that treatment with telmisartan also reduced expression of p47(phox). These results suggest that treatment with telmisartan reduces oxidative stress by local RAS activation and protects against islet beta-cell damage and dysfunction. These findings provide at least a partial explanation for the reduced incidence of new-onset diabetes that has been observed in several clinical trials involving angiotensin II type 1 receptor blockers and ACE inhibitors.

  14. Additive Effect of Qidan Dihuang Grain, a Traditional Chinese Medicine, and Angiotensin Receptor Blockers on Albuminuria Levels in Patients with Diabetic Nephropathy: A Randomized, Parallel-Controlled Trial

    PubMed Central

    Xiang, Lei; Jiang, Pingping; Zhou, Lin; Sun, Xiaomin; Bi, Jianlu; Cui, Lijuan; Nie, Xiaoli; Luo, Ren; Liu, Yanyan

    2016-01-01

    Albuminuria is characteristic of early-stage diabetic nephropathy (DN). The conventional treatments with angiotensin receptor blockers (ARB) are unable to prevent the development of albuminuria in normotensive individuals with type 2 diabetes mellitus (T2DM). Purpose. The present study aimed to evaluate the effect of ARB combined with a Chinese formula Qidan Dihuang grain (QDDHG) in improving albuminuria and Traditional Chinese Medicine Symptom (TCMS) scores in normotensive individuals with T2DM. Methods. Eligible patients were randomized to the treatment group and the control group. Results. Compared with baseline (week 0), both treatment and control groups markedly improved the 24-hour albuminuria, total proteinuria (TPU), and urinary albumin to creatinine ratio (A/C) at 4, 8, and 12 weeks. Between treatment and the control group, the levels of albuminuria in the treatment group were significantly lower than in the control group at 8 and 12 weeks (p < 0.05). In addition, treatment group markedly decreased the scores of TCMS after treatment. Conclusion. This trial suggests that QDDHG combined with ARB administration decreases the levels of albuminuria and the scores for TCMS in normotensive individuals with T2DM. PMID:27375762

  15. Patients With Newly Diagnosed Hypertension Treated With the Renin Angiotensin Receptor Blocker Azilsartan Medoxomil vs Angiotensin-Converting Enzyme Inhibitors: The Prospective EARLY Registry.

    PubMed

    Schmieder, Roland E; Potthoff, Sebastian A; Bramlage, Peter; Baumgart, Peter; Mahfoud, Felix; Buhck, Hartmut; Ouarrak, Taoufik; Ehmen, Martina; Senges, Jochen; Gitt, Anselm K

    2015-12-01

    For patients with newly diagnosed hypertension, angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) are usually the first-line therapies. There is, however, no real-life data regarding the relative clinical effectiveness and tolerability of either drug class. The prospective registry, Treatment With Azilsartan Compared to ACE Inhibitors in Antihypertensive Therapy (EARLY), was conducted to evaluate the effectiveness of the ARB azilsartan medoxomil (AZL-M) vs ACE inhibitors in real-world patients. Of the 1153 patients with newly diagnosed hypertension who were included in the registry, 789 were prescribed AZL-M and 364 were prescribed an ACE inhibitor. After multivariate adjustment, AZL-M was found to provide superior blood pressure reduction and better target blood pressure (<140/90 mm Hg) achievement. The proportion of patients with adverse events was not statistically different between groups. The authors conclude that in newly diagnosed hypertensive patients, AZL-M provides superior blood pressure control with a similar safety profile compared with ACE inhibitors.

  16. Comparative Effects of Direct Renin Inhibitor and Angiotensin Receptor Blocker on Albuminuria in Hypertensive Patients with Type 2 Diabetes. A Randomized Controlled Trial

    PubMed Central

    Uzu, Takashi; Araki, Shin-ichi; Kashiwagi, Atsunori; Haneda, Masakazu; Koya, Daisuke; Yokoyama, Hiroki; Kida, Yasuo; Ikebuchi, Motoyoshi; Nakamura, Takaaki; Nishimura, Masataka; Takahara, Noriko; Obata, Toshiyuki; Omichi, Nobuyuki; Sakamoto, Katsuhiko; Shingu, Ryosuke; Taki, Hideki; Nagai, Yoshio; Tokuda, Hiroaki; Kitada, Munehiro; Misawa, Miwa; Nishiyama, Akira; Kobori, Hiroyuki; Maegawa, Hiroshi

    2016-01-01

    Background In patients with diabetes, albuminuria is a risk marker of end-stage renal disease and cardiovascular events. An increased renin-angiotensin system activity has been reported to play an important role in the pathological processes in these conditions. We compared the effect of aliskiren, a direct renin inhibitor (DRI), with that of angiotensin receptor blockers (ARBs) on albuminuria and urinary excretion of angiotensinogen, a marker of intrarenal renin-angiotensin system activity. Methods We randomly assigned 237 type 2 diabetic patients with high-normal albuminuria (10 to <30 mg/g of albumin-to-creatinine ratio) or microalbuminuria (30 to <300 mg/g) to the DRI group or ARB group (any ARB) with a target blood pressure of <130/80 mmHg. The primary endpoint was a reduction in albuminuria. Results Twelve patients dropped out during the observation period, and a total of 225 patients were analyzed. During the study period, the systolic and diastolic blood pressures were not different between the groups. The changes in the urinary albumin-to-creatinine ratio from baseline to the end of the treatment period in the DRI and ARB groups were similar (-5.5% and -6.7%, respectively). In contrast, a significant reduction in the urinary excretion of angiotensinogen was observed in the ARB group but not in the DRI group. In the subgroup analysis, a significant reduction in the albuminuria was observed in the ARB group but not in the DRI group among high-normal albuminuria patients. Conclusion DRI and ARB reduced albuminuria in hypertensive patients with type 2 diabetes. In addition, ARB, but not DRI, reduced albuminuria even in patients with normal albuminuria. DRI is not superior to ARB in the reduction of urinary excretion of albumin and angiotensinogen. PMID:28033332

  17. Addition of hydrochlorothiazide to angiotensin receptor blocker therapy can achieve a lower sodium balance with no acceleration of intrarenal renin angiotensin system in patients with chronic kidney disease

    PubMed Central

    Fuwa, Daisuke; Fukuda, Michio; Ogiyama, Yoshiaki; Sato, Ryo; Mizuno, Masashi; Miura, Toshiyuki; Abe-Dohmae, Sumiko; Michikawa, Makoto; Kobori, Hiroyuki; Ohte, Nobuyuki

    2016-01-01

    Objective Angiotensin receptor blockers (ARBs) produce a lower sodium (Na) balance, and the natriuretic effect is enhanced under Na deprivation, despite falls in blood pressure (BP) and glomerular filtration rate (GFR). Methods The effect of additional hydrochlorothiazide (HCTZ; 12.5 mg/day) to ARB treatment (valsartan; 80 mg/day) on glomerulotubular Na balance was evaluated in 23 patients with chronic kidney disease. Results Add-on HCTZ decreased GFR, tubular Na load, and tubular Na reabsorption (tNa), although 24-hour urinary Na excretion (UNaV) remained constant. Daily urinary angiotensinogen excretion (UAGTV, 152±10→82±17 μg/g Cre) reduced (p=0.02). Changes in tubular Na load (r2=0.26) and tNa (r2=0.25) correlated with baseline 24-hour UAGTV. Changes in filtered Na load correlated with changes in nighttime systolic BP (r2=0.17), but not with changes in daytime systolic BP. The change in the tNa to filtered Na load ratio was influenced by the change in daytime UNaV (β=−0.67, F=16.8), rather than the change in nighttime UNaV. Conclusions Lower Na balance was produced by add-on HCTZ to ARB treatment without an increase of intra-renal renin-angiotensin system activity, leading to restoration of nocturnal hypertension. A further study is needed to demonstrate that the reduction of UAGTV by additional diuretics to ARBs prevents the progression of nephropathy or cardiovascular events. PMID:27283968

  18. Antihypertensive treatment using an angiotensin receptor blocker and a thiazide diuretic improves patients' quality of life: the Saga Challenge Antihypertensive Study (S-CATS).

    PubMed

    Kamura, Aoi; Inoue, Teruo; Kuroki, Shigetaka; Ishida, Shiro; Iimori, Kenichirou; Kato, Toru; Naitoh, Hirofumi; Tamesue, Satoshi; Ikeda, Hideo; Node, Koichi

    2011-12-01

    The aim of the Saga Challenge Antihypertensive Study (S-CATS), a single-arm, prospective and multi-center trial, was to evaluate the effectiveness of combined antihypertensive treatment with losartan and hydrochlorothiazide (HCTZ). Enrolled in the study were a total of 161 patients with hypertension, who in spite of treatment with an angiotensin receptor blocker (ARB) alone or an ARB and calcium channel blocker (CCB), had not been able to reach blood pressure control goals set by the Japanese Society of Hypertension Guidelines (JSH 2004). The ARBs were replaced with a combination pill containing losartan (50 mg) and HCTZ (12.5 mg), and this treatment was continued for 3 months. This change in therapy resulted in significant decreases in systolic (158±14 to 137±15 mm Hg, P<0.001) and diastolic (85±11 to 76±10 mm Hg, P<0.001) blood pressure and heart rate (73±3 to 72±3) during the study. The patients' quality of life (QOL) score, the EuroQol 5 dimensions (EQ-5D) and the visual analog scale (VAS) (n=96; 70.0 (68.8-80.0) to 80.0 (70.0-90.0), P<0.01) all improved significantly. Another QOL score, the hypertension symptom score (HSS), which we originally developed for the S-CATS trial, decreased significantly (n=93; 4.0 (1.0-9.0) to 2.0 (1.0-8.0), P<0.05). The Pittsburgh sleep quality index (PSQI), which is a psychometric assessment of subjective sleep quality, also decreased significantly (n=45; 4.0 (2.0-7.0) to 3.0 (2.0-5.0), P<0.05). There was a significant correlation between a change in HSS (baseline value -3-months value) and a decrease in systolic blood pressure (n=93; R=0.241, P<0.05). These results suggest that an anti-hypertensive treatment combined with an ARB and a thiazide diuretic may improve patients' QOL, including sleep quality.

  19. A Pilot Study on the Effect of Angiotensin Receptor Blockers on Platelet Aggregation in Hypertensive Patients- A Prospective Observational Study

    PubMed Central

    Sanji, Narendranath; Kamath, Pallavi Mahadeva; Devendrappa, Srinivas Lokikere; Hanumanthareddy, Shashikala Gowdara; Maniyar, Imran; Rudrappa, Suresh Surappla

    2016-01-01

    Introduction Thrombosis is an invariable component contributing to cardiovascular events in patients with hypertension. One of the risk factors of cardiovascular disease is increased platelet activity. One among the widely used antihypertensive agents are Angiotensin II type 1 Receptor Blockers (ARBs). Even though there are many studies involving antihypertensive agents, their antithrombotic properties remain elusive and not fully characterized. Aim To evaluate the anti-aggregatory effect of ARBs on platelets in-vivo. Materials and Methods A total of 60 subjects were included in this observational pilot study conducted in the medicine out patient department of JJM Hospital, Davanagere, Karnataka, India. Among them, 30 patients with essential hypertension attending Medicine OPD of a tertiary care hospital, who were on ARB for at least one month, were enrolled into study group. The control group consisted of 30 normotensive subjects who were not on any drug affecting platelet function. The Bleeding Time (BT) was evaluated for both the groups using Duke method of BT estimation. Data was analysed using SPSS software version 20. The test group was compared with control group using student’s unpaired t-test. Results The mean BT of study group was 2.488 minutes ± 0.0361 Standard Error of Mean (SEM) and that of control group was 1.998 minutes ± 0.0362 SEM. The result was statistically significant (p<0.001). The average duration of treatment was 2.933 years. Conclusion ARB have antiplatelet activity. Increase in BT in ARB group when compared with that of control group is a reflection of antiplatelet activity. PMID:28050394

  20. Antihypertensive efficacy of the angiotensin receptor blocker azilsartan medoxomil compared with the angiotensin-converting enzyme inhibitor ramipril

    PubMed Central

    Bönner, G; Bakris, G L; Sica, D; Weber, M A; White, W B; Perez, A; Cao, C; Handley, A; Kupfer, S

    2013-01-01

    Drug therapy often fails to control hypertension. Azilsartan medoxomil (AZL-M) is a newly developed angiotensin II receptor blocker with high efficacy and good tolerability. This double-blind, controlled, randomised trial compared its antihypertensive efficacy and safety vs the angiotensin-converting enzyme inhibitor ramipril (RAM) in patients with clinic systolic blood pressure (SBP) 150–180 mm Hg. Patients were randomised (n=884) to 20 mg AZL-M or 2.5 mg RAM once daily for 2 weeks, then force-titrated to 40 or 80 mg AZL-M or 10 mg RAM for 22 weeks. The primary endpoint was change in trough, seated, clinic SBP. Mean patient age was 57±11 years, 52.4% were male, 99.5% were Caucasian. Mean baseline BP was 161.1±7.9/94.9±9.0 mm Hg. Clinic SBP decreased by 20.6±0.95 and 21.2±0.95 mm Hg with AZL-M 40 and 80 mg vs12.2±0.95 mm Hg with RAM (P<0.001 for both AZL-M doses). Adverse events leading to discontinuation were less frequent with AZL-M 40 and 80 mg (2.4% and 3.1%, respectively) than with RAM (4.8%). These data demonstrated that treatment of stage 1–2 hypertension with AZL-M was more effective than RAM and better tolerated. PMID:23514842

  1. Impact of drug price adjustments on utilization of and expenditures on angiotensin-converting enzyme inhibitors and angiotensin receptor blockers in Taiwan

    PubMed Central

    2012-01-01

    Background A previous study has suggested that drug price adjustments allow physicians in Taiwan to gain greater profit by prescribing generic drugs. To better understand the effect of price adjustments on physician choice, this study used renin-angiotensin drugs (including angiotensin-converting enzyme inhibitors [ACEIs] and angiotensin receptor blockers [ARBs]) to examine the impact of price adjustments on utilization of and expenditures on patented and off-patent drugs with the same therapeutic indication. Methods Using the Taiwan’s Longitudinal Health Insurance Database (2005), we identified 147,157 patients received ACEIs and/or ARBs between 1997 and 2008. The annual incident and prevalent users of ACEIs, ARBs and overall renin-angiotensin drugs were examined. Box-Tiao intervention analysis was applied to assess the impact of price adjustments on monthly utilization of and expenditures on these drugs. ACEIs were divided into patented and off-patent drugs, off-patent ACEIs were further divided into original brands and generics, and subgroup analyses were performed. Results The number of incident renin-angiotensin drug users decreased over the study period. The number of prevalent ARB users increased and exceeded the cumulative number of first-time renin-angiotensin drug users starting on ARBs, implying that some patients switched from ACEIs to ARBs. After price adjustments, long term trend increases in utilization were observed for patented ACEIs and ARBs; a long-term trend decrease was observed for off-patent ACEIs; long-term trend change was not significant for overall renin-angiotensin drugs. Significant long-term trend increases in expenditures were observed for patented ACEIs after price adjustment in 2007 (200.9%, p = 0.0088) and in ARBs after price adjustments in 2001 (173.4%, p < 0.0001) and 2007 (146.3%, p < 0.0001). A significant long-term trend decrease in expenditures was observed for off-patent ACEIs after 2004 price adjustment (

  2. Renoprotective effect of calcium channel blockers in combination with an angiotensin receptor blocker in elderly patients with hypertension. A randomized crossover trial between benidipine and amlodipine.

    PubMed

    Miyagawa, Koichi; Dohi, Yasuaki; Nakazawa, Ai; Sugiura, Tomonori; Yamashita, Sumiyo; Sato, Koichi; Kimura, Genjiro

    2010-01-01

    Anti-hypertensive medication with an angiotensin II receptor blocker (ARB) is effective in slowing the progression of chronic kidney disease. The present study was designed to investigate whether calcium channel blockers (CCBs) in combination with an ARB differentially affect kidney function. Elderly hypertensive patients with chronic kidney disease (n = 17, 72 +/- 6 years old) were instructed to self-measure blood pressure. They were randomly assigned to receive either benidipine (4-8 mg/day) or amlodipine (5-10 mg/day) combined with olmesartan (10 mg/day). After 3 months, CCBs were switched in each patient and the same protocol was applied for another 3 months. At baseline, significant correlation was obtained between urine albumin (22.8 +/- 16.7 (median +/- median absolute deviation) mg/g creatinine) and self-measured blood pressure (170 +/- 23/87 +/- 10 (mean +/- SD) mmHg, r = 0.65, p < 0.01). Both regimens reduced blood pressure to a similar extent (139 +/- 22/75 +/- 11 mmHg and 133 +/- 17/72 +/- 10 mmHg, respectively; both p < 0.001), while urine albumin decreased only after combination therapy including benidipine (11.7 +/- 6.1 mg/g creatinine, p < 0.05). Benidipine, but not amlodipine, in combination with olmesartan, reduced urinary albumin excretion in elderly hypertensive patients with chronic kidney disease. The results suggest the importance of selecting medications used in combination with ARB in hypertensive patients with chronic kidney disease.

  3. Comparison of the antiproteinuric effects of the calcium channel blockers benidipine and amlodipine administered in combination with angiotensin receptor blockers to hypertensive patients with stage 3-5 chronic kidney disease.

    PubMed

    Abe, Masanori; Okada, Kazuyoshi; Maruyama, Takashi; Maruyama, Noriaki; Matsumoto, Koichi

    2009-04-01

    Benidipine, an L- and T-type calcium channel blocker, dilates both efferent and afferent arterioles and reduces glomerular pressure. Thus, it may exert renoprotective effects. We conducted an open-labeled, randomized trial to compare the blood pressure (BP)-lowering effect and antiproteinuric effect of benidipine with those of amlodipine in hypertensive patients with moderate-to-advanced-stage chronic kidney disease (CKD) (stages 3-5). These patients were already being administered the current maximum recommended doses of angiotensin receptor blockers (ARBs). Patients with BP >or=140/90 mm Hg, despite treatment with the maximum recommended dose of ARBs, were randomly assigned to two groups. The patients received either of the following treatment regimens: 4 mg day(-1) of benidipine, which was increased up to a dose of 16 mg day(-1) (B group; n=24), and 2.5 mg day(-1) of amlodipine, which was increased up to a dose of 10 mg day(-1) amlodipine (A group; n=23). After 6 months of treatment, a significant and comparable reduction in the systolic and diastolic BP was seen in both groups. The decrease in the urinary protein to creatinine ratio in the B group was significantly lower than that in the A group. Benidipine exerted antiproteinuric effect to a greater extent than did amlodipine, even in patients with diabetic nephropathy. We conclude that the addition of benidipine, rather than amlodipine, ameliorates urinary protein excretion in hypertensive patients with CKD who are already being administered ARBs. Therefore, we propose a combination therapy with benidipine and ARBs, even for patients with moderate-to-advanced-stage CKD.

  4. Fixed-Dose Combinations of Renin-Angiotensin System Inhibitors and Calcium Channel Blockers in the Treatment of Hypertension: A Comparison of Angiotensin Receptor Blockers and Angiotensin-Converting Enzyme Inhibitors.

    PubMed

    Hsiao, Fu-Chih; Tung, Ying-Chang; Chou, Shing-Hsien; Wu, Lung-Sheng; Lin, Chia-Pin; Wang, Chun-Li; Lin, Yu-Sheng; Chang, Chee-Jen; Chu, Pao-Hsien

    2015-12-01

    Fixed-dose combinations (FDCs) of different regimens are recommended in guidelines for the treatment of hypertension. However, clinical studies comparing FDCs of angiotensin receptor blocker (ARB)/calcium channel blocker (CCB) and angiotensin-converting enzyme inhibitor (ACE inhibitor)/CCB in hypertensive patients are lacking.Using a propensity score matching of 4:1 ratio, this retrospective claims database study compared 2 FDC regimens, ARB/CCB and ACE inhibitor/CCB, in treating hypertensive patients with no known atherosclerotic cardiovascular disease. All patients were followed for at least 3 years or until the development of major adverse cardiovascular events (MACEs) during the study period. In addition, the effect of medication adherence on clinical outcomes was evaluated in subgroup analysis based on different portions of days covered.There was no significant difference in MACE-free survival (hazard ratio [HR]: 1.21; 95% confidence interval [CI]: 0.98-1.50; P = 0.08) and survival free from hospitalization for heart failure (HR: 1.15; 95% CI: 082-1.61; P = 0.431), new diagnosis of chronic kidney disease (HR: 0.98; 95% CI: 071-1.36; P = 0.906), and initiation of dialysis (HR: 0.99; 95% CI: 050-1.92; P = 0.965) between the 2 study groups. The results remained the same within each subgroup of patients with different adherence statuses.ARBs in FDC regimens with CCBs in the present study were shown to be as effective as ACE inhibitors at reducing the risks of MACEs, hospitalization for heart failure, new diagnosis of chronic kidney disease, and new initiation of dialysis in hypertensive patients, regardless of the medication adherence status.

  5. Telmisartan prevented cognitive decline partly due to PPAR-{gamma} activation

    SciTech Connect

    Mogi, Masaki; Li Jianmei; Tsukuda, Kana; Iwanami, Jun; Min, Li-Juan; Sakata, Akiko; Fujita, Teppei; Iwai, Masaru; Horiuchi, Masatsugu

    2008-10-24

    Telmisartan is a unique angiotensin receptor blocker (ARB) and partial agonist of peroxisome proliferator-activated receptor (PPAR)-{gamma}. Here, we investigated the preventive effect of telmisartan on cognitive decline in Alzheimer disease. In ddY mice, intracerebroventricular injection of A{beta} 1-40 significantly attenuated their cognitive function evaluated by shuttle avoidance test. Pretreatment with a non-hypotensive dose of telmisartan significantly inhibited such cognitive decline. Interestingly, co-treatment with GW9662, a PPAR-{gamma} antagonist, partially inhibited this improvement of cognitive decline. Another ARB, losartan, which has less PPAR-{gamma} agonistic effect, also inhibited A{beta}-injection-induced cognitive decline; however the effect was smaller than that of telmisartan and was not affected by GW9662. Immunohistochemical staining for A{beta} showed the reduced A{beta} deposition in telmisartan-treated mice. However, this reduction was not observed in mice co-administered GW9662. These findings suggest that ARB has a preventive effect on cognitive impairment in Alzheimer disease, and telmisartan, with PPAR-{gamma} activation, could exert a stronger effect.

  6. Distinct properties of telmisartan on agonistic activities for peroxisome proliferator-activated receptor γ among clinically used angiotensin II receptor blockers: drug-target interaction analyses.

    PubMed

    Kakuta, Hirotoshi; Kurosaki, Eiji; Niimi, Tatsuya; Gato, Katsuhiko; Kawasaki, Yuko; Suwa, Akira; Honbou, Kazuya; Yamaguchi, Tomohiko; Okumura, Hiroyuki; Sanagi, Masanao; Tomura, Yuichi; Orita, Masaya; Yonemoto, Takako; Masuzaki, Hiroaki

    2014-04-01

    A proportion of angiotensin II type 1 receptor blockers (ARBs) improves glucose dyshomeostasis and insulin resistance in a clinical setting. Of these ARBs, telmisartan has the unique property of being a partial agonist for peroxisome proliferator-activated receptor γ (PPARγ). However, the detailed mechanism of how telmisartan acts on PPARγ and exerts its insulin-sensitizing effect is poorly understood. In this context, we investigated the agonistic activity of a variety of clinically available ARBs on PPARγ using isothermal titration calorimetry (ITC) and surface plasmon resonance (SPR) system. Based on physicochemical data, we then reevaluated the metabolically beneficial effects of telmisartan in cultured murine adipocytes. ITC and SPR assays demonstrated that telmisartan exhibited the highest affinity of the ARBs tested. Distribution coefficient and parallel artificial membrane permeability assays were used to assess lipophilicity and cell permeability, for which telmisartan exhibited the highest levels of both. We next examined the effect of each ARB on insulin-mediated glucose metabolism in 3T3-L1 preadipocytes. To investigate the impact on adipogenesis, 3T3-L1 preadipocytes were differentiated with each ARB in addition to standard inducers of differentiation for adipogenesis. Telmisartan dose-dependently facilitated adipogenesis and markedly augmented the mRNA expression of adipocyte fatty acid-binding protein (aP2), accompanied by an increase in the uptake of 2-deoxyglucose and protein expression of glucose transporter 4 (GLUT4). In contrast, other ARBs showed only marginal effects in these experiments. In accordance with its highest affinity of binding for PPARγ as well as the highest cell permeability, telmisartan superbly activates PPARγ among the ARBs tested, thereby providing a fresh avenue for treating hypertensive patients with metabolic derangement.

  7. Combined Angiotensin Receptor Antagonism and Neprilysin Inhibition

    PubMed Central

    Hubers, Scott A.; Brown, Nancy J.

    2016-01-01

    Heart failure affects approximately 5.7 million people in the United States alone. Angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, beta-blockers, and aldosterone antagonists have improved mortality in patients with heart failure and reduced ejection fraction, but mortality remains high. In July 2015, the FDA approved the first of a new class of drugs for the treatment of heart failure; valsartan/sacubitril (formerly known as LCZ696 and currently marketed by Novartis as Entresto) combines the angiotensin receptor blocker valsartan and the neprilysin inhibitor prodrug sacubitril in a 1:1 ratio in a sodium supramolecular complex. Sacubitril is converted by esterases to LBQ657, which inhibits neprilysin, the enzyme responsible for the degradation of the natriuretic peptides and many other vasoactive peptides. Thus, this combined angiotensin receptor antagonist and neprilysin inhibitor addresses two of the pathophysiologic mechanisms of heart failure - activation of the renin-angiotensin-aldosterone system and decreased sensitivity to natriuretic peptides. In the Prospective comparison of ARNI with ACEI to Determine Impact on Global Mortality and morbidity in Heart Failure (PARADIGM-HF) trial, valsartan/sacubitril significantly reduced mortality and hospitalization for heart failure, as well as blood pressure, compared to enalapril in patients with heart failure, reduced ejection fraction, and an elevated circulating level of brain natriuretic peptide or N-terminal pro-brain natriuretic peptide. Ongoing clinical trials are evaluating the role of valsartan/sacubitril in the treatment of heart failure with preserved ejection fraction and hypertension. We review here the mechanisms of action of valsartan/sacubitril, the pharmacologic properties of the drug, and its efficacy and safety in the treatment of heart failure and hypertension. PMID:26976916

  8. Combined Angiotensin Receptor Antagonism and Neprilysin Inhibition.

    PubMed

    Hubers, Scott A; Brown, Nancy J

    2016-03-15

    Heart failure affects ≈5.7 million people in the United States alone. Angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, β-blockers, and aldosterone antagonists have improved mortality in patients with heart failure and reduced ejection fraction, but mortality remains high. In July 2015, the US Food and Drug Administration approved the first of a new class of drugs for the treatment of heart failure: Valsartan/sacubitril (formerly known as LCZ696 and currently marketed by Novartis as Entresto) combines the angiotensin receptor blocker valsartan and the neprilysin inhibitor prodrug sacubitril in a 1:1 ratio in a sodium supramolecular complex. Sacubitril is converted by esterases to LBQ657, which inhibits neprilysin, the enzyme responsible for the degradation of the natriuretic peptides and many other vasoactive peptides. Thus, this combined angiotensin receptor antagonist and neprilysin inhibitor addresses 2 of the pathophysiological mechanisms of heart failure: activation of the renin-angiotensin-aldosterone system and decreased sensitivity to natriuretic peptides. In the Prospective Comparison of ARNI With ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure (PARADIGM-HF) trial, valsartan/sacubitril significantly reduced mortality and hospitalization for heart failure, as well as blood pressure, compared with enalapril in patients with heart failure, reduced ejection fraction, and an elevated circulating level of brain natriuretic peptide or N-terminal pro-brain natriuretic peptide. Ongoing clinical trials are evaluating the role of valsartan/sacubitril in the treatment of heart failure with preserved ejection fraction and hypertension. We review here the mechanisms of action of valsartan/sacubitril, the pharmacological properties of the drug, and its efficacy and safety in the treatment of heart failure and hypertension.

  9. Clinical impacts of additive use of olmesartan in hypertensive patients with chronic heart failure: the supplemental benefit of an angiotensin receptor blocker in hypertensive patients with stable heart failure using olmesartan (SUPPORT) trial.

    PubMed

    Sakata, Yasuhiko; Shiba, Nobuyuki; Takahashi, Jun; Miyata, Satoshi; Nochioka, Kotaro; Miura, Masanobu; Takada, Tsuyoshi; Saga, Chiharu; Shinozaki, Tsuyoshi; Sugi, Masafumi; Nakagawa, Makoto; Sekiguchi, Nobuyo; Komaru, Tatsuya; Kato, Atsushi; Fukuchi, Mitsumasa; Nozaki, Eiji; Hiramoto, Tetsuya; Inoue, Kanichi; Goto, Toshikazu; Ohe, Masatoshi; Tamaki, Kenji; Ibayashi, Setsuro; Ishide, Nobumasa; Maruyama, Yukio; Tsuji, Ichiro; Shimokawa, Hiroaki

    2015-04-14

    We examined whether an additive treatment with an angiotensin receptor blocker, olmesartan, reduces the mortality and morbidity in hypertensive patients with chronic heart failure (CHF) treated with angiotensin-converting enzyme (ACE) inhibitors, β-blockers, or both. In this prospective, randomized, open-label, blinded endpoint study, a total of 1147 hypertensive patients with symptomatic CHF (mean age 66 years, 75% male) were randomized to the addition of olmesartan (n = 578) to baseline therapy vs. control (n = 569). The primary endpoint was a composite of all-cause death, non-fatal acute myocardial infarction, non-fatal stroke, and hospitalization for worsening heart failure. During a median follow-up of 4.4 years, the primary endpoint occurred in 192 patients (33.2%) in the olmesartan group and in 166 patients (29.2%) in the control group [hazard ratio (HR) 1.18; 95% confidence interval (CI), 0.96-1.46, P = 0.112], while renal dysfunction developed more frequently in the olmesartan group (16.8 vs. 10.7%, HR 1.64; 95% CI 1.19-2.26, P = 0.003). Subgroup analysis revealed that addition of olmesartan to combination of ACE inhibitors and β-blockers was associated with increased incidence of the primary endpoint (38.1 vs. 28.2%, HR 1.47; 95% CI 1.11-1.95, P = 0.006), all-cause death (19.4 vs. 13.5%, HR 1.50; 95% CI 1.01-2.23, P = 0.046), and renal dysfunction (21.1 vs. 12.5%, HR 1.85; 95% CI 1.24-2.76, P = 0.003). Additive use of olmesartan did not improve clinical outcomes but worsened renal function in hypertensive CHF patients treated with evidence-based medications. Particularly, the triple combination therapy with olmesartan, ACE inhibitors and β-blockers was associated with increased adverse cardiac events. This study is registered at clinicaltrials.gov-NCT00417222.

  10. Telmisartan to Prevent Recurrent Stroke and Cardiovascular Events

    PubMed Central

    Yusuf, Salim; Diener, Hans-Christoph; Sacco, Ralph L.; Cotton, Daniel; Ôunpuu, Stephanie; Lawton, William A.; Palesch, Yuko; Martin, Reneé H.; Albers, Gregory W.; Bath, Philip; Bornstein, Natan; Chan, Bernard P.L.; Chen, Sien-Tsong; Cunha, Luis; Dahlöf, Björn; De Keyser, Jacques; Donnan, Geoffrey A.; Estol, Conrado; Gorelick, Philip; Gu, Vivian; Hermansson, Karin; Hilbrich, Lutz; Kaste, Markku; Lu, Chuanzhen; Machnig, Thomas; Pais, Prem; Roberts, Robin; Skvortsova, Veronika; Teal, Philip; Toni, Danilo; VanderMaelen, Cam; Voigt, Thor; Weber, Michael; Yoon, Byung-Woo

    2009-01-01

    BACKGROUND Prolonged lowering of blood pressure after a stroke reduces the risk of recurrent stroke. In addition, inhibition of the renin–angiotensin system in high-risk patients reduces the rate of subsequent cardiovascular events, including stroke. However, the effect of lowering of blood pressure with a renin–angiotensin system inhibitor soon after a stroke has not been clearly established. We evaluated the effects of therapy with an angiotensin-receptor blocker, telmisartan, initiated early after a stroke. METHODS In a multicenter trial involving 20,332 patients who recently had an ischemic stroke, we randomly assigned 10,146 to receive telmisartan (80 mg daily) and 10,186 to receive placebo. The primary outcome was recurrent stroke. Secondary outcomes were major cardiovascular events (death from cardiovascular causes, recurrent stroke, myocardial infarction, or new or worsening heart failure) and new-onset diabetes. RESULTS The median interval from stroke to randomization was 15 days. During a mean followup of 2.5 years, the mean blood pressure was 3.8/2.0 mm Hg lower in the telmisartan group than in the placebo group. A total of 880 patients (8.7%) in the telmisartan group and 934 patients (9.2%) in the placebo group had a subsequent stroke (hazard ratio in the telmisartan group, 0.95; 95% confidence interval [CI], 0.86 to 1.04; P = 0.23). Major cardiovascular events occurred in 1367 patients (13.5%) in the telmisartan group and 1463 patients (14.4%) in the placebo group (hazard ratio, 0.94; 95% CI, 0.87 to 1.01; P = 0.11). New-onset diabetes occurred in 1.7% of the telmisartan group and 2.1% of the placebo group (hazard ratio, 0.82; 95% CI, 0.65 to 1.04; P = 0.10). CONCLUSIONS Therapy with telmisartan initiated soon after an ischemic stroke and continued for 2.5 years did not significantly lower the rate of recurrent stroke, major cardiovascular events, or diabetes. (ClinicalTrials.gov number, NCT00153062.) PMID:18753639

  11. Effect of telmisartan on kidney function in patients with chronic kidney disease: an observational study

    PubMed Central

    Agrawal, Ashish; Kamila, Shibnath; Reddy, Swetha; Lilly, Joyal; Mariyala, MS Sadhguna

    2016-01-01

    Abstract Background: Globally the burden of chronic kidney disease (CKD) is rising, an important cause of death and loss of disability-adjusted life years. Activation of the renin-angiotensin-aldosterone system is involved in its pathogenesis. The aim of the present study was to examine the effects of telmisartan (40 mg/day), an angiotensin receptor blocker (ARB) in Indian patients with CKD in real-life setting. Method: This was a prospective observational study. Fifty-six patients (>18 years) diagnosed with CKD were enrolled into the study. Serum creatinine, 24-h urinary protein, spot urine protein-to-creatinine ratio, glomerular filtration rate (GFR) and blood pressure (BP) were assessed along with safety. Results: A total of 55 patients (96.36% hypertensive; 63.61% diabetic) with mean age of 48.23 years completed the study. At the end of 3 months treatment with telmisartan, 24-h urinary protein, spot urine protein-to-creatinine, serum creatinine and BP significantly reduced (p < .05) by 806.78 mg, 0.95, 0.44 mg/dl and 8.9/4.7 mmHg in the overall population. GFR increased from the baseline value of 52.13 to 65.01 ml/min. Telmisartan was well tolerated and treatment was discontinued in one patient because of hyperkalemia. Conclusion: This study demonstrated that telmisartan effectively and safely reduces proteinuria in chronic kidney disease patients. PMID:27994942

  12. A novel design of combining the angiotensin converting enzyme (ACE) inhibitor captopril with the angiotensin receptor blocker (ARB) losartan using homo coupling via PEG diacid linker.

    PubMed

    Hashemzadeh, Mehrnoosh; Park, Shery; Ju, Hee; Movahed, Mohammad R

    2013-12-01

    Cardiovascular disease is the leading cause of death in American adults. Furthermore, the incidence of congestive heart failure is on the rise as a major cause of hospitalization and mortality in this population. Angiotensin Converting Enzyme (ACE) inhibitors prevent the production of angiotensin II, which has been shown to reduce mortality in patients with congestive heart failure. Angiotensin II receptor blockers (ARB) were developed as a direct inhibitor of angiotensin II. ARBs have been shown to be effective in the treatment of patients with systolic heart failure but do not cause chronic coughing which is a common side effect of ACE inhibitors. In theory, a compound that has the combined effect of an ACE inhibitor and an ARB should be more effective in treating heart failure patients than either agents alone. Therefore, the purpose of this manuscript is to design and discuss the benefits of a new molecule, which combines captopril, an ACE inhibitor, with losartan, an ARB. In this experiment Captopril and Losartan were modified and synthesized separately and combined by homo or mono coupling. This was achieved by taking advantage of PEG (Polyethylene glycol) as a linker. It is expected that this molecule will have the combined modes of action of both ACEs and ARBs. Benefits from combination therapy include; increased efficacy, reduced adverse effects, convenience, compliance, and prolonged duration. Consequently, this combined molecule is expected to block the production of angiotensin II more efficiently and effectively. Although captopril and losartan work in the same system by blocking the effect of angiotensin II they have different action sites and mechanisms some patents are also discussed. Losartan blocks the AT1 receptor which is expressed on the cell surface, while captopril inhibits ACE, preventing production of angiotensin II, which is present in both the plasma and on the cell surface, especially on endothelial and smooth muscle cells.

  13. Telmisartan Ameliorates Fibrocystic Liver Disease in an Orthologous Rat Model of Human Autosomal Recessive Polycystic Kidney Disease

    PubMed Central

    Yoshihara, Daisuke; Kugita, Masanori; Sasaki, Mai; Horie, Shigeo; Nakanishi, Koichi; Abe, Takaaki; Aukema, Harold M.; Yamaguchi, Tamio; Nagao, Shizuko

    2013-01-01

    Human autosomal recessive polycystic kidney disease (ARPKD) produces kidneys which are massively enlarged due to multiple cysts, hypertension, and congenital hepatic fibrosis characterized by dilated bile ducts and portal hypertension. The PCK rat is an orthologous model of human ARPKD with numerous fluid-filled cysts caused by stimulated cellular proliferation in the renal tubules and hepatic bile duct epithelia, with interstitial fibrosis developed in the liver. We previously reported that a peroxisome proliferator activated receptor (PPAR)-γ full agonist ameliorated kidney and liver disease in PCK rats. Telmisartan is an angiotensin receptor blocker (ARB) used widely as an antihypertensive drug and shows partial PPAR-γ agonist activity. It also has nephroprotective activity in diabetes and renal injury and prevents the effects of drug-induced hepatotoxicity and hepatic fibrosis. In the present study, we determined whether telmisartan ameliorates progression of polycystic kidney and fibrocystic liver disease in PCK rats. Five male and 5 female PCK and normal control (+/+) rats were orally administered 3 mg/kg telmisartan or vehicle every day from 4 to 20 weeks of age. Treatment with telmisartan decreased blood pressure in both PCK and +/+ rats. Blood levels of aspartate amino transferase, alanine amino transferase and urea nitrogen were unaffected by telmisartan treatment. There was no effect on kidney disease progression, but liver weight relative to body weight, liver cystic area, hepatic fibrosis index, expression levels of Ki67 and TGF-β, and the number of Ki67- and TGF-β-positive interstitial cells in the liver were significantly decreased in telmisartan-treated PCK rats. Therefore, telmisartan ameliorates congenital hepatic fibrosis in ARPKD, possibly through the inhibition of signaling cascades responsible for cellular proliferation and interstitial fibrosis in PCK rats. The present results support the potential therapeutic use of ARBs for the

  14. Telmisartan ameliorates fibrocystic liver disease in an orthologous rat model of human autosomal recessive polycystic kidney disease.

    PubMed

    Yoshihara, Daisuke; Kugita, Masanori; Sasaki, Mai; Horie, Shigeo; Nakanishi, Koichi; Abe, Takaaki; Aukema, Harold M; Yamaguchi, Tamio; Nagao, Shizuko

    2013-01-01

    Human autosomal recessive polycystic kidney disease (ARPKD) produces kidneys which are massively enlarged due to multiple cysts, hypertension, and congenital hepatic fibrosis characterized by dilated bile ducts and portal hypertension. The PCK rat is an orthologous model of human ARPKD with numerous fluid-filled cysts caused by stimulated cellular proliferation in the renal tubules and hepatic bile duct epithelia, with interstitial fibrosis developed in the liver. We previously reported that a peroxisome proliferator activated receptor (PPAR)-γ full agonist ameliorated kidney and liver disease in PCK rats. Telmisartan is an angiotensin receptor blocker (ARB) used widely as an antihypertensive drug and shows partial PPAR-γ agonist activity. It also has nephroprotective activity in diabetes and renal injury and prevents the effects of drug-induced hepatotoxicity and hepatic fibrosis. In the present study, we determined whether telmisartan ameliorates progression of polycystic kidney and fibrocystic liver disease in PCK rats. Five male and 5 female PCK and normal control (+/+) rats were orally administered 3 mg/kg telmisartan or vehicle every day from 4 to 20 weeks of age. Treatment with telmisartan decreased blood pressure in both PCK and +/+ rats. Blood levels of aspartate amino transferase, alanine amino transferase and urea nitrogen were unaffected by telmisartan treatment. There was no effect on kidney disease progression, but liver weight relative to body weight, liver cystic area, hepatic fibrosis index, expression levels of Ki67 and TGF-β, and the number of Ki67- and TGF-β-positive interstitial cells in the liver were significantly decreased in telmisartan-treated PCK rats. Therefore, telmisartan ameliorates congenital hepatic fibrosis in ARPKD, possibly through the inhibition of signaling cascades responsible for cellular proliferation and interstitial fibrosis in PCK rats. The present results support the potential therapeutic use of ARBs for the

  15. Urine Eicosanoids in the Metabolic Abnormalities, Telmisartan, and HIV Infection (MATH) Trial

    PubMed Central

    Tseng, Chi-Hong; Milne, Ginger L.

    2017-01-01

    Objectives Arachidonic acid metabolites (eicosanoids) reflect oxidative stress and vascular health and have been associated with anthropometric measures and sex differences in cross-sectional analyses of HIV-infected (HIV+) persons. Telmisartan is an angiotensin receptor blocker and PPAR-γ agonist with potential anti-inflammatory and metabolic benefits. We assessed telmisartan’s effects on urine eicosanoids among HIV+ adults with central adiposity on suppressive antiretroviral therapy enrolled in a prospective clinical trial. Methods Thirty-five HIV+ adults (15 women; 20 men) completed 24 weeks of open-label oral telmisartan 40mg daily. Lumbar computed tomography quantified visceral (VAT) and subcutaneous (SAT) abdominal adipose tissue. Urine F2-isoprostane (F2-IsoP), prostaglandin E2 (PGE-M), prostacyclin (PGI-M), and thromboxane B2 (TxB-M) were quantified at baseline and 24 weeks using gas/liquid chromatography-mass spectroscopy. Mann-Whitney-U tests compared sub-group differences; Spearman’s rho assessed correlations between clinical factors and eicosanoid levels. Results Median PGE-M increased on telmisartan (p<0.01), with greater changes in men (+4.1 [p = 0.03] vs. +1.0 ng/mg cr in women; between-group p = 0.25) and participants losing >5% VAT (+3.7 ng/mg cr, p<0.01) and gaining >5% SAT (+1.7 ng/mg cr, p = 0.04). Median baseline F2-IsoP and TxB-M were slightly higher in women (both between-group p = 0.08) and did not change on telmisartan. Conclusions Urine PGE-M increased with 24 weeks of telmisartan in virally suppressed, HIV+ adults with central adiposity. Associations with favorable fat redistribution suggest increased PGE-M may reflect a beneficial response. PMID:28118376

  16. Telmisartan treatment targets inflammatory cytokines to suppress the pathogenesis of acute colitis induced by dextran sulphate sodium.

    PubMed

    Arumugam, Somasundaram; Sreedhar, Remya; Thandavarayan, Rajarajan A; Giridharan, Vijayasree V; Karuppagounder, Vengadeshprabhu; Pitchaimani, Vigneshwaran; Afrin, Mst Rejina; Miyashita, Shizuka; Nomoto, Mayumi; Harima, Meilei; Suzuki, Hiroshi; Nakamura, Takashi; Nakamura, Masahiko; Suzuki, Kenji; Watanabe, Kenichi

    2015-08-01

    The renin angiotensin system (RAS) is essential for the regulation of cardiovascular and renal functions to maintain the fluid and electrolyte homeostasis. Recent studies have demonstrated a locally expressed RAS in various tissues of mammals, which is having pathophysiological roles in those organ system. Interestingly, local RAS has important role during the inflammatory bowel disease pathogenesis. Further to delineate its role and also to identify the potential effects of telmisartan, an angiotensin receptor blocker, we have used a mouse model of acute colitis induced by dextran sulphate sodium. We have used 0.01 and 5mg/kg body weight doses of telmisartan and administered as enema to facilitate the on-site action and to reduce the systemic adverse effects. Telmisartan high dose treatment significantly reduced the disease activity index score when compared with the colitis control mice. In addition, oxidative stress and endoplasmic reticulum stress markers expression were also significantly reduced when compared with the colitis control mice. Subsequent experiments were carried out to investigate some of the mechanisms underlying its anti-inflammatory effects and identified that the mRNA levels of pro-inflammatory cytokines such as tumour necrosis factor α, interleukin 1β, interleukin 6 and monocyte chemoattractant protein 1 as well as cellular DNA damage were significantly suppressed when compared with the colitis control mice. Similarly the apoptosis marker proteins such as cleaved caspase 3 and 7 levels were down-regulated and anti-apoptotic protein Bcl2 level was significantly upregulated by telmisartan treatment. These results indicate that blockade of RAS by telmisartan can be an effective therapeutic option against acute colitis.

  17. Safety profiling of pioglitazone and telmisartan combination by sub-chronic toxicity study in rat.

    PubMed

    Sengupta, Pinaki; Das, Arindam; Ibrahim, Fuzianna; Mandal, Uttam Kumar; Chatterjee, Bappaditya; Mahmood, Syed; Das, Sreemoy Kanti; Kifayatullah, Muhammad

    2016-11-01

    It has been reported that the major cause of mortality in diabetes is cardiovascular diseases and contribution of hypertension is significant in this context. Pioglitazone, a thiazolidinedione class of therapeutic agent is used to treat type 2 diabetes mellitus. Telmisartan, an angiotensin receptor blocker antihypertensive has been reported to have beneficial effect if co-administered with pioglitazone for the management of diabetes complications. The present research work aims to evaluate the safety/toxicity profile of this combination in rat model. The investigation was carried out after co-administering the drugs to the rats for 28 days at three dose levels of 50, 100 and 150 mg/kg covering low to high dose ranges. Various hematological and biochemical parameters were studied in addition to the histopathology of the major organs in order to evaluate the toxicity profile of the combination. Absence of mortality and histopathological changes as well as unaltered hematological and biochemical parameters was observed. This preliminary investigation concludes that the combination of pioglitazone and telmisartan can primarily be stated as safe in animals, even at the dose level which is several folds higher than the intended human dose. Thus, this combination can be explored in future to develop a rational therapy regimen to treat hypertensive diabetic patients.

  18. Short-term use of telmisartan attenuates oxidation and improves Prdx2 expression more than antioxidant β-blockers in the cardiovascular systems of spontaneously hypertensive rats.

    PubMed

    Yoo, Sae Mi; Choi, Sung Hyun; Jung, Monica Dha Yea; Lim, Sung Cil; Baek, Sang Hong

    2015-02-01

    Reactive oxygen species (ROS) and antioxidant enzymes are required to maintain homeostasis. The loss of this balance can cause excessive ROS production and damage to the cardiovascular tissues. Angiotensin II receptor blockers (ARBs) and β-blockers with antioxidant effects may inhibit ROS in the cardiovascular system. In this study, we directly compared the effects of ARBs and β-blockers with antioxidant properties on cardiovascular protection and the regulation of endothelial progenitor cell (EPC) numbers in the setting of oxidative stress in hypertensive rats. To compare the effects of the drugs, animals were divided into the following groups: Wistar-Kyoto rats (WKY), untreated spontaneously hypertensive rats (SHR) and SHR treated with tempol (TEMP, 5 mg kg(-1) per day), trichlorothiazide (TCTZ, 1.6 mg kg(-1) per day), atenolol (25 mg kg(-1) per day), nebivolol (NEBL, 5 mg kg(-1) per day), carvedilol (CVDL, 30 mg kg(-1) per day) or telmisartan (TERT, 5 mg kg(-1) per day). Following 2 weeks of treatment, blood pressures (BPs) and aortic wall thicknesses were similarly reduced in each antihypertensive drug-treated group. Superoxide anion and malondialdehyde levels were significantly reduced following treatment with NEBL, CVDL and TERT. Additionally, the expression levels of NADPH oxidase subunits were also reduced in the TERT-, CVDL- and NEBL-treated groups. Furthermore, these drugs improved both EPC numbers and the expression levels of peroxiredoxin 2 (Prdx2), an antioxidant enzyme, in the heart and kidneys but not the aorta. Cardiac Prdx2 expression, in particular, was markedly improved by TERT, NEBL and CVDL treatment, and renal Prdx2 expression was enhanced by TEMP. Our data indicate that short-term treatment with TERT may have more beneficial effects on cardiovascular protection, EPC number improvements and Prdx2 expression compared with CVDL and NEBL. In conclusion, TERT may positively modulate the balance between oxidative stress

  19. The dipeptidyl peptidase inhibitor linagliptin and the angiotensin II receptor blocker telmisartan show renal benefit by different pathways in rats with 5/6 nephrectomy.

    PubMed

    Tsuprykov, Oleg; Ando, Ryotaro; Reichetzeder, Christoph; von Websky, Karoline; Antonenko, Viktoriia; Sharkovska, Yuliya; Chaykovska, Lyubov; Rahnenführer, Jan; Hasan, Ahmed A; Tammen, Harald; Alter, Markus; Klein, Thomas; Ueda, Seiji; Yamagishi, Sho-Ichi; Okuda, Seiya; Hocher, Berthold

    2016-05-01

    Dipeptidyl peptidase (DPP)-4 inhibitors delay chronic kidney disease (CKD) progression in experimental diabetic nephropathy in a glucose-independent manner. Here we compared the effects of the DPP-4 inhibitor linagliptin versus telmisartan in preventing CKD progression in non-diabetic rats with 5/6 nephrectomy. Animals were allocated to 1 of 4 groups: sham operated plus placebo; 5/6 nephrectomy plus placebo; 5/6 nephrectomy plus linagliptin; and 5/6 nephrectomy plus telmisartan. Interstitial fibrosis was significantly decreased by 48% with linagliptin but a non-significant 24% with telmisartan versus placebo. The urine albumin-to-creatinine ratio was significantly decreased by 66% with linagliptin and 92% with telmisartan versus placebo. Blood pressure was significantly lowered by telmisartan, but it was not affected by linagliptin. As shown by mass spectrometry, the number of altered peptide signals for linagliptin in plasma was 552 and 320 in the kidney. For telmisartan, there were 108 peptide changes in plasma and 363 in the kidney versus placebo. Linagliptin up-regulated peptides derived from collagen type I, apolipoprotein C1, and heterogeneous nuclear ribonucleoproteins A2/B1, a potential downstream target of atrial natriuretic peptide, whereas telmisartan up-regulated angiotensin II. A second study was conducted to confirm these findings in 5/6 nephrectomy wild-type and genetically deficient DPP-4 rats treated with linagliptin or placebo. Linagliptin therapy in wild-type rats was as effective as DPP-4 genetic deficiency in terms of albuminuria reduction. Thus, linagliptin showed comparable efficacy to telmisartan in preventing CKD progression in non-diabetic rats with 5/6 nephrectomy. However, the underlying pathways seem to be different.

  20. The path to an angiotensin receptor antagonist-neprilysin inhibitor in the treatment of heart failure.

    PubMed

    Braunwald, Eugene

    2015-03-17

    The PARADIGM-HF (Prospective comparison of ARNi with ACEi to Determine Impact on Global Mortality and Morbidity in Heart Failure) trial demonstrated that a new angiotensin receptor antagonist-neprilysin inhibitor was superior to an angiotensin-converting enzyme inhibitor in reducing mortality in patients with heart failure and reduced ejection fraction. This paper traces the research path that culminated in the development of this drug. The first phase, elucidation of the renin-angiotensin-aldosterone system, began with Tigerstedt's discovery of renin, followed by isolation of angiotensin, isolation of angiotensin-converting enzyme, and synthesis of its inhibitors and of angiotensin receptor blockers. Phase 2 began with de Bold's discovery of atrial natriuretic peptide, followed by isolation of the enzyme that degrades it (neprilysin) and its inhibitors. Phase 3 consists of blocking both the renin-angiotensin-aldosterone and atrial natriuretic peptide-degrading systems simultaneously. A molecular complex, LCZ696, developed by scientists at Novartis, combines an angiotensin receptor blocker with a neprilysin inhibitor, is well tolerated, and represents an important step in the management of heart failure and reduced ejection fraction.

  1. Telmisartan inhibits hyperalgesia and inflammatory progression in a diabetic neuropathic pain model of Wistar rats

    PubMed Central

    Al-Rejaie, Salim S.; Abuohashish, Hatem M.; Ahmed, Mohammed M.; Arrejaie, Aws S.; Aleisa, Abdulaziz M.; AlSharari, Shakir D.

    2015-01-01

    Objective: To evaluate the potential therapeutic value of telmisartan (TMT) against diabetic neuropathy (DN) and associated pain in Wistar rats. Methods: Peripheral DN was induced by a single intraperitoneal streptozotocin injection (55 mg/kg), and 3 weeks later TMT treatment was started (5 and 10 mg/kg/day), and continued for 4 weeks. Mechanical nociceptive threshold, motor coordination, and thermal nociceptive threshold tests were performed before and after TMT treatment. In serum, glucose, pro-inflammatory cytokines including tumor necrosis factor-α, interleukin-1β, and interleukin-6 were assessed. Nerve growth factor (NGF) levels and histopathological changes were estimated in the sciatic nerve. This study was conducted at the Experimental Animal Care Center, Department of Pharmacology, College of Pharmacy, King Saud University, Riyadh, Kingdom of Saudi Arabia between January 2013 and May 2014. Results: We observed a significant reduction in mechanical nociceptive threshold, motor coordination, and thermal nociceptive threshold in diabetic animals. The TMT treatment significantly enhanced the reduced mechanical nociceptive threshold. The untreated diabetic animals revealed a significant decrease in sciatic NGF, which was markedly attenuated by TMT. The elevated serum levels of cytokines in diabetic animals were inhibited by the TMT treatments. Histopathological evaluation showed obvious nerve degeneration in the diabetic group that was eliminated in the TMT treated diabetic groups. Conclusion: Telmisartan has a potential neuro-protective effect on peripheral DN; this is mediated through its anti-inflammatory effects and its dual properties as an angiotensin receptor blocker, and a partial peroxisome proliferator activator receptor-g ligand. PMID:25864063

  2. [Assessment of the utilization of angiotensin receptor blockers in hypertension].

    PubMed

    Peña Cabia, S; Ricote Lobera, I; Santos Mena, B; Hidalgo Correas, F J; Climent Florez, B; García Díaz, B

    2013-01-01

    Objetivo: Evaluar en nuestra área de Salud el grado en que la utilización de antagonistas de los receptores de la angiotensina II (ARA-II) se ajusta a los criterios propuestos por la Comunidad Autónoma de Madrid (CAM) antes de la instauración del «Plan de Actuación de ARA-II». Estudiar las indicaciones para las que se prescriben e identificar aquellos factores que han podido influir en su prescripción. Métodos: Estudio de utilización de medicamentos del tipo indicación- prescripción, descriptivo y transversal, en el que se seleccionaron pacientes con hipertensión arterial y en tratamiento con ARA-II ingresados en un Hospital General Universitario durante un periodo de estudio de 3 meses. De acuerdo con las situaciones clínicas recogidas en el Documento de la CAM «Criterios para establecer el lugar en la terapéutica de los antagonistas de los receptores de la angiotensina II», se calculó el porcentaje de pacientes con «prescripción adecuada» y «prescripción no adecuada» de ARA-II y se analizó si la edad y el sexo tenían influencia en el tipo de prescripción o en las principales indicaciones para las que se prescribieron. Resultados: De los 153 pacientes que se incluyeron en el estudio, el 67,3% tuvieron una «prescripción no adecuada», el 47,6% de ellos por prescripción de ARA-II como primer fármaco antagonista del sistema renina angiotensina aldosterona y el 34,0% por mal control de la tensión arterial con inhibidores de la enzima convertidora de angiotensina (IECA). No se encontraron diferencias estadísticamente significativas por edad o sexo en cuanto al tipo de prescripción o en las principales indicaciones para las que se prescribieron. Conclusiones: La adecuación a los criterios de uso del Documento de ARA-II se produjo en el 32,7% de los casos. Además, no se observó que factores como la edad y el sexo influyeran en el tipo de prescripción. Asimismo, se evidenciaron percep-

  3. Cardiovascular and cerebrovascular outcomes of long-term angiotensin receptor blockade: meta-analyses of trials in essential hypertension.

    PubMed

    Akioyamen, Leo; Levine, Mitchell; Sherifali, Diana; O'Reilly, Daria; Frankfurter, Claudia; Pullenayegum, Eleanor; Goeree, Ron; Tsoi, Bernice

    2016-01-01

    Angiotensin receptor blockers (ARBs) are widely used in managing essential hypertension, with considerable evidence available on their short-term efficacy in lowering blood pressure (BP). However, there currently exists limited "pooled" data examining the long-term efficacy of ARB treatment in controlling BP or mitigating cardiovascular and cerebrovascular events. The purpose of this study was to conduct a systematic review and meta-analysis assessing the long-term effects of ARBs as a class on BP control, myocardial infarction, hospitalization for heart failure, cerebrovascular events (ie, stroke), cardiovascular mortality, and all-cause mortality. MEDLINE, EMBASE, PubMed, and the Cochrane Library databases were searched from inception to March 2015. Two evaluators independently reviewed studies for eligibility. Randomized controlled hypertension trials were included if they reported on ARB efficacy in either BP control (relative to placebo for periods ≥ 6 months) or cardiovascular/cerebrovascular outcomes (relative to non-ARB antihypertensive therapies for periods ≥ 24 months). Studies were pooled with a random-effects model using weighted mean differences (WMDs) and relative risks for continuous and dichotomous outcomes, respectively. A total of 11 articles were included in the narrative synthesis, representing seven unique trials (16,864 participants). Six ARB agents were studied: candesartan, eprosartan, irbesartan, olmesartan, losartan (each represented by one trial arm), and telmisartan (represented by two arms). ARB therapy significantly reduced mean systolic BP (WMD: -4.86; 95% CI: -6.19, -3.53 mm Hg) and diastolic BP (WMD: -2.75; 95% CI: -3.65, -1.86 mm Hg] compared to placebo. The risk of stroke was reduced by 21% in the ARB group compared with alternative antihypertensives (risk ratio: 0.79; 95% CI: 0.66, 0.96). ARBs did not, however, produce statistically significant reductions in the risk of myocardial infarction, heart failure hospitalization, or

  4. Angiotensin Receptors: Structure, Function, Signaling and Clinical Applications

    PubMed Central

    Singh, Khuraijam Dhanachandra; Karnik, Sadashiva S

    2016-01-01

    Angiotensinogen – a serpin family protein predominantly produced by the liver is systematically processed by proteases of the Renin Angiotensin system (RAS) generating hormone peptides. Specific cell surface receptors for at least three distinct angiotensin peptides produce distinct cellular signals that regulate system-wide physiological response to RAS. Two well characterized receptors are angiotensin type 1 receptor (AT1 receptor) and type 2 receptor (AT2 receptor). They respond to the octapeptide hormone angiotensin II. The oncogene product MAS is a putative receptor for Ang (1–7). While these are G-protein coupled receptors (GPCRs), the in vivo angiotensin IV binding sites may be type 2 transmembrane proteins. These four receptors together regulate cardiovascular, hemodynamic, neurological, renal, and endothelial functions; as well as cell proliferation, survival, matrix-cell interactions and inflammation. Angiotensin receptors are important therapeutic targets for several diseases. Thus, researchers and pharmaceutical companies are focusing on drugs targeting AT1 receptor than AT2 receptor, MAS and AngIV binding sites. AT1 receptor blockers are the cornerstone of current treatment for hypertension, heart failure, renal failure and many types of vascular diseases including atherosclerosis, aortic aneurism and Marfan syndrome. PMID:27512731

  5. Angiotensin receptor blockade attenuates cigarette smoke-induced lung injury and rescues lung architecture in mice.

    PubMed

    Podowski, Megan; Calvi, Carla; Metzger, Shana; Misono, Kaori; Poonyagariyagorn, Hataya; Lopez-Mercado, Armando; Ku, Therese; Lauer, Thomas; McGrath-Morrow, Sharon; Berger, Alan; Cheadle, Christopher; Tuder, Rubin; Dietz, Harry C; Mitzner, Wayne; Wise, Robert; Neptune, Enid

    2012-01-01

    Chronic obstructive pulmonary disease (COPD) is a prevalent smoking-related disease for which no disease-altering therapies currently exist. As dysregulated TGF-β signaling associates with lung pathology in patients with COPD and in animal models of lung injury induced by chronic exposure to cigarette smoke (CS), we postulated that inhibiting TGF-β signaling would protect against CS-induced lung injury. We first confirmed that TGF-β signaling was induced in the lungs of mice chronically exposed to CS as well as in COPD patient samples. Importantly, key pathological features of smoking-associated lung disease in patients, e.g., alveolar injury with overt emphysema and airway epithelial hyperplasia with fibrosis, accompanied CS-induced alveolar cell apoptosis caused by enhanced TGF-β signaling in CS-exposed mice. Systemic administration of a TGF-β-specific neutralizing antibody normalized TGF-β signaling and alveolar cell death, conferring improved lung architecture and lung mechanics in CS-exposed mice. Use of losartan, an angiotensin receptor type 1 blocker used widely in the clinic and known to antagonize TGF-β signaling, also improved oxidative stress, inflammation, metalloprotease activation and elastin remodeling. These data support our hypothesis that inhibition of TGF-β signaling through angiotensin receptor blockade can attenuate CS-induced lung injury in an established murine model. More importantly, our findings provide a preclinical platform for the development of other TGF-β-targeted therapies for patients with COPD.

  6. [Angiotensin-receptor- and neprilysin-inhibition: a new option against heart failure].

    PubMed

    Bruhn, Claudia

    2016-01-01

    The molecular combination of sacubitril and valsartan (Entresto) is a new drug for reducing the risk of cardiovascular death and hospitalization for heart failure in patients with chronic heart failure (NYHA Class II-IV) and reduced ejection fraction. It is usually administered in conjunction with other heart failure therapies, instead of an ACE inhibitor or an angiotensin-receptor blocker (ARB). In studies, sacubitril/ valsartan was superior to enalapril in reducing the risks of death and hospitalization for heart failure. Possible side effects of sacubitril/valsartan are hypotension, angioedema, impaired renal function and elevation in serum potassium levels. The drug should not be used in times of pregnancy and breast feeding, in patients with servere hepatic impairment (Child-Pugh C) and in combination with aliskiren in patients with diabetes.

  7. Effects of age and sex on the pharmacokinetics of LCZ696, an angiotensin receptor neprilysin inhibitor.

    PubMed

    Gan, Lu; Langenickel, Thomas; Petruck, Jesika; Kode, Kiran; Rajman, Iris; Chandra, Priya; Zhou, Wei; Rebello, Sam; Sunkara, Gangadhar

    2016-01-01

    LCZ696, a novel angiotensin receptor neprilysin inhibitor, is in development for the treatment of heart failure. Administration of LCZ696 results in systemic exposure to sacubitril (inactive prodrug of LBQ657), LBQ657 (neprilysin inhibitor), and valsartan (angiotensin II receptor blocker). We investigated the potential effects of age and sex on the pharmacokinetics of LCZ696 analytes (LBQ657 and valsartan) in an open-label, single oral dose (400 mg), parallel-group study in healthy subjects. Among 36 enrolled subjects, there were 19 male and 17 female subjects; 18 subjects were 18-45 years old (young), and 18 subjects were 65 years of age or older (elderly). Compared with young subjects, the AUCinf and T1/2 for LBQ657 were 42% and 30% greater, respectively, in elderly subjects. The Cmax for LBQ657 was similar between age groups. The AUCinf, Cmax, and T1/2 for valsartan were 30%, 24% greater, and 3.35 hours longer, respectively, in the elderly when compared with young subjects. All pharmacokinetic parameters of LCZ696 analytes (LBQ657 and valsartan) were similar between male and female subjects, indicating no effect on the pharmacokinetics of LCZ696 analytes based on sex. Considering the magnitude of change and its clinical significance, dose adjustment based on age or sex is not considered necessary.

  8. Angiotensin receptor neprilysin inhibition in heart failure: mechanistic action and clinical impact.

    PubMed

    Buggey, Jonathan; Mentz, Robert J; DeVore, Adam D; Velazquez, Eric J

    2015-09-01

    Heart failure (HF) is an increasingly common syndrome associated with high mortality and economic burden, and there has been a paucity over the past decade of new pharmacotherapies that improve outcomes. However, recent data from a large randomized controlled trial compared the novel agent LCZ696, a dual-acting angiotensin receptor blocker and neprilysin inhibitor (ARNi), with the well established angiotensin-converting enzyme (ACE) inhibitor enalapril and found significant reduction in mortality among the chronic reduced ejection fraction HF population. Preclinical and clinical data suggest that neprilysin inhibition provides beneficial outcomes in HF patients by preventing the degradation of natriuretic peptides and thereby promoting natriuresis and vasodilatation and counteracting the negative cardiorenal effects of the up-regulated renin-angiotensin-aldosterone system. Agents such as omapatrilat combined neprilysin and ACE inhibition but had increased rates of angioedema. Goals of an improved safety profile provided the rationale for the development of the ARNi LCZ696. Along with significant reductions in mortality and hospitalizations, clinical trials suggest that LCZ696 may improve surrogate markers of HF severity. In this paper, we review the preclinical and clinical data that led to the development of LCZ696, the understanding of the underlying mechanistic action, and the robust clinical impact that LCZ696 may have in the near future.

  9. An update on non-peptide angiotensin receptor antagonists and related RAAS modulators.

    PubMed

    Aulakh, G K; Sodhi, R K; Singh, M

    2007-08-02

    The renin-angiotensin-aldosterone-system (RAAS) is an important regulator of blood pressure and fluid-electrolyte homeostasis. RAAS has been implicated in pathogenesis of hypertension, congestive heart failure, and chronic renal failure. Aliskiren is the first non-peptide orally active renin inhibitor approved by FDA. Angiotensin Converting Enzyme (ACE) Inhibitors are associated with frequent side effects such as cough and angio-oedema. Recently, the role of ACE2 and neutral endopeptidase (NEP) in the formation of an important active metabolite/mediator of RAAS, ang 1-7, has initiated attempts towards development of ACE2 inhibitors and combined ACE/NEP inhibitors. Furukawa and colleagues developed a series of low molecular weight nonpeptide imidazole analogues that possess weak but selective, competitive AT1 receptor blocking property. Till date, many compounds have exhibited promising AT1 blocking activity which cause a more complete RAAS blockade than ACE inhibitors. Many have reached the market for alternative treatment of hypertension, heart failure and diabetic nephropathy in ACE inhibitor intolerant patients and still more are waiting in the queue. But, the hallmark of this area of drug research is marked by a progress in understanding molecular interaction of these blockers at the AT1 receptor and unraveling the enigmatic influence of AT2 receptors on growth/anti-growth, differentiation and the regeneration of neuronal tissue. Different modeling strategies are underway to develop tailor made molecules with the best of properties like Dual Action (Angiotensin And Endothelin) Receptor Antagonists (DARA), ACE/NEP inhibitors, triple inhibitors, AT2 agonists, AT1/TxA2 antagonists, balanced AT1/AT2 antagonists, and nonpeptide renin inhibitors. This abstract gives an overview of these various angiotensin receptor antagonists.

  10. Aging-related dysregulation of dopamine and angiotensin receptor interaction.

    PubMed

    Villar-Cheda, Begoña; Dominguez-Meijide, Antonio; Valenzuela, Rita; Granado, Noelia; Moratalla, Rosario; Labandeira-Garcia, Jose L

    2014-07-01

    It is not known whether the aging-related decrease in dopaminergic function leads to the aging-related higher vulnerability of dopaminergic neurons and risk for Parkinson's disease. The renin-angiotensin system (RAS) plays a major role in the inflammatory response, neuronal oxidative stress, and dopaminergic vulnerability via type 1 (AT1) receptors. In the present study, we observed a counterregulatory interaction between dopamine and angiotensin receptors. We observed overexpression of AT1 receptors in the striatum and substantia nigra of young adult dopamine D1 and D2 receptor-deficient mice and young dopamine-depleted rats, together with compensatory overexpression of AT2 receptors or compensatory downregulation of angiotensinogen and/or angiotensin. In aged rats, we observed downregulation of dopamine and dopamine receptors and overexpression of AT1 receptors in aged rats, without compensatory changes observed in young animals. L-Dopa therapy inhibited RAS overactivity in young dopamine-depleted rats, but was ineffective in aged rats. The results suggest that dopamine may play an important role in modulating oxidative stress and inflammation in the substantia nigra and striatum via the RAS, which is impaired by aging.

  11. Sex chromosome complement involvement in angiotensin receptor sexual dimorphism.

    PubMed

    Dadam, Florencia M; Cisternas, Carla D; Macchione, Ana F; Godino, Andrea; Antunes-Rodrigues, José; Cambiasso, María J; Vivas, Laura M; Caeiro, Ximena E

    2017-02-27

    This study aimed to define whether sex chromosome complement (SCC) may differentially modulate sex differences in relative gene expression of basal Agtr1a, Agtr2, and Mas1 receptors at fore/hindbrain nuclei and at medulla/cortical kidney. Samples were collected from gonadectomized male (XX and XY) and female (XX and XY) mice of the "four core genotypes" model. At brain level, a SCC effect at the area postrema was demonstrated. An increase in mRNA level of Agtr1a and Agtr1a/Agtr2 ratio in XY-SCC mice was associated with a decrease in Mas1 compared to XX-SCC mice. In the renal cortex, a SCC effect for Agtr2 and Mas1 was observed. Regardless of sex (male or female), XX-SCC mice expressed higher levels of mRNA Agtr2 and Mas1 than XY-SCC mice {F(1,12) = 6,126,p < 0.05; F(1,21) = 5,143,p < 0.05}. Furthermore, XX-female mice showed a significant increase in Mas1 expression compared to XY-female mice. These results reveal a SCC modulatory effect at central and kidney level on angiotensin receptor expression, with an enhancement of the vasodilatory arm in XX-mice and an increase in the vasoconstriction arm in XY-mice, which may underlie sex differences in the regulation of arterial pressure.

  12. Angiotensin Receptor Blockade Recovers Hepatic UCP2 Expression and Aconitase and SDH Activities and Ameliorates Hepatic Oxidative Damage in Insulin Resistant Rats

    PubMed Central

    Montez, Priscilla; Vázquez-Medina, José Pablo; Rodríguez, Rubén; Thorwald, Max A.; Viscarra, José A.; Lam, Lisa; Peti-Peterdi, Janos; Nakano, Daisuke; Nishiyama, Akira

    2012-01-01

    Metabolic syndrome (MetS) is commonly associated with elevated renin-angiotensin system, oxidative stress, and steatohepatitis with down-regulation of uncoupling proteins (UCPs). However, the mechanisms linking renin-angiotensin system, steatosis, and UCP2 to hepatic oxidative damage during insulin resistance are not described. To test the hypothesis that angiotensin receptor activation contributes to decreased hepatic UCP2 expression and aconitase activity and to increased oxidative damage after increased glucose intake in a model of MetS, lean and obese Long Evans rats (n = 10/group) were randomly assigned to the following groups: 1) untreated Long Evans Tokushima Otsuka (lean, strain control), 2) untreated Otsuka Long Evans Tokushima Fatty (OLETF) (MetS model), 3) OLETF + angiotensin receptor blocker (ARB) (10 mg olmesartan/kg·d × 6 wk), 4) OLETF + high glucose (HG) (5% in drinking water × 6 wk), and 5) OLETF + ARB + HG (ARB/HG × 6 wk). HG increased body mass (37%), plasma triglycerides (TGs) (35%), plasma glycerol (87%), plasma free fatty acids (28%), and hepatic nitrotyrosine (74%). ARB treatment in HG decreased body mass (12%), plasma TG (15%), plasma glycerol (23%), plasma free fatty acids (14%), and hepatic TG content (42%), suggesting that angiotensin receptor type 1 (AT1) activation and increased adiposity contribute to the development of obesity-related dyslipidemia. ARB in HG also decreased hepatic nitrotyrosine and increased hepatic UCP2 expression (59%) and aconitase activity (40%), as well as antioxidant enzyme activities (50-120%), suggesting that AT1 activation also contributes to protein oxidation, impaired lipid metabolism, and antioxidant metabolism in the liver. Thus, in addition to promoting obesity-related hypertension, AT1 activation may also impair lipid metabolism and antioxidant capacity, resulting in steatosis via decreased UCP2 and tricarboxylic acid cycle activity. PMID:23087176

  13. Angiotensin receptor blockade recovers hepatic UCP2 expression and aconitase and SDH activities and ameliorates hepatic oxidative damage in insulin resistant rats.

    PubMed

    Montez, Priscilla; Vázquez-Medina, José Pablo; Rodríguez, Rubén; Thorwald, Max A; Viscarra, José A; Lam, Lisa; Peti-Peterdi, Janos; Nakano, Daisuke; Nishiyama, Akira; Ortiz, Rudy M

    2012-12-01

    Metabolic syndrome (MetS) is commonly associated with elevated renin-angiotensin system, oxidative stress, and steatohepatitis with down-regulation of uncoupling proteins (UCPs). However, the mechanisms linking renin-angiotensin system, steatosis, and UCP2 to hepatic oxidative damage during insulin resistance are not described. To test the hypothesis that angiotensin receptor activation contributes to decreased hepatic UCP2 expression and aconitase activity and to increased oxidative damage after increased glucose intake in a model of MetS, lean and obese Long Evans rats (n = 10/group) were randomly assigned to the following groups: 1) untreated Long Evans Tokushima Otsuka (lean, strain control), 2) untreated Otsuka Long Evans Tokushima Fatty (OLETF) (MetS model), 3) OLETF + angiotensin receptor blocker (ARB) (10 mg olmesartan/kg·d × 6 wk), 4) OLETF + high glucose (HG) (5% in drinking water × 6 wk), and 5) OLETF + ARB + HG (ARB/HG × 6 wk). HG increased body mass (37%), plasma triglycerides (TGs) (35%), plasma glycerol (87%), plasma free fatty acids (28%), and hepatic nitrotyrosine (74%). ARB treatment in HG decreased body mass (12%), plasma TG (15%), plasma glycerol (23%), plasma free fatty acids (14%), and hepatic TG content (42%), suggesting that angiotensin receptor type 1 (AT1) activation and increased adiposity contribute to the development of obesity-related dyslipidemia. ARB in HG also decreased hepatic nitrotyrosine and increased hepatic UCP2 expression (59%) and aconitase activity (40%), as well as antioxidant enzyme activities (50-120%), suggesting that AT1 activation also contributes to protein oxidation, impaired lipid metabolism, and antioxidant metabolism in the liver. Thus, in addition to promoting obesity-related hypertension, AT1 activation may also impair lipid metabolism and antioxidant capacity, resulting in steatosis via decreased UCP2 and tricarboxylic acid cycle activity.

  14. Is angiotensin-converting enzyme inhibitors/angiotensin receptor blockers therapy protective against prostate cancer?

    PubMed Central

    Mao, Yeqing; Xu, Xin; Wang, Xiao; Zheng, Xiangyi; Xie, Liping

    2016-01-01

    Emerging evidence suggests that renin-angiotensin system (RAS) may act as a molecular and therapeutic target for treating site-specific cancers, including prostate cancer. However, previous observational studies regarding the association between RAS inhibitors and prostate cancer risk have reported inconsistent results. We examined this association by performing a systematic review and meta-analysis. A total of 20,267 patients from nine cohort studies were enrolled. Compared with non-users of RAS inhibitors, individuals using RAS inhibitors had a reduced risk of prostate cancer (RR 0.92, 95 % CI 0.87-0.98), without statistically significant heterogeneity among studies (P = 0.118 for heterogeneity, I2 = 37.6 %). In addition, when subgroup analyses by study quality and number of cases, more statistically significant associations were observed in studies of high quality (RR 0.93, 95 % CI 0.88-0.97) and large sample size (RR 0.94, 95 % CI 0.91-0.98). There was no evidence of significant publication bias with Begg's test (P = 0.602) or with Egger's test (P = 0.350). Overall, this study indicates that use of RAS inhibitors may be associated with a decreased risk of prostate cancer. Large-scale well designed studies are needed to further explore this association. PMID:26760503

  15. Angiotensin receptor agonistic autoantibodies and hypertension: preeclampsia and beyond.

    PubMed

    Xia, Yang; Kellems, Rodney E

    2013-06-21

    Hypertensive disorders are life-threatening diseases with high morbidity and mortality, affecting billions of individuals worldwide. A multitude of underlying conditions may contribute to hypertension, thus the need for a plethora of treatment options to identify the approach that best meets the needs of individual patients. A growing body of evidence indicates that (1) autoantibodies that bind to and activate the major angiotensin II type I (AT₁) receptor exist in the circulation of patients with hypertensive disorders, (2) these autoantibodies contribute to disease pathophysiology, (3) antibody titers correlate to the severity of the disease, and (4) efforts to block or remove these pathogenic autoantibodies have therapeutic potential. These autoantibodies, termed AT₁ agonistic autoantibodies have been extensively characterized in preeclampsia, a life-threatening hypertensive condition of pregnancy. As reviewed here, these autoantibodies cause symptoms of preeclampsia when injected into pregnant mice. Somewhat surprisingly, these auto antibodies also appear in 3 animal models of preeclampsia. However, the occurrence of AT₁ agonistic autoantibodies is not restricted to pregnancy. These autoantibodies are prevalent among kidney transplant recipients who develop severe transplant rejection and malignant hypertension during the first week after transplantation. AT₁ agonistic autoantibodies are also highly abundant among a group of patients with essential hypertension that are refractory to standard therapy. More recently these autoantibodies have been seen in patients with the autoimmune disease, systemic sclerosis. These 3 examples extend the clinical impact of AT₁ agonistic autoantibodies beyond pregnancy. Research reviewed here raises the intriguing possibility that preeclampsia and other hypertensive conditions are autoimmune diseases characterized by the presence of pathogenic autoantibodies that activate the major angiotensin receptor, AT₁. These

  16. Telmisartan ameliorates glutamate-induced neurotoxicity: roles of AT1 receptor blockade and PPARγ activation

    PubMed Central

    Wang, Juan; Pang, Tao; Hafko, Roman; Benicky, Julius; Sanchez-Lemus, Enrique; Saavedra, Juan M.

    2014-01-01

    Sartans (Angiotensin II AT1 Receptor Blockers, ARBs) are powerful neuroprotective agents in vivo and protect against IL-1β neurotoxicity in vitro. The purpose of this research was to determine the extent of sartan neuroprotection against glutamate excitotoxicity, a common cause of neuronal injury and apoptosis. The results show that sartans are neuroprotective, significantly reducing glutamate-induced neuronal injury and apoptosis in cultured rat primary cerebellar granule cells (CGCs). Telmisartan was the most potent sartan studied, with an order of potency telmisartan > candesartan > losartan > valsartan. Mechanisms involved reduction of pro-apoptotic caspase-3 activation, protection of the survival PI3K/Akt/GSK-3β pathway, and prevention of glutamate-induced ERK1/2 activation. NMDA receptor stimulation was essential for glutamate-induced cell injury and apoptosis. Participation of AT1A receptor was supported by glutamate-induced upregulation of AT1A gene expression and AT1 receptor binding. Conversely, AT1B or AT2 receptor played no role. Glutamate-induced neuronal injury and the neuroprotective effect of telmisartan were decreased, but not abolished, in CGCs obtained from AT1A knock-out mice. This indicates that although AT1 receptors are necessary for glutamate to exert its full neurotoxic potential, part of the neuroprotective effect of telmisartan is independent of AT1 receptor blockade. PPARγ activation was also involved in the neuroprotective effects of telmisartan, as telmisartan enhanced PPARγ nuclear translocation, and the PPARγ antagonist GW9662 partially reversed the neuroprotective effects of telmisartan. The present results substantiate the therapeutic use of sartans, in particular telmisartan, in neurodegenerative diseases and traumatic brain disorders where glutamate neurotoxicity plays a significant role. PMID:24316465

  17. LCZ696, a First-in-Class Angiotensin Receptor-Neprilysin Inhibitor: The First Clinical Experience in Patients With Severe Hypertension.

    PubMed

    Kario, Kazuomi; Tamaki, Yuko; Okino, Naoko; Gotou, Hiromi; Zhu, Min; Zhang, Jack

    2016-04-01

    The safety of LCZ696, a novel angiotensin receptor-neprilysin inhibitor, was evaluated for the first time in patients with severe hypertension in this 8-week, multicenter, open-label study. Thirty-five Japanese patients with either office systolic blood pressure (SBP) ≥180 mm Hg or diastolic blood pressure (DBP) ≥110 mm Hg received LCZ696 200 mg. If blood pressure was uncontrolled, the LCZ696 dose was increased to 400 mg after 2 weeks (if there were no safety concerns; n=32), followed by an optional addition of another antihypertensive drug (except angiotensin receptor blocker and angiotensin-converting enzyme inhibitor) after 4 weeks (n=21). Reductions in office SBP/DBP (baseline, 173.4 mm Hg/112.4 mm Hg) and pulse pressure (baseline, 61.0 mm Hg) at week 8 were 35.3/22.1 mm Hg and 13.2 mm Hg, respectively. The overall incidence of adverse events was 48.6% with no reports of dizziness, hypotension, or angioedema. The LCZ696-based regimen was generally well-tolerated and could present a treatment option for severe hypertension in Asian patients especially in reducing SBP and pulse pressure.

  18. Molecular classification of an elasmobranch angiotensin receptor: quantification of angiotensin receptor and natriuretic peptide receptor mRNAs in saltwater and freshwater populations of the Atlantic stingray.

    PubMed

    Evans, Andrew N; Henning, Toni; Gelsleichter, James; Nunez, B Scott

    2010-12-01

    Among the most conserved osmoregulatory hormone systems in vertebrates are the renin-angiotensin system (RAS) and the natriuretic peptides (NPs). We examined the RAS and NP system in the euryhaline Atlantic stingray, Dasyatis sabina (Lesueur). To determine the relative sensitivity of target organs to these hormonal systems, we isolated cDNA sequences encoding the D. sabina angiotensin receptor (AT) and natriuretic peptide type-B receptor (NPR-B). We then determined the tissue-specific expression of their mRNAs in saltwater D. sabina from local Texas waters and an isolated freshwater population in Lake Monroe, Florida. AT mRNA was most abundant in interrenal tissue from both populations. NPR-B mRNA was most abundant in rectal gland tissue from both populations, and also highly abundant in the kidney of saltwater D. sabina. This study is the first to report the sequence of an elasmobranch angiotensin receptor, and phylogenetic analysis indicates that the D. sabina receptor is more similar to AT(1) vs. AT(2) proteins. This classification is further supported by molecular analysis of AT(1) and AT(2) proteins demonstrating conservation of AT(1)-specific amino acid residues and motifs in D. sabina AT. Molecular classification of the elasmobranch angiotensin receptor as an AT(1)-like protein provides fundamental insight into the evolution of the vertebrate RAS.

  19. Telmisartan in the management of diabetic nephropathy: a contemporary view.

    PubMed

    Balakumar, Pitchai; Bishnoi, Harish K; Mahadevan, Nanjaian

    2012-05-01

    Diabetic nephropathy, a complex disorder with heterogeneous etiologies, remains one of the most threatening diseases worldwide. There were around 177 million people with diabetes mellitus worldwide, and it has been estimated to be increased to 360 million by 2030. Given that about 20-30% of these people develop diabetic nephropathy, the present treatment protocols primarily aim for an efficient glucose and blood pressure control to arrest the initiation and progression of diabetic nephropathy. The treatment of diabetic nephropathy near the beginning at microalbuminuria stage with angiotensin-II-AT1 receptor blockers (ARBs) improves blood pressure control and halts disease progression of diabetic nephropathy. In fact, ARBs exert renoprotective effects independently of their blood pressure lowering effect, as they have direct defensive action on the diabetic kidney. Indubitably, it would be better if an ARB has both glucose-lowering and blood pressure controlling potentials efficiently. Intriguingly, telmisartan has such possessions considering its dual role of AT1 receptor blocking action and peroxisome proliferator-activated receptor gamma (PPARγ) partial agonistic property. The additional PPARγ agonistic potential of telmisartan could make it a distinctive intervention in the ARB class to prevent the progression of diabetic nephropathy through activation of PPARγ-mediated insulin sensitization, and renal anti-inflammatory and anti-oxidant actions. Indeed, telmisartan reduced insulin resistance and glucose intolerance, and halted the progressive renal dysfunction associated with diabetic nephropathy by inhibiting the incidence of albuminuria, and preventing the progression of glomerulosclerosis, renal interstitial inflammation and fibrosis. This review will discuss the current status of therapeutic potentials of telmisartan in treating diabetic nephropathy.

  20. Angiotensin receptor-neprilysin inhibitor (ARNi): Clinical studies on a new class of drugs.

    PubMed

    Gori, Mauro; Volterrani, Maurizio; Piepoli, Massimo; Senni, Michele

    2017-01-01

    Sacubritil∗valsartan (Entresto, Novartis, still commonly referred to as LCZ696) is a combination drug described as a new class of dual-acting angiotensin receptor-neprilysin inhibitor (ARNi). This combination drug has been successfully studied in patients with heart failure with both preserved (HFpEF) and reduced ejection fraction (HFrEF). In this review, the evidences in patients with HFpEF and HFrEF are summarized, including the results of more recent studies.

  1. Structure of the Angiotensin Receptor Revealed by Serial Femtosecond Crystallography

    DOE PAGES

    Zhang, Haitao; Unal, Hamiyet; Gati, Cornelius; ...

    2015-05-07

    We report that angiotensin II type 1 receptor (AT1R) is a G protein-coupled receptor that serves as a primary regulator for blood pressure maintenance. Although several anti-hypertensive drugs have been developed as AT1R blockers (ARBs), the structural basis for AT1R ligand-binding and regulation has remained elusive, mostly due to the difficulties of growing high quality crystals for structure determination using synchrotron radiation. By applying the recently developed method of serial femtosecond crystallography at an X-ray free-electron laser, we successfully determined the room-temperature crystal structure of the human AT1R in complex with its selective antagonist ZD7155 at 2.9 Å resolution. Themore » AT1R-ZD7155 complex structure revealed key structural features ofAT1R and critical interactions for ZD7155 binding. Finally, docking simulations of the clinically used ARBs into the AT1R structure further elucidated both the common and distinct binding modes for these anti-hypertensive drugs. Our results thereby provide fundamental insights into AT1R structure-function relationship and structure-based drug design.« less

  2. Structure of the Angiotensin Receptor Revealed by Serial Femtosecond Crystallography

    SciTech Connect

    Zhang, Haitao; Unal, Hamiyet; Gati, Cornelius; Han, Gye Won; Liu, Wei; Zatsepin, Nadia A.; James, Daniel; Wang, Dingjie; Nelson, Garrett; Weierstall, Uwe; Sawaya, Michael R.; Xu, Qingping; Messerschmidt, Marc; Williams, Garth J.; Boutet, Sébastien; Yefanov, Oleksandr M.; White, Thomas A.; Wang, Chong; Ishchenko, Andrii; Tirupula, Kalyan C.; Desnoyer, Russell; Coe, Jesse; Conrad, Chelsie E.; Fromme, Petra; Stevens, Raymond C.; Katritch, Vsevolod; Karnik, Sadashiva S.; Cherezov, Vadim

    2015-05-07

    We report that angiotensin II type 1 receptor (AT1R) is a G protein-coupled receptor that serves as a primary regulator for blood pressure maintenance. Although several anti-hypertensive drugs have been developed as AT1R blockers (ARBs), the structural basis for AT1R ligand-binding and regulation has remained elusive, mostly due to the difficulties of growing high quality crystals for structure determination using synchrotron radiation. By applying the recently developed method of serial femtosecond crystallography at an X-ray free-electron laser, we successfully determined the room-temperature crystal structure of the human AT1R in complex with its selective antagonist ZD7155 at 2.9 Å resolution. The AT1R-ZD7155 complex structure revealed key structural features ofAT1R and critical interactions for ZD7155 binding. Finally, docking simulations of the clinically used ARBs into the AT1R structure further elucidated both the common and distinct binding modes for these anti-hypertensive drugs. Our results thereby provide fundamental insights into AT1R structure-function relationship and structure-based drug design.

  3. Effects of Antihypertensive Agents on Intestinal Contractility in the Spontaneously Hypertensive Rat: Angiotensin Receptor System Downregulation by Losartan.

    PubMed

    Patten, Glen Stephen; Abeywardena, Mahinda Yapa

    2017-02-01

    Hypertension is an inflammatory condition controlled by the renin angiotensin system and is linked to kidney disease, diabetes mellitus, and recently to dysfunction of the gut. The aim of this study was to determine what effect antihypertensive drug treatments may have on intestinal function of the spontaneously hypertensive rat (SHR). In the first experiment, SHRs were treated with enalapril, hydralazine, or with no treatment as a control. In the second experiment, SHRs were treated with losartan or with no treatment as a control. All drug treatments led to significant lowering of blood pressure after 16 weeks. At termination, intact tissue sections of the ileum and colon were induced to contract ex vivo by KCl; electrical stimulation; and agonists carbachol, angiotensin II, and prostaglandin E2 (PGE2). There were no differences in ileal or colonic contractility due to hydralazine or enalapril compared with no-treatment SHR control. However, for the ileum, the losartan group responded significantly more to KCl and carbachol while responding less to angiotensin II, with no difference for PGE2 compared with the no-treatment SHR control. In contrast, the colon responded similarly to KCl, electrical stimulation, and PGE2 but responded significantly less to angiotensin II. These results demonstrate that the ileum responds differently (with KCl and carbachol as agonists) to the colon after losartan treatment, whereas there is a reduced contractile response in both the ileum and colon following losartan treatment. Although there are few well documented major contraindications for angiotensin receptor blockers, the modulation of gut contractility by losartan may have wider implications for bowel health.

  4. Effects of Antihypertensive Agents on Intestinal Contractility in the Spontaneously Hypertensive Rat: Angiotensin Receptor System Downregulation by Losartan

    PubMed Central

    Abeywardena, Mahinda Yapa

    2017-01-01

    Hypertension is an inflammatory condition controlled by the renin angiotensin system and is linked to kidney disease, diabetes mellitus, and recently to dysfunction of the gut. The aim of this study was to determine what effect antihypertensive drug treatments may have on intestinal function of the spontaneously hypertensive rat (SHR). In the first experiment, SHRs were treated with enalapril, hydralazine, or with no treatment as a control. In the second experiment, SHRs were treated with losartan or with no treatment as a control. All drug treatments led to significant lowering of blood pressure after 16 weeks. At termination, intact tissue sections of the ileum and colon were induced to contract ex vivo by KCl; electrical stimulation; and agonists carbachol, angiotensin II, and prostaglandin E2 (PGE2). There were no differences in ileal or colonic contractility due to hydralazine or enalapril compared with no-treatment SHR control. However, for the ileum, the losartan group responded significantly more to KCl and carbachol while responding less to angiotensin II, with no difference for PGE2 compared with the no-treatment SHR control. In contrast, the colon responded similarly to KCl, electrical stimulation, and PGE2 but responded significantly less to angiotensin II. These results demonstrate that the ileum responds differently (with KCl and carbachol as agonists) to the colon after losartan treatment, whereas there is a reduced contractile response in both the ileum and colon following losartan treatment. Although there are few well documented major contraindications for angiotensin receptor blockers, the modulation of gut contractility by losartan may have wider implications for bowel health. PMID:27903643

  5. Anti-remodeling effects of rapamycin in experimental heart failure: dose response and interaction with angiotensin receptor blockade.

    PubMed

    Bishu, Kalkidan; Ogut, Ozgur; Kushwaha, Sudhir; Mohammed, Selma F; Ohtani, Tomohito; Xu, Xiaolei; Brozovich, Frank V; Redfield, Margaret M

    2013-01-01

    While neurohumoral antagonists improve outcomes in heart failure (HF), cardiac remodeling and dysfunction progress and outcomes remain poor. Therapies superior or additive to standard HF therapy are needed. Pharmacologic mTOR inhibition by rapamycin attenuated adverse cardiac remodeling and dysfunction in experimental heart failure (HF). However, these studies used rapamycin doses that produced blood drug levels targeted for primary immunosuppression in human transplantation and therefore the immunosuppressive effects may limit clinical translation. Further, the relative or incremental effect of rapamycin combined with standard HF therapies targeting upstream regulators of cardiac remodeling (neurohumoral antagonists) has not been defined. Our objectives were to determine if anti-remodeling effects of rapamycin were preserved at lower doses and whether rapamycin effects were similar or additive to a standard HF therapy (angiotensin receptor blocker (losartan)). Experimental murine HF was produced by transverse aortic constriction (TAC). At three weeks post-TAC, male mice with established HF were treated with placebo, rapamycin at a dose producing immunosuppressive drug levels (target dose), low dose (50% target dose) rapamycin, losartan or rapamycin + losartan for six weeks. Cardiac structure and function (echocardiography, catheterization, pathology, hypertrophic and fibrotic gene expression profiles) were assessed. Downstream mTOR signaling pathways regulating protein synthesis (S6K1 and S6) and autophagy (LC3B-II) were characterized. TAC-HF mice displayed eccentric hypertrophy, systolic dysfunction and pulmonary congestion. These perturbations were attenuated to a similar degree by oral rapamycin doses achieving target (13.3±2.1 ng/dL) or low (6.7±2.5 ng/dL) blood levels. Rapamycin treatment decreased mTOR mediated regulators of protein synthesis and increased mTOR mediated regulators of autophagy. Losartan monotherapy did not attenuate remodeling, whereas

  6. Impact of Short-Term Treatment with Telmisartan on Cerebral Arterial Remodeling in SHR

    PubMed Central

    Foulquier, Sébastien; Lartaud, Isabelle; Dupuis, François

    2014-01-01

    Background and Purpose Chronic hypertension decreases internal diameter of cerebral arteries and arterioles. We recently showed that short-term treatment with the angiotensin II receptor blocker telmisartan restored baseline internal diameter of small cerebral arterioles in spontaneously hypertensive rats (SHR), via reversal of structural remodeling and inhibition of the angiotensin II vasoconstrictor response. As larger arteries also participate in the regulation of cerebral circulation, we evaluated whether similar short-term treatment affects middle cerebral arteries of SHR. Methods Baseline internal diameters of pressurised middle cerebral arteries from SHR and their respective controls, Wistar Kyoto rats (WKY) and responses to angiotensin II were studied in a small vessel arteriograph. Pressure myogenic curves and passive internal diameters were measured following EDTA deactivation, and elastic modulus from stress-strain relationships. Results Active baseline internal diameter was 23% lower in SHR compared to WKY, passive internal diameter (EDTA) 28% lower and elastic modulus unchanged. Pressure myogenic curves were shifted to higher pressure values in SHR. Telmisartan lowered blood pressure but had no effect on baseline internal diameter nor on structural remodeling (passive internal diameter and elastic modulus remained unchanged compared to SHR). Telmisartan shifted the pressure myogenic curve to lower pressure values than SHR. Conclusion In the middle cerebral arteries of SHR, short-term treatment with telmisartan had no effect on structural remodeling and did not restore baseline internal diameter, but allowed myogenic tone to adapt towards lower pressure values. PMID:25333878

  7. Redefining beta-blocker use in hypertension: selecting the right beta-blocker and the right patient.

    PubMed

    Mann, Samuel J

    2017-01-01

    Randomized controlled trials have concluded that the cardiovascular outcome of first-step treatment of hypertension with traditional vasoconstricting beta-blockers is inferior to treatment with other antihypertensive drug classes. Beta-blocker use is also associated with undesirable side effects. Consequently, some recent guidelines consider beta-blockers an inferior option for first-step treatment of hypertension. Despite this, beta-blockers are still widely prescribed, and likely overused, in the management of hypertension. It is the contention of this perspective that beta-blockers do have an important role in treating hypertension, but their use needs to be much better targeted, by better identification of both the right patient and the right beta-blocker. Identifying the right patient involves consideration of underlying mechanisms of hypertension. In the absence of comorbidities for which a beta-blocker is indicated, beta-blockers would not seem to be the preferred treatment for patients with either sodium/volume-mediated hypertension, for which they are usually ineffective, or for those with renin-angiotensin system-mediated hypertension, for which angiotensin-converting enzyme inhibitors and angiotensin receptor blockers provide equal antihypertensive efficacy with evidence of better outcome and fewer adverse effects. Beta-blockers would instead appear to be best suited for patients with sympathetically driven, that is, neurogenic, hypertension, whether as a first-step drug, such as in patients with hypertension in the acute post-stroke period, in so-called "hyperkinetic" patients, and in patients with labile hypertension, or as an add-on drug in patients with resistant hypertension. In choosing among the beta-blockers, combined alpha/beta-blockade offers advantages over beta-blocker monotherapy and merits greater clinical and research attention. Finally, unreliable bioavailability greatly interferes with the effectiveness of lipophilic, but not

  8. Angiotensin receptor-neprilysin inhibitors: clinical potential in heart failure and beyond

    PubMed Central

    Singh, Jagdeep SS; Lang, Chim C

    2015-01-01

    Heart failure remains a major concern across the globe as life expectancies and delivery of health care continue to improve. There has been a dearth of new developments in heart failure therapies in the last decade until last year, with the release of the results from the PARADIGM-HF Trial heralding the arrival of a promising new class of drug, ie, the angiotensin receptor-neprilysin inhibitor. In this review, we discuss the evolution of our incremental understanding of the neurohormonal mechanisms involved in the pathophysiology of heart failure, which has led to our success in modulating its various pathways. We start by examining the renin-angiotensin-aldosterone system, followed by the challenges of modulating the natriuretic peptide system. We then delve deeper into the pharmacology and mechanisms by which angiotensin receptor-neprilysin inhibitors achieve their significant cardiovascular benefits. Finally, we also consider the potential application of this new class of drug in other areas, such as heart failure with preserved ejection fraction, hypertension, patients with renal impairment, and following myocardial infarction. PMID:26082640

  9. Angiotensin receptor-neprilysin inhibitors: clinical potential in heart failure and beyond.

    PubMed

    Singh, Jagdeep S S; Lang, Chim C

    2015-01-01

    Heart failure remains a major concern across the globe as life expectancies and delivery of health care continue to improve. There has been a dearth of new developments in heart failure therapies in the last decade until last year, with the release of the results from the PARADIGM-HF Trial heralding the arrival of a promising new class of drug, ie, the angiotensin receptor-neprilysin inhibitor. In this review, we discuss the evolution of our incremental understanding of the neurohormonal mechanisms involved in the pathophysiology of heart failure, which has led to our success in modulating its various pathways. We start by examining the renin-angiotensin-aldosterone system, followed by the challenges of modulating the natriuretic peptide system. We then delve deeper into the pharmacology and mechanisms by which angiotensin receptor-neprilysin inhibitors achieve their significant cardiovascular benefits. Finally, we also consider the potential application of this new class of drug in other areas, such as heart failure with preserved ejection fraction, hypertension, patients with renal impairment, and following myocardial infarction.

  10. [Efficacy and Safety of a Fixed Combination of Perindopril Arginine and Amlodipine in Patients With Hypertension Uncontrolled by Treatment With Angiotensin II Receptor Blockers in Real Clinical Practice. Results of the PREVOSHODSTVO (SUPERIORITY) Program].

    PubMed

    Ostroumova, O D

    2017-01-01

    The article presents preliminary results of a subanalysis of PREVOSHODSTVO (SUPERIORITY) phase IV study. Aim of this subanalysis was to assess efficacy and tolerability of a fixed-dose perindopril/amlodipine combination (FDPAC) in patients with arterial hypertension (AP) uncontrolled on previous treatment with angiotensin receptor blockers (ARBs).

  11. Is there an embryopathy associated with first-trimester exposure to angiotensin-converting enzyme inhibitors and angiotensin receptor antagonists? A critical review of the evidence.

    PubMed

    Polifka, Janine E

    2012-08-01

    Drugs that interfere with the renin-angiotensin system, such as angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs), are widely used to manage hypertension and heart failure. Adequate functioning of the RAS is essential for normal fetal kidney development. The potential for ACEIs and ARBs to impair fetal and neonatal renal function if taken after the first trimester of pregnancy has been well documented. Although these drugs were not found to be teratogenic in animals, until recently little was known about the teratogenic effects of ACEIs and ARBs in humans when exposure was limited to the first trimester of pregnancy. New evidence from epidemiologic studies indicates that there may be an elevated teratogenic risk when these drugs are taken during the first trimester of pregnancy. However, this elevated risk does not appear to be specific to ACEIs and ARBs, but is instead related to maternal factors and diseases that typically coexist with hypertension in pregnancy, such as diabetes, advanced maternal age, and obesity. Women who become pregnant while being treated with an ACEI or ARB should be advised to avoid exposure to these drugs during the second and third trimesters of pregnancy by switching to a different class of antihypertensive drugs between weeks 8 and 10 after conception.

  12. Angiotensin receptor blockade mediated amelioration of mucopolysaccharidosis type I cardiac and craniofacial pathology

    PubMed Central

    Webber, Beau R.; McElmurry, Ronald T.; Rudser, Kyle D.; DeFeo, Anthony P.; Muradian, Michael; Petryk, Anna; Hallgrimsson, Benedikt; Blazar, Bruce R.; Tolar, Jakub

    2017-01-01

    Mucopolysaccharidosis type I (MPS IH) is a lysosomal storage disease (LSD) caused by inactivating mutations to the alpha-L-iduronidase (IDUA) gene. Treatment focuses on IDUA enzyme replacement and currently employed methods can be non-uniform in their efficacy particularly for the cardiac and craniofacial pathology. Therefore, we undertook efforts to better define the pathological cascade accounting for treatment refractory manifestations and demonstrate a role for the renin angiotensin system (RAS) using the IDUA−/− mouse model. Perturbation of the RAS in the aorta was more profound in male animals suggesting a causative role in the observed gender dimorphism and angiotensin receptor blockade (ARB) resulted in improved cardiac function. Further, we show the ability of losartan to prevent shortening of the snout, a common craniofacial anomaly in IDUA−/− mice. These data show a key role for the RAS in MPS associated pathology and support the inclusion of losartan as an augmentation to current therapies. PMID:27743312

  13. AT1A Angiotensin Receptors in the Renal Proximal Tubule Regulate Blood Pressure

    PubMed Central

    Gurley, Susan B.; Riquier, Anne D. M.; Schnermann, Jurgen; Sparks, Matthew A.; Allen, Andrew M.; Haase, Volker H.; Snouwaert, John N.; Le, Thu H.; McDonough, Alicia A.; Koller, Beverley H.; Coffman, Thomas M.

    2011-01-01

    Summary Hypertension affects more than 1.5 billion people worldwide but the precise cause of elevated blood pressure (BP) cannot be determined in most affected individuals. Nonetheless, blockade of the renin-angiotensin system (RAS) lowers BP in the majority of patients with hypertension. Despite its apparent role in hypertension pathogenesis, the key cellular targets of the RAS that control BP have not been clearly identified. Here we demonstrate that RAS actions in the epithelium of the proximal tubule have a critical and non-redundant role in determining the level of BP. Abrogation of AT1 angiotensin receptor signaling in the proximal tubule alone is sufficient to lower BP, despite intact vascular responses. Elimination of this pathway reduces proximal fluid reabsorption and alters expression of key sodium transporters, modifying pressure-natriuresis and providing substantial protection against hypertension. Thus, effectively targeting epithelial functions of the proximal tubule of the kidney should be a useful therapeutic strategy in hypertension. PMID:21459331

  14. International Union of Basic and Clinical Pharmacology. XCIX. Angiotensin Receptors: Interpreters of Pathophysiological Angiotensinergic Stimuli

    PubMed Central

    Unal, Hamiyet; Kemp, Jacqueline R.; Tirupula, Kalyan C.; Eguchi, Satoru; Vanderheyden, Patrick M. L.; Thomas, Walter G.

    2015-01-01

    The renin angiotensin system (RAS) produced hormone peptides regulate many vital body functions. Dysfunctional signaling by receptors for RAS peptides leads to pathologic states. Nearly half of humanity today would likely benefit from modern drugs targeting these receptors. The receptors for RAS peptides consist of three G-protein–coupled receptors—the angiotensin II type 1 receptor (AT1 receptor), the angiotensin II type 2 receptor (AT2 receptor), the MAS receptor—and a type II trans-membrane zinc protein—the candidate angiotensin IV receptor (AngIV binding site). The prorenin receptor is a relatively new contender for consideration, but is not included here because the role of prorenin receptor as an independent endocrine mediator is presently unclear. The full spectrum of biologic characteristics of these receptors is still evolving, but there is evidence establishing unique roles of each receptor in cardiovascular, hemodynamic, neurologic, renal, and endothelial functions, as well as in cell proliferation, survival, matrix-cell interaction, and inflammation. Therapeutic agents targeted to these receptors are either in active use in clinical intervention of major common diseases or under evaluation for repurposing in many other disorders. Broad-spectrum influence these receptors produce in complex pathophysiological context in our body highlights their role as precise interpreters of distinctive angiotensinergic peptide cues. This review article summarizes findings published in the last 15 years on the structure, pharmacology, signaling, physiology, and disease states related to angiotensin receptors. We also discuss the challenges the pharmacologist presently faces in formally accepting newer members as established angiotensin receptors and emphasize necessary future developments. PMID:26315714

  15. Glucocorticoid-induced fetal programming alters the functional complement of angiotensin receptor subtypes within the kidney.

    PubMed

    Gwathmey, TanYa M; Shaltout, Hossam A; Rose, James C; Diz, Debra I; Chappell, Mark C

    2011-03-01

    We examined the impact of fetal programming on the functional responses of renal angiotensin receptors. Fetal sheep were exposed in utero to betamethasone (BMX; 0.17 mg/kg) or control (CON) at 80 to 81 days gestation with full-term delivery. Renal nuclear and plasma membrane fractions were isolated from sheep age 1.0 to 1.5 years for receptor binding and fluorescence detection of reactive oxygen species (ROS) or nitric oxide (NO). Mean arterial blood pressure and blood pressure variability were significantly higher in the BMX-exposed adult offspring versus CON sheep. The proportion of nuclear AT(1) receptors sensitive to losartan was 2-fold higher (67 ± 6% vs 27 ± 9%; P<0.01) in BMX compared with CON. In contrast, the proportion of AT(2) sites was only one third that of controls (BMX, 25 ± 11% vs CON, 78 ± 4%; P<0.01), with a similar reduction in sites sensitive to the Ang-(1-7) antagonist D-Ala7-Ang-(1-7) with BMX exposure. Functional studies revealed that Ang II stimulated ROS to a greater extent in BMX than in CON sheep (16 ± 3% vs 6 ± 4%; P<0.05); however, NO production to Ang II was attenuated in BMX (26 ± 7% vs 82 ± 14%; P<0.05). BMX exposure was also associated with a reduction in the Ang-(1-7) NO response (75 ± 8% vs 131 ± 26%; P<0.05). We conclude that altered expression of angiotensin receptor subtypes may be one mechanism whereby functional changes in NO- and ROS-dependent signaling pathways may favor the sustained increase in blood pressure evident in fetal programming.

  16. Telmisartan

    MedlinePlus

    ... to the rest of the body) and diabetic nephropathy (kidney disease in people with diabetes and high blood pressure). ... diuretics ('water pills') including spironolactone (Aldactone, in Aldactazide); lithium (Lithobid); and potassium supplements. Your doctor may need ...

  17. Alpha Blockers

    MedlinePlus

    ... conditions such as high blood pressure and benign prostatic hyperplasia. Find out more about this class of medication. ... these conditions: High blood pressure Enlarged prostate (benign prostatic hyperplasia) Though alpha blockers are commonly used to treat ...

  18. Beta Blockers

    MedlinePlus

    Diseases and Conditions High blood pressure (hypertension) Beta blockers, also called beta-adrenergic blocking agents, treat a variety of conditions, such as high blood pressure and migraines. Find out more about this ...

  19. Efficacy and safety of two fixed-dose combinations of S-amlodipine and telmisartan (CKD-828) versus S-amlodipine monotherapy in patients with hypertension inadequately controlled using S-amlodipine monotherapy: an 8-week, multicenter, randomized, double-blind, Phase III clinical study

    PubMed Central

    Ihm, Sang-Hyun; Jeon, Hui-Kyung; Cha, Tae-Joon; Hong, Taek-Jong; Kim, Sang-Hyun; Lee, Nae-Hee; Yoon, Jung Han; Yoon, Namsik; Hwang, Kyung-Kuk; Jo, Sang-Ho; Youn, Ho-Joong

    2016-01-01

    Purpose To evaluate the blood pressure (BP) lowering efficacy and safety of CKD-828, a fixed-dose combination of S-amlodipine (the more active isomer of amlodipine besylate, which is calcium channel blocker) and telmisartan (long acting angiotensin receptor blocker), in patients with hypertension inadequately controlled with S-amlodipine monotherapy. Patients and methods Eligible patients (N=187) who failed to respond after 4-week S-amlodipine 2.5 mg monotherapy (sitting diastolic blood pressure [sitDBP] ≥90 mmHg) to receive CKD-828 2.5/40 mg (n=63), CKD-828 2.5/80 mg (n=63), or S-amlodipine 2.5 mg (n=61) for 8 weeks. The primary efficacy endpoint, mean sitDBP change from baseline to Week 8, was compared between the combination (CKD-828 2.5/40 mg and CKD-828 2.5/80 mg) and S-amlodipine monotherapy groups. The safety was assessed based on adverse events, vital signs, and physical examination findings. Results After the 8-week treatment, changes in sitDBP/systolic BP (SBP) were −9.67±6.50/−12.89±11.78, −10.72±6.19/−13.79±9.41, and −4.93±7.26/−4.55±11.27 mmHg in the CKD-828 2.5/40 mg (P<0.0001/P<0.0001), CKD-828 2.5/80 mg (P<0.0001/P<0.0001), and S-amlodipine 2.5 mg (P<0.0001/P=0.0027) groups, respectively, which were all significant BP reductions. At Week 8, the CKD-828 2.5/40 mg (sitDBP/SBP: P=0.0002/P<0.0001) and CKD-828 2.5/80 mg (sitDBP/SBP: P=0.0001/P<0.0001) showed superior BP-lowering effects to S-amlodipine 2.5 mg (P<0.001). At Week 4, all groups showed significant antihypertensive effects but both CKD-828 combinations (CKD-828 2.5/40 mg and CKD-828 2.5/80 mg) exhibited superior BP-lowering effects to that of S-amlodipine 2.5 mg (sitDBP/SBP: P=0.0028/P=0.0001 and P<0.0001/P=0.0012, respectively). The adverse event incidence was significantly lower in the CKD-828 2.5/40 mg (9.52%, P=0.0086) than in the S-amlodipine 2.5 mg group (27.87%) and increasing the telmisartan dose induced no unexpected adverse events, suggesting the safety of CKD

  20. Effect of angiotensin receptor blockade on central aortic systolic blood pressure in hypertensive Asians measured using radial tonometry: an open prospective cohort study

    PubMed Central

    Teong, Hui Hwang; Chin, Adeline Mei Lin; Sule, Ashish Anil; Tay, Jam Chin

    2016-01-01

    INTRODUCTION Central aortic systolic pressure (CASP) has been shown to be a stronger predictor of cardiovascular events than brachial blood pressure (BP). Different classes of drugs have differential effects on CASP and brachial BP. This open prospective cohort study aimed to observe changes in CASP (measured using radial tonometry) among hypertensive Asians after 12 weeks of treatment with valsartan, an angiotensin receptor blocker (ARB). METHODS Patients with treatment-naïve hypertension or uncontrolled hypertension who were on non-ARB therapy were eligible for inclusion. Patients with uncontrolled BP (i.e. ≥ 140/90 mmHg) received valsartan for 12 weeks. The patients’ brachial systolic and diastolic BP (SBP and DBP), and CASP changes were monitored using the BPro® watch. RESULTS The mean age of the 44 enrolled patients was 35 years. At baseline, the mean BP and CASP were 150.2/91.4 ± 10.6/9.4 mmHg and 136.3 ± 12.2 mmHg, respectively. Valsartan reduced SBP, DBP and CASP by 14.9 ± 10.7 mmHg, 10.9 ± 8.4 mmHg and 15.3 ± 10.9 mmHg, respectively (all p < 0.001). Every 1.0-mmHg reduction in brachial SBP resulted in a 0.8-mmHg reduction in CASP (p < 0.001). A CASP cut-off of 122.5 mmHg discriminated between controlled and uncontrolled BP (sensitivity 74%, specificity 88%). CONCLUSION Using radial tonometry, we demonstrated good correlation between CASP and brachial SBP reductions after 12 weeks of treatment with valsartan in our study cohort. Correlation analysis between CASP and SBP reductions may be useful for demonstrating whether a drug is able to lower CASP beyond lowering SBP. PMID:26875683

  1. Angiotensin-2-Mediated Ca2+ Signaling in the Retinal Pigment Epithelium: Role of Angiotensin-Receptor- Associated-Protein and TRPV2 Channel

    PubMed Central

    Barro-Soria, Rene; Stindl, Julia; Müller, Claudia; Foeckler, Renate; Todorov, Vladimir; Castrop, Hayo; Strauß, Olaf

    2012-01-01

    Angiotensin II (AngII) receptor (ATR) is involved in pathologic local events such as neovascularisation and inflammation including in the brain and retina. The retinal pigment epithelium (RPE) expresses ATR in its AT1R form, angiotensin-receptor-associated protein (Atrap), and transient-receptor-potential channel-V2 (TRPV2). AT1R and Atrap co-localize to the basolateral membrane of the RPE, as shown by immunostaining. Stimulation of porcine RPE (pRPE) cells by AngII results in biphasic increases in intracellular free Ca2+inhibited by losartan. Xestospongin C (xest C) and U-73122, blockers of IP3R and PLC respectively, reduced AngII-evoked Ca2+response. RPE cells from Atrap−/− mice showed smaller AngII-evoked Ca2+peak (by 22%) and loss of sustained Ca2+elevation compared to wild-type. The TRPV channel activator cannabidiol (CBD) at 15 µM stimulates intracellular Ca2+-rise suggesting that porcine RPE cells express TRPV2 channels. Further evidence supporting the functional expression of TRPV2 channels comes from experiments in which 100 µM SKF96365 (a TRPV channel inhibitor) reduced the cannabidiol-induced Ca2+-rise. Application of SKF96365 or reduction of TRPV2 expression by siRNA reduced the sustained phase of AngII-mediated Ca2+transients by 53%. Thus systemic AngII, an effector of the local renin-angiotensin system stimulates biphasic Ca2+transients in the RPE by releasing Ca2+from cytosolic IP3-dependent stores and activating ATR/Atrap and TRPV2 channels to generate a sustained Ca2+elevation. PMID:23185387

  2. Angiotensin receptor-mediated oxidative stress is associated with impaired cardiac redox signaling and mitochondrial function in insulin-resistant rats

    PubMed Central

    Vázquez-Medina, José Pablo; Popovich, Irina; Thorwald, Max A.; Viscarra, Jose A.; Rodriguez, Ruben; Sonanez-Organis, Jose G.; Lam, Lisa; Peti-Peterdi, Janos; Nakano, Daisuke; Nishiyama, Akira

    2013-01-01

    Activation of angiotensin receptor type 1 (AT1) contributes to NADPH oxidase (Nox)-derived oxidative stress during metabolic syndrome. However, the specific role of AT1 in modulating redox signaling, mitochondrial function, and oxidative stress in the heart remains more elusive. To test the hypothesis that AT1 activation increases oxidative stress while impairing redox signaling and mitochondrial function in the heart during diet-induced insulin resistance in obese animals, Otsuka Long Evans Tokushima Fatty (OLETF) rats (n = 8/group) were treated with the AT1 blocker (ARB) olmesartan for 6 wk. Cardiac Nox2 protein expression increased 40% in OLETF compared with age-matched, lean, strain-control Long Evans Tokushima Otsuka (LETO) rats, while mRNA and protein expression of the H2O2-producing Nox4 increased 40–100%. ARB treatment prevented the increase in Nox2 without altering Nox4. ARB treatment also normalized the increased levels of protein and lipid oxidation (nitrotyrosine, 4-hydroxynonenal) and increased the redox-sensitive transcription factor Nrf2 by 30% and the activity of antioxidant enzymes (SOD, catalase, GPx) by 50–70%. Citrate synthase (CS) and succinate dehydrogenase (SDH) activities decreased 60–70%, whereas cardiac succinate levels decreased 35% in OLETF compared with LETO, suggesting that mitochondrial function in the heart is impaired during obesity-induced insulin resistance. ARB treatment normalized CS and SDH activities, as well as succinate levels, while increasing AMPK and normalizing Akt, suggesting that AT1 activation also impairs cellular metabolism in the diabetic heart. These data suggest that the cardiovascular complications associated with metabolic syndrome may result from AT1 receptor-mediated Nox2 activation leading to impaired redox signaling, mitochondrial activity, and dysregulation of cellular metabolism in the heart. PMID:23771688

  3. Angiotensin receptor-mediated oxidative stress is associated with impaired cardiac redox signaling and mitochondrial function in insulin-resistant rats.

    PubMed

    Vázquez-Medina, José Pablo; Popovich, Irina; Thorwald, Max A; Viscarra, Jose A; Rodriguez, Ruben; Sonanez-Organis, Jose G; Lam, Lisa; Peti-Peterdi, Janos; Nakano, Daisuke; Nishiyama, Akira; Ortiz, Rudy M

    2013-08-15

    Activation of angiotensin receptor type 1 (AT1) contributes to NADPH oxidase (Nox)-derived oxidative stress during metabolic syndrome. However, the specific role of AT1 in modulating redox signaling, mitochondrial function, and oxidative stress in the heart remains more elusive. To test the hypothesis that AT1 activation increases oxidative stress while impairing redox signaling and mitochondrial function in the heart during diet-induced insulin resistance in obese animals, Otsuka Long Evans Tokushima Fatty (OLETF) rats (n = 8/group) were treated with the AT1 blocker (ARB) olmesartan for 6 wk. Cardiac Nox2 protein expression increased 40% in OLETF compared with age-matched, lean, strain-control Long Evans Tokushima Otsuka (LETO) rats, while mRNA and protein expression of the H₂O₂-producing Nox4 increased 40-100%. ARB treatment prevented the increase in Nox2 without altering Nox4. ARB treatment also normalized the increased levels of protein and lipid oxidation (nitrotyrosine, 4-hydroxynonenal) and increased the redox-sensitive transcription factor Nrf2 by 30% and the activity of antioxidant enzymes (SOD, catalase, GPx) by 50-70%. Citrate synthase (CS) and succinate dehydrogenase (SDH) activities decreased 60-70%, whereas cardiac succinate levels decreased 35% in OLETF compared with LETO, suggesting that mitochondrial function in the heart is impaired during obesity-induced insulin resistance. ARB treatment normalized CS and SDH activities, as well as succinate levels, while increasing AMPK and normalizing Akt, suggesting that AT1 activation also impairs cellular metabolism in the diabetic heart. These data suggest that the cardiovascular complications associated with metabolic syndrome may result from AT1 receptor-mediated Nox2 activation leading to impaired redox signaling, mitochondrial activity, and dysregulation of cellular metabolism in the heart.

  4. Gene expression profiles linked to AT1 angiotensin receptors in the kidney

    PubMed Central

    Makhanova, Natalia A.; Crowley, Steven D.; Griffiths, Robert C.

    2010-01-01

    To characterize gene expression networks linked to AT1 angiotensin receptors in the kidney, we carried out genome-wide transcriptional analysis of RNA from kidneys of wild-type (WT) and AT1A receptor-deficient mice (KOs) at baseline and after 2 days of angiotensin II infusion (1,000 ng·kg−1·min−1). At baseline, 405 genes were differentially expressed (>1.5×) between WT and KO kidneys. Of these, >80% were upregulated in the KO group including genes involved in inflammation, oxidative stress, and cell proliferation. After 2 days of angiotensin II infusion in WT mice, expression of ≈805 genes was altered (18% upregulated, 82% repressed). Genes in metabolism and ion transport pathways were upregulated while there was attenuated expression of genes protective against oxidative stress including glutathione synthetase and mitochondrial superoxide dismutase 2. Angiotensin II infusion had little effect on blood pressure in KOs. Nonetheless, expression of >250 genes was altered in kidneys from KO mice during angiotensin II infusion; 14% were upregulated, while 86% were repressed including genes involved in immune responses, angiogenesis, and glutathione metabolism. Between WT and KO kidneys during angiotensin II infusion, 728 genes were differentially expressed; 10% were increased and 90% were decreased in the WT group. Differentially regulated pathways included those involved in ion transport, immune responses, metabolism, apoptosis, cell proliferation, and oxidative stress. This genome-wide assessment should facilitate identification of critical distal pathways linked to blood pressure regulation. PMID:20807774

  5. Angiotensin Receptor Blockades Effect on Peripheral Muscular and Central Aortic Arterial Stiffness: A Meta-Analysis of Randomized Controlled Trials and Systematic Review

    PubMed Central

    Yen, Chih-Hsuan; Lai, Yau-Huei; Hung, Chung-Lieh; Lee, Ping-Ying; Kuo, Jen-Yuan; Yeh, Hung-I; Hou, Charles Jia-Yin; Chien, Kuo-Liong

    2014-01-01

    Background Previous clinical trials have demonstrated the impact of blocking upstream renin-angiotensin-axis with angiotensin converting enzyme inhibitors (ACEIs) on arterial stiffness as evaluated by pulse-wave velocity (PWV). We ran a meta-analysis to evaluate the anti-stiffness effect of powerful downstream angiotensin receptor blockades (ARBs) on peripheral and central arterial stiffness (brachial to ankle, ba-PWV; carotid to femoral, cf-PWV, respectively), using a systematic review to assess the clinical arterial stiffness issues. Methods For our study, we searched the PubMed and Cochrane Library databases from inception to June 2013, targeting randomized controlled trials. ARBs along with other antihypertensive agents, ACEIs, calcium channel blockers (CCBs), beta-blockers and diuretics were evaluated to ascertain their comparable effect on ba-PWV and cf-PWV, respectively. A meta-analysis was conducted utilizing the fixed or random effect of the weighted mean change difference between the ARB and comparator groups, depending on the I2 statistic heterogeneity measurement. Results In 2 trials treating patients with ARBs (n = 30), the ARBs insignificantly reduced levels of ba-PWV (pooled mean change difference -188, 95% CI -687, 311, p = 0.24 with significant heterogeneity) as compared to other hypertensive agents (ACEIs and CCBs, n = 77). Interestingly, ARBs (n = 20) had a superior capacity to reduce levels of ba-PWV than CCBs (n = 20) in single study results (mean change difference -400, 95% CI -477, -322, p < 0.05). In 7 trials which included a total of 653 patients, treatment with ARBs (n = 308) also insignificantly reduced cf-PWV (pool mean change difference -0.197, 95% CI -0.54, 0.14, p = 0.218) as compared to other anti-hypertensive agents. Conclusions Our data suggested that ARBs had a similar effect as other anti-hypertensive agents in reducing ba-PWV and cf-PWV. Upon systematic review, the renin-angiotensin-axis system mechanism seems more significant

  6. Angiotensin receptors in an Australian marsupial, the brushtail possum Trichosurus vulpecula

    SciTech Connect

    Sernia, C.; Lello, P.; Thomas, W.G. )

    1990-01-01

    In this study, the binding properties of angiotensin receptors were examined in the liver, adrenal, brain, and vascular tissue of the brushtail possum, Trichosurus vulpecula. With 125I-Ile5-angiotensin II as the radioligand, the binding affinity (Ka) and receptor number (R0) were estimated for the liver (Ka = 3.60 +/- 0.31 liters/nmol; R0 = 23.8 +/- 1.30 pmol/g tissue; n = 8) and adrenal (Ka = 1.68 +/- 0.29 liters/nmol; R0 = 1.67 +/- 0.23 pmol/g tissue; n = 8). Specific binding was not found in any of seven areas of the possum brain (n = 6), whereas the expected binding was present in similar areas of the rat brain. Using angiotensin III or the antagonist Sar1-Ala8-angiotensin II as radioligands or changing the composition of the incubation buffer did not alter the outcome. Moreover, the intracerebroventricular injection of 1 and 5 nmol of angiotensin II did not elicit an increase in blood pressure which could be attributed to brain angiotensin II (AII) receptors. Ligand affinities of the adrenal and liver receptors were found to be in the following decreasing order: Val5-AII greater than Ile5-AII = Ile5-AIII greater than Sar1-Ala8-AII greater than Sar1-Gly8-AII greater than Sar1-Leu8-AII greater than Ile5-AI greater than hexapeptide greater than Phe3-Tyr8-AII. The cardiovascular AII receptor was investigated by generating dose-response curves of the pressor activity of Ile5-AII and six AII analogs infused intravenously. It was concluded that liver, adrenal, and vascular AII receptors in the marsupial possum have characteristics similar to those in eutherian mammals. However, the failure to find brain AII receptors raises the possibility that those functions mediated by such receptors in the eutherian brain are absent in the possum and perhaps other marsupials.

  7. H2 blockers

    MedlinePlus

    ... ulcer disease - H2 blockers; PUD - H2 blockers; Gastroesophageal reflux - H2 blockers ... blockers are used to: Relieve symptoms of acid reflux, or gastroesophageal reflux disease (GERD). This is a ...

  8. Cardiovascular Protective Effect of Metformin and Telmisartan: Reduction of PARP1 Activity via the AMPK-PARP1 Cascade

    PubMed Central

    Shang, Fenqing; Zhang, Jiao; Li, Zhao; Zhang, Jin; Yin, Yanjun; Wang, Yaqiong; Marin, Traci L.; Gongol, Brendan; Xiao, Han; Zhang, You-yi; Chen, Zhen; Shyy, John Y-J; Lei, Ting

    2016-01-01

    Hyperglycemia and hypertension impair endothelial function in part through oxidative stress-activated poly (ADP-ribose) polymerase 1 (PARP1). Biguanides and angiotensin II receptor blockers (ARBs) such as metformin and telmisartan have a vascular protective effect. We used cultured vascular endothelial cells (ECs), diabetic and hypertensive rodent models, and AMPKα2-knockout mice to investigate whether metformin and telmisartan have a beneficial effect on the endothelium via AMP-activated protein kinase (AMPK) phosphorylation of PARP1 and thus inhibition of PARP1 activity. The results showed that metformin and telmisartan, but not glipizide and metoprolol, activated AMPK, which phosphorylated PARP1 Ser-177 in cultured ECs and the vascular wall of rodent models. Experiments using phosphorylated/de-phosphorylated PARP1 mutants show that AMPK phosphorylation of PARP1 leads to decreased PARP1 activity and attenuated protein poly(ADP-ribosyl)ation (PARylation), but increased endothelial nitric oxide synthase (eNOS) activity and silent mating type information regulation 2 homolog 1 (SIRT1) expression. Taken together, the data presented here suggest biguanides and ARBs have a beneficial effect on the vasculature by the cascade of AMPK phosphorylation of PARP1 to inhibit PARP1 activity and protein PARylation in ECs, thereby mitigating endothelial dysfunction. PMID:26986624

  9. Telmisartan ameliorates carbon tetrachloride-induced acute hepatotoxicity in rats.

    PubMed

    Atawia, Reem T; Esmat, Ahmed; Elsherbiny, Doaa A; El-Demerdash, Ebtehal

    2017-02-01

    This study assessed the potential hepatoprotective effect of telmisartan (TLM), a selective angiotensin II type 1 (AT1 ) receptor blocker, on carbon tetrachloride (CCl4 )-induced acute hepatotoxity in rats. Intraperitoneal injection of male Wistar rats with CCl4 1 mL kg(-1) , 1:1 mixture with corn oil for 3 days increased serum alanine transaminase, aspartate transaminase, and alkaline phosphatase activities as well as total bilirubin, triglycerides and total cholesterol levels. This is in addition to the disrupted histological architecture in the CCl4 group. Rats receiving CCl4 and co-treated with TLM (3 and 10 mg kg(-1) , orally) showed ameliorated serum biochemical and histological changes almost to the control level. Nevertheless, rats treated with TLM (1 mg kg(-1) ) didn't show any significant changes compared to CCl4 intoxicated group. In addition, TLM rectified oxidative status disrupted by CCl4 intoxication. Interestingly, TLM protected against CCl4 -induced expressions of nuclear factor-κB, inducible nitric oxide synthase and cyclooxygenase-II, in a dose related manner. Moreover, TLM (3 and 10 mg kg(-1) ) significantly modified CCl4 -induced elevation in tumor necrosis factor-α and nitric oxide levels. Furthermore, TLM showed a marked decline in CD68+ cells stained areas and reduced activity of myeloperoxidase enzyme compared to CCl4 -intoxicated group. In conclusion, both doses of TLM (3 and 10 mg kg(-1) ) showed significant hepato-protective effects. However, TLM at a dose of 10 mg kg(-1) didn't show significant efficacy above 3 mg kg(-1) which is nearly equivalent to the human anti-hypertensive dose of 40 mg. Thus, may be effective in guarding against several hepatic complications due to its antioxidant and anti-inflammatory activities. © 2016 Wiley Periodicals, Inc. Environ Toxicol 32: 359-370, 2017.

  10. Therapeutic considerations in the African-American patient with hypertension: considerations with calcium channel blocker therapy.

    PubMed

    Flack, John M; Sica, Domenic A

    2005-04-01

    African Americans have a higher prevalence, earlier onset, and more rapid progression of hypertensive end-organ disease, as well as excessive hypertensive mortality compared with other racial/ethnic groups. Most differences in hypertension and pressure-related complications between African Americans and whites appear to be quantitative and not qualitative. Improving the diagnosis, treatment, and control of hypertension in this highly vulnerable population is a major health care goal for the new millennium. In this regard the dietary pattern to be promoted for reduction of hypertension risk in African Americans is one of increased consumption of dairy products, fruit, and vegetables as well as a continued emphasis on decreased Na+ intake. When pharmacologic therapy is considered, multi-drug approaches are generally required, with diuretics, angiotensin-converting enzyme inhibitors (or angiotensin receptor blockers), and calcium channel blocker therapy as oft-selected components of most such treatment regimens.

  11. New Evidence Supporting the Use of Mineralocorticoid Receptor Blockers in Drug-Resistant Hypertension.

    PubMed

    Narayan, Hafid; Webb, David J

    2016-04-01

    Treatment resistant hypertension (TRH), defined as a blood pressure above goal despite treatment with optimally tolerated doses of 3 antihypertensive agents of different classes, ideally including a diuretic, remains a significant problem and its management an area of uncertainty for physicians. One hypothesis is that resistant hypertension is due to abnormal sodium retention, mediated by aldosterone breakthrough occurring despite blockade of the renin-angiotensin-aldosterone system with angiotensin converting enzyme inhibitors (ACEi) or angiotensin receptor blockers (ARB). Thus, there has been renewed interest in the use of mineralocorticoid receptor blockers (MRB) to treat this condition. This article critically evaluates new evidence supporting the use of MRB in TRH published in the last 3 years. We conclude that there is now sufficient evidence to recommend MRB, in particular spironolactone, as the first choice medication to treat this condition, and for its inclusion in future guidelines.

  12. How should we manage heart failure developing in patients already treated with angiotensin-converting enzyme inhibitors and beta-blockers for hypertension, diabetes or coronary disease?

    PubMed

    Gustafsson, Finn; Segura, Julian; Ruilope, Luis M

    2010-08-01

    An increasing number of patients in the community are being treated with angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs) and beta-blockers for hypertension, coronary disease or diabetic renal and vascular complications. Some of these patients will develop heart failure despite such treatment. Based on data from hypertension trials it can be estimated that approximately 5% of treated patients will develop heart failure over 5 years. It is unclear whether patients developing heart failure on and off ACE-inhibitors or beta-blockers, respectively, at the time of heart failure diagnosis have similar prognosis.Treatment options for patients developing heart failure while already treated with ACE inhibitors/ARBs and beta-blockers are very limited if current heart failure guidelines are followed. In this review possible strategies are outlined and important areas for research are identified. It is suggested that trials are designed specifically to address prognosis and treatment in this growing population.

  13. Telmisartan, a possible PPAR-δ agonist, reduces TNF-α-stimulated VEGF-C production by inhibiting the p38MAPK/HSP27 pathway in human proximal renal tubular cells

    SciTech Connect

    Kimura, Hideki; Mikami, Daisuke; Kamiyama, Kazuko; Sugimoto, Hidehiro; Kasuno, Kenji; Takahashi, Naoki; Yoshida, Haruyoshi; Iwano, Masayuki

    2014-11-14

    Highlights: • TNF-α increased VEGF-C expression by enhancing phosphorylation of p38MAPK and HSP27. • Telmisartan decreased TNF-α-stimulated expression of VEGF-C. • Telmisartan suppressed TNF-α-induced phosphorylation of p38MAPK and HSP27. • Telmisartan activated endogenous PPAR-δ protein. • Telmisartan suppressed p38MAPK phosphorylation in a PPAR-δ-dependent manner. - Abstract: Vascular endothelial growth factor-C (VEGF-C) is a main inducer of inflammation-associated lymphangiogenesis in various inflammatory disorders including chronic progressive kidney diseases, for which angiotensin II receptor type 1 blockers (ARBs) are widely used as the main treatment. Although proximal renal tubular cells may affect the formation of lymphatic vessels in the interstitial area by producing VEGF-C, the molecular mechanisms of VEGF-C production and its manipulation by ARB have not yet been examined in human proximal renal tubular epithelial cells (HPTECs). In the present study, TNF-α dose-dependently induced the production of VEGF-C in HPTECs. The TNF-α-induced production of VEGF-C was mediated by the phosphorylation of p38MAPK and HSP27, but not by that of ERK or NFkB. Telmisartan, an ARB that can activate the peroxisome proliferator-activated receptor (PPAR), served as a PPAR-δ activator and reduced the TNF-α-stimulated production of VEGF-C. This reduction was partially attributed to a PPAR-δ-dependent decrease in p38MAPK phosphorylation. Our results indicate that TNF-α induced the production of VEGF-C in HPTECs by activating p38MAPK/HSP27, and this was partially inhibited by telmisartan in a PPAR-δ dependent manner. These results provide a novel insight into inflammation-associated lymphangiogenesis.

  14. Structural Basis for Ligand Recognition and Functional Selectivity at Angiotensin Receptor*♦

    PubMed Central

    Zhang, Haitao; Unal, Hamiyet; Desnoyer, Russell; Han, Gye Won; Patel, Nilkanth; Katritch, Vsevolod; Karnik, Sadashiva S.; Cherezov, Vadim; Stevens, Raymond C.

    2015-01-01

    Angiotensin II type 1 receptor (AT1R) is the primary blood pressure regulator. AT1R blockers (ARBs) have been widely used in clinical settings as anti-hypertensive drugs and share a similar chemical scaffold, although even minor variations can lead to distinct therapeutic efficacies toward cardiovascular etiologies. The structural basis for AT1R modulation by different peptide and non-peptide ligands has remained elusive. Here, we report the crystal structure of the human AT1R in complex with an inverse agonist olmesartan (BenicarTM), a highly potent anti-hypertensive drug. Olmesartan is anchored to the receptor primarily by the residues Tyr-351.39, Trp-842.60, and Arg-167ECL2, similar to the antagonist ZD7155, corroborating a common binding mode of different ARBs. Using docking simulations and site-directed mutagenesis, we identified specific interactions between AT1R and different ARBs, including olmesartan derivatives with inverse agonist, neutral antagonist, or agonist activities. We further observed that the mutation N1113.35A in the putative sodium-binding site affects binding of the endogenous peptide agonist angiotensin II but not the β-arrestin-biased peptide TRV120027. PMID:26420482

  15. Angiotensin Receptor Blockers and Statins Could Alleviate Atrial Fibrosis via Regulating Platelet-Derived Growth Factor/Rac1 /Nuclear Factor-Kappa B Axis

    PubMed Central

    Yang, Dongfang; Yuan, Jia; Liu, Gan; Ling, Zhiyu; Zeng, Haiyan; Chen, Yunqing; Zhang, Yue; She, Qiang; Zhou, Xue

    2013-01-01

    Aims: To investigate whether the administration of renin-angiotensin system (RAS) inhibitors and statins could alleviate atrial fibrosis via platelet-derived growth factor (PDGF)/Rac1 /nuclear factor-kappa B (NF-κB) axis. Methods and Results: In human left atrium, the degree of atrial fibrosis, as well as the expression levels of PDGF, Rac1 and NF-κB increased 1.5 to 2.9 folds in patients with atrial fibrillation compared to that with sinus rhythm, (P<0.0001). There were strongly positive correlations between angiotensin II (Ang II) or procollagen type III-alpha-1 (COL3A1) with PDGF, Rac1, NF-κB, and among PDGF, Rac1 and NF-κB (all P<0.05). At 3 weeks after the transverse aorta constriction (TAC) operation in rat model and with intervention of irbesartan or/and simvastatin, the collagen volume fraction (CVF) and atrial natriuretic peptide (ANP) values respectively increased 6-folds and 3.5-folds in the TAC group compared to SHAM group (P<0.0001), but these levels decreased by 16% to 63% with following drug intervention (all P<0.0001), the combined treatment was the lowest. Accordingly, the expression levels of PDGF (3-folds), Rac1 (1.6-folds), NF-κB (7-folds) and AngII (12-folds) significantly increased in the TAC group compared to the SHAM group, and these levels were also reduced by 25% to 64% with following drug intervention. The highest reduction could be seen after treatment with irbesartan and simvastatin in combination (all P<0.001).There were strongly positive correlations between AngII or CVF with PDGF, Rac1, NF-κB, and among PDGF, Rac1 and NF-κB (all P<0.05). Conclusions: Irbesartan or/and simvastatin can improve atrial fibrosis by regulating PDGF/Rac1/NF-κB axis. PMID:23794945

  16. Effect of add-on aliskiren to type 1 angiotensin receptor blocker therapy on endothelial function and autonomic nervous system in hypertensive patients with ischemic heart disease.

    PubMed

    Ozeki, Atsuko; Amiya, Eisuke; Watanabe, Masafumi; Hosoya, Yumiko; Takata, Munenori; Watanabe, Aya; Kawarasaki, Shuichi; Nakao, Tomoko; Watanabe, Shogo; Omori, Kazuko; Yamada, Namie; Tahara, Yukiko; Hirata, Yasunobu; Nagai, Ryozo

    2014-08-01

    The aim of this study was to evaluate the add-on effect of aliskiren to valsartan on endothelial-dependent vasodilation in hypertensive patients with ischemic heart disease (IHD). After 4 weeks of treatment with 80 mg of valsartan, 28 patients were allocated to either continued treatment with valsartan or an add-on treatment with valsartan plus 150 mg of aliskiren. Aliskiren significantly decreased plasma renin activity, whereas endothelium-dependent vasodilation measured by flow-mediated dilation (FMD) did not change. In contrast, heart rate significantly decreased (73.1 ± 9.8 to 66.3 ± 7.0 beats per minute at baseline and 24 weeks, respectively [P = .009]) and the standard deviation of the R-R intervals (SDNN) significantly increased in the aliskiren group. The add-on aliskiren to valsartan therapy may not improve endothelial functions, although it significantly reduced resting heart rate via regulation of the autonomic nervous system in hypertensive patients with IHD.

  17. Comparative effects of Aliskiren and Telmisartan in high fructose diet-induced metabolic syndrome in rats.

    PubMed

    Rabie, Esraa M; Heeba, Gehan H; Abouzied, Mekky M; Khalifa, Mohamed M A

    2015-08-05

    Fructose is a commonly used sweetener associated with diets that increase the prevalence of metabolic syndrome (MS). Inhibition of the renin-angiotensin system (RAS) has been consistently demonstrated to reduce MS. However, there has been no direct comparison among different pharmacological modes of inhibiting the RAS concerning their effects on MS. This study investigated the effect of aliskiren, a direct renin inhibitor, versus telmisartan, an angiotensin II-receptor blocker, in the treatment of fructose-induced MS in rats. MS was induced by high fructose (FRC) diet feeding for 12 weeks. Oral administrations of telmisartan (TEL, 5 mg/kg), aliskiren (ALS, 30 mg/kg) or vehicle were started in the last 4 weeks. Results showed that administration of either TEL or ALS with FRC diet equally ameliorated the metabolic parameters (glucose level, oral glucose tolerance test, insulin resistance and serum lipids profile), systolic blood pressure and oxidative stress markers (malondialdehyde, nitric oxide, reduced glutathione levels and catalase activity). Additionally, the effects of TEL and ALS were associated with a decrease in body composition index and attenuation of liver index, serum liver enzyme activities and hepatic expressions of inflammatory and fibrotic markers (tumor necrosis factor-α, nuclear factor kappa-B and transforming growth factor-β) with a significant increase in hepatic glucose transporter-2 and peroxisome proliferator-activated receptors-alpha and gamma expressions. The results suggested that, at indicated dosage, ALS has ameliorative effect equal to that of TEL against FRC-induced metabolic and hepatic disorders; implying that drugs which inhibit the RAS, by different mode of inhibition, profoundly affect fructose-induced MS in rats.

  18. Effects of angiotensin II receptor blockers on the relationships between ambulatory blood pressure and anti-hypertensive effects, autonomic function, and health-related quality of life.

    PubMed

    Okano, Yasuko; Tamura, Kouichi; Masuda, Shinitirou; Ozawa, Motoko; Tochikubo, Osamu; Umemura, Satoshi

    2009-11-01

    The aim of the present study was to examine the relationships between the anti-hypertensive effects, autonomic function, and health-related quality of life (HRQOL) following treatment of hypertensive subjects with angiotensin receptor blockers (ARBs) in hypertensives. Nineteen patients with hypertension were assigned randomly to daily treatment with ARBs. After 16 weeks of treatment, blood pressure (BP) and 24 h the ratio of low frequency to high frequency component (LF/HF), an index of sympathovagal balance were decreased by ARBs. The HRQOL scores improved during the study. In this study, ARB therapy was associated with an improvement in BP, autonomic function, and HRQOL.

  19. Disposition and metabolism of [(14)C] Sacubitril/Valsartan (formerly LCZ696) an angiotensin receptor neprilysin inhibitor, in healthy subjects.

    PubMed

    Flarakos, Jimmy; Du, Yancy; Bedman, Timothy; Al-Share, Qusai; Jordaan, Pierre; Chandra, Priya; Albrecht, Diego; Wang, Lai; Gu, Helen; Einolf, Heidi J; Huskey, Su-Er; Mangold, James B

    2016-11-01

    1. Sacubitril/valsartan (LCZ696) is an angiotensin receptor neprilysin inhibitor (ARNI) providing simultaneous inhibition of neprilysin (neutral endopeptidase 24.11; NEP) and blockade of the angiotensin II type-1 (AT1) receptor. 2. Following oral administration, [(14)C]LCZ696 delivers systemic exposure to valsartan and AHU377 (sacubitril), which is rapidly metabolized to LBQ657 (M1), the biologically active neprilysin inhibitor. Peak sacubitril plasma concentrations were reached within 0.5-1 h. The mean terminal half-lives of sacubitril, LBQ657 and valsartan were ∼1.3, ∼12 and ∼21 h, respectively. 3. Renal excretion was the dominant route of elimination of radioactivity in human. Urine accounted for 51.7-67.8% and feces for 36.9 to 48.3 % of the total radioactivity. The majority of the drug was excreted as the active metabolite LBQ657 in urine and feces, total accounting for ∼85.5% of the total dose. 4. Based upon in vitro studies, the potential for LCZ696 to inhibit or induce cytochrome P450 (CYP) enzymes and cause CYP-mediated drug interactions clinically was found to be low.

  20. Glucocorticoid Effects on the Programming of AT1b Angiotensin Receptor Gene Methylation and Expression in the Rat

    PubMed Central

    Bogdarina, Irina; Haase, Andrea; Langley-Evans, Simon; Clark, Adrian J. L.

    2010-01-01

    Adverse events in pregnancy may ‘programme’ offspring for the later development of cardiovascular disease and hypertension. Previously, using a rodent model of programmed hypertension we have demonstrated the role of the renin-angiotensin system in this process. More recently we showed that a maternal low protein diet resulted in undermethylation of the At1b angiotensin receptor promoter and the early overexpression of this gene in the adrenal of offspring. Here, we investigate the hypothesis that maternal glucocorticoid modulates this effect on fetal DNA methylation and gene expression. We investigated whether treatment of rat dams with the 11β-hydroxylase inhibitor metyrapone, could prevent the epigenetic and gene expression changes we observed. Offspring of mothers subjected to a low protein diet in pregnancy showed reduced adrenal Agtr1b methylation and increased adrenal gene expression as we observed previously. Treatment of mothers with metyrapone for the first 14 days of pregnancy reversed these changes and prevented the appearance of hypertension in the offspring at 4 weeks of age. As a control for non-specific effects of programmed hypertension we studied offspring of mothers treated with dexamethasone from day 15 of pregnancy and showed that, whilst they had raised blood pressure, they failed to show any evidence of Agtr1b methylation or increase in gene expression. We conclude that maternal glucocorticoid in early pregnancy may induce changes in methylation and expression of the Agtr1b gene as these are clearly reversed by an 11 beta-hydroxylase inhibitor. However in later pregnancy a converse effect with dexamethasone could not be demonstrated and this may reflect either an alternative mechanism of this glucocorticoid or a stage-specific influence. PMID:20169056

  1. Structural determinants for binding to angiotensin converting enzyme 2 (ACE2) and angiotensin receptors 1 and 2

    PubMed Central

    Clayton, Daniel; Hanchapola, Iresha; Thomas, Walter G.; Widdop, Robert E.; Smith, Alexander I.; Perlmutter, Patrick; Aguilar, Marie-Isabel

    2015-01-01

    Angiotensin converting enzyme 2 (ACE2) is a zinc carboxypeptidase involved in the renin–angiotensin system (RAS) and inactivates the potent vasopressive peptide angiotensin II (Ang II) by removing the C-terminal phenylalanine residue to yield Ang1–7. This conversion inactivates the vasoconstrictive action of Ang II and yields a peptide that acts as a vasodilatory molecule at the Mas receptor and potentially other receptors. Given the growing complexity of RAS and level of cross-talk between ligands and their corresponding enzymes and receptors, the design of molecules with selectivity for the major RAS binding partners to control cardiovascular tone is an on-going challenge. In previous studies we used single β-amino acid substitutions to modulate the structure of Ang II and its selectivity for ACE2, AT1R, and angiotensin type 2 (AT2R) receptor. We showed that modification at the C-terminus of Ang II generally resulted in more pronounced changes to secondary structure and ligand binding, and here, we further explore this region for the potential to modulate ligand specificity. In this study, (1) a library of 47 peptides derived from the C-terminal tetrapeptide sequence (-IHPF) of Ang II was synthesized and assessed for ACE2 binding, (2) the terminal group requirements for high affinity ACE2 binding were explored by and N- and C-terminal modification, (3) high affinity ACE2 binding chimeric AngII analogs were then synthesized and assessed, (4) the structure of the full-length Ang II analogs were assessed by circular dichroism, and (5) the Ang II analogs were assessed for AT1R/AT2R selectivity by cell-based assays. Studies on the C-terminus of Ang II demonstrated varied specificity at different residue positions for ACE2 binding and four Ang II chimeric peptides were identified as selective ligands for the AT2 receptor. Overall, these results provide insight into the residue and structural requirements for ACE2 binding and angiotensin receptor selectivity. PMID

  2. Combination effect of calcium channel blocker and valsartan on cardiovascular event prevention in patients with high-risk hypertension: ancillary results of the KYOTO HEART Study.

    PubMed

    Sawada, Takahisa; Yamada, Hiroyuki; Shiraishi, Jun; Kimura, Shinzo; Matsubara, Hiroaki

    2012-01-01

    The ancillary analysis of the KYOTO HEART Study (n = 3031) was designed to assess the combined treatment with calcium channel blocker (CCB) plus valsartan for high-risk hypertension. With-CCB (n = 1807) showed less primary events than without-CCB (n = 1224) (P = .037), in which acute myocardial infarction was significantly reduced. With-CCB plus valsartan (n = 773) showed lower incidence than with-CCB plus non-angiotensin receptor blocker (ARB) (n = 1034) (P = .0002), in which angina pectoris and heart failure were significantly reduced. Without-CCB plus valsartan (n = 744) was superior to without-CCB plus non-ARB (n = 480) (P = .0013), in which stroke was reduced. CCB-based therapy was useful, and CCB plus valsartan combination provided a more efficient prevention for high-risk hypertensive patients.

  3. β-Adrenergic blockers.

    PubMed

    Frishman, William H; Saunders, Elijah

    2011-09-01

    KEY POINTS AND PRACTICAL RECOMMENDATIONS: •  β-Blockers are appropriate treatment for patients with hypertension and those who have concomitant ischemic heart disease, heart failure, obstructive cardiomyopathy, or certain arrhythmias. •  β-Blockers can be used in combination with other antihypertensive drugs to achieve maximal blood pressure control. Labetalol can be used in hypertensive emergencies and urgencies. •  β-Blockers may be useful in patients having hyperkinetic circulation (palpitations, tachycardia, hypertension, and anxiety), migraine headache, and essential tremor. •  β-Blockers are highly heterogeneous with respect to various pharmacologic effects: degree of intrinsic sympathomimetic activity, membrane-stabilizing activity, β(1) selectivity, α(1) -adrenergic-blocking effect, tissue solubility, routes of systemic elimination, potencies and duration of action, and specific effects may be important in the selection of a drug for clinical use. •  β-Blocker usage to reduce perioperative ischemia and cardiovascular complications may not benefit as many patients as was once hoped and may actually cause harm in some individuals. Currently the best evidence supports β-blocker use in two patient groups: patients undergoing vascular surgery with known ischemic heart disease or multiple risk factors for it and for patients already receiving β-blockers for known cardiovascular conditions.

  4. Beta blockers in hypertension.

    PubMed

    Thadani, U

    1983-11-10

    Beta-adrenoceptor antagonists are effective in the management of patients with mild-to-moderate hypertension. Noncardioselective agents, cardioselective agents and beta blockers with intrinsic sympathomimetic activity (ISA) are equally effective, provided they are used in equipotent doses. Beta blockers can be used as first-line therapy in the management of hypertension and can be safely combined with diuretics, vasodilators, or both, for a better control of blood pressure. The exact mechanism by which beta blockers decrease blood pressure remains speculative, but they all reduce cardiac output during long-term therapy; drugs with ISA lower cardiac output and heart rate less than do drugs without ISA. Pharmacokinetic properties of beta blockers differ widely; drugs metabolized by the liver have shorter plasma half-lives than drugs primarily excreted by the kidneys. Although many of the side effects of various beta blockers are similar, differences in water and lipid solubility account for a higher incidence of central nervous system side effects with lipid-soluble drugs (such as propranolol and metoprolol) than with hydrophilic drugs (such as atenolol and timolol). The incidence of cold extremities has been reported to be less with drugs with ISA, and the incidence of bronchospasm less with cardioselective drugs. In the management of uncomplicated mild-to-moderate hypertension, all beta blockers are equally effective and produce less troublesome side effects than alternative antihypertensive agents. For effective therapy beta blockers can be used in 2 divided daily doses or even once daily.(ABSTRACT TRUNCATED AT 250 WORDS)

  5. A fluorescence study on the interaction of telmisartan in triblock polymers pluronic P123 and F127

    NASA Astrophysics Data System (ADS)

    Mohanty, Maneesha Esther; Rao, Vaidya Jayathirtha; Mishra, Ashok Kumar

    2014-03-01

    Telmisartan is a poorly soluble drug used in treatment of hypertension. There is a recent interest to use pluronic for improving the solubility and bioavailability of these drugs. In this study the interaction of telmisartan with P123 and F127 has been carried out using steady state and time dependent fluorescence study. Quenching of telmisartan fluorescence by potassium iodide is controlled by interactions arising from collisions and complex formation. A comparison of the fluorescence of telmisartan in pluronics with the well understood fluorescence of 8-anilino-1-naphthalene-sulfonic acid, a known fluorescent molecular probe, indicates that telmisartan is generally present in a relatively polar microenvironment with restricted diffusive motion.

  6. Attenuation of apoptosis by telmisartan in atherosclerotic plaques of apolipoprotein E-/- mice: evaluation using technetium 99m-annexin A5.

    PubMed

    Zhao, Yan; Zhao, Songji; Kuge, Yuji; Strauss, H William; Blankenberg, Francis G; Tamaki, Nagara

    2013-01-01

    Technetium 99m (99mTc)-annexin A5, a marker of ongoing apoptosis, is supposed to be useful in the detection of metabolically active atheroma. The aim of this study was to determine the potential of 99mTc-annexin A5 for evaluating the therapeutic effects of an angiotensin II receptor type 1 blocker (ARB) (telmisartan) on atherosclerosis. Male apolipoprotein E-/- mice were divided into telmisartan-treated (3 mg/kg/d, n  =  10) and control (n  =  10) groups. After 16 to 21 weeks of treatment, 99mTc-annexin A5 was injected and cryostat sections of aortic tissues (n  =  10-12/aorta) were prepared. The 99mTc-annexin A5 accumulation level in the plaques was evaluated by autoradiography. Serial sections of the plaques were histologically examined to identify the lesion phenotypes (normal vessels, early lesions, atheromatous lesions, and fibrotic lesions), plaque size, macrophage infiltration levels, and lipid deposition levels. Telmisartan treatment significantly decreased the plaque size (0.05 ± 0.05 vs 0.11 ± 0.08, mm2), macrophage infiltration level (0.02 ± 0.02 vs 0.03 ± 0.02, mm2), lipid deposition level (0.01 ± 0.01 vs 0.02 ± 0.02, mm2), and 99mTc-annexin A5 accumulation level (1.30 ± 1.09 vs 2.15 ± 1.91, × 10-6/g). 99mTc-annexin A5 accumulation levels in the plaques positively correlated with macrophage infiltration (r  =  .69, p < .05) and lipid deposition (r  =  .66, p < .05) levels. Apoptosis imaging with 99mTc-annexin A5 may be useful for evaluating the therapeutic effects of ARBs on atherosclerosis.

  7. Difference in the effects of switching from Candesartan to Olmesartan or Telmisartan to Olmesartan in hypertensive patients with type 2 diabetes: the COTO study

    PubMed Central

    Daikuhara, Hiroyuki; Fukunaga, Kensaku; Ohshima, Tomie

    2014-01-01

    Purpose This open-label controlled study compared the therapeutic efficacy of three representative angiotensin II receptor blockers (ARBs) in hypertensive patients with type 2 diabetes attending a hospital outpatient clinic. The primary measure in this study was morning home blood pressure (BP). Patients and methods Two studies were done concurrently to investigate the effects of switching from two different ARBs to olmesartan. Patients prescribed candesartan (8 mg once daily in the morning) or telmisartan (40 mg once daily in the morning) for 16 weeks were switched to olmesartan (20 mg once daily in the morning) for 16 weeks. Then, they were switched back to candesartan (CO group) or telmisartan (TO group) for another 16 weeks. Results Data from all patients in the CO group (n=165) and the TO group (n=152) were analyzed. Clinic and morning home BP and urinary albumin levels showed a significant decrease from baseline at 16 weeks after switching to olmesartan in both the CO and the TO group (clinic BP, morning home diastolic BP, and urinary albumin, P<0.05; morning home systolic BP, P<0.01). In contrast, clinic BP, morning home BP, and urinary albumin were significantly increased again 16 weeks after switching back to candesartan or telmisartan (clinic BP, morning home diastolic BP, and urinary albumin, P<0.05; morning home systolic BP, P<0.01). No subjects experienced an adverse reaction that required withdrawal from the study. No adverse reactions attributable to the study drugs were observed. Conclusion Olmesartan is a promising ARB for BP control in hypertensive type 2 diabetics. PMID:24600204

  8. Telmisartan ameliorates cisplatin-induced nephrotoxicity by inhibiting MAPK mediated inflammation and apoptosis.

    PubMed

    Malik, Salma; Suchal, Kapil; Gamad, Nanda; Dinda, Amit Kumar; Arya, Dharamvir Singh; Bhatia, Jagriti

    2015-02-05

    Nephrotoxicity is a major adverse effect of the widely used anticancer drug cisplatin. Oxidative stress, inflammation and apoptosis are implicated in the pathophysiology of cisplatin-induced acute renal injury. Moreover, cisplatin activates many signal transduction pathways involved in cell injury and death, particularly mitogen activated protein kinase (MAPK) pathway. With this background, we aimed to investigate the protective effect of telmisartan, a widely used antihypertensive drug, in cisplatin-induced nephrotoxicity model in rats. To accomplish this, male albino wistar rats (150-200 g) were divided into 6 groups: Normal, cisplatin-control, telmisartan (2.5, 5 and 10 mg/kg) and telmisartan per se treatment groups. Normal saline or telmisartan was administered orally to rats for 10 days and cisplatin was given on 7th day (8 mg/kg; i.p.) to induce nephrotoxicity. On 10th day, rats were killed and both the kidneys were harvested for biochemical, histopathological and molecular studies. Cisplatin injected rats showed depressed renal function, altered proxidant-antioxidant balance and acute tubular necrosis which was significantly normalized by telmisartan co-treatment. Furthermore, cisplatin administration activated MAPK pathway that caused tubular inflammation and apoptosis in rats. Telmisartan treatment significantly prevented MAPK mediated inflammation and apoptosis. Among the three doses studied telmisartan at 10 mg/kg dose showed maximum nephroprotective effect which could be due to maintenance of cellular redox status and inhibition of MAPK activation.

  9. Effects of telmisartan and pioglitazone on high fructose induced metabolic syndrome in rats.

    PubMed

    Shahataa, Mary Girgis; Mostafa-Hedeab, Gomaa; Ali, Esam Fouaad; Mahdi, Emad Ahmed; Mahmoud, Fatma Abd Elhaleem

    2016-08-01

    Metabolic syndrome (MS) is a cluster of hypertension, insulin resistance, dyslipidaemia, and hyperuricemia. This study was designed to assess the effect of telmisartan and pioglitazone on high fructose induced MS. Thirty-five male albino rats were classified into 5 groups: A, normal diet; B, high-fructose diet (HFD) subdivided into B1 (HFD only), B2 (telmisartan, 5 mg/kg), B3 (pioglitazone, 10 mg/kg), and B4 (telmisartan + pioglitazone). Administration of the drugs was started after the rats had been on HFD for 4 weeks and continued for 4 weeks. Body mass (BM), blood pressure (BP), uric acid (UA), total cholesterol, triglycerides (TG), high-density lipoprotein (HDL-c), low-density lipoprotein (LDL-c), blood urea nitrogen (BUN), creatinine, and nitric oxide (NO) were measured and the levels of fasting glucose and fasting insulin were estimated. Compared with group B1, telmisartan treatment significantly decreased BP, BM, serum glucose, insulin, UA, urea, cholesterol, TGA, and LDL and significantly increased HDL, whereas pioglitazone treatment significantly decreased BP, serum glucose, insulin, UA, urea, creatinine, cholesterol, TGA, and LDL and significantly increased HDL. Co-administration of pioglitazone + telmisartan significantly decreased insulin, urea, and creatinine compared with telmisartan alone. Combined telmisartan + pioglitazone allowed better control of BP, hyperglycaemia, insulin resistance, and the amelioration of BM increase that may be associated with pioglitazone treatment.

  10. Prevention of metabolic disorders with telmisartan and indapamide in a Chinese population with high-normal blood pressure.

    PubMed

    Peng, Jie; Zhao, Yingxin; Zhang, Hua; Liu, Zhendong; Wang, Zhihao; Tang, Mengxiong; Zhong, Ming; Lu, Fanghong; Zhang, Wei

    2015-02-01

    High-normal blood pressure is considered a precursor of stage 1 hypertension that is associated with metabolic disorders. This study aims to investigate whether the pharmacologic treatment of high-normal blood pressure affects metabolism, especially in abdominally obese individuals, and the pharmacoeconomics of two antihypertensive agents, telmisartan and indapamide. Subjects with high-normal blood pressure were randomly assigned to receive telmisartan, indapamide or placebo for 3 years. All the subjects were instructed to modify their lifestyle to reduce blood pressure throughout the study. A total of 221 subjects were randomly assigned to telmisartan, 213 to indapamide and 230 to placebo. After the 3-year intervention, blood pressure was lower in the telmisartan and indapamide groups (P<0.05), FPG in the telmisartan group was lower during the first 2 years (P<0.05) and no characteristic differences were found in those with abdominal obesity among the three groups (P>0.05). The percentage of subjects with metabolic syndrome was significantly decreased in the telmisartan and indapamide groups (P<0.05), but was only significantly decreased in the telmisartan group for subjects with abdominal obesity (P<0.05). The acquisition cost for telmisartan was ~1.86 times higher than for indapamide for a similar antihypertensive effect. The intervention for high-normal blood pressure with telmisartan and indapamide appeared to be feasible and reduced the risk of metabolic syndrome. Telmisartan was more effective, whereas indapamide had better pharmacoeconomic benefits.

  11. Delayed protective effect of telmisartan on lung ischemia/reperfusion injury in valve replacement operations

    PubMed Central

    Fan, Yongfeng; Zhang, Daguo; Xiang, Daokang

    2016-01-01

    The present study aimed to investigate the delayed protective effect of telmisartan on lung ischemic/reperfusion injury in patients undergoing heart valve replacement operations. In total, 180 patients diagnosed with rheumatic valve diseases were randomly divided into the telmisartan (T), captopril (C) and placebo (P) groups. In the telmisartan group, the patients were pretreated with telmisartan (1 mg/kg/day), at the time period 96–48 h before the operation, whereas in the C group, the patients were treated with captopril (1 mg/kg/day) at the time period 96–48 h prior to the operation control group. Each drug treatment group included a corresponding placebo treatment. The variables pulmonary vascular resistance (PVR) and A-aDO2 were measured prior to CPB and at 1, 3, 6 and 12 h after CPB. Pulmonary neutrophil (PMN) count in the left and right atrium blood as well as SOD malondialdehyde (MDA), NO, angiotensin II (AngII) value in the left atrium blood, were measured 30 min prior to and after CPB. The PVR parameters of the telmisartan and captopril groups were significantly lower than those of the placebo group (P<0.05). The A-aDO2 values in the telmisartan and captopril groups were significantly lower than those in the placebo group at 1, 3 and 6 h following CPB treatment. The difference between the right and left atrium blood PMN was significantly lower in the telmisartan and captopril intervention groups compared to that in the placebo group 30 min following CPB treatment. The left atrium blood SOD and NO values were significantly higher, whereas the MDA value was significantly lower in the telmisartan group compared to the control group 30 min following CPB treatment. As for AngII, there was no difference between the C and T groups, compared with the P group. In the two groups 30 min after treatment with CPB, 24 patients experienced varying degrees of cough, with the telmisartan group showing a significant difference (P<0.05). The hospitalization time was

  12. Pharmacogenetics of beta-blockers.

    PubMed

    Shin, Jaekyu; Johnson, Julie A

    2007-06-01

    Beta-blockers are an important cardiovascular drug class, recommended as first-line treatment of numerous diseases such as heart failure, hypertension, and angina, as well as treatment after myocardial infarction. However, responses to a beta-blocker are variable among patients. Results of numerous studies now suggest that genetic polymorphisms may contribute to variability in responses to beta-blockers. This review summarizes the pharmacogenetic data for beta-blockers in patients with various diseases and discusses the potential implications of beta-blocker pharmacogenetics in clinical practice.

  13. Absorbance correction method for estimation of telmisartan and metoprolol succinate in combined tablet dosage forms

    PubMed Central

    Patel, Komal; Patel, Amit; Dave, Jayant; Patel, Chaganbhai

    2012-01-01

    Aim and Background: The present manuscript describes simple, sensitive, rapid, accurate, precise and economical spectrophotometric method for the simultaneous determination of telmisartan and metoprolol succinate in combined tablet dosage form. Materials and Methods: The method is based on the absorbance correction equations for analysis of both the drugs using methanol as solvent. Telmisartan has absorbance maxima at 296 nm and metoprolol succinate has absorbance maxima at 223 nm in methanol. The linearity was obtained in the concentration range of 2-16 μg/ ml and 3-24 μg/ml for telmisartan and metoprolol succinate, respectively. The concentrations of the drugs were determined by using absorbance correction method at both the wavelengths. The method was successfully applied to pharmaceutical dosage form because no interference from the tablet excipients was found. The suitability of this method for the quantitative determination of telmisartan and metoprolol succinate was proved by validation. The proposed method was found to be simple and sensitive for the quality control application of telmisartan and metoprolol succinate in pharmaceutical dosage form. Result: The result of analysis has been validated statistically and by recovery studies. Recoveries were found in the range of 98.08-100.55% of telmisartan and 98.41-101.87% of metoprolol succinate. PMID:23781489

  14. Effects of calcium channel blocker-based combinations on intra-individual blood pressure variability: post hoc analysis of the COPE trial

    PubMed Central

    Umemoto, Seiji; Ogihara, Toshio; Matsuzaki, Masunori; Rakugi, Hiromi; Ohashi, Yasuo; Saruta, Takao; Ogihara, T; Saruta, T; Matsuzaki, M; Eto, T; Fujita, T; Higaki, J; Ito, S; Kamiya, A; Kikuchi, K; Matsuoka, H; Suzuki, H; Tei, C; Matsuoka, H; Kumagai, H; Ohashi, Y; Rakugi, H; Shimamoto, K; Takishita, S; Umemoto, S; Shimada, K; Hayashi, K; Kario, K; Kawana, M; Kitagawa, K; Makino, H; Matsumoto, M; Yoshikawa, J; Abe, K; Matsuura, H; Ohashi, Y; Otsuka, K; Tanabe, K; Suzuki, N; Nogawa, S; Utsunomiya, K; Yoshikawa, T; Yumura, W; Ohashi, Y; Umemoto, S; Kikuchi, K; Hasebe, N; Bunya, M; Fujii, W; Funayama, N; Gima, M; Hashizume, K; Hirayama, Y; Matsuhashi, H; Morimoto, H; Myojo, T; Ohori, K; Omiya, H; Ota, T; Sato, A; Shiokoshi, T; Tanaka, H; Yamazaki, K; Yoshie, H; Shimamoto, K; Abiru, M; Adachi, M; Fujise, Y; Hanawa, K; Ishii, K; Kadono, Y; Kaku, T; Kaneta, S; Kato, M; Kato, N; Kobayashi, H; Komakine, T; Matsumoto, T; Mita, T; Miura, N; Mukai, H; Nagao, K; Nakagawa, H; Nakagawa, M; Nakajima, N; Nishimiya, T; Nishino, Y; Nunokawa, A; Ohata, J; Ooiwa, H; Sato, R; Satoh, S; Shibata, S; Takada, M; Takagawa, Y; Takagi, Y; Takeichi, S; Tanaka, S; Togashi, N; Ura, N; Wakabayashi, C; Yoshida, D; Yoshida, H; Yoshida, K; Kitabatake, A; Tsutsui, H; Akutsu, M; Fujii, S; Furumoto, T; Kakinoki, S; Kawasaki, H; Kimura, T; Makiguchi, M; Matsuo, H; Okamoto, H; Oyama, Y; Shimokawa, J; Tsuzuki, N; Ito, S; Imai, Y; Domon, R; Ebina, H; Egawa, S; Haruyama, T; Hashimoto, H; Hayakawa, T; Inomata, H; Katahira, Y; Katakura, T; Kikuchi, R; Kimura, H; Kyogoku, S; Kyogoku, Y; Matsuo, K; Nakazawa, H; Odakura, H; Okuguchi, F; Ohtomo, E; Ouchi, H; Seino, M; Tadokoro, M; Tanno, Y; Uchida, N; Yamanaka, T; Yunomura, K; Okumura, K; Hatayama, T; Kanehira, Y; Kaneko, H; Kimura, M; Maeda, N; Mikuniya, A; Narita, H; Ono, M; Osanai, T; Sato, M; Yoshino, H; Momomura, S; Ono, M; Inoue, M; Iwase, T; Miyazaki, K; Taki, M; Aizawa, T; Hasunuma, Y; Makino, H; Okabayashi, H; Hosoda, S; Sumiyoshi, T; Abe, M; Kira, Y; Nagayama, M; Sakai, K; Yoshikawa, O; Ide, M; Kimura, N; Matsuzaka, S; Miyajima, Y; Sawai, K; Sumi, T; Takada, R; Toma, M; Yamada, Y; Yoda, K; Yokokawa, T; Yokoyama, S; Kanmatsuse, K; Kushiro, T; Anazawa, T; Ebuchi, T; Fujita, H; Katsumata, N; Masubuchi, K; Migita, T; Osada, T; Otsuka, Y; Saito, F; Shimoda, S; Sugino, K; Takahashi, A; Tani, S; Yumi, K; Daida, H; Arino, T; Iesaki, T; Inomata, Y; Nakahara, H; Shiraishi, H; Sudo, H; Degawa, T; Araki, T; Itaya, H; Komatsu, H; Kuwana, H; Mikawa, T; Nomoto, H; Ogawa, N; Sato, H; Takase, H; Toyoda, H; Yamamoto, M; Obayashi, K; Akabane, I; Hamamoto, H; Kanbara, R; Kato, H; Kimura, H; Mori, N; Yamada, K; Yamamuro, M; Isobe, M; Emoto, H; Inaba, O; Inazawa, T; Inomata, H; Isobe, K; Ito, Y; Komura, M; Kosuge, H; Maejima, Y; Miwa, N; Nishimori, T; Otomo, K; Sakurai, K; Sawada, M; Seya, M; Shimizu, M; Takagi, T; Tamura, M; Tanaka, K; Tezuka, D; Tokunaga, T; Yagishita, A; Yamashina, A; Hara, T; Hayashi, S; Hirayama, Y; Hirooka, Y; Iitaka, M; Ishiyama, T; Kijima, F; Kobayashi, H; Kobayashi, Y; Kondo, K; Kuwabara, T; Mugishima, M; Nakayama, Y; Nishizato, Y; Osamura, Y; Sakomura, Y; Saneshige, S; Shindo, N; Takao, N; Takata, Y; Tomiyama, H; Ishimaru, S; Obitsu, Y; Shigematsu, H; Baba, T; Fukushima, H; Hirayama, T; Magari, K; Makimura, S; Nagae, T; Osada, K; Osada, T; Shimizu, T; Suesada, H; Tamura, K; Yamazaki, T; Hirai, A; Fukasawa, T; Ono, H; Yamakado, M; Shiba, T; Otomi, S; Uehata, A; Takazawa, K; Aizawa, A; Iketani, T; Kino, M; Kobayashi, H; Morishima, T; Sakamoto, N; Sakamoto, T; Yamakawa, H; Kasanuki, H; Nagai, R; Kadowaki, T; Tanaka, J; Yamazaki, T; Takagi, M; Ui, S; Baba, S; Fujita, K; Hasegawa, T; Tajima, K; Tanaka, M; Yamato, N; Kuwajima, I; Harada, K; Miyata, H; Mizuno, S; Ueda, S; Sugi, K; Ando, H; Mishima, K; Moroi, M; Nishizawa, S; Suzuki, S; Yamazaki, J; Nakanishi, R; Nakano, H; Tokuyasu, K; Aoyagi, T; Fujioka, M; Kobayakawa, N; Nakajima, K; Hirayama, A; Tsukamoto, K; Araki, Y; Hara, H; Hara, K; Saruya, T; Umemura, S; Arima, M; Endo, T; Furumi, K; Hatori, Y; Ikeda, Y; Ikeya, Y; Kaneda, T; Kawada, T; Kawano, T; Kawashima, T; Kihara, M; Kikuta, M; Kitamura, A; Kobayashi, H; Kobayashi, S; Kuji, T; Masuda, S; Minamimoto, Y; Minamisawa, K; Mitsuhashi, T; Miyazaki, N; Nagashima, Z; Nakatogawa, T; Nakayama, R; Nyui, N; Ogawa, M; Onishi, T; Saka, K; Sano, T; Sato, A; Shiba, K; Shionoiri, F; Sugiyama, H; Suzuki, H; Takasaki, I; Tamura, K; Tokita, Y; Umemura, M; Yamaguchi, S; Yasuda, G; Nakamura, S; Takayanagi, K; Hayashi, T; Ichihara, M; Kobayashi, S; Sakai, Y; Uchida, T; Yaguchi, I; Komuro, I; Aoki, S; Hashimoto, Y; Ibuki, C; Isobe, Y; Kumasaka, R; Matsuda, M; Mizuno, K; Murakami, D; Nakamura, S; Nakatani, M; Ohba, T; Ohara, T; Okumura, T; Saito, A; Sakurai, T; Sato, S; Sato, W; Seimiya, K; Seino, Y; Shimizu, K; Takano, M; Tokuyama, K; Uchida, D; Yodogawa, K; Oshima, S; Kurabayashi, M; Baba, N; Furushima, Y; Goto, T; Hosoi, T; Iijima, T; Ito, K; Iwata, Y; Kubo, H; Matsumoto, M; Miyazaki, M; Naganuma, F; Nakada, K; Tokushima, M; Tsunoda, K; Wakamatsu, S; Yagihara, Y; Aizawa, Y; Aizawa, M; Aizawa, M; Hayashi, N; Hori, T; Kobayashi, H; Kodama, M; Maeda, K; Miura, K; Okada, K; Okura, Y; Sasagawa, Y; Takizawa, S; Tamura, M; Yamamoto, T; Murohara, T; Awaji, Y; Funahashi, H; Hayashi, D; Iida, M; Ishihara, D; Ishikawa, S; Kamide, S; Kanashiro, M; Kurebayashi, N; Kyo, S; Matsui, H; Matsuo, K; Morishima, M; Noda, H; Noda, T; Okumura, N; Ota, T; Shimizu, S; Somura, F; Takada, Y; Takeichi, Y; Takezawa, H; Uchikawa, T; Yoshikawa, D; Kimura, G; Ando, Y; Hoshiai, M; Okuda, N; Suzuki, S; Takada, K; Takada, N; Yamada, K; Hishida, H; Furuta, T; Hayashi, H; Ito, K; Kato, K; Nomura, M; Ota, T; Ohtsuki, M; Tabata, T; Taga, S; Tateishi, R; Ito, T; Fukuda, M; Iwa, T; Wakida, Y; Yonemoto, T; Watarai, M; Ito, M; Kawai, H; Murata, Y; Nomoto, S; Takemoto, K; Tsuboi, N; Yoshida, Y; Inoue, N; Ishikawa, M; Matsumoto, M; Muramatsu, T; Yoshida, R; Ono, M; Hanaki, Y; Sano, H; Shibata, Y; Sakai, K; Ajioka, M; Asano, H; Okamoto, R; Osanai, H; Uemura, Y; Yokoi, K; Tanaka, T; Kamiya, H; Miki, K; Niwa, M; Fujiwara, H; Minatoguchi, S; Arai, T; Kato, S; Kobayashi, H; Minagawa, T; Mori, N; Nakahara, K; Shimizu, Y; Tadokoro, M; Takahashi, N; Shigemasa, T; Kobayashi, I; Nakano, T; Ito, M; Fukui, A; Higashi, Y; Ito, T; Kano, U; Makino, K; Nakai, K; Nakajima, M; Nakajima, T; Sekoguchi, K; Tanaka, T; Tanigawa, T; Takekoshi, N; Enyama, H; Hirakawa, T; Ito, J; Ito, T; Kakuda, H; Kigoshi, T; Kondo, K; Masuya, K; Matoba, M; Nakagawa, A; Nakahashi, T; Nakato, H; Okada, H; Okuro, M; Takeuchi, Y; Tsugawa, H; Urata, T; Yasuhara, M; Shimizu, M; Ino, H; Araki, T; Fujino, N; Haraki, T; Hayashi, K; Hifumi, S; Konno, T; Minamoto, M; Miyamoto, S; Mori, M; Nakanishi, C; Sakamoto, Y; Sakata, K; Takeda, S; Ueda, K; Uchiyama, K; Takata, S; Kaneko, S; Aburadani, I; Inoki, I; Kitano, K; Kobayashi, D; Kontani, K; Maekawa, M; Maruyama, M; Matsunuma, K; Nagai, Y; Nagata, Y; Okajima, M; Otowa, K; Sekiguchi, Y; Shinmura, K; Usui, S; Yokoyama, H; Yonejima, M; Nakao, K; Hiraiwa, N; Ko, T; Masuda, I; Nagae, T; Nishino, K; Sakamoto, M; Kita, T; Nakagawa, Y; Kimura, T; Doi, T; Horiuchi, H; Kinoshita, M; Mizuno, M; Ohnishi, M; Shigemoto, K; Wada, A; Yamada, T; Yoshida, H; Nakagawa, M; Matsubara, H; Furukawa, K; Hatta, T; Inoue, A; Katsume, H; Masui, A; Matsumoto, S; Seki, T; Takeda, K; Taniguchi, Y; Tsuji, H; Saito, Y; Fukuoka, Y; Iwano, M; Katsuyama, T; Nakatani, A; Sakaguchi, Y; Konishi, T; Izumi, T; Toda, I; Kamimoto, A; Nagai, Y; Matsuwaka, E; Matsuwaka, R; Takei, K; Ueda, R; Wakaki, N; Iwasaka, T; Hamada, H; Hamada, S; Koga, H; Koito, H; Kono, K; Kurihara, H; Maeda, J; Morimoto, S; Takayama, Y; Aoyama, T; Imai, M; Ii, T; Kashii, S; Maenaka, M; Ohashi, H; Suyama, T; Matsuda, M; Aoyagi, Y; Kunisada, K; Mori, T; Mori, T; Uemura, J; Yokoi, Y; Morioka, N; Ozaki, T; Kanamasa, K; Ishikawa, K; Miyazaki, S; Arima, S; Kai, T; Kurooka, A; Shimada, I; Takewa, M; Taniguchi, M; Hattori, R; Haba, K; Yokota, R; Matsui, H; Tone, E; Yamahira, H; Kawarabayashi, T; Inaba, H; Sakaguchi, Y; Yamamoto, Y; Ito, H; Date, M; Dodo, M; Fujii, K; Imai, M; Inoue, K; Kanoh, Y; Komura, N; Senpuku, S; Takeda, M; Tateyama, H; Yasui, K; Yoneda, R; Morita, H; Kawanami, M; Tahara, A; Sado, T; Takamura, T; Taniwa, M; Kitaura, Y; Fukuda, M; Hanada, H; Nakamura, K; Sawada, K; Yamaguchi, M; Kodama, K; Higo, T; Hirata, A; Kanzaki, M; Komatsu, S; Matsuo, K; Murakawa, T; Nakanishi, H; Nemoto, T; Nishio, M; Ogasawara, N; Okuyama, Y; Ueda, Y; Imanishi, M; Kitamura, Y; Sakakibara, T; Yoshida, H; Yoshimi, H; Ogihara, T; Rakugi, H; Akiyama, M; Ikuno, Y; Imai, N; Imamura, Y; Inoyama, T; Kamide, K; Katahira, K; Katsuya, S; Katsuya, T; Kurokawa, Y; Matsuki, O; Matsuo, M; Nakamura, T; Ogura, E; Ohishi, M; Sasaki, R; Sugimoto, K; Tachi, J; Tanaka, H; Tanaka, H; Tsunetoshi, T; Yoshino, M; Hori, M; Awata, N; Fukukawa, T; Iimori, Y; Iwamoto, S; Sawami, K; Okamura, M; Kanayama, Y; Nagano, F; Nakayama, H; Suzuki, H; Amano, T; Tachibana, K; Arita, Y; Kirino, M; Sakuyama, K; Shukawa, M; Nishida, Y; Sakamoto, T; Yanagi, S; Hirota, K; Majima, T; Ota, T; Tanaka, T; Nohara, R; Funauchi, T; Isogai, O; Takashima, S; Koike, H; Nishimoto, M; Kawase, Y; Tojo, O; Chimori, Y; Harada, H; Takeoka, H; Kishi, S; Yokoyama, M; Hirata, K; Ejiri, J; Emoto, R; Furuta, Y; Hattori, K; Kuroda, R; Maehashi, N; Monnaka, H; Ohashi, Y; Okada, T; Suzuki, H; Takeuchi, M; Ohyanagi, M; Masai, M; Masuyama, T; Kawabata, M; Kajiya, T; Daito, N; Fujisawa, T; Fujita, S; Hasegawa, M; Hirakoba, M; Hirano, T; Ikeda, Y; Imai, N; Marumoto, K; Masuda, S; Miki, T; Mitsunaga, M; Mitsuoka, H; Miyachi, Y; Mukohara, N; Nagao, T; Nakada, K; Nishian, K; Nishioka, S; Ogura, T; Onishi, Y; Sakaguchi, K; Sano, I; Sano, W; Shigenobu, M; Tabuchi, A; Takashima, J; Taniguchi, Y; Uchida, H; Ueda, T; Urabe, N; Makino, H; Harada, S; Hirakawa, S; Hirata, H; Ishii, J; Koten, K; Nagake, Y; Nakajima, T; Nakamura, Y; Terami, T; Mitsudo, K; Fujii, M; Fujita, K; Iwano, E; Kadota, K; Nishihara, Y; Takaya, Y; Yamamoto, H; Yamamoto, T; Shigemasa, C; Hisatome, I; Kato, T; Miyakoda, H; Sakamoto, M; Shimoyama, M; Shimada, T; Tanabe, K; Goto, Y; Hanada, Y; Kawakami, K; Kitamura, J; Kitamura, K; Nakata, H; Oyake, N; Sugiura, H; Tsukihashi, H; Matsuzaki, M; Umemoto, S; Aoyagi, S; Aoyama, H; Fujino, T; Fukuta, S; Hiroyama, N; Ikeda, Y; Inamoto, Y; Kametani, R; Kamiya, A; Kanamaru, Y; Kotoku, S; Matsushima, A; Morita, J; Murano, Y; Nakatsuka, M; Nishimura, S; Nisnimura, Y; Okamura, T; Okuda, F; Onaka, U; Ozaki, M; Shimizu, A; Takata, C; Tamitani, M; Watada, T; Watada, T; Yamamoto, K; Yamauchi, M; Yorozu, T; Yoshikane, H; Yoshino, F; Higaki, J; Doiuchi, J; Fukuoka, T; Hashimoto, H; Igase, M; Kadota, H; Kaneko, H; Komatsu, S; Matsubara, Y; Miyoshi, K; Murakami, K; Murao, S; Niiya, T; Ochi, T; Satoh, A; Seki, T; Takahashi, H; Yamashita, T; Yoshino, T; Kohno, M; Fujita, N; Fukui, T; Hamamoto, T; Hasegawa, K; Hitomi, H; Ihara, K; Kiyomoto, H; Masugata, H; Matsumoto, I; Takahashi, N; Yoshikawa, K; Doi, Y; Arisawa, M; Egawa, T; Fukuda, M; Kawada, Y; Kusunose, H; Maeda, T; Minami, N; Nishinaga, M; Noguchi, T; Okabayashi, K; Sato, K; Satomi, T; Takada, J; Tamura, S; Usui, T; Yamada, M; Irahara, M; Azuma, H; Fujimura, M; Fujino, H; Fujino, M; Harada, E; Harada, S; Hiasa, Y; Hosokawa, S; Kawahara, K; Koshiba, K; Murakami, M; Nakaya, Y; Nii, H; Nozaki, S; Ota, A; Ozaki, T; Sone, K; Tsutsui, Y; Ueta, S; Nobuyoshi, M; Fujishima, Y; Hisano, K; Ikezono, H; Imawatari, R; Izumi, Y; Kanai, H; Nakamura, T; Nakamura, T; Noda, T; Ono, E; Tanaka, S; Tsuiki, T; Yanai, T; Sasaguri, T; Akimitsu, S; Dohmen, K; Fujisawa, K; Fukuyo, K; Harashima, S; Hayashi, T; Hirata, M; Hirata, Y; Ikeda, N; Ikematsu, H; Ikematsu, W; Kajiyama, W; Kawakami, Y; Kawasaki, I; Kondo, H; Kusuhara, H; Maeda, N; Miyahara, H; Motomura, A; Nakamura, K; Noguchi, T; Okinaga, T; Sato, M; Shimada, I; Shin, H; Soejima, K; Sugi, K; Taniguchi, T; Uwatoku, T; Yamaga, S; Yamaji, K; Yanagi, J; Yano, H; Saku, K; Enomoto, M; Hiratsuka, T; Imoto, K; Kamei, R; Kanaya, H; Kohara, M; Kusuda, M; Nishikawa, H; Sako, H; Imaizumi, T; Yano, K; Maemura, K; Ashizawa, N; Hazama, M; Ishida, Y; Ito, T; Kanda, M; Kimura, M; Noguchi, T; Oku, Y; Seto, S; Suzuki, S; Ogawa, H; Goto, K; Honjio, K; Horio, Y; Jinnouchi, H; Kaku, Y; Kawano, S; Kimura, T; Kiyohara, Y; Maki, A; Matsumoto, N; Misumi, K; Sakamoto, T; Sasaki, K; Sugiyama, S; Tanaka, E; Uemura, S; Tei, C; Arima, K; Daitoku, Y; Eto, H; Hashino, T; Ichinari, K; Ikeda, Y; Iriki, A; Kiyonaga, K; Kubota, K; Makise, Y; Masuzaki, S; Miyata, M; Mizoguchi, H; Niiyama, T; Samejima, Y; Yonezawa, S

    2016-01-01

    Visit-to-visit blood pressure (BP) variability is an important predictor of stroke. However, which antihypertensive drug combination is better at reducing visit-to-visit BP variability and therefore at reducing stroke incidence remains uncertain. We have previously reported that the dihydropyridine calcium channel blocker benidipine combined with a β-blocker appeared to be less beneficial in reducing the risk of stroke than a combination of benidipine and thiazide. Here, we further compare the visit-to-visit BP variability among three benidipine-based regimens, namely angiotensin receptor blocker (ARB), β-blocker and thiazide combinations. The present post hoc analysis included 2983 patients without cardiovascular events or death during the first 18 months after randomization. We compared the BP variability (defined as the s.d. and the coefficient of variation (CV)), maximum systolic BP (SBP) and diastolic BP (DBP) of the clinic mean on-treatment BPs obtained at 6-month intervals, starting 6 months after the treatment initiation, among the 3 treatments (ARB, n=1026; β-blocker, n=966; thiazide, n=991). During the first 6–36 months after randomization, both the s.d. and CV-BPs were lower in the benidipine–thiazide group than in the benidipine–β-blocker group (s.d.-SBP, P=0.019; s.d.-DBP, P=0.030; CV-SBP, P=0.012; CV-DBP, P=0.022). The s.d. and CV in the ARB group did not reach statistical significance compared with the other two groups. The maximum BPs did not differ among the three treatments. These findings suggest that the benidipine–thiazide combination may reduce visit-to-visit BP variability more than the benidipine–β-blocker combination. PMID:26490089

  15. Immunohistochemical detection of angiotensin receptors AT1 and AT2 in normal rat pituitary gland, estrogen-induced rat pituitary tumor and human pituitary adenomas.

    PubMed

    Pawlikowski, Marek

    2006-01-01

    Male rat pituitary glands, diethylstilbestrol (DES)-induced rat pituitary tumors and 12 human pituitary adenomas were immunostained with antibodies raised against AT1 and AT2 angiotensin receptor proteins. Positive immunostaining of AT1 was observed in a subpopulation of anterior and intermediate pituitary lobe cells as well as in some nerve endings of the neurohypophysis. In the DES-induced rat pituiary tumors, the subpopulation of AT1-immunnopositive cells was smaller than in the non-tumoral anterior pituitary. In human pituitary adenomas, weak AT1 immunostaining was found in 5 tumors. In the remaining adenomas, the AT1 immunostaining was trace (doubtful) or absent. The AT1 immunostaining in the peritumoral non-neoplastic pituitary tissue was stronger than that observed in the tumors. The normal rat pituitaries and rat tumors did not show immunostaining with anti-AT2 antibody. In human pituitary adenomas, the tumoral cells were AT2- negative but moderate to strong AT2 immunostaining was observed in intratumoral blood vessel walls. The data suggest that the experimental (in rat) and spontaneous (in man) pituitary tumorigenesis is associated with the down-regulation of AT1 receptors. The expression of AT2 receptors, in turn, may be connected with the process of tumoral neo-angiogenesis.

  16. Pre-treatment with LCZ696, an orally active angiotensin receptor neprilysin inhibitor, prevents ischemic brain damage.

    PubMed

    Bai, Hui-Yu; Mogi, Masaki; Nakaoka, Hirotomo; Kan-No, Harumi; Tsukuda, Kana; Chisaka, Toshiyuki; Wang, Xiao-Li; Kukida, Masayoshi; Shan, Bao-Shuai; Yamauchi, Toshifumi; Higaki, Akinori; Iwanami, Jun; Horiuchi, Masatsugu

    2015-09-05

    Angiotensin II receptor blockers (ARBs) are known to prevent ischemic brain damage after stroke. Natriuretic peptides, which are increased by a neprilysin inhibitor, are also reported to protect against brain damage. Therefore, we investigated the possible protective effect of valsartan (VAL) compared with LCZ696 (VAL+ neprilysin inhibitor; 1:1) after middle cerebral artery (MCA) occlusion. Eight-week-old male C57BL/6J mice were treated with VAL (3mg/kg per day) or LCZ696 (6mg/kg per day) for 2 weeks before MCA occlusion. Blood pressure and heart rate were measured by telemetry. Cerebral blood flow (CBF) was determined by laser-Doppler flowmetry. Ischemic area was evaluated by triphenytetrasodium chloride staining, and oxidative stress was determined by dihydroethidium staining. Blood pressure and heart rate were not significantly different before and after treatment. Pre-treatment with LCZ696 or VAL reduced the ischemic area, and this effect of LCZ696 was more marked than that of VAL pre-treatment. The decrease in CBF in the peripheral region of the ischemic area was significantly attenuated by pre-treatment with LCZ696 or VAL, without any significant effect on CBF in the core region. VAL or LCZ696 pre-treatment significantly decreased the increase of superoxide anion production in the cortex on the ischemic side. However, no significant difference in CBF and superoxide anion production was observed between VAL and LCZ696 pre-treatment. The preventive effect of LCZ696 on ischemic brain damage after stroke was more marked than that of VAL. LCZ696 could be used as a new approach to prevent brain damage after stroke. (246 words).

  17. Beta-Blockers and Calcium Channel Blockers: First Line Agents.

    PubMed

    Pascual, Isaac; Moris, Cesar; Avanzas, Pablo

    2016-08-01

    Beta-blockers and calcium channel blockers (CCB) are milestones in the treatment of stable coronary ischaemic disease. Their main effects are particularly suited for the management of effort-induced angina because of the reduction of oxygen demand they achieve. The clinical benefits of these drugs are highly reproducible and have been shown to improve overall clinical outcomes. Despite the availability of other, and newer antianginal drugs, treatment guidelines continue to recommend the use of beta-blockers and calcium channel blockers as first line therapies.

  18. Effect of dietary fiber on the level of free angiotensin II receptor blocker in vitro.

    PubMed

    Iwazaki, Ayano; Takahashi, Kazuhiro; Tamezane, Yui; Tanaka, Kenta; Nakagawa, Minami; Imai, Kimie; Nakanishi, Kunio

    2014-01-01

    The interaction between angiotensin II type 1 (AT1) receptor blockers (ARBs), such as losartan potassium (LO), candesartan (CA), and telmisartan (TE), and dietary fiber was studied as to the level of free ARB in vitro. When ARB was incubated with soluble (sodium alginate, pectin, and glucomannan) or insoluble (cellulose and chitosan) dietary fiber, the levels of free LO, TE, and CA decreased. This resulted only from mixing the dietary fiber with the ARBs and differed among the types of dietary fiber, and the pH and electrolytes in the mixture. The levels of free LO and TE tended to decrease with a higher concentration of sodium chloride in pH 1.2 fluid. These results suggest that it is important to pay attention to the possible interactions between ARBs and dietary fiber.

  19. Formulation development and evaluation of fast dissolving film of telmisartan.

    PubMed

    Londhe, Vaishali Y; Umalkar, Kashmira B

    2012-03-01

    Hypertension is a major cause of concern not just in the elderly but also in the youngsters. An effort was made to formulate a fast dissolving film containing telmisartan which is used in the treatment of hypertension with a view to improve the onset of action, therapeutic efficacy, patient compliance and convenience. The major challenge in formulation of oral films of telmisatran is that it shows very less solubility in the pH range of 3-9. Various film forming agents and polyhydric alcohols were evaluated for optimizing composition of fast dissolving films. Fast dissolving films using hydroxypropyl methylcellulose, polyvinyl alcohol, glycerol, sorbitol, menthol and an alkalizer were formulated using solvent casting method. Optimized formulations were evaluated for their weight, thickness, folding endurance, appearance, tensile strength, disintegration time and dissolution profile.

  20. Formulation Development and Evaluation of Fast Dissolving Film of Telmisartan

    PubMed Central

    Londhe, Vaishali Y.; Umalkar, Kashmira B.

    2012-01-01

    Hypertension is a major cause of concern not just in the elderly but also in the youngsters. An effort was made to formulate a fast dissolving film containing telmisartan which is used in the treatment of hypertension with a view to improve the onset of action, therapeutic efficacy, patient compliance and convenience. The major challenge in formulation of oral films of telmisatran is that it shows very less solubility in the pH range of 3–9. Various film forming agents and polyhydric alcohols were evaluated for optimizing composition of fast dissolving films. Fast dissolving films using hydroxypropyl methylcellulose, polyvinyl alcohol, glycerol, sorbitol, menthol and an alkalizer were formulated using solvent casting method. Optimized formulations were evaluated for their weight, thickness, folding endurance, appearance, tensile strength, disintegration time and dissolution profile. PMID:23325992

  1. Resistive index as a predictor of renal progression in patients with moderate renal dysfunction regardless of angiotensin converting enzyme inhibitor or angiotensin receptor antagonist medication

    PubMed Central

    Kim, Jae Hoon; Lee, Su Mi; Son, Young Ki; Kim, Seong Eun; An, Won Suk

    2017-01-01

    Background Previous studies have shown that a higher resistive index (RI) on renal duplex ultrasonography was related with renal progression and acute kidney injury, especially in patients with chronic kidney disease (CKD) using an angiotensin converting enzyme inhibitor (ACEI) or angiotensin receptor antagonist (ARB). We evaluated whether a RI value is a predictive factor for renal progression regardless of ACEI or ARB medication in patients with moderate renal dysfunction. Methods We retrospectively analyzed 119 patients with moderate renal dysfunction that had been evaluated with renal duplex ultrasonography from February 2011 to April 2015. Moderate renal dysfunction was defined as a stage 3 to 4 CKD. Renal progression was defined as a doubling of the baseline serum creatinine (sCr), a decrease of baseline glomerular filtration rate by > 50%, or initiation of renal replacement therapy. Results The mean age was 64.7 ± 11.0 years and sCr level was 2.1 ± 1.2 mg/dL. The RI ≥ 0.79 group showed a higher incidence of renal progression (P = 0.004, log-rank test) compared with the RI < 0.79 group, irrespective of ACEI or ARB usage. In the Cox proportional hazard model, RI ≥ 0.79 was an independent prognostic factor after adjusting for age, sex, diabetes mellitus, sCr, proteinuria, and use of ACEI or ARB (hazard ratio, 4.88; 95% confidence interval, 1.06–22.53; P = 0.043). Conclusion RI ≥ 0.79 on the renal duplex ultrasonography can be a helpful predictor for renal progression in patients with moderate renal dysfunction, regardless of their ACEI or ARB usage.

  2. Enhanced peripheral dopamine impairs post-ischemic healing by suppressing angiotensin receptor type 1 expression in endothelial cells and inhibiting angiogenesis.

    PubMed

    Sarkar, Chandrani; Ganju, Ramesh K; Pompili, Vincent J; Chakroborty, Debanjan

    2017-02-01

    Increased circulating catecholamines have been linked with cardiovascular anomalies as well as with peripheral vascular diseases. Although the roles of epinephrine and norepinephrine have received considerable attention, the role of the other catecholamine, dopamine, has been less studied. Since dopamine is a potent endogenous inhibitor of angiogenesis and as angiogenesis is essential for ischemic healing, we therefore studied the role played by dopamine during ischemic healing using dopamine D2 receptor knockout (KOD2) mice. Although concentration of dopamine and its rate-limiting enzyme, tyrosine hydroxylase, was considerably high in the muscle tissues of wild-type and KOD2 mice with unilateral hind limb ischemia (HLI), recovery was significantly faster in the KOD2 mice compared to the wild-type controls, thereby indicating that peripheral dopamine might have a role in this healing process. In addition, we observed significant differences in post-ischemic angiogenesis between these two groups. Our study further revealed that elevated dopamine independently suppressed activation of local tissue-based renin-angiotensin system (RAS), a critical growth factor system stimulating angiogenesis in ischemia. Angiotensin II (ATII) and its receptor, angiotensin receptor type 1 (AT1R), are the key players in RAS-mediated angiogenesis. Dopamine acting through its D2 receptors in endothelial cells inhibited ATII-mediated angiogenesis by suppressing the expression of AT1R in these cells. This study thus for the first time demonstrates the role played by dopamine in prolonging post-ischemic recovery. Therefore, pharmacological intervention inhibiting the action of dopamine holds promise as future therapeutic strategy for the treatment of HLI and other peripheral arterial diseases.

  3. Beta-blockers in hypertension.

    PubMed

    Ram, C Venkata S

    2010-12-15

    Beta blockers have been used in the treatment of cardiovascular conditions for decades. Despite a long history and status as a guideline-recommended treatment option for hypertension, recent meta-analyses have brought into question whether β blockers are still an appropriate therapy given outcomes data from other antihypertensive drug classes. However, β blockers are a heterogenous class of agents with diverse pharmacologic and physiologic properties. Much of the unfavorable data revealed in the recent meta-analyses were gleaned from studies involving nonvasodilating, traditional β blockers, such as atenolol. However, findings with traditional β blockers may not be extrapolated to other members of the class, particularly those agents with vasodilatory activity. Vasodilatory β blockers (i.e., carvedilol and nebivolol) reduce blood pressure in large part through reducing systemic vascular resistance rather than by decreasing cardiac output, as is observed with traditional β blockers. Vasodilating ability may also ameliorate some of the concerns associated with traditional β blockade, such as the adverse effects on metabolic and lipid parameters, including an increased risk for new-onset diabetes. Furthermore, vasodilating ability is physiologically relevant and important in treating a condition with common co-morbidities involving metabolic and lipid abnormalities such as hypertension. In patients with hypertension and diabetes or coronary artery disease, vasodilating β blockers provide effective blood pressure control with neutral or beneficial effects on important parameters for the co-morbid disease. In conclusion, it is time for a reexamination of the clinical evidence for the use of β blockers in hypertension, recognizing that there are patients for whom β blockers, particularly those with vasodilatory actions, are an appropriate treatment option.

  4. Efficacy and Safety of Combination Therapy Consisting of Angiotensin II Type 1 Receptor Blocker, Calcium Channel Blocker and Hydrochlorothiazide in Patients With Hypertension

    PubMed Central

    Shiga, Yuhei; Miura, Shin-ichiro; Motozato, Kota; Yoshimine, Yuka; Norimatsu, Kenji; Arimura, Tadaaki; Koyoshi, Rie; Morii, Joji; Kuwano, Takashi; Inoue, Ken; Shirotani, Tetsuro; Fujisawa, Kazuaki; Matsunaga, Eiyu; Saku, Keijiro

    2017-01-01

    Background Many patients continue to have high blood pressure (BP) even after treatment with high-dose (H)-angiotensin II type 1 receptor blocker (ARB)/calcium channel blocker (CCB) or middle-dose (M)-ARB/CCB/hydrochlorothiazide (HCTZ). Methods Thirty-two hypertensive patients who had the use of H-ARB/CCB or M-ARB/CCB/HCTZ were enrolled in this study. We applied a changeover with a switch to H-ARB (telmisartan 80 mg/day)/CCB (amlodipine 5 mg/day or nifedipine CR 40 mg/day)/HCTZ (12.5 mg/day). Results Systolic BP (SBP) and diastolic BP (DBP) were significantly decreased in all patients and in the H-ARB/CCB and M-ARB/CCB/HCTZ groups after 3 months. Percentage (%) of patients who reached the target BP after 3 months (72%) in all patients was significantly higher than that at 0 months (19%). There were no serious adverse effects in any of the patients. Conclusions Combination therapy with H-ARB/CCB/HCTZ was associated with a significant reduction of BP. PMID:28090225

  5. Telmisartan, a possible PPAR-δ agonist, reduces TNF-α-stimulated VEGF-C production by inhibiting the p38MAPK/HSP27 pathway in human proximal renal tubular cells.

    PubMed

    Kimura, Hideki; Mikami, Daisuke; Kamiyama, Kazuko; Sugimoto, Hidehiro; Kasuno, Kenji; Takahashi, Naoki; Yoshida, Haruyoshi; Iwano, Masayuki

    2014-11-14

    Vascular endothelial growth factor-C (VEGF-C) is a main inducer of inflammation-associated lymphangiogenesis in various inflammatory disorders including chronic progressive kidney diseases, for which angiotensin II receptor type 1 blockers (ARBs) are widely used as the main treatment. Although proximal renal tubular cells may affect the formation of lymphatic vessels in the interstitial area by producing VEGF-C, the molecular mechanisms of VEGF-C production and its manipulation by ARB have not yet been examined in human proximal renal tubular epithelial cells (HPTECs). In the present study, TNF-α dose-dependently induced the production of VEGF-C in HPTECs. The TNF-α-induced production of VEGF-C was mediated by the phosphorylation of p38MAPK and HSP27, but not by that of ERK or NFkB. Telmisartan, an ARB that can activate the peroxisome proliferator-activated receptor (PPAR), served as a PPAR-δ activator and reduced the TNF-α-stimulated production of VEGF-C. This reduction was partially attributed to a PPAR-δ-dependent decrease in p38MAPK phosphorylation. Our results indicate that TNF-α induced the production of VEGF-C in HPTECs by activating p38MAPK/HSP27, and this was partially inhibited by telmisartan in a PPAR-δ dependent manner. These results provide a novel insight into inflammation-associated lymphangiogenesis.

  6. Solubilization of the poorly water soluble drug, telmisartan, using supercritical anti-solvent (SAS) process.

    PubMed

    Park, Junsung; Cho, Wonkyung; Cha, Kwang-Ho; Ahn, Junhyun; Han, Kang; Hwang, Sung-Joo

    2013-01-30

    Telmisartan is a biopharmaceutical classification system (BCS) class II drug that has extremely low water solubility but is freely soluble in highly alkalized solutions. Few organic solvents can dissolve telmisartan. This solubility problem is the main obstacle achieving the desired bioavailability. Because of its unique characteristics, the supercritical anti-solvent (SAS) process was used to BCS class II drug in a variety of ways including micronization, amorphization and solid dispersion. Solid dispersions were prepared using hydroxypropylmethylcellulose/polyvinylpyrrolidone (HPMC/PVP) at 1:0.5, 1:1, and 1:2 weight ratios of drug to polymer, and pure telmisartan was also treated using the SAS process. Processed samples were characterized for morphology, particle size, crystallinity, solubility, dissolution rate and polymorphic stability. After the SAS process, all samples were converted to the amorphous form and were confirmed to be hundreds nm in size. Solubility and dissolution rate were increased compared to the raw material. Solubility tended to increase with increases in the amount of polymer used. However, unlike the solubility results, the dissolution rate decreased with increases in polymer concentration due to gel layer formation of the polymer. Processed pure telmisartan showed the best drug release even though it had lower solubility compared to other solid dispersions; however, because there were no stabilizers in processed pure telmisartan, it recrystallized after 1 month under severe conditions, while the other solid dispersion samples remained amorphous form. We conclude that after controlling the formulation of solid dispersion, the SAS process could be a promising approach for improving the solubility and dissolution rate of telmisartan.

  7. Differential surface properties of commercial crystalline telmisartan samples.

    PubMed

    Laad, Preksha; Shete, Ganesh; Modi, Sameer R; Bansal, Arvind Kumar

    2013-05-13

    The aim of the present study was to investigate differences in surface chemistry of commercially available telmisartan (TMS) samples in Indian market and to correlate them to the surface molecular environment. Comprehensive characterization of material properties of four TMS samples from different sources showed that all samples exhibited same polymorphic form, but different particle shape, particle size distribution, surface energetics and surface chemistry. Wettability and surface free energy were determined using sessile drop contact angle technique. TMS samples exhibited significant variations in their wetting behavior. The role of crystal shape, particle size distribution, surface energetics and surface chemistry in controlling TMS powder wettability was collectively explored by contact angle experiments. Evaluation of work of adhesion (Wa), immersion (Wi) and spreading (Ws) indicated that samples had differential wetting behavior. The surface chemistry was elucidated by X-ray photoelectron spectroscopy (XPS). The surface polarity index was determined by XPS and expressed as (oxygen+nitrogen)-to-(carbon) atomic concentration ratio. It was found to be different for all four TMS samples. Crystal morphology of TMS polymorph A was predicted using Bravais-Friedel Donnay-Harker (BFDH) method. Molecular lipophilic surface potential (MLSP) data for TMS showed the varied surface lipophilic environment throughout the molecule. Hence it can be concluded that the differential abundance of surface elements play an important role in controlling the biopharmaceutical performance of TMS powder samples.

  8. The effect of angiotensin receptor neprilysin inhibitor, sacubitril/valsartan, on central nervous system amyloid-β concentrations and clearance in the cynomolgus monkey.

    PubMed

    Schoenfeld, Heidi A; West, Tim; Verghese, Philip B; Holubasch, Mary; Shenoy, Neeta; Kagan, David; Buono, Chiara; Zhou, Wei; DeCristofaro, Marc; Douville, Julie; Goodrich, Geoffrey G; Mansfield, Keith; Saravanan, Chandra; Cumin, Frederic; Webb, Randy L; Bateman, Randall J

    2017-03-15

    Sacubitril/valsartan (LCZ696) is the first angiotensin receptor neprilysin inhibitor approved to reduce cardiovascular mortality and hospitalization in patients with heart failure with reduced ejection fraction. As neprilysin (NEP) is one of several enzymes known to degrade amyloid-β (Aβ), there is a theoretical risk of Aβ accumulation following long-term NEP inhibition. The primary objective of this study was to evaluate the potential effects of sacubitril/valsartan on central nervous system clearance of Aβ isoforms in cynomolgus monkeys using the sensitive Stable Isotope Labeling Kinetics (SILK™)-Aβ methodology. The in vitro selectivity of valsartan, sacubitril, and its active metabolite sacubitrilat was established; sacubitrilat did not inhibit other human Aβ-degrading metalloproteases. In a 2-week study, sacubitril/valsartan (50mg/kg/day) or vehicle was orally administered to female cynomolgus monkeys in conjunction with SILK™-Aβ. Despite low cerebrospinal fluid (CSF) and brain penetration, CSF exposure to sacubitril was sufficient to inhibit NEP and resulted in an increase in the elimination half-life of Aβ1-42 (65.3%; p=0.026), Aβ1-40 (35.2%; p=0.04) and Aβtotal (29.8%; p=0.04) acutely; this returned to normal as expected with repeated dosing for 15days. CSF concentrations of newly generated Aβ (AUC(0-24h)) indicated elevations in the more aggregable form Aβ1-42 on day 1 (20.4%; p=0.039) and day 15 (34.7%; p=0.0003) and in shorter forms Aβ1-40 (23.4%; p=0.009), Aβ1-38 (64.1%; p=0.0001) and Aβtotal (50.45%; p=0.00002) on day 15. However, there were no elevations in any Aβ isoforms in the brains of these monkeys on day 16. In a second study cynomolgus monkeys were administered sacubitril/valsartan (300mg/kg) or vehicle control for 39weeks; no microscopic brain changes or Aβ deposition, as assessed by immunohistochemical staining, were present. Further clinical studies are planned to address the relevance of these findings.

  9. Safety and efficacy of LCZ696, a first-in-class angiotensin receptor neprilysin inhibitor, in Japanese patients with hypertension and renal dysfunction

    PubMed Central

    Ito, Sadayoshi; Satoh, Minoru; Tamaki, Yuko; Gotou, Hiromi; Charney, Alan; Okino, Naoko; Akahori, Mizuki; Zhang, Jack

    2015-01-01

    This 8-week, multi-center, open-label study assessed the safety and efficacy of LCZ696, a first-in-class angiotensin receptor neprilysin inhibitor, in Japanese patients with hypertension and renal dysfunction. Patients (n=32) with mean sitting systolic blood pressure (msSBP) ⩾140 mm Hg (after a 2–5-week washout of previous antihypertensive medications) and estimated glomerular filtration rate (eGFR) ⩾15 and <60 ml min−1 1.73 m−2 received LCZ696 100 mg with an optional titration to 200 and 400 mg in a sequential manner starting from Week 2 in patients with inadequate BP control (msSBP ⩾130 mm Hg and mean sitting diastolic blood pressure (msDBP) ⩾80 mm Hg) and without safety concerns. Safety was assessed by monitoring and recording all adverse events (AEs) and change in potassium and creatinine. Efficacy was assessed as change from baseline in msSBP/msDBP. The mean baseline BP was 151.6/86.9 mm Hg, urinary albumin/creatinine ratio (UACR) geometric mean was 7.3 mg mmol−1 and eGFR was ⩾30 and <60 in 25 (78.1%) patients and was ⩾15 and <30 in 7 (21.9%) patients. Fourteen (43.8%) patients reported at least one AE, which were mild in severity. No severe AEs or deaths were reported. There were no clinically meaningful changes in creatinine, potassium, blood urea nitrogen and eGFR. The geometric mean reduction in UACR was 15.1%, and the mean reduction in msSBP and msDBP was 20.5±11.3 and 8.3±6.3 mm Hg, respectively, from baseline to Week 8 end point. LCZ696 was generally safe and well tolerated and showed effective BP reduction in Japanese patients with hypertension and renal dysfunction without a decline in renal function. PMID:25693859

  10. Safety and efficacy of LCZ696, a first-in-class angiotensin receptor neprilysin inhibitor, in Japanese patients with hypertension and renal dysfunction.

    PubMed

    Ito, Sadayoshi; Satoh, Minoru; Tamaki, Yuko; Gotou, Hiromi; Charney, Alan; Okino, Naoko; Akahori, Mizuki; Zhang, Jack

    2015-04-01

    This 8-week, multi-center, open-label study assessed the safety and efficacy of LCZ696, a first-in-class angiotensin receptor neprilysin inhibitor, in Japanese patients with hypertension and renal dysfunction. Patients (n=32) with mean sitting systolic blood pressure (msSBP) ⩾140 mm Hg (after a 2-5-week washout of previous antihypertensive medications) and estimated glomerular filtration rate (eGFR) ⩾15 and <60 ml min(-1) 1.73 m(-2) received LCZ696 100 mg with an optional titration to 200 and 400 mg in a sequential manner starting from Week 2 in patients with inadequate BP control (msSBP ⩾130 mm Hg and mean sitting diastolic blood pressure (msDBP) ⩾80 mm Hg) and without safety concerns. Safety was assessed by monitoring and recording all adverse events (AEs) and change in potassium and creatinine. Efficacy was assessed as change from baseline in msSBP/msDBP. The mean baseline BP was 151.6/86.9 mm Hg, urinary albumin/creatinine ratio (UACR) geometric mean was 7.3 mg mmol(-1) and eGFR was ⩾30 and <60 in 25 (78.1%) patients and was ⩾15 and <30 in 7 (21.9%) patients. Fourteen (43.8%) patients reported at least one AE, which were mild in severity. No severe AEs or deaths were reported. There were no clinically meaningful changes in creatinine, potassium, blood urea nitrogen and eGFR. The geometric mean reduction in UACR was 15.1%, and the mean reduction in msSBP and msDBP was 20.5±11.3 and 8.3±6.3 mm Hg, respectively, from baseline to Week 8 end point. LCZ696 was generally safe and well tolerated and showed effective BP reduction in Japanese patients with hypertension and renal dysfunction without a decline in renal function.

  11. Real role of β-blockers in regression of left ventricular mass in hypertension patients

    PubMed Central

    Xing, FuWei; Chen, Jialin; Zhao, BinLiang; Jiang, Jingzhou; Tang, Anli; Chen, Yili

    2017-01-01

    Abstract Background: Left ventricular hypertrophy (LVH) is commonly present in patients with hypertension (HT). According to the expert consensus document from American, angiotensin-converting enzyme inhibitor (ACEI) and angiotensin receptor blockers (ARBs) were recommended as 1st-line therapeutic drugs. However, none noticed the different efficacy between fat-soluble and selective β1-receptor blockers (FS-β-B) and other β-blockers on regression of LVH before. The aim of this analysis was to compare the efficacy of FS-β-B with the other 4 different classes of antihypertensive drugs (ACEI, ARBs, calcium channel blockers [CCBs], and diuretics) on regression of LVH. Methods: Relative trials were identified in the PubMed, Web of Science, OVID EBM Reviews and Cochrane databases, and the relevant papers were examined. We performed both traditional and Bayesian meta-analysis of randomized controlled trials (RCTs) about the regression of LVH. Sensitivity analysis and regression analysis were performed to explore possible sources of heterogeneity. Inconsistency analysis was performed to check whether the analysis of the trials in the network was indeed consistent. Results: A total of 41 RCTs involving 2566 patients with HT and LVH were included in this analysis. Bayesian network meta-analysis indicated no statistically significant differences between these groups: FS-β-B and ACEI (MD, −7.09; 95% CI, −14.99, 1.27); FS-β-B and ARB (MD, −2.66; 95% Cl, −12.02, 6.31). Although FS-β-B showed greater efficacy when compared with diuretic (MD, 13.04; 95% CI, 3.38, 22.59) or CCB (MD, 10.90; 95% CI, 1.98, 19.49). The probabilities of being among the most efficacious treatments were: FS-β-B (72%), ARB (27%), ACEI (0.01%), CCB (0.00%), and diuretic (0.00%). Conclusion: Evidence from our analysis reveals that FS-β-B have potential to become 1st-line therapeutic drugs in HT and LVH patients. However, the real efficacy of FS-β-B on regression of LVH should be confirmed by

  12. Telmisartan activates endothelial nitric oxide synthase via Ser1177 phosphorylation in vascular endothelial cells.

    PubMed

    Myojo, Masahiro; Nagata, Daisuke; Fujita, Daishi; Kiyosue, Arihiro; Takahashi, Masao; Satonaka, Hiroshi; Morishita, Yoshiyuki; Akimoto, Tetsu; Nagai, Ryozo; Komuro, Issei; Hirata, Yasunobu

    2014-01-01

    Because endothelial nitric oxide synthase (eNOS) has anti-inflammatory and anti-arteriosclerotic functions, it has been recognized as one of the key molecules essential for the homeostatic control of blood vessels other than relaxation of vascular tone. Here, we examined whether telmisartan modulates eNOS function through its pleiotropic effect. Administration of telmisartan to mice significantly increased the phosphorylation level of eNOS (Ser1177) in the aortic endothelium, but administration of valsartan had no effect. Similarly, telmisartan treatment of human umbilical vein endothelial cells significantly increased the phosphorylation levels of AMP-activated protein kinase (Thr172) and eNOS and the concentration of intracellular guanosine 3',5'-cyclic monophosphate (cGMP). Furthermore, pretreatment with a p38 mitogen-activated protein kinase (p38 MAPK) inhibitor suppressed the increased phosphorylation level of eNOS and intracellular cGMP concentration. These data show that telmisartan increases eNOS activity through Ser1177 phosphorylation in vascular endothelial cells mainly via p38 MAPK signaling.

  13. Telmisartan Activates Endothelial Nitric Oxide Synthase via Ser1177 Phosphorylation in Vascular Endothelial Cells

    PubMed Central

    Myojo, Masahiro; Nagata, Daisuke; Fujita, Daishi; Kiyosue, Arihiro; Takahashi, Masao; Satonaka, Hiroshi; Morishita, Yoshiyuki; Akimoto, Tetsu; Nagai, Ryozo; Komuro, Issei; Hirata, Yasunobu

    2014-01-01

    Because endothelial nitric oxide synthase (eNOS) has anti-inflammatory and anti-arteriosclerotic functions, it has been recognized as one of the key molecules essential for the homeostatic control of blood vessels other than relaxation of vascular tone. Here, we examined whether telmisartan modulates eNOS function through its pleiotropic effect. Administration of telmisartan to mice significantly increased the phosphorylation level of eNOS (Ser1177) in the aortic endothelium, but administration of valsartan had no effect. Similarly, telmisartan treatment of human umbilical vein endothelial cells significantly increased the phosphorylation levels of AMP-activated protein kinase (Thr172) and eNOS and the concentration of intracellular guanosine 3′,5′-cyclic monophosphate (cGMP). Furthermore, pretreatment with a p38 mitogen-activated protein kinase (p38 MAPK) inhibitor suppressed the increased phosphorylation level of eNOS and intracellular cGMP concentration. These data show that telmisartan increases eNOS activity through Ser1177 phosphorylation in vascular endothelial cells mainly via p38 MAPK signaling. PMID:24827148

  14. Captopril and telmisartan treatments attenuate cadmium-induced testicular toxicity in rats.

    PubMed

    Fouad, Amr A; Jresat, Iyad

    2013-04-01

    The possible protective effect of captopril, an angiotensin-converting enzyme inhibitor, vs. telmisartan, an angiotensin II-receptor antagonist, was investigated in rats with testicular injury induced by a single i.p. injection of cadmium chloride (2 mg/kg). Captopril (60 mg/kg/day, p.o.) and telmisartan (10 mg/kg/day, p.o.) were given for five consecutive days, starting 3 days before cadmium administration. Both agents significantly increased serum testosterone level, which was reduced by cadmium, suppressed lipid peroxidation, restored the depleted reduced glutathione, decreased the elevations of nitric oxide, tumor necrosis factor-α, and cadmium ion levels, and attenuated the reductions of selenium and zinc ions in testicular tissue resulted from cadmium administration. Immunohistochemical analysis revealed that both captopril and telmisartan significantly reduced the cadmium-induced expression of inducible nitric oxide synthase, nuclear factor-κB, Fas ligand, and caspase-3 in testicular tissue. The differences between the results obtained with captopril and telmisartan were insignificant, suggesting that both drugs equally protected the testicular tissue from the detrimental effects of cadmium.

  15. Efficacy of Leflunomide, Telmisartan, and Clopidogrel for Immunoglobulin A Nephropathy: A Randomized Controlled Trial

    PubMed Central

    Wu, Jie; Duan, Shu-Wei; Sun, Xue-Feng; Li, Wen-Ge; Wang, Ya-Ping; Liu, Wen-Hu; Zhang, Jian-Rong; Lun, Li-De; Li, Xue-Mei; Zhou, Chun-Hua; Li, Ji-Jun; Liu, Shu-Wen; Xie, Yuan-Sheng; Cai, Guang-Yan; Ma, Lu; Huang, Wen; Wu, Hua; Jia, Qiang; Chen, Xiang-Mei

    2016-01-01

    Background: The efficacy and safety of telmisartan combined with clopidogrel, leflunomide, or both drugs for immunoglobulin A nephropathy (IgAN) are unclear. This study was designed to evaluate the efficacy and safety of telmisartan combined with clopidogrel, leflunomide, or both drugs for IgAN. Methods: It is a multicenter, prospective, double-dummy randomized controlled trial. Primary IgAN patients were recruited in 13 renal units across Beijing, China, from July 2010 to June 2012. After a 4-week telmisartan (80 mg/d) wash-in, 400 patients continuing on 80 mg/d telmisartan were randomly assigned to additionally receive placebo (Group A), 50 mg/d clopidogrel (Group B), 20 mg/d leflunomide (Group C), or 50 mg/d clopidogrel and 20 mg/d leflunomide (Group D). The 24-week intervention was completed by 360 patients. The primary endpoint was change in 24-h proteinuria at 24 weeks. A linear mixed-effect model was used to analyze the changes at 4, 12, and 24 weeks. Generalized estimating equations were used to evaluate changes in hematuria grade. This trial was registered at the Chinese Clinical Trial Registry. Results: The effects of telmisartan combined with leflunomide on changes in proteinuria (0.36 [95% confidence interval (CI) 0.18–0.55] g/d, P < 0.001), in serum uric acid (76.96 [95% CI 57.44–96.49] μmol/L, P < 0.001), in serum creatinine (9.49 [95% CI 6.54–12.44] μmol/L, P < 0.001), and in estimated glomerular filtration rate (−6.72 [95% CI −9.46 to −3.98] ml∙min−1∙1.73 m−2, P < 0.001) were statistically significant, whereas they were not statistically significant on changes in systolic and diastolic blood pressure and weight (P > 0.05). Telmisartan combined with clopidogrel had no statistical effect on any outcome, and there was no interaction between the interventions. No obvious adverse reactions were observed. Conclusions: Telmisartan combined with leflunomide, not clopidogrel, is safe and effective for decreasing proteinuria in certain

  16. Concentration-dependent mode of interaction of angiotensin II receptor blockers with uric acid transporter.

    PubMed

    Iwanaga, Takashi; Sato, Masanobu; Maeda, Tomoji; Ogihara, Toshio; Tamai, Ikumi

    2007-01-01

    Serum uric acid (SUA) is currently recognized as a risk factor for cardiovascular disease. It has been reported that an angiotensin II receptor blocker (ARB), losartan, decreases SUA level, whereas other ARBs, such as candesartan, have no lowering effect. Because the renal uric acid transporter (URAT1) is an important factor controlling the SUA level, we examined the involvement of URAT1 in those differential effects of various ARBs on SUA level at clinically relevant concentrations. This study was done by using URAT1-expressing Xenopus oocytes. Losartan, pratosartan, and telmisartan exhibited cis-inhibitory effects on the uptake of uric acid by URAT1, whereas at higher concentrations, only telmisartan did, and these ARBs reduced the uptake in competitive inhibition kinetics. On the other hand, candesartan, EXP3174 [2-n-butyl-4-chloro-1-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yI)methyl]imidazole-5-carboxylic acid] (a major metabolite of losartan), olmesartan, and valsartan were not inhibitory. Preloading of those ARBs in the oocytes enhanced the URAT1-mediated uric acid uptake, showing a trans-stimulatory effect. The present study is a first demonstration of the differential effects of ARBs on URAT1 that some ARBs are both cis-inhibitory and trans-stimulatory, depending on concentration, whereas others exhibit either a trans-stimulatory or cis-inhibitory effect alone, which could explain the clinically observed differential effects of ARBs on SUA level. Furthermore, it was found that such differential effects of ARBs on URAT1 could be predicted from the partial chemical structures of ARBs, which will be useful information for the appropriate use and development of ARBs without an increase of SUA.

  17. Telmisartan reduced cerebral edema by inhibiting NLRP3 inflammasome in mice with cold brain injury.

    PubMed

    Wei, Xin; Hu, Chen-Chen; Zhang, Ya-Li; Yao, Shang-Long; Mao, Wei-Ke

    2016-08-01

    The aim of this study was to investigate the possible beneficial role of telmisartan in cerebral edema after traumatic brain injury (TBI) and the potential mechanisms related to the nucleotide-binding oligomerization domain (NOD)-like receptor (NLR) pyrin domain-containing 3 (NLRP3) inflammasome activation. TBI model was established by cold-induced brain injury. Male C57BL/6 mice were randomly assigned into 3, 6, 12, 24, 48 and 72 h survival groups to investigate cerebral edema development with time and received 0, 5, 10, 20 and 40 mg/kg telmisartan by oral gavage, 1 h prior to TBI to determine the efficient anti-edemic dose. The therapeutic window was identified by post-treating 30 min, 1 h, 2 h and 4 h after TBI. Blood-brain barrier (BBB) integrity, the neurological function and histological injury were assessed, at the same time, the mRNA and protein expression levels of NLRP3 inflammasome, IL-1β and IL-18 concentrations in peri-contused brain tissue were measured 24 h post TBI. The results showed that the traumatic cerebral edema occurred from 6 h, reached the peak at 24 h and recovered to the baseline 72 h after TBI. A single oral dose of 5, 10 and 20 mg/kg telmisartan could reduce cerebral edema. Post-treatment up to 2 h effectively limited the edema development. Furthermore, prophylactic administration of telmisartan markedly inhibited BBB impairment, NLRP3, apoptotic speck-containing protein (ASC) and Caspase-1 activation, as well as IL-1β and IL-18 maturation, subsequently improved the neurological outcomes. In conclusion, telmisartan can reduce traumatic cerebral edema by inhibiting the NLRP3 inflammasome-regulated IL-1β and IL-18 accumulation.

  18. Tuning Photochromic Ion Channel Blockers

    PubMed Central

    2011-01-01

    Photochromic channel blockers provide a conceptually simple and convenient way to modulate neuronal activity with light. We have recently described a family of azobenzenes that function as tonic blockers of Kv channels but require UV-A light to unblock and need to be actively switched by toggling between two different wavelengths. We now introduce red-shifted compounds that fully operate in the visible region of the spectrum and quickly turn themselves off in the dark. Furthermore, we have developed a version that does not block effectively in the dark-adapted state, can be switched to a blocking state with blue light, and reverts to the inactive state automatically. Photochromic blockers of this type could be useful for the photopharmacological control of neuronal activity under mild conditions. PMID:22860175

  19. The effects of simultaneous administration of dietary conjugated linoleic acid and telmisartan on cardiovascular risks in rats.

    PubMed

    Abdullah, Mohammad M; Xu, Zuyuan; Pierce, Grant N; Moghadasian, Mohammed H

    2007-09-01

    Dietary conjugated linoleic acid (CLA) and the antihypertensive drug, telmisartan, have both been shown to modify cardiovascular risks. The effects of a combination of these two agents have, however, not been investigated. This 20 week study sought to assess the therapeutic potential of a CLA/telmisartan co-administration in rats fed a high-fructose high-fat diet. Thirty-three male Sprague-Dawley rats were randomly assigned to five experimental groups, including control, losartan, telmisartan, CLA, and CLA + telmisartan-treated animals. Body weight, blood pressure, and blood levels of lipids, glucose, insulin, and inflammatory markers were measured. Co-administration of CLA and telmisartan resulted in significant (P < 0.05) reductions in body weight, visceral fat, serum total cholesterol, triglycerides, glucose, plasma insulin concentrations, and systolic blood pressure compared with those in the control group. Moreover, plasma levels of IL1-alpha and IFN-gamma were reduced and levels of IL1-beta, IL-4, IL-6, and IL-10, plus TNF-alpha were increased in the co-therapy group, compared with controls. In conclusion, this study suggests that a combination of CLA with telmisartan may modify several risk factors of cardiovascular disease commonly seen in metabolic syndrome. This combination of nutraceuticals and pharmaceuticals may be a safe and cost-effective strategy in a number of high-risk subjects. Future studies will further document clinical benefits of such combination therapy.

  20. How Do Beta Blocker Drugs Affect Exercise?

    MedlinePlus

    ... Aneurysm More How do beta blocker drugs affect exercise? Updated:Aug 5,2015 Beta blockers are a ... about them: Do they affect your ability to exercise? The answer can vary a great deal, depending ...

  1. Can Beta Blockers Cause Weight Gain?

    MedlinePlus

    Diseases and Conditions High blood pressure (hypertension) Can beta blockers cause weight gain? Answers from Sheldon G. Sheps, ... can occur as a side effect of some beta blockers, especially the older ones, such as atenolol (Tenormin) ...

  2. Dapagliflozin reduces albuminuria in patients with diabetes and hypertension receiving renin‐angiotensin blockers

    PubMed Central

    Johnsson, E.; Gause‐Nilsson, I.; Cain, V. A.; Sjöström, C. D.

    2016-01-01

    Aims To characterize the effect of dapagliflozin on albuminuria and estimated glomerular filtration rate (eGFR) and to determine whether effects on albuminuria were mediated through changes in glycated haemoblogin (HbA1c), systolic blood pressure (SBP), body weight or eGFR. Methods We conducted a post hoc analysis of data pooled from two phase III clinical trials in hypertensive patients with type 2 diabetes (T2DM) on stable angiotensin‐converting enzyme inhibitor or angiotensin receptor blocker therapy, randomly assigned to dapagliflozin 10 mg/day or matched placebo. This analysis included only patients with microalbuminuria or macroalbuminuria at baseline. Results Patients were randomized to receive dapagliflozin 10 mg (n = 167) or placebo (n = 189). Dapagliflozin resulted in greater 12‐week reductions in albuminuria compared with placebo: −33.2% [95% confidence interval (CI) −45.4, −18.2]. The reduction in albuminuria was also present after adjusting for age, sex and changes in HbA1c, SBP, body weight and eGFR: −23.5% (95% CI −37.6, −6.3). There was a decrease in eGFR with dapagliflozin versus placebo that was readily reversed 1 week after last dose. No serious renal‐related adverse events were observed in any group. Conclusions Dapagliflozin was effective in lowering albuminuria in patients with T2DM and hypertension using renin‐angiotensin system blockade therapy. Reductions in albuminuria were still present after adjusting for changes in HbA1c, SBP, body weight and eGFR. Dapagliflozin‐induced improvements in glycaemic control and reductions in SBP, coupled with other potentially beneficial renal effects, may lead to a reduced long‐term renal and cardiovascular risk. PMID:26936519

  3. Renoprotective effects of renin–angiotensin system inhibitor combined with calcium channel blocker or diuretic in hypertensive patients

    PubMed Central

    Cheng, Yiming; Huang, Rongshuang; Kim, Sehee; Zhao, Yuliang; Li, Yi; Fu, Ping

    2016-01-01

    Abstract Objectives: To conduct a meta-analysis of studies comparing the renoprotective effects of angiotensin-converting enzyme inhibitor/angiotensin receptor blocker (ACEI/ARB) combined with either calcium channel blocker (CCB) or diuretic, but not both, in hypertensive patients. Data sources: Pubmed, Embase, Medline, and Cochrane databases were searched to identify randomized controlled trials (RCTs) of blood pressure lowering treatments in patients with hypertension. Study selection: RCTs comparing the renoprotective effects of ACEI/ARB plus CCB with ACEI/ARB plus diuretic in hypertensive patients, with at least one of the following reported outcomes: urinary protein, estimated glomerular filtration rate/creatinine clearance (eGFR/CrCl), or serum creatinine. Results: Based on 14 RCTs with 18,125 patients, statistically significant benefits were found in ACEI/ARB plus CCB for maintaining eGFR/CrCl (standardized mean difference [SMD] = 0.36; 95% confidence interval [CI]: 0.20–0.53; P < 0.001), serum creatinine reduction (mean difference [MD] = −0.05 mg/dL; 95% CI: −0.07 to −0.03; P < 0.001). However, no statistical differences were found between the 2 therapeutic strategies in terms of urinary protein (MD = 7.48%; 95% CI: –6.13% to 21.08%; P = 0.28; I2 = 92%). Conclusions: This meta-analysis concluded that ACEI/ARB plus CCB have a stronger effect on the maintenance of renal function in patients with hypertension than ACEI/ARB plus diuretic. PMID:27428210

  4. Determining the structural relaxation times deep in the glassy state of the pharmaceutical Telmisartan

    NASA Astrophysics Data System (ADS)

    Adrjanowicz, K.; Paluch, M.; Ngai, K. L.

    2010-03-01

    By using the dielectric relaxation method proposed recently by Casalini and Roland (2009 Phys. Rev. Lett. 102 035701), we were able to determine the structural α-relaxation times deep in the glassy state of the pharmaceutical, Telmisartan. Normally, deep in the glassy state τα is so long that it cannot be measured but τβ, which is usually much shorter, can be directly determined. The method basically takes advantage of the connection between the α-relaxation and the secondary β-relaxation of the Johari-Goldstein kind, including a relation between their relaxation times τα and τβ, respectively. Thus, τα of Telmisartan were determined by monitoring the change of the dielectric β-loss, ɛ'', with physical aging time at temperatures well below the vitrification temperature. The values of τα were compared with those expected by the coupling model (CM). Unequivocal comparison cannot be made in the case of Telmisartan because its β-loss peak is extremely broad, and the CM predicts only an order of magnitude agreement between the primitive relaxation frequency and the β-peak frequency. We also made an attempt to analyze all isothermal and aging susceptibility data after transformation into the electric modulus representation. The τα found in the glass state by using the method of Casalini and Roland in the modulus representation are similar to those obtained in the susceptibility representation. However, it is remarkable that the stretching parameter βKWW - M = 0.51 in the electric modulus representation gives more precise fits to the aging data than in the susceptibility representation with βKWW = 0.61. Our results suggest that the electric modulus representation may be useful as an alternative to analyze aging data, especially in the case of highly polar glassformers having a large ratio of low frequency and high frequency dielectric constants, such as the Telmisartan studied.

  5. What is a preferred angiotensin II receptor blocker-based combination therapy for blood pressure control in hypertensive patients with diabetic and non-diabetic renal impairment?

    PubMed Central

    2012-01-01

    Hypertension has a major associated risk for organ damage and mortality, which is further heightened in patients with prior cardiovascular (CV) events, comorbid diabetes mellitus, microalbuminuria and renal impairment. Given that most patients with hypertension require at least two antihypertensives to achieve blood pressure (BP) goals, identifying the most appropriate combination regimen based on individual risk factors and comorbidities is important for risk management. Single-pill combinations (SPCs) containing two or more antihypertensive agents with complementary mechanisms of action offer potential advantages over free-drug combinations, including simplification of treatment regimens, convenience and reduced costs. The improved adherence and convenience resulting from SPC use is recognised in updated hypertension guidelines. Despite a wide choice of SPCs for hypertension treatment, clinical evidence from direct head-to-head comparisons to guide selection for individual patients is lacking. However, in patients with evidence of renal disease or at greater risk of developing renal disease, such as those with diabetes mellitus, microalbuminura and high-normal BP or overt hypertension, guidelines recommend renin-angiotensin system (RAS) blocker-based combination therapy due to superior renoprotective effects compared with other antihypertensive classes. Furthermore, RAS inhibitors attenuate the oedema and renal hyperfiltration associated with calcium channel blocker (CCB) monotherapy, making them a good choice for combination therapy. The occurrence of angiotensin-converting enzyme (ACE) inhibitor-induced cough supports the use of angiotensin II receptor blockers (ARBs) for RAS blockade rather than ACE inhibitors. In this regard, ARB-based SPCs are available in combination with the diuretic, hydrochlorothiazide (HCTZ) or the calcium CCB, amlodipine. Telmisartan, a long-acting ARB with preferential pharmacodynamic profile compared with several other ARBs, and the

  6. Study of effect of variables on particle size of telmisartan nanosuspensions using box-Behnken design.

    PubMed

    Rao, M R P; Bajaj, A

    2014-12-01

    Telmisartan, an orally active nonpeptide angiotensin II receptor antagonist is a BCS Class II drug having aqueous solubility of 9.9 µg/ml and hence oral bioavailability of 40%. The present study involved preparation of nanosuspensions by evaporative antisolvent precipitation technique to improve the saturation solubility and dissolution rate of telmisartan. Various stabilizers such as TPGS, PVPK 30, PEG 6000 were investigated of which TPGS was found to provide maximum decrease in particle size and accord greater stability to the nanosuspensions. Box-Behnken design was used to investigate the effect of independent variables like stabilizer concentration, time and speed of stirring on particle size of nanosuspensions. Pharmacodynamic studies using Goldblatt technique were undertaken to evaluate the effect of nano-sizing on the hypotensive effect of the drug. Concentration of TPGS and speed of rotation were found to play an important role in particle size of the nanosuspensions whereas time of stirring displayed an exponential relationship with particle size. Freeze dried nanocrystals obtained from nanosuspension of least particle size were found to have increased saturation solubility of telmisartan in different dissolution media. The reconstituted nanosuspension was found to reduce both systolic and diastolic blood pressure without affecting pulse pressure and heart rate. Statistical tools can be used to identify key process and formulation parameters which play a significant role in controlling the particle size in nanosuspensions.

  7. Symmetrical drug-related intertriginous and flexural exanthema (SDRIFE) induced by telmisartan-hydrochlorothiazide.

    PubMed

    Ferreira, Olga; Mota, Alberto; Morais, Paulo; Cunha, Ana Paula; Azevedo, Filomena

    2010-12-01

    Symmetrical drug-related intertriginous and flexural exanthema (SDRIFE) is a drug-related eruption that characteristically involves the intertriginous or flexural folds and gluteal areas. We report the case of a 48-year-old woman with the presence of a sharply demarcated erythema of the inferior cervical folds, axillae, and gluteal area that started 4 days after the introduction of telmisartan-hydrochlorothiazide administration to treat hypertension. Skin biopsy revealed a dense perivascular and periadnexal lymphohistiocytic infiltrate in the superficial dermis, with some eosinophils and mast cells. A cutaneous drug adverse reaction was suspected, administration of telmisartan-hydrochlorothiazide was suspended, and medium-potency topical corticosteroids were prescribed, with subsequent significant improvement of the lesions. Eight months later, epicutaneous patch tests were performed in previously lesional and nonlesional skin. To the best of our knowledge, this is the first case of SDRIFE related to telmisartan-hydrochlorothiazide and illustrates an uncommon presentation of a skin-related drug reaction to an antihypertensive medication and the role of the dermatologist in diagnosis and management, in particular in follow-up of the patient.

  8. The pharmacological research of Tek-1 relevance to anti-neuroinflammation, a candidate compound based on Telmisartan

    PubMed Central

    Yang, Jianbo; Cui, Changcong

    2015-01-01

    In this paper, BV-2 mouse small glial cell inflammation model induced by LPS is established. The experiment used 0.1–10 μM of telmisartan and Tek-1 to incubate with small glial cell and used telmisartan and Tek-1 to incubate with PPAR gamma special heterosexual antagonistic anti-agent GW9662. The article used ELISA method to dectect TNF-a effect on small glial cell for telmisartan and Tek-1. The article used real-time quantitative PCR method to dectect mRNA level expression effect of CD11b, CD16 and iNOS on small glial cell for telmisartan and Tek-1 and used Western Blot method to dectect MAPKs signal pathway and NF-κb signal turned guide pathway effect on small glial cell for telmisartan and Tek-1. Results show that Tek-1 had high affinity with AT1 receptor and inhibited intracellular calcium ion activation which can be for the AT1 receptor antagonists. Meanwhile, Tek-1 can partially activate PPAR gamma compared with full agonists of rosiglitazone. PMID:28352734

  9. [Applications for bronchial blockers in thoracic surgery].

    PubMed

    García-Guasch, R; Campos, J H; Granell, M; Peña, J J

    2007-11-01

    One-lung ventilation is commonly used to facilitate visualization of the field during thoracic surgery. New devices for performing this technique that have become available over the past 2 decades include the Univent bronchial blocker incorporated in a single-lumen tube, the Arndt endobronchial blocker, and the Cohen endobronchial blocker. Although insertion of a double-lumen tube is still the method used most often to isolate the lung, bronchial blockade is an increasingly common technique and, in certain clinical settings, provides advantages over the double-lumen tube. This review provides an update on new concepts in the use of bronchial blockers as a technique for lung isolation and one-lung ventilation. The literature search was performed on MEDLINE through PubMed using the keywords bronchial blockers and thoracic surgery. The search span started with 1982-the year the first modern bronchial blocker was described - and ended with February 2006.

  10. Are ACE-inhibitors or ARB's still needed for cardiovascular prevention in high risk patients? Insights from profess and transcend.

    PubMed

    Van Mieghem, W; Billiouw, J M; Brohet, C; Dupont, A G; Gazagnes, M D; Heller, F; Krzesinski, J M; Missault, L; Persu, A; Piérard, L; Rottiers, R; Vanhooren, G; Vervaet, P; Herman, A G

    2010-01-01

    The HOPE and EUROPA clinical studies have shown that treatment with the angiotensin-converting enzyme (ACE) inhibitors, ramipril and perindopril, may reduce the occurrence of major cardiovascular events in patients with proven atherosclerotic disease. The recently published results of the PRoFESS and TRANSCEND trials completed the much needed information concerning the use of an angiotensin receptor blocker for patients at high risk of cardiovascular events. PROFESS compared a therapy of telmisartan 80 mg daily with placebo in patients with a recent ischemic stroke. The difference in the primary outcome of first recurrent stroke was not statistically significant between telmisartan and placebo. The secondary outcome of major cardiovascular events showed a relative risk reduction (RRR) of 7% in favour of telmisartan. This tended to be significant (p = 0.06) despite a rather short follow-up period of only 28 months. In TRANSCEND 5926 patients at high risk for cardiovascular events were randomized to a treatment with telmisartan 80 mg daily or placebo for a mean duration of follow-up of 56 months. The primary composite outcome of cardiovascular death, myocardial infarction, stroke or hospitalization for heart failure showed a non-significant 8% RRR in favour of the telmisartan treated patients. The main secondary outcome of cardiovascular death and myocardial infarction or stroke as used in the HOPE trial showed a non-significant RRR of 13% in favour of telmisartan treated patients (p = 0.068 adjusted for multiplicity of comparisons). In comparing the Kaplan-Meier curves for the endpoint of major cardiovascular events used in HOPE, EUROPA, TRANSCEND and PRoFESS, the trends are similar. Results of most of the recently published trials have been neutral.This could partly be explained by major improvements in the optimal background therapy of the patients included. Nevertheless, the results of PRoFESS and TRANSCEND do not contradict the results from previous studies with

  11. Effect of hydrochlorothiazide in addition to telmisartan/amlodipine combination for treating hypertensive patients uncontrolled with telmisartan/amlodipine: a randomized, double-blind study

    PubMed Central

    Higaki, Jitsuo; Komuro, Issei; Shiki, Kosuke; Lee, Ganghyuck; Taniguchi, Atsushi; Ikeda, Hiroshi; Kuroki, Daisuke; Nishimura, Seiichiro; Ogihara, Toshio

    2017-01-01

    The efficacy and safety of telmisartan 80 mg/amlodipine 5 mg plus hydrochlorothiazide 12.5 mg (T80/A5/H12.5) was examined for its ability to treat hypertension in Japanese patients whose hypertension is uncontrolled with telmisartan 80 mg/amlodipine 5 mg (T80/A5). Patients aged ⩾20 years who had essential hypertension despite taking two or three antihypertensive drugs entered a 6-week run-in period on T80/A5. Patients whose hypertension remained uncontrolled were randomly assigned to either the T80/A5/H12.5 group (n=149) or the T80/A5 group (n=160), once daily for 8 weeks. After 8 weeks, patients in the T80/A5/H12.5 group showed a significantly greater adjusted mean reduction in both seated diastolic blood pressure and seated systolic blood pressure than those in the T80/A5 group. Furthermore, more patients achieved a diastolic/systolic blood pressure of <90/140 mm Hg in the T80/A5/H12.5 group compared with the T80/A5 group. The most common adverse events were nasopharyngitis, elevated blood uric acid levels and hyperuricemia, and the latter two events were more frequent in the T80/A5/H12.5 group than in the T80/A5 group. Overall, T80/A5/H12.5 administered for 8 weeks significantly reduced systolic and diastolic blood pressure and was well tolerated by patients with hypertension uncontrolled with T80/A5. PMID:27761000

  12. Prescription of renin–angiotensin system blockers and risk of acute kidney injury: a population-based cohort study

    PubMed Central

    Nitsch, Dorothea; Smeeth, Liam; Bhaskaran, Krishnan; Tomlinson, Laurie A

    2016-01-01

    Objective To investigate whether there is an association between use of ACE inhibitors (ACEI) and angiotensin receptor blockers (ARB) and risk of acute kidney injury (AKI). Study design We conducted a new-user cohort study of the rate of AKI among users of common antihypertensives. Setting UK primary care practices contributing to the Clinical Practice Research Datalink (CPRD) eligible for linkage to hospital records data from the Hospital Episode Statistics (HES) database between April 1997 and March 2014. Participants New users of antihypertensives: ACEI/ARB, β-blockers, calcium channel blockers and thiazide diuretics. Outcomes The outcome was first episode of AKI. We estimated incidence rate ratio (RR) for AKI during time exposed to ACEI/ARB compared to time unexposed, adjusting for age, sex, comorbidities, use of other antihypertensive drugs and calendar period using Poisson regression. Covariates were time updated. Results Among 570 445 participants, 303 761 were prescribed ACEI/ARB with a mean follow-up of 4.1 years. The adjusted RR of AKI during time exposed to ACEI/ARB compared to time unexposed was 1.12 (95% CI 1.07 to 1.17). This relative risk varied depending on absolute risk of AKI, with lower or no increased relative risk from the drugs among those at greatest absolute risk. For example, among people with stage 4 chronic kidney disease (who had 6.69 (95% CI 5.57 to 8.03) times higher rate of AKI compared to those without chronic kidney disease), the adjusted RR of AKI during time exposed to ACEI/ARB compared to time unexposed was 0.66 (95% CI 0.44 to 0.97) in contrast to 1.17 (95% CI 1.09 to 1.25) among people without chronic kidney disease. Conclusions Treatment with ACEI/ARB is associated with only a small increase in AKI risk while individual patient characteristics are much more strongly associated with the rate of AKI. The degree of increased risk varies between patient groups. PMID:28003286

  13. Renoprotective effect of a combination of garlic and telmisartan against ischemia/reperfusion-induced kidney injury in obese rats.

    PubMed

    Ali, Sousou Ibrahim; Alhusseini, Naglaa Fathy; Atteia, Hebatallah Husseini; Idris, Reham Abd El-Satar; Hasan, Rehab Abdallah

    2016-09-01

    Obesity enhances the frequency and severity of acute kidney injury (AKI). Telmisartan pre-treatment was used experimentally in the amelioration of ischemia/reperfusion (IR)-induced AKI. However, there is a lack of evidence regarding its beneficial effects on AKI in obese animals. The present study, therefore, aimed to explore the protective effects of garlic and/or telmisartan against renal damage induced by unilateral IR in obese rats. Meloxicam was used as a standard anti-inflammatory agent. Prophylactic oral administration of meloxicam (3 mg kg(-1)), garlic (500 mg kg(-1)) and/or telmisartan (5 and 10 mg kg(-1)) for 4 wk protected against renal function deterioration induced by IR in obese rats. Both doses of telmisartan significantly reduced serum total cholesterol and triacyglycerol levels as well as peri-renal adipocytes size and renal fibrosis. Renal nuclear factor-kappa B immunoreactivity, tumor necrosis factor-alpha content as well as interleukin-10, adiponectin receptor 1 and macrophages (M1, M2) polarization markers (CD11c, CD206) mRNA expressions were down-regulated in ischemic kidney tissues and white adipose tissues around them by all treatments. Moreover, garlic, telmisartan and their combinations significantly suppressed oxidative stress in renal ischemic tissues. Histological picture was also improved by these treatments. Interestingly, the combinations provided a greater protection than their monotherapy in a dose-dependent manner. We suppose that this combination may be a promising prophylactic regimen for managing AKI in case of obesity. Thus, future experimental and clinical large-scale studies are necessary.

  14. Enhancement of dissolution of Telmisartan through use of solid dispersion technique - surface solid dispersion

    PubMed Central

    Patel, Bhumika; Parikh, R. H.; Swarnkar, Deepali

    2012-01-01

    The present study was aimed to increase the solubility of the poorly water soluble drug Telmisartan by using Surface solid dispersion (SSD) made of polymers like Poloxamer 407, PEG 6000 by Solvent evaporation method. The drug was solubilized by surfactants and/or polymers then adsorbed onto the surface of extremely fine carriers to increase its surface area and to form the SSD which give the more Surface area for absorption of the drug. A 22 full factorial design was used to investigate for each carrier the joint influence of formulation variables: Amount of carrier and adsorbent. Saturation solubility studies shows the improvement in solubility of drug batch SSD 8 give more solubility improvement than the other batch, in-vitro dissolution of pure drug, physical mixtures and SSDs were carried out in that SSDs were found to be effective in increasing the dissolution rate of Telmisartan in form of SSD when compared to pure drug. Also FT-IR spectroscopy, differential scanning calorimetry and X-ray diffractometry studies were carried out in order to characterize the drug and Surface solid dispersion. Furthermore, both DSC and X-ray diffraction showed a decrease in the melting enthalpy and reduced drug crystallinity consequently in SSDs. However, infrared spectroscopy revealed no drug interactions with the carriers. PMID:23066211

  15. Effects of calcium channel blocker benidipine-based combination therapy on target blood pressure control and cardiovascular outcome: a sub-analysis of the COPE trial.

    PubMed

    Umemoto, Seiji; Ogihara, Toshio; Matsuzaki, Masunori; Rakugi, Hiromi; Ohashi, Yasuo; Saruta, Takao

    2017-04-01

    We compared three benidipine-based regimens-that is, benidipine plus angiotensin receptor blocker (ARB), β-blocker (BB) or thiazide-and found that the benidipine-BB combination was less beneficial in reducing the risk of stroke than the benidipine-thiazide combination. This sub-analysis sought to compare the effects of reaching a target blood pressure (BP) (<140/90 mm Hg) on the cardiovascular outcomes among the three benidipine-based treatment groups in the Combination Therapy of Hypertension to Prevent Cardiovascular Events trial. This sub-analysis included 3001 subjects to evaluate the achievement of target BP at a minimum of three points at 6-month intervals of clinical BP measurements during the study period. After randomization, the patients were categorized into two groups on the basis of achieved on-treatment target BP: a good control (GC) group achieving a BP⩾66.7% of the target and a poor control (PC) group with a BP <66.6% of the target. For each of the two control groups, outcomes were compared among the three treatment groups. The event rates for cardiovascular composite endpoints, stroke and hard cardiovascular events were higher in the PC group than the GC group (P=0.041, P=0.042 and P=0.038, respectively). Within the PC group, hazard ratios for the incidence of cardiovascular events were lower in the benidipine-thiazide group than in the benidipine-BB group (composite cardiovascular events: 2.04, P=0.033; stroke: 4.14, P=0.005; and hard cardiovascular events: 3.52, P=0.009). Within the GC group, the incidence of cardiovascular events was not different among the three treatment regimens. The benidipine-thiazide combination may provide better cardiovascular outcomes than the benidipine-BB combination even in patients with poor BP control.

  16. Heart failure therapeutics on the basis of a biased ligand of the angiotensin-2 type 1 receptor. Rationale and design of the BLAST-AHF study (Biased Ligand of the Angiotensin Receptor Study in Acute Heart Failure).

    PubMed

    Felker, G Michael; Butler, Javed; Collins, Sean P; Cotter, Gad; Davison, Beth A; Ezekowitz, Justin A; Filippatos, Gerasimos; Levy, Phillip D; Metra, Marco; Ponikowski, Piotr; Soergel, David G; Teerlink, John R; Violin, Jonathan D; Voors, Adriaan A; Pang, Peter S

    2015-03-01

    The BLAST-AHF (Biased Ligand of the Angiotensin Receptor Study in Acute Heart Failure) study is designed to test the efficacy and safety of TRV027, a novel biased ligand of the angiotensin-2 type 1 receptor, in patients with acute heart failure (AHF). AHF remains a major public health problem, and no currently-available therapies have been shown to favorably affect outcomes. TRV027 is a novel biased ligand of the angiotensin-2 type 1 receptor that antagonizes angiotensin-stimulated G-protein activation while stimulating β-arrestin. In animal models, these effects reduce afterload while increasing cardiac performance and maintaining stroke volume. In initial human studies, TRV027 appears to be hemodynamically active primarily in patients with activation of the renin-angiotensin-aldosterone system, a potentially attractive profile for an AHF therapeutic. BLAST-AHF is an international prospective, randomized, phase IIb, dose-ranging study that will randomize up to 500 AHF patients with systolic blood pressure ≥120 mm Hg and ≤200 mm Hg within 24 h of initial presentation to 1 of 3 doses of intravenous TRV027 (1, 5, or 25 mg/h) or matching placebo (1:1:1:1) for at least 48 h and up to 96 h. The primary endpoint is a composite of 5 clinical endpoints (dyspnea, worsening heart failure, length of hospital stay, 30-day rehospitalization, and 30-day mortality) combined using an average z-score. Secondary endpoints will include the assessment of dyspnea and change in amino-terminal pro-B-type natriuretic peptide. The BLAST-AHF study will assess the efficacy and safety of a novel biased ligand of the angiotensin-2 type 1 receptor in AHF.

  17. The angiotensin receptor type 1-Gq protein-phosphatidyl inositol phospholipase Cbeta-protein kinase C pathway is involved in activation of proximal tubule Na+-ATPase activity by angiotensin(1-7) in pig kidneys.

    PubMed

    Lara, Lucienne S; Correa, Juliana S; Lavelle, Anouchka B; Lopes, Anibal G; Caruso-Neves, Celso

    2008-05-01

    In a previous study, we observed that angiotensin(1-7) (Ang(1-7)) stimulates proximal tubule Na+-ATPase activity through the angiotensin receptor type 1 (AT1R). Here we aimed to study the signalling pathways involved. Our results show that the stimulatory effect of Ang(1-7) on Na+-ATPase activity through AT1R involves a Gq protein-phosphatidyl inositol-phospholipase Cbeta (PI-PLCbeta) pathway because: (1) the effect was reversed by GDPbetaS, a non-hydrolysable GDP analogue, and by a monoclonal Gq protein antibody; (2) the effect was similar and not additive to that of GTPgammaS, a non-hydrolysable GTP analogue; (3) Ang(1-7) induced a rapid decrease (30 s) in phosphatidylinositol 4,5-bisphosphate levels, a PI-PLCbeta substrate; and (4) U73122, a specific inhibitor of PI-PLCbeta, abolished Ang(1-7)-induced stimulation of Na+-ATPase activity. Angiotensin(1-7) increased the protein kinase C (PKC) activity similarly to phorbol-12-myristate-13-acetate (PMA), an activator of PKC. This effect was reversed by losartan, a specific antagonist of AT1R. The stimulatory effects of Ang(1-7) and PMA on Na+-ATPase activity are similar, non-additive and reversed by calphostin C, a specific inhibitor of PKC. A catalytic subunit of PKC (PKC-M) increased the Na+-ATPase activity. These data show that Ang(1-7) stimulates Na+-ATPase activity through the AT1R-Gq protein-PI-PLCbeta-PKC pathway. This effect is similar to that described for angiotensin II, showing for the first time that these compounds could have similar effects in the renal system.

  18. Evaluation and Comparison of Anticonvulsant Activity of Telmisartan and Olmesartan in Experimentally Induced Animal Models of Epilepsy

    PubMed Central

    V H, Pushpa; R N, Suresha; M K, Jayanthi; V, Ashwini; P S, Vaibhavi

    2014-01-01

    Background: Epilepsy is one common neurological disorder requiring newer targets and newer drugs for its efficient management. In the recent days brain renin angiotensin system has gained immense importance because of its involvement in seizure regulation. Objective: To evaluate and compare antiepileptic activity of different doses olmesartan and telmisartan on MES and PTZ induced seizure models. Materials and Methods: Swiss albino mice weighing around 25-30g of either sex were divided into 6 groups: Control ( Distilled Water- 10ml/kg), Standard – Sodium valproate (40mg/kg), O1 – Olmesartan (2.5mg/kg), O2 – Olmesartan (5mg/kg), T1 - Telmisartan (5mg/kg), T2 – Telmisartan (10mg/kg). After 1hour of administration of control , test and standard drugs (orally), convulsions were induced by administering PTZ (70mg/kg – i.p.) in PTZ model. Seizure latency was the parameter recorded. In MES model, suppression of tonic hind limb extension was taken as measure of efficacy. Result: The results were analysed by one-way-ANOVA followed by Bonferroni’s multiple comparison test. In MES test, dose dependently olmesartan and telmisartan significantly reduced the duration of tonic hindlimb extension in comparison to control (p<0.05). T2 – 9 + 0.89secs significantly reduced the tonic hind limb extension compared to other test groups (p<0.05). The percentage inhibition of seizure was T2-44.3%, O2-28.2%, T1-17.5%, O1- 12.3% respectively. In PTZ test, dose dependently olmesartan and telmisartan produced significant increase in seizure latency (p<0.05). T2 - 206.6+9.83secs significantly increased seizure latency compared to other test groups (p<0.05). Percentage protection from seizure is T2-52.6%, O2- 45.13%, T1- 37.5%, O1- 38.4% respectively. Conclusion: AT1 receptor antagonist, telmisartan and olmesartan in a dose dependent manner showed increase in antiepileptic activity. Temisartan at higher dose produced significant antiepileptic activity in comparison to olmesartan

  19. Inhibition of tumor necrosis factor-alpha-induced interleukin-6 expression by telmisartan through cross-talk of peroxisome proliferator-activated receptor-gamma with nuclear factor kappaB and CCAAT/enhancer-binding protein-beta.

    PubMed

    Tian, Qingping; Miyazaki, Ryohei; Ichiki, Toshihiro; Imayama, Ikuyo; Inanaga, Keita; Ohtsubo, Hideki; Yano, Kotaro; Takeda, Kotaro; Sunagawa, Kenji

    2009-05-01

    Telmisartan, an angiotensin II type 1 receptor antagonist, was reported to be a partial agonist of peroxisome proliferator-activated receptor-gamma. Although peroxisome proliferator-activated receptor-gamma activators have been shown to have an anti-inflammatory effect, such as inhibition of cytokine production, it has not been determined whether telmisartan has such effects. We examined whether telmisartan inhibits expression of interleukin-6 (IL-6), a proinflammatory cytokine, in vascular smooth muscle cells. Telmisartan, but not valsartan, attenuated IL-6 mRNA expression induced by tumor necrosis factor-alpha (TNF-alpha). Telmisartan decreased TNF-alpha-induced IL-6 mRNA and protein expression in a dose-dependent manner. Because suppression of IL-6 mRNA expression was prevented by pretreatment with GW9662, a specific peroxisome proliferator-activated receptor-gamma antagonist, peroxisome proliferator-activated receptor-gamma may be involved in the process. Telmisartan suppressed IL-6 gene promoter activity induced by TNF-alpha. Deletion analysis suggested that the DNA segment between -150 bp and -27 bp of the IL-6 gene promoter that contains nuclear factor kappaB and CCAAT/enhancer-binding protein-beta sites was responsible for telmisartan suppression. Telmisartan attenuated TNF-alpha-induced nuclear factor kappaB- and CCAAT/enhancer-binding protein-beta-dependent gene transcription and DNA binding. Telmisartan also attenuated serum IL-6 level in TNF-alpha-infused mice and IL-6 production from rat aorta stimulated with TNF-alpha ex vivo. These data suggest that telmisartan may attenuate inflammatory process induced by TNF-alpha in addition to the blockade of angiotensin II type 1 receptor. Because both TNF-alpha and angiotensin II play important roles in atherogenesis through enhancement of vascular inflammation, telmisartan may be beneficial for treatment of not only hypertension but also vascular inflammatory change.

  20. On the top of ARB N/L type Ca channel blocker leads to less elevation of aldosterone

    PubMed Central

    Konoshita, Tadashi; Kaeriyama, Saori; Urabe, Machi; Nakaya, Takahiro; Yamada, Mika; Ichikawa, Mai; Yamamoto, Katsushi; Sato, Satsuki; Imagawa, Michiko; Fujii, Miki; Makino, Yasukazu; Zenimaru, Yasuo; Wakahara, Shigeyuki; Suzuki, Jinya; Ishizuka, Tamotsu; Nakamura, Hiroyuki

    2016-01-01

    The activation of the renin–angiotensin system (RAS) is one of the unfavourable characteristics of calcium channel blocker (CCB). N type calcium channel is thought to be involved in renin gene transcription and adrenal aldosterone release. Accordingly, N/L type CCB has a possibility of less elevation of plasma aldosterone concentrations (PAC) among CCBs. In a monotherapy study, we had already demonstrated that N/L type CCB leads to less activation of the RAS compared with L type CCB. The objective of this study is to substantiate the hypothesis that at the condition of additive administration on the top of an angiotensin receptor blocker (ARB), still N/L type CCB leads to less elevation of PAC compared with L type one. Subjects were 60 hypertensives administered with valsartan. As an open label study, amlodipine (L type) or cilnidipine (N/L type) were administered on the top of valsartan (ARB) in a cross-over manner. Results were as follows (valsartan+amlodipine compared with valsartan+cilnidipine): systolic blood pressure (SBP)/diastolic blood pressure (DBP) (mmHg): 132±10/76±10 compared with 131±10/77±9, P=0.95/0.48, plasma renin activity (PRA) (ng/ml·h): 2.41±2.67 compared with 2.00±1.50 P=0.20, PAC (pg/ml): 77.3±31.0 compared with 67.4±24.8, P<0.05, urinary albumin excretion (UAE) (mg/gCr): 105.9±216.1 compared with 73.9±122.2, P<0.05. Thus, PAC at cilnidipine was significantly lower than those at amlodipine in spite of the comparable BP reductions. Besides, UAE was significantly lower at cilnidipine. In conclusion, on the top of the ARB, it is suggested that cilnidipine administration might lead to less elevation of PAC and reduction in UAE compared with amlodipine. PMID:27515419

  1. The effects of telmisartan alone or with hydrochlorothiazide on morning and 24-h ambulatory BP control: results from a practice-based study (SURGE 2).

    PubMed

    Parati, Gianfranco; Bilo, Grzegorz; Redon, Josep

    2013-04-01

    Observational studies have shown that 24-h and morning ambulatory blood pressure (BP) control is low. This large-scale, practice-based study evaluated the effects of telmisartan 40 or 80 mg alone or in combination with hydrochlorothiazide (HCTZ) 12.5 mg on these BP parameters over 8 weeks; treatment was adjusted if clinic BP remained ≥140/90 mm Hg. A total of 863 patients were evaluated (baseline mean clinic BP, morning and 24-h ambulatory BP: 155±15/93±10 mm Hg, 137±15/83±11 mm Hg, 133±14/79±10 mm Hg, respectively; 68% were previously treated at baseline). Telmisartan with/without HCTZ significantly reduced the mean morning ambulatory BP (-8.2/-4.9 mm Hg), daytime ambulatory BP (-8.0/-4.7 mm Hg), 24-h ambulatory BP (-7.9/-4.7 mm Hg) and clinic BP (-22.3/-13.2 mm Hg) (all P<0.001) in previously untreated and in treated patients who switched to telmisartan and telmisartan/HCTZ. After treatment with telmisartan with/without HCTZ, the morning ambulatory BP control increased from 36.5 to 64.4%; daytime ambulatory BP control increased from 40.8 to 67.6%; 53.0% of patients achieved 24-h ambulatory BP <125/80 mm Hg and 62% achieved <130/80 mm Hg targets. Only 0.8% (7/863) reported an adverse event. In summary, telmisartan and telmisartan/HCTZ increased smooth 24-h BP control in daily management of hypertension.

  2. Misperceptions About β-Blockers and Diuretics

    PubMed Central

    Ubel, Peter A; Jepson, Christopher; Asch, David A

    2003-01-01

    BACKGROUND Based on a series of clinical trials showing no difference in the effectiveness or tolerability of most major classes of antihypertensive medications, the Joint National Commission on High Blood Pressure Treatment recommends that physicians prescribe β-blockers or diuretics as initial hypertensive therapy unless there are compelling indications for another type of medication. Nevertheless, many physicians continue to favor more expensive medications like angiotensin-converting enzyme (ACE) inhibitors and calcium channel blockers as first line agents. The persistent use of these agents raises questions as to whether physicians perceive ACE inhibitors and calcium channel blockers to be better than β-blockers and diuretics. METHODS We surveyed 1,200 primary care physicians in 1997, and another 500 primary care physicians in 2000, and asked them to estimate the relative effectiveness and side effects of 4 classes of medication in treating a hypothetical patient with uncomplicated hypertension: ACE inhibitors, β-blockers, calcium channel blockers, and diuretics. In addition, we asked them to indicate whether they ever provided free samples of hypertension medications to their patients. RESULTS Perceptions of the relative effectiveness and side effects of the 4 classes of hypertension medications did not significantly change over the 3 years, nor did prescription recommendations. Physicians perceive that diuretics are less effective at lowering blood pressure than the other 3 classes (P < .001). They also perceive that β-blockers are less tolerated than the other 3 classes (P < .001). In a multivariate model, perceptions of effectiveness and tolerability displayed significant associations with prescription preference independent of background variables. The only other variable to contribute significantly to the model was provision of free medication samples to patients. CONCLUSIONS Despite numerous clinical trials showing no difference in the effectiveness

  3. Adsorption of beta blockers to environmental surfaces.

    PubMed

    Kibbey, Tohren C G; Paruchuri, Rajiv; Sabatini, David A; Chen, Lixia

    2007-08-01

    Beta-adrenergic blocking agents (beta blockers) are widely used pharmaceuticals which have been detected in the environment. Predicting the transport and ultimate fate of beta blockers in the environment requires understanding their adsorption to soils and sediments, something for which little information is currently available. The objective of this work was to examine the adsorption of three beta blockers, propranolol, metoprolol and nadolol, to a natural alluvial material, as well as to six minerals present as components of the alluvial material. Batch adsorption experiments indicate that, for most of the minerals studied, compound hydrophobicity is an important predictor of adsorption, with propranolol,the most hydrophobic compound studied, adsorbing to the greatest extent. Results further suggest that, for the minerals studied, electrostatic effects are not a good predictor of adsorption; adsorption extent was not well-predicted by either surface zeta potential or by the difference between experiment pH and point of zero charge, despite the cationic nature af the three beta blockers at experiment pH values. Experiments were conducted to examine the effect of an anionic surfactant, sodium dodecyl benzene sulfonate (SDBS), on adsorption. Results indicate that SDBS significantly increases the adsorption of propranolol to two different sorbents. This result is potentially important because surfactants such as SDBS are likely to be present in wastewater effluents with beta blockers and could influence their mobility in the environment.

  4. Effect of telmisartan and enalapril on ventricular remodeling and kidney prognosis of patients with coronary artery disease complicated with diabetic nephropathy

    PubMed Central

    Hou, Yuyan; Zhang, Fucheng; Liu, Zhiqiang; Su, Shuhong; Wu, Xiao; Wang, Zhifang

    2017-01-01

    The aim of the present study was to compare the value of telmisartan and enalapril on ventricular remodeling and kidney prognosis of patients with coronary artery disease complicated with diabetic nephropathy, and provide discussion on clinical reasonably chosen medicine. A total of 60 cases of coronary artery disease complicated with diabetic nephropathy were randomly divided for telmisartan (80 mg/day) treatment (n=32), enalapril (10 mg/day) treatment (n=28), while the rest of the therapy was kept the same. After 12 weeks, the clinical effects were compared between different groups. It was found that in comparison with enalapril group, the left ventricular ejection fraction of telmisartan group was significantly higher, and left ventricular end-diastolic diameter was significantly lower (P<0.05). The serum creatinine level and 24-h protein of telmisartan group were significantly lower than that for the enalapril group (P<0.05). In conclusion, the regular telmisartan treatment for patients with coronary artery disease complicated with diabetic nephropathy is better than enalapril on ventricular remodeling and kidney prognosis. PMID:28123481

  5. Telmisartan mediates anti-inflammatory and not cognitive function through PPAR-γ agonism via SARM and MyD88 signaling.

    PubMed

    Prathab Balaji, S; Vijay Chand, C; Justin, A; Ramanathan, M

    2015-10-01

    Telmisartan (TM), an angiotensin II receptor I (AT1) blocker, has been reported to have agonist property with respect to PPAR-γ. Activation of PPAR-γ receptor by TM attenuated the lipopolysaccharide (LPS) mediated TLR4 central downstream inflammatory responses. However, the missing link between PPAR-γ and TLR4 signaling with TM stimulation has not been clarified. Hence, the present study has been designed to evaluate the molecular mechanism involving PPARγ-TLR4 signaling with TM stimulation in LPS induced inflammatory model. LPS was administered in rats through ICV and the rats were treated with either PPAR-γ antagonist GW9662 (GW) or TM or both. After 14days of LPS administration, the rats were subjected to behavioral tests and their brains were isolated for blotting techniques. The protein study includes NF-κB, PPAR-γ receptors, and their downstream proteins (MyD88 & SARM). The pro-inflammatory cytokines (TNF-α, IL-1β, IL-6) levels were measured by ELISA and cresyl violet staining in the hippocampus region to measure the neuroprotective activity. Results have shown that TM significantly increased the motor co-ordination, cognitive functions, and activated SARM and PPAR-γ protein levels. Also, TM treatment decreased the NF-κB, MyD88 activation, and cytokines release in LPS rats. The co-administration of GW attenuated the TM responses in the parameters studied except cognitive functions. TM (10mg/kg) has significantly reduced the LPS mediated inflammatory responses. This resulted in effective regeneration of hippocampal neurons as observed by cresyl violet staining. It can be concluded that the activation of PPAR-γ receptors may increase the SARM and decrease the MyD88 and NF-κB expression. This negative regulation of SARM dependent inflammation control could be a possible mechanism for TM anti-neuroinflammatory activity. This study of TM in neuro-inflammatory model may further confirm the dual activities of TM that controls hypertension and cognition

  6. Investigation and correlation of physical stability, dissolution behaviour and interaction parameter of amorphous solid dispersions of telmisartan: a drug development perspective.

    PubMed

    Dukeck, R; Sieger, P; Karmwar, P

    2013-07-16

    The aim of this study was to investigate if amorphous solid dispersions of telmisartan, prepared in presence of different polymers, exhibit different structural and thermodynamic characteristics and whether these differences can be correlated to their physical stability (time to crystallisation) and dissolution behaviour. Amorphous samples were prepared by melt quenching. The resulting amorphous materials were characterised using X-ray diffraction, Raman spectroscopy and differential scanning calorimetry. All freshly prepared samples were completely X-ray amorphous (with a halo being the only feature in the diffractograms). The shape of the halos in the diffractograms varied suggesting structural variations in the near order of the molecules between the different amorphous solid dispersions (ASDs). Principal component analysis of the Raman spectra of the various ASD revealed that the samples clustered in the scores plot, again suggesting structural differences due to the presence of different drug-polymer interaction. The ranking of the samples with respect to physical stability and interaction parameter was: ASD of telmisartan:eudragit>ASD of telmisartan:soluplus>ASD of telmisartan:HPMC>ASD of telmisartan:PVP>amorphous telmisartan. The interaction parameter, calculated by using the Flory Huggins theory, showed a good correlation with the experimentally determined stability whereas a weak correlation was found with dissolution behaviour of different ASD. This study showed that correlation of physical stability and dissolution behaviour with calculated interaction parameter is possible for the same amorphous systems prepared by using different polymers. This could aid in selecting the most appropriate polymer for the development of optimised formulations containing amorphous drugs. It can be concluded that ASD prepared by using different polymers have different structural and thermal properties. These differences affect the physical stability and dissolution

  7. Comparison of the effects of barnidipine+losartan compared with telmisartan+hydrochlorothiazide on several parameters of insulin sensitivity in patients with hypertension and type 2 diabetes mellitus.

    PubMed

    Derosa, Giuseppe; Querci, Fabrizio; Franzetti, Ivano; Dario Ragonesi, Pietro; D'Angelo, Angela; Maffioli, Pamela

    2015-10-01

    The aim of this study was to evaluate the effects of barnidipine+losartan compared with telmisartan+hydrochlorothiazide on several parameters of insulin sensitivity in patients with hypertension and type 2 diabetes mellitus. We enrolled 148 normocholesterolemic patients with mild-to-moderate hypertension and type 2 diabetes mellitus. Patients were treated with barnidipine, 20 mg day(-1), in combination with losartan, 100 mg day(-1), or with telmisartan+hydrochlorothiazide, 80/12.5 mg day(-1), for 6 months. We assessed blood pressure (BP) on a monthly basis; additionally, blood samples were collected to assess, at baseline and after 6 months, the following parameters: fasting plasma glucose; glycated hemoglobin; fasting plasma insulin; HOMA index; and some adipocytokines, such as adiponectin (ADN), resistin, leptin, visfatin and vaspin. Patients were also subjected to an euglycemic hyperinsulinemic clamp to assess the M value and glucose infusion rate to ascertain their insulin sensitivity. One hundred and forty-one patients completed the study. The BP was reduced in both groups, although the reduction was greater with barnidipine+losartan (P<0.001 vs. baseline and P<0.01 vs. telmisartan+hydrochlorothiazide). Barnidipine+losartan increased the M value and glucose infusion rate during the euglycemic hyperinsulinemic clamp (P<0.05 vs. baseline and vs. telmisartan+hydrochlorothiazide). With respect to the levels of adipocytokines, ADN was increased (P<0.05), and resistin and leptin were reduced from baseline with barnidipine+losartan (P<0.05 vs. baseline), but they were not reduced with telmisartan+hydrochlorothiazide. Visfatin and vaspin were reduced by barnidipine+losartan compared with baseline (P<0.05). The adipocytokine levels obtained with barnidipine+losartan were significantly better than those obtained with telmisartan+hydrochlorothiazide (P<0.05 for all parameters). In addition to providing a greater BP reduction, barnidipine+losartan improved the insulin

  8. Effect of aliskiren, telmisartan and torsemide on cardiac dysfunction in l-nitro arginine methyl ester (l-NAME) induced hypertension in rats

    PubMed Central

    Sadek, Sawsan A.; Rashed, Laila A.; Bassam, Amira M.; Said, Eman S.

    2014-01-01

    Comparative study of cardio protective effect of aliskiren, telmisartan, and torsemide was carried out on l-nitro arginine methyl ester (l-NAME) induced hypertension in rats. The three drugs were given daily for 8 weeks simultaneously with l-NAME, with a control group for each drug and l-NAME. The degree of protection was assessed by measurement of systolic blood pressure and heart rate of animals every two weeks. At the end of the experimental period blood sampling was carried out for estimation of the level of NO2−/NO3−. After which animals were sacrificed for heart dissection to detect collagen types I and III gene expression. Histopathological study was done to evaluate the extension of collagen deposits. The study revealed that the three drugs decreased blood pressure significantly compared to l-NAME. There was no significant difference between aliskiren and telmisartan in all measurements, but there was significant decrease in measurements of both aliskiren and telmisartan treated groups compared to torsemide starting from 4th week. There were insignificant changes in pulse rate values between the three l-NAME treated groups through the experiment. The three drugs significantly increased NO compared to l-NAME. Collagen I and III gene expression was significantly decreased by the three drugs but the highest percentage of inhibition was with telmisartan compared to l-NAME. Comparing the percentage inhibition of cardiac fibrosis, there was insignificant difference between telmisartan and torsemide treated groups while both were superior to aliskiren. In conclusion, further experimental studies are required to elucidate the potential cardioprotective mechanisms of aliskiren, telmisartan and torsemide, and assess their efficacy in treatment of heart failure. PMID:26644935

  9. Calcium channel blockers, beta-blockers and digitalis poisoning: management in the emergency room.

    PubMed

    Ojetti, V; Migneco, A; Bononi, F; De Lorenzo, A; Gentiloni Silveri, N

    2005-01-01

    Calcium channel blockers and beta-blockers intoxications account for up to 65% of deaths for cardiovascular drugs, causing severe clinical symptoms refractory to standard medications. The most serious poisonings are those resulting from verapamil and propanolol ingestion. Both support and antidotic therapy are necessary for these potentially unstable patients. Supportive measures and the use of digoxin-specific antibody fragments are first line treatment for digitalis glycoside poisoning.

  10. Optimal Use of Beta-Blockers for Congestive Heart Failure.

    PubMed

    Lee, Hae-Young; Baek, Sang Hong

    2016-01-01

    Beta-blockers are the cornerstone treatment for congestive heart failure (HF). Current HF guidelines commonly recommend β-blockers for the treatment of HF with reduced left ventricular ejection fraction (LVEF). The effect of β-blockers, however, is less clear for HF patients with preserved LVEF, unstable severe acute HF, or right ventricular failure. This review summarizes the effect of β-blockers in various clinical situations and suggests a strategy for optimal use. (Circ J 2016; 80: 565-571).

  11. [Beta-blockers and chronic obstructive pulmonary disease].

    PubMed

    Sova, Milan; Kamasová, Monika; Václavík, Jan; Sovová, Eliška; Hajdová, Lenka; Kolek, Vítězslav

    2016-04-01

    This general article discusses the problems of beta-blockers use in patients with chronic obstructive pulmonary disease (COPD). Its aim is to refute exaggerated concerns of physicians over possible undesirable effects of beta-blockers on the patient respiratory functions and present new data on the effects of beta-blockers on the extent of COPD exacerbations, bronchial reactivity and mortality of patients.

  12. Angiotensin System Blockade Combined With Calcium Channel Blockers Is Superior to Other Combinations in Cardiovascular Protection With Similar Blood Pressure Reduction: A Meta-Analysis in 20,451 Hypertensive Patients.

    PubMed

    Chi, Chen; Tai, Chenhui; Bai, Bin; Yu, Shikai; Karamanou, Marianna; Wang, Jiguang; Protogerou, Athanase; Blacher, Jacques; Safar, Michel E; Zhang, Yi; Xu, Yawei

    2016-08-01

    The authors aimed to investigate the superiority of angiotensin system blockade (angiotensin-converting enzyme [ACE] inhibitor/angiotensin receptor blocker [ARB]) plus a calcium channel blocker (CCB) (A+C) over other combination therapies in antihypertensive treatment. A meta-analysis in 20,451 hypertensive patients from eight randomized controlled trials was conducted to compare the A+C treatment with other combination therapies in terms of blood pressure (BP) reduction, clinical outcomes, and adverse events. The results showed that BP reduction did not differ significantly among the A+C therapy and other combination therapies in systolic and diastolic BP (P=.87 and P=.56, respectively). However, A+C therapy, compared with other combination therapies, achieved a significantly lower incidence of cardiovascular composite endpoints, including cardiovascular mortality, nonfatal myocardial infarction, and nonfatal stroke (risk ratio [RR], 0.80; 95% confidence interval [CI], 0.70-0.91; P<.001), but similar all-cause mortality (RR, 0.90; 95% CI, 0.77-1.04; P=.15) and stroke rates (RR, 0.90; 95% CI, 0.77-1.04; P=.09). Moreover, A+C therapy yielded a 4.21 mL/min/1.73 m(2) lower estimated glomerular filtration rate reduction than other combinations (P<.001). Finally, A+C therapy showed a similar incidence of adverse events as other combination therapies (P=.34) but presented a significantly lower incidence of serious adverse events (RR, 0.85; 95% CI, 0.73-0.98; P=.03). In conclusion, A+C therapy is superior to other combinations of antihypertensive treatment as it shows a lower incidence of cardiovascular events and adverse events, while it has similar effects in lowering BP and preserving renal function.

  13. Validated spectrophotometric methods for the simultaneous determination of telmisartan and atorvastatin in bulk and tablets

    PubMed Central

    Ilango, Kaliappan; Kumar, Pushpangadhan S. Shiji

    2012-01-01

    Aim: Three simple, accurate, and reproducible spectrophotometric methods have been developed and validated for simultaneous estimation of telmisartan (TELM) atorvastatin (ATV) in combined tablet dosage form. Materials and Methods: The first method is based on first-order derivative spectroscopy. The sampling wavelengths were 223 nm (zero crossing of TELM) where ATV showed considerable absorbance and 272 nm (zero crossing of ATV) where TELM showed considerable absorbance. The second method Q-analysis (absorbance ratio), involves formation of Q-absorbance equation using respective absorptivity values at 280.9 nm (isobestic point) and 296.0 nm (λmax of TELM). The third method involves determination using multicomponent mode method; sampling wavelengths selected were 296.0 and 246.9 nm. Results: TELM and ATV followed linearity in the concentration range of 5–40 and 4–32 μg/ml for method I, 5–30 μg/ml and 2–24 μg/ml for method II and III, respectively. Mean recoveries for all three methods were found satisfactory. All methods were validated according to International Conference on Harmonization Q2B guidelines. Conclusion: The developed methods are simple, precise, rugged, and economical. The utility of methods has been demonstrated by analysis of commercially available tablet dosage form. PMID:23781490

  14. Amorphous ternary cyclodextrin nanocomposites of telmisartan for oral drug delivery: improved solubility and reduced pharmacokinetic variability.

    PubMed

    Sangwai, Mayur; Vavia, Pradeep

    2013-09-10

    Despite of advancements in dosage form design and use of multifunctional excipients, improvement in dissolution characteristics of molecules like Telmisartan (TEL) having exceedingly pH dependent and poor solubility profile is still challenging. The present research work explores an innovative particle engineering approach which synergistically coalesce two principally different solubility enhancement strategies namely ternary β-cyclodextrin complexation and top-down nanonization in a unit process. The research was aimed to improve solubility and reduce in vivo variability in pharmacokinetic parameters of TEL irrespective to physiological pH conditions. Ternary β-cyclodextrin nanocomposites of TEL were prepared with high pressure homogenization using meglumine as ternary component. TEL nanocomposites were thoroughly characterized for particle size, surface topology, surface charge, inclusion complexation, crystalinity, dissolution and in vivo pharmacokinetic performance in male wistar rats at fed and fasted state. TEL nanocomposites exhibited average particle size of 698 ± 23 nm. Remarkable improvement in in vitro dissolution characteristics in multimedia and biorelevant media was observed in comparison with plain drug and marketed formulation. Results of in vivo pharmacokinetic studies revealed that, nanocomposites effectively bypass variation in pharmacokinetic parameters at fed and fasted states with 346%, 315%, 301% and 321% increase in relative bioavailability compared to marketed formulation and pure TEL in fed and fasted conditions respectively.

  15. Preparation and Characterization of Liquisolid Compacts for Improved Dissolution of Telmisartan

    PubMed Central

    Narra, Nataraj; Rama Rao, Tadikonda

    2014-01-01

    The objective of the present work was to obtain pH independent and improved dissolution profile for a poorly soluble drug, telmisartan using liquisolid compacts. Liquisolid compacts were prepared using Transcutol HP as vehicle, Avicel PH102 as carrier, and Aerosil 200 as a coating material. The formulations were evaluated for drug excipient interactions, change in crystallinity of drug, flow properties, and general quality control tests of tablets using Fourier transform infrared (FTIR) spectroscopy, differential scanning calorimetry (DSC), X-ray diffraction (XRD), angle of repose, and various pharmacopoeial tests. In vitro dissolution studies were performed at three pH conditions (1.2, 4.5 and 7.4). Stability studies were performed at 40°C and 75% RH for three months. The formulation was found to comply with Indian pharmacopoeial limits for tablets. FTIR studies confirmed no interaction between drug and excipients. XRD and DSC studies indicate change/reduction in crystallinity of drug. Dissolution media were selected based on the solubility studies. The optimized formulation showed pH independent release profile with significant improvement (P < 0.005) in dissolution compared to plain drug and conventional marketed formulation. No significant difference was seen in the tablet properties, and drug release profile after storage for 3 months. PMID:25371826

  16. In-Vitro Characterization and Oral Bioavailability of Organic Solvent-free Solid Dispersions Containing Telmisartan

    PubMed Central

    Cao, Yue; Shi, Li-Li; Cao, Qing-Ri; Yang, Mingshi; Cui, Jing-Hao

    2016-01-01

    Poorly water-soluble drugs often suffer from limited or irreproducible clinical response due to their low solubility and dissolution rate. In this study, organic solvent-free solid dispersions (OSF-SDs) containing telmisartan (TEL) were prepared using polyvinylpyrrolidone K30 (PVP K30) and polyethylene glycol 6000 (PEG 6000) as hydrophilic polymers, sodium hydroxide (NaOH) as an alkalizer, and poloxamer 188 as a surfactant by a lyophilization method. In-vitro dissolution rate and physicochemical properties of the OSF-SDs were characterized using the USP I basket method, differential scanning calorimetry (DSC), X-ray diffractometry (XRD) and fourier transform-infrared (FT-IR) spectroscopy. In addition, the oral bioavailability of OSF-SDs in rats was evaluated by using TEL bulk powder as a reference. The dissolution rates of the OSF-SDs were significantly enhanced as compared to TEL bulk powder. The results from DSC, XRD showed that TEL was molecularly dispersed in the OSF-SDs as an amorphous form. The FT-IR results suggested that intermolecular hydrogen bonding had formed between TEL and its carriers. The OSF-SDs exhibited significantly higher AUC0–24 h and Cmax, but similar Tmax as compared to the reference. This study demonstrated that OSF-SDs can be a promising method to enhance the dissolution rate and oral bioavailability of TEL. PMID:27642309

  17. Beta-blockers in anxiety disorders.

    PubMed

    Hayes, P E; Schulz, S C

    1987-01-01

    Studies evaluating the antianxiety and antipanic properties of beta-blockers do not support their routine use in treating either generalized anxiety disorder or panic disorder. The use of propranolol for anxiety disorders accompanied by physical symptoms, especially cardiovascular complaints, may be effective in some patients when combined with benzodiazepines or perhaps in some non-responders to conventional treatment. Better designed studies are needed to evaluate the exact role of beta-blocking agents in treating anxiety. The efficacy of propranolol in patients with panic disorder has not been widely researched, but preliminary results have not been encouraging. Propranolol may provide symptomatic relief in some patients with residual somatic complaints (i.e., palpitations and tachycardia), when combined with the patient's ongoing drug regimen. Because beta-blockers may induce depression, they should be used cautiously--if at all--in panic patients with concurrent depressive illness.

  18. Telmisartan/hydrochlorothiazide versus valsartan/hydrochlorothiazide in obese hypertensive patients with type 2 diabetes: the SMOOTH study

    PubMed Central

    Sharma, Arya M; Davidson, Jaime; Koval, Stephen; Lacourcière, Yves

    2007-01-01

    Background The Study of Micardis (telmisartan) in Overweight/Obese patients with Type 2 diabetes and Hypertension (SMOOTH) compared hydrochlorothiazide (HCTZ) plus telmisartan or valsartan fixed-dose combination therapies on early morning blood pressure (BP), using ambulatory BP monitoring (ABPM). Methods SMOOTH was a prospective, randomized, open-label, blinded-endpoint, multicentre trial. After a 2- to 4-week, single-blind, placebo run-in period, patients received once-daily telmisartan 80 mg or valsartan 160 mg for 4 weeks, with add-on HCTZ 12.5 mg for 6 weeks (T/HCTZ or V/HCTZ, respectively). At baseline and week 10, ambulatory blood pressure (ABP) was measured every 20 min and hourly means were calculated. The primary endpoint was change from baseline in mean ambulatory systolic and diastolic blood pressure (SBP; DBP) during the last 6 hours of the 24-hour dosing interval. Results In total, 840 patients were randomized. At week 10, T/HCTZ provided significantly greater reductions versus V/HCTZ in the last 6 hours mean ABP (differences in favour of T/HCTZ: SBP 3.9 mm Hg, p < 0.0001; DBP 2.0 mm Hg, p = 0.0007). T/HCTZ also produced significantly greater reductions than V/HCTZ in 24-hour mean ABP (differences in favour of T/HCTZ: SBP 3.0 mm Hg, p = 0.0002; DBP 1.6 mm Hg, p = 0.0006) and during the morning, daytime and night-time periods (p < 0.003). Both treatments were well tolerated. Conclusion In high-risk, overweight/obese patients with hypertension and type 2 diabetes, T/HCTZ provides significantly greater BP lowering versus V/HCTZ throughout the 24-hour dosing interval, particularly during the hazardous early morning hours. PMID:17910747

  19. Method development and validation: quantitation of telmisartan bulk drug and its tablet formulation by (1) H NMR spectroscopy.

    PubMed

    Jadeja, Yashwantsinh; Chomal, Bhagyawanti; Patel, Madhavi; Jebaliya, Hetal; Khunt, Ranjan; Shah, Anamik

    2016-12-14

    The quantitative NMR (qNMR) spectroscopy is nowadays a new tool for the determination of pharmaceutical potent biologically active molecules in bulk drug and its tablet formulation than the other analytical techniques. Herein, qNMR method was developed for an anti-hypertensive drug, telmisartan in bulk drug and its tablet formulation. The precise method was developed by using malononitrile as an internal standard. The methylene signal of telmisartan appeared at δ = 5.46 ppm (singlet) relative to the signal of malononitrile at δ = 3.59 ppm (singlet) in CDCl3 , as an NMR solvent. The development and validation of the method were carried out as per International Conference on Harmonization guidelines. The method was found to be linear (r(2)  = 0.9999) for 0.5 to 3.5 mg/ml in the drug concentration range. The relative standard deviation for accuracy and precession was not more than 2.0%. The sensitivity of the method was carried out by limit of detection and a limit of quantification, at 0.05 and 0.2 mg/ml, respectively, concentration. The robustness of the method was studied by changing parameters as well as different solvent manufacturer company. The result shows that method was accurately developed for quantification of telmisartan in pharmaceutical dosage form. The developed method by (1) H NMR spectroscopy is comparatively easy and more precise with respect to the other analytical tools. Copyright © 2016 John Wiley & Sons, Ltd.

  20. Lessons from ONTARGET.

    PubMed

    Berlaimont, V; Billiouw, J-M; Brohet, C; Dupont, A G; Gazagnes, M-D; Heller, F; Krzesinski, J M; Missault, L; Persu, A; Piérard, L; Rottiers, R; Vanhooren, G; Van Mieghem, W; Vervaet, P; Herman, A G

    2008-01-01

    The recently published results of the ONTARGET trial shed a new light on the cardiovascular protection of patients at high risk of a cardiovascular event. Despite a number of trials looking at the efficacy of Angiotensin Converting Enzyme inhibitors (ACEis) or Angiotensin Receptor Blockers (ARBs) in the prevention of cardiovascular events in patients with specific high risk profiles, the question of the equivalence of ACEis and ARBs remained unanswered. The ONTARGET trial has shown that telmisartan 80 mg administered for a median duration of 4.5 years to patients at high risk of developing a major cardiovascular event, is equally effective to ramipril 10 mg. In addition, telmisartan was slightly better tolerated. The comparator ramipril has been chosen as it is currently the gold standard ACEi since the results of the HOPE study, in terms of the composite outcome of cardiovascular death, myocardial infarction and stroke. Moreover, ONTARGET is the first trial to test the hypothesis of superiority of adding an ARB (telmisartan 80 mg) to an ACEi (ramipril 10 mg) over the ACEi ramipril monotherapy in cardiovascular protection of the same broad range of high-risk patients. Surprisingly, despite a more pronounced blood pressure lowering, the combination of the two agents did not lead to an additional decrease in the number of events, but had significantly more side-effects compared to ramipril monotherapy. ONTARGET is a landmark study, performed according to the highest statistical and clinical standards, providing compelling evidence and clear answers to two important clinical questions.

  1. Combination therapy of hypertension in the elderly: a subgroup analysis of the Combination of OLMesartan and a calcium channel blocker or diuretic in Japanese elderly hypertensive patients trial

    PubMed Central

    Ogihara, Toshio; Saruta, Takao; Rakugi, Hiromi; Saito, Ikuo; Shimamoto, Kazuaki; Matsuoka, Hiroaki; Teramukai, Satoshi; Higaki, Jitsuo; Ito, Sadayoshi; Shimada, Kazuyuki

    2015-01-01

    Combination of OLMesartan and a calcium channel blocker or a diuretic in Japanese elderly hypertensive patients (COLM) trial demonstrated that olmesartan combinations with a CCB or diuretic have similar effects on reducing cardiovascular risk in elderly hypertensive patients. However, the safety profiles suggest that olmesartan combined with CCB may be preferable to olmesartan combined with diuretic. In this subgroup analysis, we further evaluated the effects and safety of these combinations in elderly (65–74 years old (y.o.)) and very elderly (75–84 y.o.) hypertensive patients. In the COLM trial, 5141 patients (2918 elderly and 2223 very elderly) were randomly assigned to receive olmesartan-based therapy with either CCB or diuretic. The hazard ratios and 95% confidence intervals, respectively, in the elderly age group and in the very elderly group were: 1.04 (0.72–1.50; olmesartan plus CCB vs. olmesartan plus diuretic, P=0.85) and 0.71 (0.51–0.99, P=0.045) for the primary composite end point, and 1.07 (0.67–1.72, P=0.77) and 0.64 (0.42–0.98, P=0.036) for the composite of hard end points. The hazard ratios for stroke (fatal and non-fatal) were 1.48 (0.88–2.48; olmesartan plus CCB vs. olmesartan plus diuretic, P=0.13) and 0.63 (0.39–1.02, P=0.059) (interaction-P=0.019). Withdrawal rates from the trial, withdrawal due to serious adverse event and the incidence of any adverse event were higher in the olmesartan plus diuretic group than in the olmesartan plus CCB group in both age groups. In conclusion, angiotensin receptor blocker (ARB) and CCB combination may be preferable to an ARB and diuretic combination in the very elderly hypertensive patients for the reduction of cardiovascular risk, particularly for the reduction in stroke risk. PMID:25253583

  2. Telmisartan provides protection against development of impaired vasodilation independently of metabolic effects in SHRSP.Z-Lepr(fa)/IzmDmcr rats with metabolic syndrome.

    PubMed

    Kagota, Satomi; Tada, Yukari; Nejime, Namie; Nakamura, Kazuki; Kunitomo, Masaru; Shinozuka, Kazumasa

    2011-05-01

    Metabolic syndrome is known to facilitate the development of cardiovascular disease. We have demonstrated that mesenteric arteries of SHRSP.Z-Lepr(fa)/IzmDmcr (SHRSP-fatty) rats with metabolic syndrome display an impaired vasorelaxation response mediated by nitric oxide. We examined whether the condition could be alleviated by treatment with telmisartan, an angiotensin II type 1 (AT1) receptor antagonist with PPAR-γ-activating properties and compared the results with those from pioglitazone, a PPAR-γ agonist. Telmisartan (5 mg·kg(-1)·day(-1)) or pioglitazone (2.5 mg·kg(-1)·day(-1)) was orally administered to male SHRSP-fatty rats for 8 weeks. Serum triglyceride and cholesterol levels were determined, and the oral glucose tolerance test was performed to evaluate insulin resistance. Vasodilations in response to acetylcholine and nitroprusside were determined by wire myographs under isometric tension conditions, protein expressions of soluble guanylyl cyclase in mesenteric arteries by Western blotting, and the contents of 3-nitrotyrosine in aortas by high-performance liquid chromatography with electrochemical detection. Telmisartan exerted antihypertensive effects, while pioglitazone ameliorated metabolic abnormalities in SHRSP-fatty rats. Telmisartan increased acetylcholine- and nitroprusside-induced relaxation and soluble guanylyl cyclase protein expression in mesenteric arteries and reduced 3-nitrotyrosine content in aortas. Pioglitazone displayed no such alleviating effects on vascular functions. These findings indicate that telmisartan protects against vasodilation disturbance through anti-oxidative and -nitrative stress independently of metabolic effects in SHRSP-fatty rats with metabolic syndrome.

  3. Influence of G-protein β-Polypeptide 3 C825T Polymorphism on Antihypertensive Response to Telmisartan and Amlodipine in Chinese Patients

    PubMed Central

    Zhang, Zan-Lin; Li, Hui-Lan; Wen, Zhi-Peng; Yang, Guo-Ping; Zhang, Wei; Chen, Xiao-Ping

    2016-01-01

    Background: G-protein β-polypeptide 3 (GNB3) is a β subunit isoform of G-protein that plays important role in signal transduction of membrane G-protein coupled receptors (GPCRs). The GNB3 splice variant C825T (rs5443) is associated with risk for essential hypertension (EH) and efficacy of therapeutic drugs targeting GPCRs. It is unknown whether the polymorphism is associated with blood pressure (BP) response to telmisartan or amlodipine, two widely prescribed antihypertensive drugs. Methods: A total of 93 subjects initially diagnosed as EH were recruited and underwent a 4-week treatment with telmisartan (42 patients) or amlodipine (51 patients) monotherapy. Both baseline and after-treatment BP were measured. GNB3 C825T polymorphism was genotyped by polymerase chain reaction-restriction fragment length polymorphism. Results: Baseline systolic BP (SBP) and diastolic BP (DBP) were comparable among C825T genotypes in both telmisartan and amlodipine treatment groups. Patients with the CT or TT genotypes showed significantly lower body mass index (BMI) as compared with CC homozygotes in both groups (P < 0.05, respectively). GNB3 825TT homozygotes showed significantly higher after-treatment DBP and mean arterial pressure (MAP) than those carrying at least one 825C allele (P < 0.01) in the telmisartan treatment group. No difference in after-treatment SBP, DBP, and MAP levels among C825T genotypes was observed in the amlodipine treatment group. No significant difference in absolute changes in BP levels was observed among the genotypes in either treatment group. Conclusion: The GNB3 C825T splice variant is associated with the DBP-lowering effect of telmisartan but not amlodipine in Chinese EH patients. PMID:26712426

  4. Sodium channel blockers in neuropathic pain.

    PubMed

    Kalso, Eija

    2005-01-01

    Subtypes of tetrodotoxin resistant voltage-gated sodium channels are involved in the development of certain types of neuropathic pains. After nerve injury hyperexcitability and spontaneous firing develop at the site of injury and also in the dorsal root ganglion cell bodies. This hyperexcitability results at least partly from accumulation of sodium channels at the site of injury. The facts that these sodium channels seem to exist in peripheral nerves only and that they can be blocked at the resting state (use-dependent block) offer the possibility to develop drugs, which selectively block these damaged, overexcited nerves. At the moment no such drugs are available. However, some of the most potent drugs that are currently used to manage neuropathic pain e.g. amitriptyline and other tricyclic antidepressants, also block these channels in addition to having several other mechanisms of action. Also most anticonvulsants that are used to alleviate neuropathic pain are sodium channel blockers. Lidocaine, the prototype drug, has been shown to be effective in peripheral neuropathic pain. Its use is limited by the fact that it cannot be administered orally. An oral local anesthetic type sodium channel blocker, mexiletine is an antiarrhythmic agent that is effective in neuropathic pain. However, effective doses may be difficult to achieve because of adverse effects.

  5. H2-blocker modulates heart rate variability.

    PubMed

    Ooie, T; Saikawa, T; Hara, M; Ono, H; Seike, M; Sakata, T

    1999-01-01

    The use of H2-blockers in the treatment of patients with peptic ulcer has become popular. However, this treatment has adverse cardiovascular effects. The aim of this study was to investigate proarrhythmic rhythm and autonomic nervous activity by analyzing heart rate variability in patients treated with omeprazole, ranitidine, and plaunotol. Nineteen patients (mean age 67.5 +/- 2.7 years) with active gastric ulcer were treated with omeprazole (20 mg/day) for 8 weeks, then ranitidine (300 mg/day) for the next 4 months, and finally plaunotol (240 mg/day). At each stage of the treatment, Holter electrocardiography was performed, and heart rate variability and arrhythmias analyzed. Heart rate variability yielded power in the low- (0.04-0.15 Hz) and high-frequency components (0.15-0.4 Hz). Although both ranitidine and omeprazole induced little change in cardiac rhythm, the high-frequency power was higher (10.3 +/- 0.8 vs 8.6 +/- 0.6 ms, P < 0.05) and the ratio of low-to-high frequency power was lower (1.41 +/-0.10 vs 1.59 +/- 0.09. P < 0.05) during ranitidine than during plaunotol treatment. Cosinor analysis of heart rate variability revealed a decreased amplitude of low-frequency power during omeprazole compared with during ranitidine and plaunotol treatment. Ranitidine modulated high-frequency power which may be related to the adverse cardiovascular effects of H2-blocker.

  6. Antitumoral, antihypertensive, antimicrobial, and antioxidant effects of an octanuclear copper(II)-telmisartan complex with an hydrophobic nanometer hole.

    PubMed

    Islas, María S; Martínez Medina, Juan J; López Tévez, Libertad L; Rojo, Teófilo; Lezama, Luis; Griera Merino, Mercedes; Calleros, Laura; Cortes, María A; Rodriguez Puyol, Manuel; Echeverría, Gustavo A; Piro, Oscar E; Ferrer, Evelina G; Williams, Patricia A M

    2014-06-02

    A new Cu(II) complex with the antihypertensive drug telmisartan, [Cu8Tlm16]·24H2O (CuTlm), was synthesized and characterized by elemental analysis and electronic, FTIR, Raman and electron paramagnetic resonance spectroscopy. The crystal structure (at 120 K) was solved by X-ray diffraction methods. The octanuclear complex is a hydrate of but otherwise isostructural to the previously reported [Cu8Tlm16] complex. [Cu8Tlm16]·24H2O crystallizes in the tetragonal P4/ncc space group with a = b = 47.335(1), c = 30.894(3) Å, Z = 4 molecules per unit cell giving a macrocyclic ring with a double helical structure. The Cu(II) ions are in a distorted bipyramidal environment with a somewhat twisted square basis, cis-coordinated at their core N2O2 basis to two carboxylate oxygen and two terminal benzimidazole nitrogen atoms. Cu8Tlm16 has a toroidal-like shape with a hydrophobic nanometer hole, and their crystal packing defines nanochannels that extend along the crystal c-axis. Several biological activities of the complex and the parent ligand were examined in vitro. The antioxidant measurements indicate that the complex behaves as a superoxide dismutase mimic with improved superoxide scavenger power as compared with native sartan. The capacity of telmisartan and its copper complex to expand human mesangial cells (previously contracted by angiotensin II treatment) is similar to each other. The antihypertensive effect of the compounds is attributed to the strongest binding affinity to angiotensin II type 1 receptor and not to the antioxidant effects. The cytotoxic activity of the complex and that of its components was determined against lung cancer cell line A549 and three prostate cancer cell lines (LNCaP, PC-3, and DU 145). The complex displays some inhibitory effect on the A549 line and a high viability decrease on the LNCaP (androgen-sensitive) line. From flow cytometric analysis, an apoptotic mechanism was established for the latter cell line. Telmisartan and CuTlm show

  7. Evaluation of safety and efficacy of telmisartan-amlodipine combination in treating hypertension.

    PubMed

    Faruqui, Arif A

    2008-09-01

    The objective of this open, non-comparative, prospective postmarketing surveillance (PMS) study was to identify, validate and quantify the safety and efficacy associated with the use of fixed dose combination (FDC) of telmisartan 40 mg + amlodipine 5 mg (T40+A5) in hypertensive patients with or without concomitant diabetes. The data was collected from 72 centres from all over India during the period of June 2007 to February 2008. A total of 251 patients of either sex and those who were newly diagnosed stage II hypertension, or those who were uncontrolled on monotherapy with or without diabetes mellitus were included in this study. Patients were prescribed with T40+A5 combination orally. Systolic BP (SBP), diastolic BP (DBP) and heart rate (HR) were measured at the start and at the end of 2, 4 and 8 weeks of treatment. Primary efficacy end points were reduction in clinical SBP/ DBP from baseline to study end and number of patients achieving JNC VII goals. Tolerability was assessed by treatment-emergent adverse events. Out of 251 patients, 208 patients had completed the study (120 males and 88 females), 42 were lost to follow-up the study and one patient was withdrawn due to adverse effects. The mean age of the patients was 54.5 +/- 0.98 years for males and 52.94 +/- 1.078 years for females. Diabetes mellitus was seen in 64.9% of cases, dyslipidaemia in 2.88%, previous IHD in 7.2% cases and chronic obstructive pulmonary disease (COPD) in 0.50% of cases. Reduction in the mean SBP was found to be 12.08%, 18.92% and 22.90% at the end of 2, 4 and 8 weeks respectively (p < 0.001). Reduction in the mean DBP was found to be 10.09%, 14.55% and 17.19% at the end of 2, 4 and 8 weeks respectively (p < 0.001). At the end of the study it was found that 86.3% of the hypertensive patients and 70% diabetic hypertensive patients achieved the JNC VII recommended goals. The overall incidence of ADRs was 7.69% with headache (1.92%) and vertigo (1.44%), as the commonest side

  8. Proteinase inhibitor homologues as potassium channel blockers.

    PubMed

    Lancelin, J M; Foray, M F; Poncin, M; Hollecker, M; Marion, D

    1994-04-01

    We report here the NMR structure of dendrotoxin I, a powerful potassium channel blocker from the venom of the African Elapidae snake Dendroaspis polylepis polylepis (black mamba), calculated from an experimentally-derived set of 719 geometric restraints. The backbone of the toxin superimposes on bovine pancreatic trypsin inhibitor (BPTI) with a root-mean-square deviation of < 1.7 A. The surface electrostatic potential calculated for dendrotoxin I and BPTI, reveal an important difference which might account for the differences in function of the two proteins. These proteins may provide examples of adaptation for specific and diverse biological functions while at the same time maintaining the overall three-dimensional structure of a common ancestor.

  9. Antibody to dihydropyridine calcium entry blockers

    SciTech Connect

    Thayer, S.; Minaskanian, G.; Fairhurst, A.

    1986-03-05

    Antibodies that recognize dihydropyridine calcium entry blockers were elicited from rabbits. A sensitive and specific radioimmunoassay for dihydropyridines was developed and its specificity compared to the DHP binding site in skeletal muscle membranes. The antibody bound (/sup 3/H)nitrendipine with a higher affinity (K/sub D/ = 0.155 nM) than did the DHP receptor of skeletal muscle (K/sub D/ = 1-3 nM). However, in contrast to the DHP receptor, the antibody recognized only those DHP drugs with meta-nitrophenyl substituents at the 4-position on the DHP ring, and thus reflected the meta position of the nitro group on the DHP hapten used as an antigen. Both the antibody and the receptor exhibited stereospecificity, with each site recognizing the (+) isomer of nicardipine as the more potent. This antibody should prove useful in the studies of some potentially irreversible DHP molecules and for use in the production of anti-idotype antibodies.

  10. Beta-Adrenergic Receptor Blockers in Hypertension: Alive and Well.

    PubMed

    Frishman, William H

    2016-10-27

    βeta-Adrenergic receptor blockers (β-blockers) are an appropriate treatment for patients having systemic hypertension (HTN) who have concomitant ischemic heart disease (IHD), heart failure, obstructive cardiomyopathy, aortic dissection or certain cardiac arrhythmias. β-blockers can be used in combination with other antiHTN drugs to achieve maximal blood pressure control. Labetalol can be used in HTN emergencies and urgencies. β-blockers may be useful in HTN patients having a hyperkinetic circulation (palpitations, tachycardia, HTN, and anxiety), migraine headache, and essential tremor. β-blockers are highly heterogeneous with respect to various pharmacologic properties: degree of intrinsic sympathomimetic activity , membrane stabilizing activity , β1 selectivity, α1-adrenergic blocking effects, tissue solubility, routes of systemic elimination, potencies and duration of action, and specific properties may be important in the selection of a drug for clinical use. β-blocker usage to reduce perioperative myocardial ischemia and cardiovascular (CV) complications may not benefit as many patients as was once hoped, and may actually cause harm in some individuals. Currently the best evidence supports perioperative β-blocker use in two patient groups: patients undergoing vascular surgery with known IHD or multiple risk factors for it, and for those patients already receiving β-blockers for known CV conditions.

  11. Calcium channel blockers in cardiovascular pharmacotherapy.

    PubMed

    Godfraind, Theophile

    2014-11-01

    This paper summarizes the pharmacological properties of calcium channel blockers (CCBs), their established therapeutic uses for cardiovascular disorders and the current improvement of their clinical effects through drug combinations. Their identification resulted from study of small molecules including coronary dilators, which were named calcium antagonists. Further experiments showed that they reduced contraction of arteries by inhibiting calcium entry and by interacting with binding sites identified on voltage-dependent calcium channels. This led to the denomination calcium channel blockers. In short-term studies, by decreasing total peripheral resistance, CCBs lower arterial pressure. By unloading the heart and increasing coronary blood flow, CCBs improve myocardial oxygenation. In long-term treatment, the decrease in blood pressure is more pronounced in hypertensive than in normotensive patients. A controversy on the safety of CCBs ended after a large antihypertensive trial (ALLHAT) sponsored by the National Heart, Lung, and Blood Institute. There are two main types of CCBs: dihydopyridine and non-dihydropyridine; the first type is vascular selective. Dihydropyrines are indicated for hypertension, chronic, stable and vasospastic angina. Non-dihydropyridines have the same indications plus antiarrythmic effects in atrial fibrillation or flutter and paroxysmal supraventricular tachycardia. In addition, CCBs reduced newly formed coronary lesions in atherosclerosis. In order to reach recommended blood pressure goals, there is a recent therapeutic move by combination of CCBs with other antihypertensive agents particularly with inhibitors acting at the level of the renin-angiotensin system. They are also combined with statins. Prevention of dementia has been reported in hypertensive patients treated with nitrendipine, opening a way for further studies on CCBs' beneficial effect in cognitive deterioration associated with aging.

  12. High-dose insulin therapy in beta-blocker and calcium channel-blocker poisoning.

    PubMed

    Engebretsen, Kristin M; Kaczmarek, Kathleen M; Morgan, Jenifer; Holger, Joel S

    2011-04-01

    INTRODUCTION. High-dose insulin therapy, along with glucose supplementation, has emerged as an effective treatment for severe beta-blocker and calcium channel-blocker poisoning. We review the experimental data and clinical experience that suggests high-dose insulin is superior to conventional therapies for these poisonings. PRESENTATION AND GENERAL MANAGEMENT. Hypotension, bradycardia, decreased systemic vascular resistance (SVR), and cardiogenic shock are characteristic features of beta-blocker and calcium-channel blocker poisoning. Initial treatment is primarily supportive and includes saline fluid resuscitation which is essential to correct vasodilation and low cardiac filling pressures. Conventional therapies such as atropine, glucagon and calcium often fail to improve hemodynamic status in severely poisoned patients. Catecholamines can increase blood pressure and heart rate, but they also increase SVR which may result in decreases in cardiac output and perfusion of vascular beds. The increased myocardial oxygen demand that results from catecholamines and vasopressors may be deleterious in the setting of hypotension and decreased coronary perfusion. METHODS. The Medline, Embase, Toxnet, and Google Scholar databases were searched for the years 1975-2010 using the terms: high-dose insulin, hyperinsulinemia-euglycemia, beta-blocker, calcium-channel blocker, toxicology, poisoning, antidote, toxin-induced cardiovascular shock, and overdose. In addition, a manual search of the Abstracts of the North American Congress of Clinical Toxicology and the Congress of the European Association of Poisons Centres and Clinical Toxicologists published in Clinical Toxicology for the years 1996-2010 was undertaken. These searches identified 485 articles of which 72 were considered relevant. MECHANISMS OF HIGH-DOSE INSULIN BENEFIT. There are three main mechanisms of benefit: increased inotropy, increased intracellular glucose transport, and vascular dilatation. EFFICACY OF HIGH

  13. Decreased Androgen Levels and Improved Menstrual Pattern after Angiotensin II Receptor Antagonist Telmisartan Treatment in Four Hypertensive Patients with Polycystic Ovary Syndrome: Case Series

    PubMed Central

    Jensterle, Mojca; Janez, Andrej; Vrtovec, Bojan; Meden-Vrtovec, Helena; Pfeifer, Marija; Prezelj, Janez; Kocjan, Tomaz

    2007-01-01

    We describe 4 consecutive hypertensive women with polycystic ovary syndrome, classified according to the National Institute of Child Health and Human Development (NICHD) criteria, treated with telmisartan 40 mg/d for six months. Blood pressure, menstrual pattern, body mass index (BMI), homeostasis model assessment of insulin resistance, testosterone, dehydroepiandrosterone sulfate (DHEAS), and androstenedione were recorded and measured before and after telmisartan treatment. Obese hypertensive polycystic ovary syndrome patients had a decrease in systolic blood pressure. Marked drop-off in serum androgen concentrations was observed in all four patients. Three patients improved their menstrual cyclicity. The improvements were independent of changes in weight. The reduction of androgen concentrations and improvement in menstrual pattern was achieved despite a non-significant change of fasting insulin levels in patients, who were not considered severely insulin resistant at baseline. These findings may provide a new basis for a proper choice of the antihypertensive drug in hypertensive women with polycystic ovary syndrome. PMID:18074422

  14. Decreased androgen levels and improved menstrual pattern after angiotensin II receptor antagonist telmisartan treatment in four hypertensive patients with polycystic ovary syndrome: case series.

    PubMed

    Jensterle, Mojca; Janez, Andrej; Vrtovec, Bojan; Meden-Vrtovec, Helena; Pfeifer, Marija; Prezelj, Janez; Kocjan, Tomaz

    2007-12-01

    We describe 4 consecutive hypertensive women with polycystic ovary syndrome, classified according to the National Institute of Child Health and Human Development (NICHD) criteria, treated with telmisartan 40 mg/d for six months. Blood pressure, menstrual pattern, body mass index (BMI), homeostasis model assessment of insulin resistance, testosterone, dehydroepiandrosterone sulfate (DHEAS), and androstenedione were recorded and measured before and after telmisartan treatment. Obese hypertensive polycystic ovary syndrome patients had a decrease in systolic blood pressure. Marked drop-off in serum androgen concentrations was observed in all four patients. Three patients improved their menstrual cyclicity. The improvements were independent of changes in weight. The reduction of androgen concentrations and improvement in menstrual pattern was achieved despite a non-significant change of fasting insulin levels in patients, who were not considered severely insulin resistant at baseline. These findings may provide a new basis for a proper choice of the antihypertensive drug in hypertensive women with polycystic ovary syndrome.

  15. Beta-blockers in COPD: time for reappraisal.

    PubMed

    Lipworth, Brian; Wedzicha, Jadwiga; Devereux, Graham; Vestbo, Jørgen; Dransfield, Mark T

    2016-09-01

    The combined effects on the heart of smoking and hypoxaemia may contribute to an increased cardiovascular burden in chronic obstructive pulmonary disease (COPD). The use of beta-blockers in COPD has been proposed because of their known cardioprotective effects as well as reducing heart rate and improving systolic function. Despite the proven cardiac benefits of beta-blockers post-myocardial infarction and in heart failure they remain underused due to concerns regarding potential bronchoconstriction, even with cardioselective drugs. Initiating treatment with beta-blockers requires dose titration and monitoring over a period of weeks, and beta-blockers may be less well tolerated in older patients with COPD who have other comorbidities. Medium-term prospective placebo-controlled safety studies in COPD are warranted to reassure prescribers regarding the pulmonary and cardiac tolerability of beta-blockers as well as evaluating their potential interaction with concomitant inhaled long-acting bronchodilator therapy. Several retrospective observational studies have shown impressive reductions in mortality and exacerbations conferred by beta-blockers in COPD. However, this requires confirmation from long-term prospective placebo-controlled randomised controlled trials. The real challenge is to establish whether beta-blockers confer benefits on mortality and exacerbations in all patients with COPD, including those with silent cardiovascular disease where the situation is less clear.

  16. Type 2 Diabetes and ADP Receptor Blocker Therapy

    PubMed Central

    Samoš, Matej; Fedor, Marián; Kovář, František; Mokáň, Michal; Bolek, Tomáš; Galajda, Peter; Kubisz, Peter; Mokáň, Marián

    2016-01-01

    Type 2 diabetes (T2D) is associated with several abnormalities in haemostasis predisposing to thrombosis. Moreover, T2D was recently connected with a failure in antiplatelet response to clopidogrel, the most commonly used ADP receptor blocker in clinical practice. Clopidogrel high on-treatment platelet reactivity (HTPR) was repeatedly associated with the risk of ischemic adverse events. Patients with T2D show significantly higher residual platelet reactivity on ADP receptor blocker therapy and are more frequently represented in the group of patients with HTPR. This paper reviews the current knowledge about possible interactions between T2D and ADP receptor blocker therapy. PMID:26824047

  17. Beta-Blockers: Current State of Knowledge and Perspectives.

    PubMed

    Ogrodowczyk, Magdalena; Dettlaff, Katarzyna; Jelinska, Anna

    2016-01-01

    It has been over half a century since propranolol, the first beta-blocker, was developed for medical treatment. Since that time a large number of compounds from this group have been synthesised and many are now in clinical use. The structure, function, pharmacokinetics, and mechanism of beta-blockers have been established. The possibilities for their use in treating different conditions continue to evolve. Since the discovery of later generation beta-blockers, such as carvedilol and nebivolol, the search for new compounds continues, and may include known substances with beta-blocking properties which could extend their therapeutic potential.

  18. Anxiolytics not acting at the benzodiazepine receptor: beta blockers.

    PubMed

    Tyrer, P

    1992-01-01

    1. Although there is clear evidence for many controlled trials in the past 25 years that beta blockers are effective in anxiety disorders clear indications for their use are lacking. 2. The balance of evidence suggests that the mechanism of action of beta-blocking drugs is through peripheral blockade of beta-mediated symptoms. 3. Most evidence to the efficacy of beta-blockers comes from study of their use in generalized anxiety and in acute stress. 4. Because beta-blockers carry no risks of pharmacological dependence they may be preferred to many other anti-anxiety drugs.

  19. Effect of angiotensin-converting enzyme inhibitors and receptor blockers on appropriate implantable cardiac defibrillator shock in patients with severe systolic heart failure (from the GRADE Multicenter Study).

    PubMed

    AlJaroudi, Wael A; Refaat, Marwan M; Habib, Robert H; Al-Shaar, Laila; Singh, Madhurmeet; Gutmann, Rebecca; Bloom, Heather L; Dudley, Samuel C; Ellinor, Patrick T; Saba, Samir F; Shalaby, Alaa A; Weiss, Raul; McNamara, Dennis M; Halder, Indrani; London, Barry

    2015-04-01

    Sudden cardiac death (SCD) is a leading cause of mortality in patients with cardiomyopathy. Although angiotensin-converting enzyme inhibitors (ACEi) and angiotensin receptor blockers (ARBs) decrease cardiac mortality in these cohorts, their role in preventing SCD has not been well established. We sought to determine whether the use of ACEi or ARB in patients with cardiomyopathy is associated with a lower incidence of appropriate implantable cardiac defibrillator (ICD) shocks in the Genetic Risk Assessment of Defibrillator Events study that included subjects with an ejection fraction of ≤30% and ICDs. Treatment with ACEi/ARB versus no-ACEi/ARB was physician dependent. There were 1,509 patients (mean age [SD] 63 [12] years, 80% men, mean [SD] EF 21% [6%]) with 1,213 (80%) on ACEi/ARB and 296 (20%) not on ACEi/ARB. We identified 574 propensity-matched patients (287 in each group). After a mean (SD) of 2.5 (1.9) years, there were 334 (22%) appropriate shocks in the entire cohort. The use of ACEi/ARB was associated with lower incidence of shocks at 1, 3, and 5 years in the matched cohort (7.7%, 16.7%, and 18.5% vs 13.2%, 27.5%, and 32.0%; RR = 0.61 [0.43 to 0.86]; p = 0.005). Among patients with glomerular filtration rate (GFR) >60 and 30 to 60 ml/min/1.73 m(2), those on no-ACEi/ARB were at 45% and 77% increased risk of ICD shock compared with those on ACEi/ARB, respectively. ACEi/ARB were associated with significant lower incidence of appropriate ICD shock in patients with cardiomyopathy and GFR ≥30 ml/min/1.73 m(2) and with neutral effect in those with GFR <30 ml/min/1.73 m(2).

  20. The effects of dual and triple combinations of trandolapril, telmisartan, and verapamil on overt proteinuria in the patients with diabetic nephropathy.

    PubMed

    Albayrak, Bülent; Cankaya, Erdem; Cetinkaya, Ramazan; Cerrah, Serkan; Bilen, Yusuf

    2016-05-01

    Diabetic nephropathy (DN) is one of the most important causes of the end-stage renal failure and its prevalence is found to be increasing. The presence of hypertension and progressive proteinuria is among the important findings. In this study, the effects of double and triple combinations of trandolapril, telmisartan, and verapamil on proteinuria were investigated in diabetic patients with nephropathy. Seventy-eight patients (mean age: 56.11 ± 11.26 years; 47 females and 31 males) with overt proteinuria and DN were included in this study. The patients were divided into four groups: Group I (n: 18, trandolapril + telmisartan), Group II (n: 20, trandolapril + verapamil), Group III (n: 20, trandolapril +telmisartan + verapamil), and Group IV (n: 20, telmisartan + verapamil). At the end of a three-month therapy, within and between group comparisons were done about the effects of the use of double or triple drug combinations on proteinuria, glomerular filtration rate (GFR), electrolytes, serum albumin, low-density lipoprotein (LDL)- cholesterol, and HbA1C. There was no significant difference among groups in terms of age, gender, diabetes duration, body mass index, and retinopathy frequency. The decreases in proteinuria and mean arterial blood pressure (MABP) were significant in all groups. The decrease in proteinuria was independent of the decrease in MABP [the reduction rate in proteinuria was 39% (P <0.001) in Group I, 37% (P <0.001) in Group II, 42% (P <0.001) in Group III, and 43% (P <0.001) in Group IV; the reduction rate in MABP was 10.6% (P <0.001) in Group I, 13.7% (P <0.001) in Group II, 17.5% (P <0.001) in Group III, and 15.4% (P <0.001) in Group IV]. Decrease in HbA1C (before and after treatment) was significant in Groups III and IV when com- pared to Groups I and II. Any adverse event, like hyperkalemia, was not observed. There was no significant difference among the groups in terms of GFR, LDL-cholesterol, albumin, and potassium. All the patients tolerated

  1. Marine Bivalve Cellular Responses to Beta Blocker Exposures

    EPA Science Inventory

    β blockers are prescription drugs used for medical treatment of hypertension and arrhythmias. They prevent binding of agonists such as catecholamines to β adrenoceptors. In the absence of agonist induced activation of the receptor, adenylate cyclase is not activated whi...

  2. Renal vascular effects of calcium channel blockers in hypertension.

    PubMed

    Benstein, J A; Dworkin, L D

    1990-12-01

    Recent evidence suggests that calcium channel blockers have specific effects on renal hemodynamics in patients with hypertension and may also slow the progression of chronic renal failure. When these agents are studied in vitro, their predominant effect is to reverse afferent arteriolar vasoconstriction induced by catecholamines or angiotensin II. Because efferent resistance may remain high, glomerular filtration rate rises while renal blood flow remains low. The effects in vivo are less consistent. In human hypertension, calcium channel blockers lower renal resistance and may raise both renal blood flow and glomerular filtration rate. In experimental models of chronic renal disease, calcium channel blockers slow the progression of renal damage; however, variable effects on renal hemodynamics have been found. Other factors implicated in the progression of renal damage, including compensatory renal hypertrophy, platelet aggregation, and calcium deposition, may also be favorably influenced by these agents. Recent studies suggest that calcium channel blockers may have similar protective effects in patients with hypertension and chronic renal disease.

  3. Angiotensin receptor blockade and angiotensin-converting-enzyme inhibition limit adverse remodeling of infarct zone collagens and global diastolic dysfunction during healing after reperfused ST-elevation myocardial infarction.

    PubMed

    Jugdutt, Bodh I; Idikio, Halliday; Uwiera, Richard R E

    2007-09-01

    To determine whether therapy with the angiotensin II type 1 receptor blocker (ARB) candesartan and the comparator angiotensin-converting-enzyme inhibitor (ACEI) enalapril during healing after reperfused ST-elevation myocardial infarction (RSTEMI) limit adverse remodeling of infarct zone (IZ) collagens and left ventricular (LV) diastolic dysfunction, we randomized 24 dogs surviving anterior RSTEMI (90-min coronary occlusion) to placebo, candesartan, and enalapril therapy between day 2 and 42. Six other dogs were sham. We measured regional IZ and non-infarct zone (NIZ) collagens (hydroxyproline; types I/III; cross-linking), transforming growth factor-beta (TGF-beta) and topography at 6 weeks, and hemodynamics, LV diastolic and systolic function, and remodeling over 6 weeks. Compared to sham, placebo-RSTEMI differentially altered regional collagens, with more pronounced increase in TGF-beta, hydroxyproline, and type I, insoluble, and cross-linked collagens in the IZ than NIZ, and increased IZ soluble and type III collagens at 6 weeks, and induced persistent LV filling pressure elevation, diastolic and systolic dysfunction, and LV remodeling over 6 weeks. Compared to placebo-RSTEMI, candesartan and enalapril limited adverse regional collagen remodeling, with normalization of type III, soluble and insoluble collagens and decrease in pyridinoline cross-linking in the IZ at 6 weeks, and attenuation of LV filling pressure, diastolic dysfunction, and remodeling over 6 weeks. The results suggest that candesartan and enalapril during healing after RSTEMI prevent rather than worsen adverse remodeling of IZ collagens and LV diastolic dysfunction, supporting the clinical use of ARBs and ACEIs during subacute RSTEMI.

  4. [Takotsubo cardiomyopathy: a novel beta-adrenergic blocker withdrawal syndrome].

    PubMed

    Tomcsányi, János; Jávor, Kinga; Arabadzisz, Hrisula; Zsoldos, András; Wagner, Vince; Sármán, Balázs

    2013-02-17

    The authors describe two cases of takotsubo cardiomyopathy developing after an abrupt withdrawal of carvedilol and bisoprolol. Takotsubo or stress cardiomyopathy is characterized by acute and reversible cardiac dysfunction without coronary artery disease. It is triggered by acute emotional or physical stress, drugs or drug withdrawal. The immediate discontinuation of the long acting vasodilator beta-blocker, carvedilol has not yet been described to cause takotsubo cardiomyopathy. The authors recommend cautious withdrawal of beta-blockers.

  5. [40 years beta-adrenoceptor blockers in psychiatry].

    PubMed

    Kornischka, J; Cordes, J; Agelink, M W

    2007-04-01

    Beta-adrenoceptor blockers belong to the most successful drug classes of medicine. Mainly they are used in internal medicine. 40 years ago beta-adrenoceptor blockers have occasionally been used in psychiatry for the treatment of anxiety disorders. Over the past four decades, the effects of beta-adrenoceptor blockers in the treatment of schizophrenic and manic psychoses, withdrawal syndromes and aggressive behaviour with temper outbursts has been investigated. Beta-adrenoceptor blockers are also used in the treatment of side-effects of psychopharmacological agents like neuroleptic or antidepressant-induced tachycardias, lithium-induced tremor, antipsychotic-induced akathisia or tardive dyskinesia as well. Since the mid-nineties it has been attempted to improve the efficacy of antidepressant agents by means of the 5-HT-(1a)-receptorantagonist pindolol. Presumedly memory consolidation of traumatic events can be enhanced by adrenergic activation. Therefore some open clinical trials investigated the effects of propranolol, a lipid soluble drug, which crosses the blood-brain barrier easily, to reduce the manifestation of PTSD. The present review presents the results of the literature with respect to the indications for beta-blockers in psychiatry. Considering evidence-based-medicine criteria beta-blockers are indicated to treat lithium-induced tremor, antipsychotic-induced akathisia and to reduce aggressive behavior of patients with brain-injuries.

  6. Formulary considerations in selection of beta-blockers.

    PubMed

    Yedinak, K C

    1993-08-01

    Selection of beta-adrenergic blockers for formulary addition can be a difficult task, especially with the increasing availability of new beta-blockers, as well as the numerous differences in pharmacodynamic and pharmacokinetic properties of currently available agents. Nevertheless, appropriate evaluation of the important characteristics of beta-blockers should allow selection of the most cost-effective agents for formulary addition. Most importantly, differences in efficacy, product formulation and cost should be carefully considered when making formulary decisions. Notably, evidence from clinical trials indicates differences in efficacy among beta-blockers for post-myocardial infarction prophylaxis, situational anxiety, essential tremor, thyrotoxicosis, migraine prophylaxis and prevention of bleeding associated with oesophageal varices. For many clinical situations, it is also important to select an effective agent that is available in both an oral and intravenous formulation, especially for cardioprotection after acute myocardial infarction and for use in supraventricular arrhythmias. In addition, availability of sustained release products and generic formulations should be considered for their potential to increase compliance and decrease cost, respectively. Comparative drug costs, as well as costs associated with decreased compliance, should also be carefully evaluated. Differences in beta-receptor selectivity, duration of action and presence of intrinsic sympathomimetic activity (ISA) are also important considerations in the selection of beta-blockers for formulary consideration. Although degree of selectivity is relative, beta 1-selective agents may be less likely to induce bronchospasm in patients with chronic obstructive pulmonary disease (COPD) and may be less likely to affect glucose homeostasis in patients with diabetes mellitus. Duration of action of a beta-blocker is an important consideration for evaluation of efficacy throughout the recommended

  7. Stress degradation studies on Telmisartan and development of a validated method by UV spectrophotometry in bulk and pharmaceutical dosage forms

    PubMed Central

    Patel, Komal; Dhudasia, Komal; Patel, Amit; Dave, Jayant; Patel, Chaganbhai

    2011-01-01

    Aim and Background: To develop and validate a simple, precise, accurate, and stability indicating a UV-method for estimation of Telmisartan (TELM). UV, HPLC, HPTLC, and many more experiments were carried out by taking single drug and also by combining with other drugs. However, Such type of studies was not reported. Materials and Methods: In both methods, TELM has the absorbance maxima at 296 nm. Method A involves method development and validation and Method B involves forced degradation study. In these methods, methanol was used as a solvent. Linearity was observed in the concentration range of 4–16 μg/ml. Validation experiments were performed to demonstrate system suitability, specificity, precision, linearity, accuracy, robustness, LOD, and LOQ as per International Conference on Harmonization guidelines. Furthermore stability studies of TELM were carried out under acidic, alkali, neutral, oxidation, photolytic, and thermal degradation as per stability indicating assay methods. Results: The results of analysis have been validated, and recovery studies were carried out using a standard addition method by adding specific drug amount (80%, 100%, and 120%) and show recovery studies in the range (99.26–101.26)%. Conclusion: The proposed method can be successfully applied for method development, validation, and stability study of TELM. PMID:23781466

  8. Voltage-gated sodium channel blockers as immunomodulators.

    PubMed

    Roselli, Francesco; Livrea, Paolo; Jirillo, Emilio

    2006-01-01

    Several Voltage-Gated Sodium Channels (VGSC) are widely expressed on lymphocytes and macrophages but their role in immune function is still debated. Nevertheless, Na(+) influx through VGSC is required for lymphocytes activation and proliferation, since these responses are blocked by Na(+)-free medium or by VGSC blockers. These effects may be mediated by the reduced intracellular Na(+) levels, which in turn may impair the activity of Na(+)/Ca(++) exchanger resulting in reduced intracellular Ca(++) levels during lymphocyte activation. Furthermore, in Jurkat cell line VGSC appear to be involved in cell volume regulation, migration in artificial matrix and cell death by apoptosis. VGSC play a role in macrophage function as well, and VGSC blockers impair both phagocytosis and inflammatory responses. Several VGSC blockers have shown immunomodulatory properties in mice models, skewing the immune response toward a Th2-mediated response, while suppressing Th1-mediated responses, and VGSC already used in clinical practice are known to modulate immunoglobulin (Ig) levels both in mice and in humans. These effects suggest that VGSC blockers may find clinical application in the treatment of autoimmune and inflammatory disease. However, many of these drugs induce a number of severe side effects. The relevance of VGSC function in immune regulation suggest that the testing of newly patented VGSC blockers for their effect on immunity may be worthwhile.

  9. Beta-blocker therapy and the risk of anaphylaxis.

    PubMed Central

    Toogood, J H

    1987-01-01

    Beta-blocker therapy is associated with an increase in the severity and, possibly, the incidence of acute anaphylaxis. The population at risk consists of people with allergic conditions who are given a beta-blocker for an unrelated condition. Anaphylaxis under these conditions may be severe, protracted and resistant to conventional treatment because of the beta-adrenergic blockade. Severe or fatal attacks have been triggered by insect stings, the ingestion of allergenic foods or drugs, and injections of radiocontrast media, antisera or immunotherapy antigens. These occurrences are probably infrequent, but their incidence is unknown. At least two fatal cases have recently occurred in Canada. Clinical allergists, internists and family practitioners in particular should be aware of the need for aggressive and prolonged support in patients who experience anaphylaxis while receiving beta-blocker therapy and should report all such occurrences to the federal registry of adverse drug reactions. Allergy skin testing or immunotherapy is inadvisable in patients who take a beta-blocker orally or in the form of ophthalmic eyedrops. The list of relative contraindications to beta-blocker use should be extended to include susceptibility to recurrent anaphylaxis, whether it is idiopathic or due to an identifiable cause. PMID:2882832

  10. T-type Calcium Channel Blockers as Neuroprotective Agents

    PubMed Central

    Kopecky, Benjamin J.; Liang, Ruqiang; Bao, Jianxin

    2014-01-01

    T-type calcium channels are expressed in many diverse tissues, including neuronal, cardiovascular, and endocrine. T-type calcium channels are known to play roles in the development, maintenance, and repair of these tissues but have also been implicated in disease when not properly regulated. Calcium channel blockers have been developed to treat various diseases and their use clinically is widespread due to both their efficacy as well as their safety. Aside from their established clinical applications, recent studies have suggested neuroprotective effects of T-type calcium channels blockers. Many of the current T-type calcium channel blockers could act on other molecular targets besides T-type calcium channels making it uncertain whether their neuroprotective effects are solely due to blocking of T-type calcium channels. In this review, we discuss these drugs as well as newly developed chemical compounds that are designed to be more selective for T-type calcium channels. We review in vitro and in vivo evidence of neuroprotective effects by these T-type calcium channel blockers. We conclude by discussing possible molecular mechanisms underlying neuroprotective effects by T-type calcium channel blockers. PMID:24563219

  11. Dual angiotensin receptor and neprilysin inhibition as an alternative to angiotensin-converting enzyme inhibition in patients with chronic systolic heart failure: rationale for and design of the Prospective comparison of ARNI with ACEI to Determine Impact on Global Mortality and morbidity in Heart Failure trial (PARADIGM-HF)

    PubMed Central

    McMurray, John J. V.; Packer, Milton; Desai, Akshay S.; Gong, Jim; Lefkowitz, Martin P.; Rizkala, Adel R.; Rouleau, Jean; Shi, Victor C.; Solomon, Scott D.; Swedberg, Karl; Zile, Michael R.

    2013-01-01

    Aims Although the focus of therapeutic intervention has been on neurohormonal pathways thought to be harmful in heart failure (HF), such as the renin–angiotensin–aldosterone system (RAAS), potentially beneficial counter-regulatory systems are also active in HF. These promote vasodilatation and natriuresis, inhibit abnormal growth, suppress the RAAS and sympathetic nervous system, and augment parasympathetic activity. The best understood of these mediators are the natriuretic peptides which are metabolized by the enzyme neprilysin. LCZ696 belongs to a new class of drugs, the angiotensin receptor neprilysin inhibitors (ARNIs), which both block the RAAS and augment natriuretic peptides. Methods Patients with chronic HF, NYHA class II–IV symptoms, an elevated plasma BNP or NT-proBNP level, and an LVEF of ≤40% were enrolled in the Prospective comparison of ARNI with ACEI to Determine Impact on Global Mortailty and morbidity in Heart Failure trial (PARADIGM-HF). Patients entered a single-blind enalapril run-in period (titrated to 10 mg b.i.d.), followed by an LCZ696 run-in period (100 mg titrated to 200 mg b.i.d.). A total of 8436 patients tolerating both periods were randomized 1:1 to either enalapril 10 mg b.i.d. or LCZ696 200 mg b.i.d. The primary outcome is the composite of cardiovascular death or HF hospitalization, although the trial is powered to detect a 15% relative risk reduction in cardiovascular death. Perspectives PARADIGM-HF will determine the place of the ARNI LCZ696 as an alternative to enalapril in patients with systolic HF. PARADIGM-HF may change our approach to neurohormonal modulation in HF. Trial registration NCT01035255 PMID:23563576

  12. HPLC Enantioseparation of β-Blockers on Ovomucoid Stationary Phase.

    PubMed

    Imre, Silvia; Ormenişan, Anca; Tero-Vescan, Amelia; Muntean, Daniela-Lucia; Vari, Camil-Eugen

    2016-07-07

    The purpose of this study was to separate single and multiple pairs of six β-blockers enantiomers by high performance liquid chromatography on ovomucoid (OM) column in optimal conditions. The separation was performed isocratically or in gradient elution at 25°C, flow rate of 1 mL/min and 220 nm. The mobile phase consisted of phosphate buffer/acetonitrile or methanol. The effect of the organic modifier, the influence of pH and the percentage of the aqueous phase on resolution were investigated. The elution order of propranolol (PRP) enantiomers was established as well as the detection and quantification limits. The results show that OM was suitable for enantiomeric separation of the nonselective β-blockers carvedilol, PRP, pindolol and oxprenolol, and not for the two β-1 selective blockers, atenolol and metoprolol. A hypothesis regarding a possible correlation between structure-pharmacological activity-chromatographic behavior is proposed.

  13. Influence of alpha stimulants and beta blockers on yohimbine toxicity.

    PubMed

    Bourin, M; Malinge, M; Colombel, M C; Larousse, C

    1988-01-01

    1. Potentiation of yohimbine-induced sublethality has been largely used to predict antidepressant action. 2. Several products were tested in order to understand the mechanism of this toxicity better: an alpha-1 central stimulant (adrafinil); an alpha-2 central stimulant (clonidine); and 4 beta-blockers (propranolol, atenolol, penbutolol and metoprolol). 3. It was found that atenolol and adrafinil could not antagonize toxicity, whereas clonidine and the other 3 beta-blockers could. 4. It is suggested that a central beta-origin toxicity exists since only beta-blockers which cross the blood-brain barrier are capable of antagonizing this activity. 5. The fact that clonidine also antagonized this toxicity may be explained by the beta-antagonist action of this substance at the high doses used.

  14. Interaction of grapefruit juice and calcium channel blockers.

    PubMed

    Sica, Domenic A

    2006-07-01

    Drug-drug interactions are commonly recognized occurrences in the hypertensive population. Drug-nutrient interactions, however, are less well appreciated. The grapefruit juice-calcium channel blocker interaction is one that has been known since 1989. The basis for this interaction has been diligently explored and appears to relate to both flavanoid and nonflavanoid components of grapefruit juice interfering with enterocyte CYP3A4 activity. In the process, presystemic clearance of susceptible drugs decreases and bioavailability increases. A number of calcium channel blockers are prone to this interaction, with the most prominent interaction occurring with felodipine. The calcium channel blocker and grapefruit juice interaction should be incorporated into the knowledge base of rational therapeutics for the prescribing physician.

  15. The putative P-gp inhibitor telmisartan does not affect the transcellular permeability and cellular uptake of the calcium channel antagonist verapamil in the P-glycoprotein expressing cell line MDCK II MDR1

    PubMed Central

    Saaby, Lasse; Tfelt-Hansen, Peer; Brodin, Birger

    2015-01-01

    Verapamil is used in high doses for the treatment of cluster headache. Verapamil has been described as a P-glycoprotein (P-gp, ABCB1) substrate. We wished to evaluate in vitro whether co administration of a P-gp inhibitor with verapamil could be a feasible strategy for increasing CNS uptake of verapamil. Fluxes of radiolabelled verapamil across MDCK II MDR1 monolayers were measured in the absence and presence of the putative P-gp inhibitor telmisartan (a clinically approved drug compound). Verapamil displayed a vectorial basolateral-to-apical transepithelial efflux across the MDCK II MDR1 monolayers with a permeability of 5.7 × 10−5 cm sec−1 compared to an apical to basolateral permeability of 1.3 × 10−5 cm sec-1. The efflux could be inhibited with the P-gp inhibitor zosuquidar. Zosuquidar (0.4 μmol/L) reduced the efflux ratio (PB-A/PA-B) for verapamil 4.6–1.6. The presence of telmisartan, however, only caused a slight reduction in P-gp-mediated verapamil transport to an efflux ratio of 3.4. Overall, the results of the present in vitro approach indicate, that clinical use of telmisartan as a P-gp inhibitor may not be an effective strategy for increasing brain uptake of verapamil by co-administration with telmisartan. PMID:26171231

  16. Cellular Responses to Beta Blocker Exposures in Marine Bivalves

    EPA Science Inventory

    β blockers are prescription drugs used for medical treatment of hypertension and arrhythmias. They prevent activation of adenylate cyclase and increases in blood pressure by limiting cAMP production and protein kinase A activation. After being taken therapeutically, β b...

  17. The safety of H(2)-blockers use during pregnancy.

    PubMed

    Matok, Ilan; Gorodischer, Rafael; Koren, Gideon; Sheiner, Eyal; Wiznitzer, Arnon; Uziel, Elia; Levy, Amalia

    2010-01-01

    Little data exist on the safety of H(2)-blockers during pregnancy. A computerized database of medications dispensed from 1998 to 2007 to all women registered in the "Clalit" health maintenance organization, in the Southern District of Israel, was linked with computerized databases containing maternal and infant hospitalization records from the district hospital. The following confounders were controlled for: parity, maternal age, ethnic group, maternal diabetes, smoking, and peripartum fever. Also, therapeutic pregnancy termination data were analyzed. A total of 117 960 infants were born during the study period, 84 823 of them (72%) to women registered at Clalit; 1148 of the latter were exposed to H(2)-blockers during the first trimester of pregnancy. Exposure to H(2)-blockers was not associated with an increased risk for congenital malformations (adjusted odds ratio [OR] = 1.03, 95% confidence interval [CI]: 0.80-1.32); also, no such association was found when therapeutic pregnancy terminations were included in the analysis (adjusted OR = 1.17, 95% CI: 0.93-1.46). Exposure to H(2)-blockers was not associated with perinatal mortality, premature delivery, low birth weight, or low Apgar scores.

  18. Diabetes mellitus reduces the antiarrhythmic effect of ion channel blockers.

    PubMed

    Ito, Isao; Hayashi, Yukio; Kawai, Yusuke; Iwasaki, Mitsuo; Takada, Koji; Kamibayashi, Takahiko; Yamatodani, Atsushi; Mashimo, Takashi

    2006-09-01

    We designed the present study to examine whether diabetes mellitus affects the antiarrhythmic effect of flecainide, a sodium channel blocker, E-4031, a potassium channel blocker, and verapamil, a calcium channel blocker, in diabetic rats. The experiments were performed in intact and diabetic rats 2, 4, and 6 wk after administration of streptozotocin. Rats were anesthetized with halothane and monitored continuously for arterial blood pressure and premature ventricular contractions. The arrhythmogenic dose of epinephrine was defined as the smallest dose producing 3 or more premature ventricular contractions within a 15-s period. The arrhythmogenic doses of epinephrine in the presence of flecainide were 8.2 +/- 2.2 (mean +/- sd), 7.4 +/- 6.1, 5.5 +/- 2.8, and 2.0 +/- 0.5 microg/kg in intact and diabetic rats 2, 4, and 6 wk after streptozotocin administration, respectively. Similarly, the arrhythmogenic doses of epinephrine in the presence of E-4031 were 7.7 +/- 2.6, 2.3 +/- 0.7, 2.0 +/- 0.7, and 1.2 +/- 0.5 microg/kg, and those in the presence of verapamil were 8.2 +/- 2.1, 3.1 +/- 1.2, 2.3 +/- 0.9, and 1.5 +/- 0.5 microg/kg. Insulin partially recovered the antiarrhythmic effect of the blockers. We concluded that diabetes mellitus reduces the antiarrhythmic effects of flecainide, E-4031, and verapamil.

  19. Peptide toxins and small-molecule blockers of BK channels

    PubMed Central

    Yu, Mu; Liu, San-ling; Sun, Pei-bei; Pan, Hao; Tian, Chang-lin; Zhang, Long-hua

    2016-01-01

    Large conductance, Ca2+-activated potassium (BK) channels play important roles in the regulation of neuronal excitability and the control of smooth muscle contractions. BK channels can be activated by changes in both the membrane potential and intracellular Ca2+ concentrations. Here, we provide an overview of the structural and pharmacological properties of BK channel blockers. First, the properties of different venom peptide toxins from scorpions and snakes are described, with a focus on their characteristic structural motifs, including their disulfide bond formation pattern, the binding interface between the toxin and BK channel, and the functional consequence of the blockage of BK channels by these toxins. Then, some representative non-peptide blockers of BK channels are also described, including their molecular formula and pharmacological effects on BK channels. The detailed categorization and descriptions of these BK channel blockers will provide mechanistic insights into the blockade of BK channels. The structures of peptide toxins and non-peptide compounds could provide templates for the design of new channel blockers, and facilitate the optimization of lead compounds for further therapeutic applications in neurological disorders or cardiovascular diseases. PMID:26725735

  20. Beta-Blockers and Nitrates: Pharmacotherapy and Indications.

    PubMed

    Facchini, Emanuela; Degiovanni, Anna; Cavallino, Chiara; Lupi, Alessandro; Rognoni, Andrea; Bongo, Angelo S

    2015-01-01

    Many clinically important differences exist between beta blockers. B1-selectivity is of clinical interest because at clinically used doses, b1- selective agents block cardiac b-receptors while having minor effects on bronchial and vascular b-receptors. Beta-adrenergic blocking agents significantly decrease the frequency and duration of angina pectoris, instead the prognostic benefit of beta-blockers in stable angina has been extrapolated from studies of post myocardial infarction but has not yet been documented without left ventricular disfunction or previous myocardial infarction. Organic nitrates are among the oldest drugs, but they still remain a widely used adjuvant in the treatment of symptomatic coronary artery disease. While their efficacy in relieving angina pectoris symptoms in acute settings and in preventing angina before physical or emotional stress is undisputed, the chronic use of nitrates has been associated with potentially important side effects such as tolerance and endothelial dysfunction. B-blockers are the firstline anti-anginal therapy in stable stable angina patients without contraindications, while nitrates are the secondline anti-anginal therapy. Despite 150 years of clinical practice, they remain fascinating drugs, which in a chronic setting still deserve investigation. This review evaluated pharmacotherapy and indications of Beta-blockers and nitrates in stable angina.

  1. Bio-inspired voltage-dependent calcium channel blockers.

    PubMed

    Yang, Tingting; He, Lin-Ling; Chen, Ming; Fang, Kun; Colecraft, Henry M

    2013-01-01

    Ca(2+) influx via voltage-dependent CaV1/CaV2 channels couples electrical signals to biological responses in excitable cells. CaV1/CaV2 channel blockers have broad biotechnological and therapeutic applications. Here we report a general method for developing novel genetically encoded calcium channel blockers inspired by Rem, a small G-protein that constitutively inhibits CaV1/CaV2 channels. We show that diverse cytosolic proteins (CaVβ, 14-3-3, calmodulin and CaMKII) that bind pore-forming α1-subunits can be converted into calcium channel blockers with tunable selectivity, kinetics and potency, simply by anchoring them to the plasma membrane. We term this method 'channel inactivation induced by membrane-tethering of an associated protein' (ChIMP). ChIMP is potentially extendable to small-molecule drug discovery, as engineering FK506-binding protein into intracellular sites within CaV1.2-α1C permits heterodimerization-initiated channel inhibition with rapamycin. The results reveal a universal method for developing novel calcium channel blockers that may be extended to develop probes for a broad cohort of unrelated ion channels.

  2. [Obtaining antibodies to 1,4-dihydropyridine calcium channel blockers].

    PubMed

    Burkin, A A; Murkin, M A

    2008-01-01

    Immunization of rabbits with amlodipine conjugated with horseradish peroxidase resulted in raising polyclonal antibodies that allowed group determination of 1,4-dihydropyridine calcium channel blockers in aqueous solutions by ELISA with a sensitivity of 0.1 to 1.0 ng/ml for amlodipine, felodipine, nifedipine, and isradipine.

  3. Effects of Ramipril and Telmisartan on Plasma Concentrations of Low Molecular Weight and Protein Thiols and Carotid Intima Media Thickness in Patients with Chronic Kidney Disease

    PubMed Central

    Sotgiu, Elisabetta; Ena, Sara; Arru, Dionigia; Assaretti, Stefano; Baralla, Angela; Satta, Andrea E.

    2016-01-01

    Hypertension, a common feature in chronic kidney disease (CKD), is an independent risk factor for CKD progression and cardiovascular disease. Although inhibitors of the renin-angiotensin system (RAS) exert salutary effects on blood pressure control and proteinuria in CKD patients, their activity towards traditional and novel oxidative markers is largely unknown. We studied the effects of 6-month treatment with telmisartan versus a combination of telmisartan and ramipril on plasma concentrations of low molecular mass (LMW, including homocysteine and cysteine) and protein thiols (PSH) plasma concentration and their relationships with carotid intima media thickness (IMT), in 24 hypertensive CKD patients (age 60 ± 12 years, 8 females and 16 males). Pretreatment PSH concentrations were independently associated with IMT (r = −0.42, p = 0.039). Neither treatment affected plasma LMW thiols, in both reduced and total form. By contrast, both treatments increased PSH plasma concentrations and reduced IMT, although significant differences were only observed in the combined treatment group. Our results suggest that the beneficial effects of combined RAS inhibitor treatment on IMT in hypertensive CKD patients may be mediated by a reduction of oxidative stress markers, particularly PSH. PMID:27881888

  4. Experimental design approach for the optimisation of a HPLC-fluorimetric method for the quantitation of the angiotensin II receptor antagonist telmisartan in urine.

    PubMed

    Torrealday, N; González, L; Alonso, R M; Jiménez, R M; Ortiz Lastra, E

    2003-08-08

    A high performance liquid chromatographic method with fluorimetric detection has been developed for the quantitation of the angiotensin II receptor antagonist (ARA II) 4-((2-n-propyl-4-methyl-6-(1-methylbenzimidazol-2-yl)-benzimidazol-1-yl)methyl)biphenyl-2-carboxylic acid (telmisartan) in urine, using a Novapak C18 column 3.9 x 150 mm, 4 microm. The mobile phase consisted of a mixture acetonitrile-phosphate buffer (pH 6.0, 5 mM) (45:55, v/v) pumped at a flow rate of 0.5 ml min(-1). Effluent was monitored at excitation and emission wavelengths of 305 and 365 nm, respectively. Separation was carried out at room temperature. Chromatographic variables were optimised by means of experimental design. A clean-up step was used for urine samples consisting of a solid-phase extraction procedure with C8 cartridges and methanol as eluent. This method proved to be accurate (RE from -12 to 6%), precise (intra- and inter-day coefficients of variation (CV) were lower than 8%) and sensitive enough (limit of quantitation (LOQ), ca. 1 microg l(-1)) to be applied to the determination of the active drug in urine samples obtained from hypertensive patients. Concentration levels of telmisartan at different time intervals (from 0 up to 36 h after oral intake) were monitored.

  5. [Beta-blockers in septic shock: a review].

    PubMed

    Vela-Vásquez, R S; Grigorov-Tzenkov, I; Aguilar, J L

    2015-02-01

    In septic shock, high adrenergic stress is associated with cardiovascular and systemic adverse effects, which can negatively affect the results. Beta-adrenergic receptor block has been shown to be effective in controlling the disproportionate increase in heart rate, maintaining a favorable hemodynamic profile and apparently improving the efficiency of the cardiovascular system in order to maintain tissue perfusion. They have also been shown to modulate favorably catecholamine-induced immunosuppression and to decrease insulin resistance, protein catabolism, and proinflammatory cytokine expression associated with cardiovascular dysfunction. Selective beta-1 blockers appear to provide better results than non-selective blockers, even suggesting a positive impact on mortality. Future clinical trials are still needed to confirm these findings and define the scope of their benefits.

  6. Use of β-Blockers in Pulmonary Hypertension.

    PubMed

    Perros, Frédéric; de Man, Frances S; Bogaard, Harm J; Antigny, Fabrice; Simonneau, Gérald; Bonnet, Sébastien; Provencher, Steeve; Galiè, Nazzareno; Humbert, Marc

    2017-04-01

    Contrasting with the major attention that left heart failure has received, right heart failure remains understudied both at the preclinical and clinical levels. However, right ventricle failure is a major predictor of outcomes in patients with precapillary pulmonary hypertension because of pulmonary arterial hypertension, and in patients with postcapillary pulmonary hypertension because of left heart disease. In pulmonary hypertension, the status of the right ventricle is one of the most important predictors of both morbidity and mortality. Paradoxically, there are currently no approved therapies targeting the right ventricle in pulmonary hypertension. By analogy with the key role of β-blockers in the management of left heart failure, some authors have proposed to use these agents to support the right ventricle function in pulmonary hypertension. In this review, we summarize the current knowledge on the use of β-blockers in pulmonary hypertension.

  7. Influence of calcium blockers on the SPR of erythrocytes

    NASA Astrophysics Data System (ADS)

    Shynkarenko, Olena V.; Tril, Orest; Wojnarowska, Renata; Prohorenko, Sergiy; Shergii, E. M.

    2016-12-01

    One of the promising areas of research is the impact of calcium channel blockers (CB) of biological fluids. This paper shows that the CB impact on a biological fluid can be efficiently combine with the surface plasmon resonance (SPR). It is shown that the addition of CB at the SPR measurements affect the stability of membranes and acts differently on the kinetics of erythrocytes ligament in the different groups of people.

  8. Dark and bright blocker soliton interaction in defocusing waveguide arrays.

    PubMed

    Smirnov, Eugene; Rüter, Christian E; Stepić, Milutin; Shandarov, Vladimir; Kip, Detlef

    2006-11-13

    We experimentally demonstrate the interaction of an optical probe beam with both bright and dark blocker solitons formed with low optical light power in a saturable defocusing waveguide array in photorefractive lithium niobate. A phase insensitive interaction of the beams is achieved by means of counterpropagating light waves. Partial and full reflection (blocking) of the probe beam on the positive or negative light-induced defect is obtained, respectively, in good agreement with numerical simulations.

  9. Cellular Responses to Beta Blocker Exposures in Marine ...

    EPA Pesticide Factsheets

    β blockers are prescription drugs used for medical treatment of hypertension and arrhythmias. They prevent activation of adenylate cyclase and increases in blood pressure by limiting cAMP production and protein kinase A activation. After being taken therapeutically, β blockers may make their way to coastal habitats via discharge from waste water treatment plants, posing a potential risk to aquatic organisms. The aim of our research is to evaluate cellular biomarkers of β blocker exposure using two drugs, propranolol and metoprolol, in three commercially important marine bivalves -Crassostrea virginica, Mytilus edulis and Mercenaria mercenaria. Bivalves were obtained from Narragansett Bay (Rhode Island, USA) and acclimated in the laboratory. Following acclimation, gills and hepatopancreas tissues were harvested and separately exposed to 0, 1, 10, 100 and 1000 ng/l of each drug for 24 hours. Samples were preserved for cellular biomarker assays. Elevated cellular damage and changes in enzymatic activities were noted at environmentally relevant concentrations, and M. mercenaria was found to be the most sensitive bivalve out of the three species tested. These studies enhance our understanding of the potential impacts of commonly used prescription medication on organisms in coastal ecosystems, and demonstrate that filter feeders such as marine bivalves may serve as good model organisms to examine the effects of water soluble drugs. Evaluating a suite of biomarkers

  10. Marine Bivalve Cellular Responses to Beta Blocker Exposures ...

    EPA Pesticide Factsheets

    β blockers are prescription drugs used for medical treatment of hypertension and arrhythmias. They prevent binding of agonists such as catecholamines to β adrenoceptors. In the absence of agonist induced activation of the receptor, adenylate cyclase is not activated which in turn limits cAMP production and protein kinase A activation, preventing increases in blood pressure and arrhythmias. After being taken therapeutically, commonly prescribed β blockers may make their way to coastal habitats via discharge from waste water treatment plants (WWTP) posing a potential risk to aquatic organisms. The aim of our research is to evaluate cellular responses of three commercially important marine bivalves - Eastern oysters, blue mussels and hard clams - upon exposure to two β blocker drugs, propranolol and metoprolol, and to find molecular initiating events (MIEs) indicative of the exposure. Bivalves were obtained from Narragansett Bay (Rhode Island, USA) and acclimated in the laboratory. Following acclimation, gills and hepatopancreas (HP) tissues were harvested and separately exposed to 0, 1, 10, 100 and 1000 ng/l of each drug. Tissues were bathed in 30 parts per thousand (ppt) filtered seawater, antibiotic mix, Leibovitz nutrient media, and the test drug. Exposures were conducted for 24 hours and samples were saved for cellular biomarker assays. A lysosomal destabilization assay, which is a marker of membrane damage, was also performed at the end of each exposure.

  11. The Clinical Relevance of Beta Blockers in Ovarian Carcinoma

    PubMed Central

    Hefner, J.; Csef, H.

    2016-01-01

    The last ten years have seen hardly any improvement in the prognosis of ovarian carcinoma. There is a great need for new treatment strategies, and a recent retrospective study showing a survival advantage with the use of beta blockers met with a very positive response. This systematic review summarizes the current state of knowledge and research on the topic: A database analysis identified six clinical studies showing inconsistent results with respect to the administration of beta blockers and disease course. The 13 preclinical studies identified showed almost without exception both that catecholamines had detrimental effects on tumour progression, and that these effects could be influenced by pharmacological blockade. Overall the available evidence does not justify the use of beta blockers in clinical practice for ovarian carcinoma at the present time. This article also outlines details of research design required for further studies needed on the subject. Preclinical research findings are however very impressive: They not only form an important basis for the development of future clinical studies but also, through revealing new pathomechanisms, they already make an important contribution towards the development of new treatment strategies for ovarian carcinoma. PMID:27761025

  12. Photolysis of beta-blockers in environmental waters.

    PubMed

    Piram, Anne; Salvador, Arnaud; Verne, Cécilia; Herbreteau, Bernard; Faure, René

    2008-11-01

    Many drugs such as beta-blockers have been shown to occur in aquatic environments. Even if adequate ecotoxicity data are not available, it is of primary importance to get informations about their fate in environmental waters, particularly about their photofate in sewage treatment plant effluents (STP). The main difficulties when studying pharmaceutical photochemical behaviour in environmental waters, are linked to the very low environmentally relevant concentrations (ng L(-1) to microg L(-1)) which can generate problems in terms of analytical sensitivity. Moreover, the complexity of environmental matrices can modify micropollutants degradation kinetics. The photodegradation of beta-blockers has been compared at two concentration levels (10 microg L(-1) and 10 mg L(-1)) and in two different matrices (pure water and STP effluent). It has been shown that the concentration does not influence beta-blockers degradation pathways, thus allowing the identification of degradation compounds using the 10 mg L(-1) solutions. Although environmental waters speed up the degradation process, the same photoproducts were appeared in both matrices. Using LC-MS/MS, hydroxyl radical additions have been identified as an important degradation pathway for especially pindolol, propranolol and timolol, leading to several positional isomers, corresponding to mono-, di- or tri-hydroxylations. Kinetics of appearance/disappearance of these photoproducts have been studied in STP effluents.

  13. A Comparative Effectiveness Meta-Analysis of Drugs for the Prophylaxis of Migraine Headache

    PubMed Central

    2015-01-01

    Objective To compare the effectiveness and side effects of migraine prophylactic medications. Design We performed a network meta-analysis. Data were extracted independently in duplicate and quality was assessed using both the JADAD and Cochrane Risk of Bias instruments. Data were pooled and network meta-analysis performed using random effects models. Data Sources PUBMED, EMBASE, Cochrane Trial Registry, bibliography of retrieved articles through 18 May 2014. Eligibility Criteria for Selecting Studies We included randomized controlled trials of adults with migraine headaches of at least 4 weeks in duration. Results Placebo controlled trials included alpha blockers (n = 9), angiotensin converting enzyme inhibitors (n = 3), angiotensin receptor blockers (n = 3), anticonvulsants (n = 32), beta-blockers (n = 39), calcium channel blockers (n = 12), flunarizine (n = 7), serotonin reuptake inhibitors (n = 6), serotonin norepinephrine reuptake inhibitors (n = 1) serotonin agonists (n = 9) and tricyclic antidepressants (n = 11). In addition there were 53 trials comparing different drugs. Drugs with at least 3 trials that were more effective than placebo for episodic migraines included amitriptyline (SMD: -1.2, 95% CI: -1.7 to -0.82), -flunarizine (-1.1 headaches/month (ha/month), 95% CI: -1.6 to -0.67), fluoxetine (SMD: -0.57, 95% CI: -0.97 to -0.17), metoprolol (-0.94 ha/month, 95% CI: -1.4 to -0.46), pizotifen (-0.43 ha/month, 95% CI: -0.6 to -0.21), propranolol (-1.3 ha/month, 95% CI: -2.0 to -0.62), topiramate (-1.1 ha/month, 95% CI: -1.9 to -0.73) and valproate (-1.5 ha/month, 95% CI: -2.1 to -0.8). Several effective drugs with less than 3 trials included: 3 ace inhibitors (enalapril, lisinopril, captopril), two angiotensin receptor blockers (candesartan, telmisartan), two anticonvulsants (lamotrigine, levetiracetam), and several beta-blockers (atenolol, bisoprolol, timolol). Network meta-analysis found amitriptyline to be better than several other medications including

  14. Treatment for calcium channel blocker poisoning: A systematic review

    PubMed Central

    Dubé, P.-A.; Gosselin, S.; Guimont, C.; Godwin, J.; Archambault, P. M.; Chauny, J.-M.; Frenette, A. J.; Darveau, M.; Le sage, N.; Poitras, J.; Provencher, J.; Juurlink, D. N.; Blais, R.

    2014-01-01

    Context Calcium channel blocker poisoning is a common and sometimes life-threatening ingestion. Objective To evaluate the reported effects of treatments for calcium channel blocker poisoning. The primary outcomes of interest were mortality and hemodynamic parameters. The secondary outcomes included length of stay in hospital, length of stay in intensive care unit, duration of vasopressor use, functional outcomes, and serum calcium channel blocker concentrations. Methods Medline/Ovid, PubMed, EMBASE, Cochrane Library, TOXLINE, International pharmaceutical abstracts, Google Scholar, and the gray literature up to December 31, 2013 were searched without time restriction to identify all types of studies that examined effects of various treatments for calcium channel blocker poisoning for the outcomes of interest. The search strategy included the following Keywords: [calcium channel blockers OR calcium channel antagonist OR calcium channel blocking agent OR (amlodipine or bencyclane or bepridil or cinnarizine or felodipine or fendiline or flunarizine or gallopamil or isradipine or lidoflazine or mibefradil or nicardipine or nifedipine or nimodipine or nisoldipine or nitrendipine or prenylamine or verapamil or diltiazem)] AND [overdose OR medication errors OR poisoning OR intoxication OR toxicity OR adverse effect]. Two reviewers independently selected studies and a group of reviewers abstracted all relevant data using a pilot-tested form. A second group analyzed the risk of bias and overall quality using the STROBE (STrengthening the Reporting of OBservational studies in Epidemiology) checklist and the Thomas tool for observational studies, the Institute of Health Economics tool for Quality of Case Series, the ARRIVE (Animal Research: Reporting In Vivo Experiments) guidelines, and the modified NRCNA (National Research Council for the National Academies) list for animal studies. Qualitative synthesis was used to summarize the evidence. Of 15,577 citations identified in

  15. Telmisartan prevents hepatic fibrosis and enzyme-altered lesions in liver cirrhosis rat induced by a choline-deficient L-amino acid-defined diet

    SciTech Connect

    Jin Haiyan; Yamamoto, Naoki; Uchida, Koichi; Terai, Shuji; Sakaida, Isao

    2007-12-28

    Rennin-angiotensin system is involved in liver fibrogenesis through activating hepatic stellate cells (HSCs). Telmisartan (Tel) is an angiotensin II type 1 receptor antagonist, could function as a selective peroxisome proliferator-activated receptor {gamma} activator. Here we studied the effect of Tel on liver fibrosis, pre-neoplastic lesions in vivo and primary HSCs in vitro. In vivo study, we used the choline-deficient L-amino acid-defined (CDAA)-diet induced rat NASH model. The rats were fed the CDAA diet for 8 weeks to induce liver fibrosis and pre-neoplastic lesions, and then co-administrated with Tel for another 10 weeks. Tel prevented liver fibrogenesis and pre-neoplastic lesions by down-regulating TGF{beta}1 and TIMP-1, 2 and increasing MMP-13 expression. Tel inhibited HSCs activation and proliferation. These results suggested that Tel could be a promising drug for NASH related liver fibrosis.

  16. Angiotensin receptors and actions in guinea pig enteric nervous system.

    PubMed

    Wang, Guo-Du; Wang, Xi-Yu; Hu, Hong-Zhen; Fang, Xiu-Cai; Liu, Sumei; Gao, Na; Xia, Yun; Wood, Jackie D

    2005-09-01

    Actions of ANG II on electrical and synaptic behavior of enteric neurons in the guinea pig small intestine were studied. Exposure to ANG II depolarized the membrane potential and elevated neuronal excitability. The number of responding neurons was small, with responses to ANG II in 32% of submucosal neurons and 25% of myenteric neurons. Hyperpolarizing responses were evoked by ANG II in 45% of the neurons. The hyperpolarizing responses were suppressed by alpha2-noradrenergic receptor antagonists, which suggested that the hyperpolarizing responses reflected stimulation of norepinephrine release from sympathetic neurons. Exposure to ANG II enhanced the amplitude and prolonged the duration of noradrenergic inhibitory postsynaptic potentials and suppressed the amplitude of both fast and slow excitatory postsynaptic potentials. The selective ANG II(1) receptor (AT1R) antagonists, ZD-7115 and losartan, but not a selective AT2R antagonist (PD-123319), suppressed the actions of ANG II. Western blot analysis and RT-PCR confirmed expression of AT1R protein and the mRNA transcript for the AT1R in the enteric nervous system. No expression of AT2R protein or mRNA was found. Immunoreactivity for AT1R was expressed by the majority of neurons in the gastric antrum and small and large intestine. AT1R immunoreactivity was coexpressed with calbindin, choline acetyltransferase, calretinin, neuropeptide Y, and nitric oxide synthase in subpopulations of neurons. The results suggest that formation of ANG II might have paracrine-like actions in the enteric nervous system, which include alterations in neuronal excitability and facilitated release of norepinephrine from sympathetic postganglionic axons. The enhanced presence of norepinephrine is expected to suppress fast and slow excitatory neurotransmission in the enteric microcircuits and to suppress neurogenic mucosal secretion.

  17. Noninvasive Imaging of Angiotensin Receptors After Myocardial Infarction

    PubMed Central

    Verjans, Johan W. H.; Lovhaug, Dagfinn; Narula, Navneet; Petrov, Artiom D.; Indrevoll, Bård; Bjurgert, Emma; Krasieva, Tatiana B.; Petersen, Lizette B.; Kindberg, Grete M.; Solbakken, Magne; Cuthbertson, Alan; Vannan, Mani A.; Reutelingsperger, Chris P. M.; Tromberg, Bruce J.; Hofstra, Leonard; Narula, Jagat

    2010-01-01

    OBJECTIVES The purpose of this study was to evaluate the feasibility of noninvasive imaging of angiotensin II (AT) receptor upregulation in a mouse model of post-myocardial infarction (MI) heart failure (HF). BACKGROUND Circulating AT levels do not reflect the status of upregulation of renin-angiotensin axis in the myocardium, which plays a central role in ventricular remodeling and evolution of HF after MI. Appropriately labeled AT or AT receptor blocking agents should be able to specifically target AT receptors by molecular imaging techniques. METHODS AT receptor imaging was performed in 29 mice at various time points after permanent coronary artery ligation or in controls using a fluoresceinated angiotensin peptide analog (APA) and radiolabeled losartan. The APA was used in 19 animals for intravital fluorescence microscopy on a beating mouse heart. Tc-99m losartan was used for in vivo radionuclide imaging and quantitative assessment of AT receptor expression in 10 mice. After imaging, hearts were harvested for pathological characterization using confocal and 2-photon microscopy. RESULTS No or little APA uptake was observed in control animals or within infarct regions on days 0 and 1. Distinct uptake occurred in the infarct area at 1 to 12 weeks after MI; the uptake was at maximum at 3 weeks and reduced markedly at 12 weeks after MI. Ultrasonographic examination demonstrated left ventricular remodeling, and pathologic characterization revealed localization of the APA tracer with collagen-producing myofibroblasts. Tc-99m losartan uptake in the infarct region (0.524 ± 0.212% injected dose/g) increased 2.4-fold as compared to uptake in the control animals (0.215 ± 0.129%; p < 0.05). CONCLUSIONS The present study demonstrates the feasibility of in vivo molecular imaging of AT receptors in the remodeling myocardium. Noninvasive imaging studies aimed at AT receptor expression could play a role in identification of subjects likely to develop heart failure. In addition, such a strategy could allow for optimization of anti-angiotensin therapy in patients after MI. PMID:19356449

  18. Angiotensin receptor binding and pressor effects in cat subretrofacial nucleus

    SciTech Connect

    Allen, A.M.; Dampney, R.A.L.; Mendelsohn, F.A.O. Univ. of Sydney )

    1988-11-01

    Central administration of angiotensin II (ANG II) increases arterial blood pressure via increased sympathetic activity. The authors have examined the possibility that one site of action of ANG II is the subretrofacial (SRF) nucleus in the rostral ventrolateral medulla, since this nucleus is known to play a critical role in the tonic and phasic control of arterial pressure. In vitro autoradiography, employing {sup 125}I-labeled (Sar{sup 1}, Ile{sup 8})ANG II as radioligand, was used to localize binding sites for ANG-II in the cat ventrolateral medulla. A high density of ANG II-receptor binding sites was found confined to the SRF nucleus. In a second group of experiments in anesthetized cats, microinjections of ANG II, in doses ranging from 10 to 50 pmol, were made into histologically identified sites within and outside the SRF nucleus. Microinjections into the nucleus resulted in a dose-dependent increase in arterial pressure, which was abolished by systemic administration of the ganglion-blocking drug hexamethonium bromide. In contrast, microinjections just outside the SRF nucleus had no effect on arterial pressure. It is concluded that activation of ANG II-receptor binding sites within the SRF nucleus leads to an increase in arterial pressure via increased sympathetic efferent activity.

  19. Etoricoxib-induced life-threatening hyperkalemia and acute kidney dysfunction against the background of telmisartan and a low sodium diet

    PubMed Central

    Dash, Suresh Chandra

    2010-01-01

    Drug-induced hyperkalemia is not uncommon and may be life-threatening when presenting acutely in the emergency department. We present a case of severe hyperkalemia precipitated acutely by etoricoxib in a patient who was on telmisartan and a low sodium (potassium chloride-rich) diet. A 75-year-old male with a past medical history of well-controlled diabetes and hypertension was prescribed etoricoxib (90 mg daily) for 3 days for musculoskeletal backache. He had been taking his routine medications including telmisartan and a potassium-rich salt substitute for many years, without any recent change in dosage or quantity. There was evidence of microalbuminurea; however, the renal functions and electrolytes prior to starting etoricoxib were normal. He presented to the emergency department with signs and symptoms of life-threatening hyperkalemia (serum potassium 7.7 mEq/dl), accelerated hypertension, congestive heart failure, pulmonary edema and acute renal failure. Acute medical management and withholding all drugs that could cause hyperkalemia improved his serum potassium levels over 24 h and renal parameters within 5 days. All the other drugs except etoricoxib were restarted under observation over 8 weeks with no recurrence of the acute episode. Non-steroidal analgesics and other COX-2 inhibitors (rofecoxib and celecoxib) have been known to precipitate renal failure and hyperkalemia specially in patients at risk for the same; although not unexpected, this may be the first reported case of life-threatening hyperkalemia precipitated by etoricoxib in a previously stable patient having increased risk of renal failure and hyperkalemia. PMID:21373319

  20. Clinical review of beta-blockers in anxiety.

    PubMed

    Kelly, D

    1980-09-01

    Anxiety has three essential elements: the subjective experience, autonomic symptoms and avoidance behaviour. Various theories are considered which highlight the psychic and somatic aspects of anxiety. Beta-adrenergic receptor blocking drugs have been used with advantage to treat everyday stresses. These include the anxiety produced by the civil disturbances in Northern Ireland, performing surgery, dentistry, musical instruments or speaking in public, as well as examination nerves. The profile of symptoms such as tachycardia, palpitations and tremor which are most likely to respond to beta-blockers are discussed as well as their side-effects. Their mode of action is different from other anxiolytics, with which they can be combined.

  1. [Effects of H2-blockers on alcohol dehydrogenase (ADH) activity].

    PubMed

    Jelski, Wojciech; Orywal, Karolina; Szmitkowski, Maciej

    2008-12-01

    First-pass metabolism (FPM) of alcohol is demonstrated by lower blood alcohol concentrations after oral than intravenous administration of the same dose. FPM occurs predominantly in the stomach and has been attributed to class IV of alcohol dehydrogenase (ADH) isoenzyme localizated in the gastric mucosa. A number of factors that influence on gastric ADH activity and thereby modulate FPM have been identified. These include age, sex, ethnicity, concentrations and amounts of alcohol consumed and drugs. Several H2-receptor antagonists, including cimetidine and ranitidine, inhibit gastric ADH activity and reduce FPM, resulting in higher blood alcohol concentrations after H2-blockers administration.

  2. New Insight into Effects of β-Blockers on Arterial Functions

    PubMed Central

    Eguchi, Kazuo

    2016-01-01

    The effects of β-blockers on arterial properties are not well investigated. In our recent study, we compared the effects of the two β-blockers celiprolol and bisoprolol on blood pressure, baroreflex sensitivity (BRS), flow-mediated vasodilatation, and vascular stiffness. We found that bisoprolol achieved a greater reduction in the pulse rate and improved BRS and vascular stiffness, whereas celiprolol reduced the central blood pressure level. In this review, the mechanisms of different types of β-blockers and their effects on arteries are discussed, and the appropriate use of β-blockers in hypertensive subjects will be proposed. PMID:27195240

  3. New Insight into Effects of β-Blockers on Arterial Functions.

    PubMed

    Eguchi, Kazuo

    2016-04-01

    The effects of β-blockers on arterial properties are not well investigated. In our recent study, we compared the effects of the two β-blockers celiprolol and bisoprolol on blood pressure, baroreflex sensitivity (BRS), flow-mediated vasodilatation, and vascular stiffness. We found that bisoprolol achieved a greater reduction in the pulse rate and improved BRS and vascular stiffness, whereas celiprolol reduced the central blood pressure level. In this review, the mechanisms of different types of β-blockers and their effects on arteries are discussed, and the appropriate use of β-blockers in hypertensive subjects will be proposed.

  4. β-Blockers and Vascular Hemodynamics in Patients With Peripheral Arterial Disease.

    PubMed

    Schlager, Oliver; Gajdosova Kovacicova, Ludmila; Senn, Oliver; Amann-Vesti, Beatrice; Wilkinson, Ian B; Jacomella, Vincenzo; Husmann, Marc

    2016-12-01

    Aortic augmentation index (AIx) is a marker of central aortic pressure burden and is modulated by antihypertensive drugs. In patients with peripheral arterial disease (PAD) undergoing antihypertensive treatment, aortic pressures parameters, heart rate-adjusted augmentation index (AIx75), and unadjusted AIx were determined. The (aortic) systolic and diastolic blood pressure did not differ between PAD patients who were taking β-blockers (n=61) and those who were not taking β-blockers (n=80). In patients taking β-blockers, augmentation pressure and pulse pressure were higher than in patients who did not take β-blockers (augmentation pressure, P=.02; pulse pressure, P=.005). AIx75 was lower in PAD patients taking β-blockers than in patients not taking β-blockers (P=.04), while the AIx did not differ between PAD patients taking and not taking β-blockers. The present study demonstrates that β-blockers potentially affect markers of vascular hemodynamics in patients with PAD. Because these markers are surrogates of cardiovascular risk, further studies are warranted to clarify the impact of selective β-blocker treatment on clinical outcome in patients with PAD.

  5. Model studies of the function of blockers on the small conductance potassium ion channel.

    PubMed

    Ciechanowicz-Rutkowska, M; Lewinski, K; Oleksyn, B; Stec, B

    2003-09-01

    A correlation between KI (equilibrium dissociation constants) and IC50 (concentration at 50% inhibition) inhibitors for the family of blockers of the small conductance potassium ion channels and their intrinsic characteristics like molecular mass and volume have been investigated. Most of the blockers in the family are not selective, in contrast to apamin - an 18 amino acid bee venom toxin - that is known to be a highly potent and selective blocker of these channels. Differences and similarities between the blockers have been analyzed, pointing toward the origin of their selectivity and relative potency. In conclusion, an ion channel blocking is a process controlled mainly by diffusion, in accordance with previous experimental results.

  6. Kinetic Hairpin Oligonucleotide Blockers for Selective Amplification of Rare Mutations

    PubMed Central

    Jia, Yanwei; Sanchez, J. Aquiles; Wangh, Lawrence J.

    2014-01-01

    Detection of rare mutant alleles in an excess of wild type alleles is increasingly important in cancer diagnosis. Several methods for selective amplification of a mutant allele via the polymerase chain reaction (PCR) have been reported, but each of these methods has its own limitations. A common problem is that Taq DNA polymerase errors early during amplification generate false positive mutations which also accumulate exponentially. In this paper, we described a novel method using hairpin oligonucleotide blockers that can selectively inhibit the amplification of wild type DNA during LATE-PCR amplification. LATE-PCR generates double-stranded DNA exponentially followed by linear amplification of single-stranded DNA. The efficiency of the blocker is optimized by adjusting the LATE-PCR temperature cycling profile. We also demonstrate that it is possible to minimize false positive signals caused by Taq DNA polymerase errors by using a mismatched excess primer plus a modified PCR profile to preferentially enrich for mutant target sequences prior to the start of the exponential phase of LATE-PCR amplification. In combination these procedures permit amplification of specific KRAS mutations in the presence of more than 10,000 fold excess of wild type DNA without false positive signals. PMID:25082368

  7. Role of β-blocker therapy in pediatric heart failure.

    PubMed

    Patel, Akash R; Shaddy, Robert E

    2010-01-01

    Heart failure is becoming an increasingly common and significant problem in the field of pediatric cardiology. The numerous types of cardiomyopathies, and more recently, long-term survival of patients with congenital heart disease, have added to a growing patient population. Over the last several decades, our knowledge base regarding mechanisms of disease and therapeutic intervention in adult patients with heart failure has drastically changed. The most recent and important breakthrough in the pharmacologic treatment of heart failure has been the particular role of β-blocker therapy. This medication has led to significant improvements in survival and symptoms in adults, with less convincing findings in limited studies in pediatrics. The ability to study the benefits of this therapy in patients has been challenging owing to the heterogeneity of the patient population and lack of large sample sizes. However, as we investigate the mechanisms behind the disease process, the differences that exist between disease conditions and ages, and the significant alterations that may exist at the molecular and genetic level, our understanding of β-blocker therapy in pediatric heart failure will improve, and ultimately may lead to patient-specific therapy.

  8. Metaflumizone is a novel sodium channel blocker insecticide.

    PubMed

    Salgado, V L; Hayashi, J H

    2007-12-15

    Metaflumizone is a novel semicarbazone insecticide, derived chemically from the pyrazoline sodium channel blocker insecticides (SCBIs) discovered at Philips-Duphar in the early 1970s, but with greatly improved mammalian safety. This paper describes studies confirming that the insecticidal action of metaflumizone is due to the state-dependent blockage of sodium channels. Larvae of the moth Spodoptera eridania injected with metaflumizone became paralyzed, concomitant with blockage of all nerve activity. Furthermore, tonic firing of abdominal stretch receptor organs from Spodoptera frugiperda was blocked by metaflumizone applied in the bath, consistent with the block of voltage-dependent sodium channels. Studies on native sodium channels, in primary-cultured neurons isolated from the CNS of the larvae of the moth Manduca sexta and on Para/TipE sodium channels heterologously expressed in Xenopus (African clawed frog) oocytes, confirmed that metaflumizone blocks sodium channels by binding selectively to the slow-inactivated state, which is characteristic of the SCBIs. The results confirm that metaflumizone is a novel sodium channel blocker insecticide.

  9. Clinical Profile of Eprosartan: A Different Angiotensin II Receptor Blocker

    PubMed Central

    Blankestijn, P. J; Rupp, H

    2008-01-01

    Rationale. The goal of antihypertensive treatment is to reduce risk of cardiovascular morbidity and mortality. Apart from blood pressure lowering per se, also reducing the activities of the renin-angiotensin system and sympathetic nervous system appears to be important. Angiotensin II receptor blocker drugs (ARBs) have provided a useful class of anti-hypertensive drugs. Eprosartan is a relatively new ARB which is chemically distinct (non-biphenyl, non-tetrazole) from all other ARBs (biphenyl tetrazoles). An analysis has been made on available experimental and clinical data on eprosartan which not only is an effective and well tolerated antihypertensive agent, but also lowers the activities of the renin-angiotensin system and sympathetic nervous system. Experimental and pharmacokinetic studies on eprosartan have shown differences with the other ARBs. The distinct properties of this non-biphenyl, non-tetrazole ARB might be relevant in the effort to reduce cardiovascular risk, also beyond its blood pressure lowering capacity. PMID:18855637

  10. Effects of Beta-blockers on Punished Responding and on Heart Rate in Pigeons

    DTIC Science & Technology

    1986-06-17

    previous behavioral and/or pharmacological history. Heart rate increases during punished responding were decreased by the beta - blockers . Propranolol and...higher doses. With the beta - blockers , larger increases in punished responding were generally associated with greater heart rate decreases.

  11. Beta-Adrenergic blockers as antiarrhythmic and antifibrillatory compounds: an overview.

    PubMed

    Singh, Bramah N

    2005-06-01

    Beta-Adrenergic blockers have a wide spectrum of action for controlling cardiac arrhythmias that is larger than initially thought. Data from the past several decades indicate that, as an antiarrhythmic class, beta-blockers remain among the very few pharmacologic agents that reduce the incidence of sudden cardiac death, prolong survival, and ameliorate symptoms caused by arrhythmias in patients with cardiac disease. As a class of compounds, beta-blockers have a fundamental pharmacologic property that attenuates the effects of competitive adrenergic receptors. However, the net clinical effects of the different beta-receptor blockers may vary quantitatively because of variations in associated intrinsic sympathomimetic agonism and in their intrinsic potency for binding to beta-receptors. These individual compounds also differ in their selectivity for beta(1)- and beta(2)-receptors. Metoprolol is a beta(1)-selective blocker, whereas carvedilol is a nonselective beta(1)- and beta(2)-blocker, an antioxidant, and has a propensity to inhibit alpha(1)-receptors and endothelin. Evolving data from controlled and uncontrolled clinical trials suggest that there are clinically significant differences among this class of drugs. Recent evidence also suggests that the antiarrhythmic actions of certain beta-receptor blockers such as carvedilol and metoprolol extend beyond the ventricular tissue to encompass atrial cells and help maintain sinus rhythm in patients with atrial fibrillation, especially in combination with potent antifibrillatory agents such as amiodarone. This introduction provides a current perspective on these newer developments in the understanding of the antiarrhythmic and antifibrillatory actions of beta-blockers.

  12. Prediction and experimental validation of acute toxicity of beta-blockers in Ceriodaphnia dubia.

    PubMed

    Fraysse, Benoit; Garric, Jeanne

    2005-10-01

    Acute toxicity of beta-adrenoceptor blockers (beta-blockers) was studied with beta-blockers as single compounds or in mixture using the standardized acute 2-d Ceriodaphnia dubia immobility test. The tested compounds were selected according to their selectivity for the beta1-adrenoceptor, with three beta1-selective blockers (acebutolol, atenolol, and metoprolol) and three non-beta1-selective blockers (nadolol, oxprenolol, and propranolol). The acute toxicity (median effective concentration) of the six single compounds ranged from 1.4 mg/L for propranolol to 163 mg/L for nadolol. According to European Union directive 93/67EEC, these values range from toxic for aquatic organisms to nonclassified. The more toxic compounds, propranolol and oxprenolol, are both characterized by a membrane-stabilizing activity, a strong affinity for the beta1-adrenoceptor, and a high octanol-water partition coefficient (log Kow). The property of beta-receptor selectivity seems not to be involved in the observed acute toxicity of the single compounds for C. dubia. Nevertheless, the toxicity of the selected compounds in mixture can be defined according to the beta1-selectivity. Two main joint effects have been detected: An independent action for the beta1-selective blockers, and an additive effect when either the nonselective beta1-selective blockers or the six compounds are tested together. The concentration addition model seems to be appropriate, providing a reasonable worst-case estimation of beta-blocker mixture toxicity for regulatory purposes.

  13. Alpha-adrenergic blocker mediated osteoblastic stem cell differentiation

    SciTech Connect

    Choi, Yoon Jung; Lee, Jue Yeon; Lee, Seung Jin; Chung, Chong-Pyoung; Park, Yoon Jeong

    2011-12-16

    Highlights: Black-Right-Pointing-Pointer Doxazocin directly up-regulated bone metabolism at a low dose. Black-Right-Pointing-Pointer Doxazocin induced osteoblastic stem cell differentiation without affecting cell proliferation. Black-Right-Pointing-Pointer This osteogenic stem cell differentiation is mediated by ERK-signal dependent pathway. -- Abstract: Recent researches have indicated a role for antihypertensive drugs including alpha- or beta-blockers in the prevention of bone loss. Some epidemiological studies reported the protective effects of those agents on fracture risk. However, there is limited information on the association with those agents especially at the mechanism of action. In the present study, we investigated the effects of doxazosin, an alpha-blocker that is clinically used for the treatment of benign prostatic hyperplasia (BPH) along with antihypertensive medication, on the osteogenic stem cell differentiation. We found that doxazosin increased osteogenic differentiation of human mesenchymal stem cells, detected by Alizarin red S staining and calcein. Doxazosin not only induced expression of alkaline phosphatase, type I collagen, osteopontin, and osteocalcin, it also resulted in increased phosphorylation of extracellular signal-regulated kinase (ERK1/2), a MAP kinase involved in osteoblastic differentiation. Treatment with U0126, a MAP kinase inhibitor, significantly blocked doxazosin-induced osteoblastic differentiation. Unrelated to activation of osteogenic differentiation by doxazosin, we found that there were no significant changes in adipogenic differentiation or in the expression of adipose-specific genes, including peroxisome proliferator-activated receptor {gamma}, aP2, or LPL. In this report, we suggest that doxazosin has the ability to increase osteogenic cell differentiation via ERK1/2 activation in osteogenic differentiation of adult stem cells, which supports the protective effects of antihypertensive drug on fracture risk and

  14. Shortening baroreflex delay in hypertrophic cardiomyopathy patients – an unknown effect of β-blockers

    PubMed Central

    Katarzynska-Szymanska, Agnieszka; Ochotny, Romuald; Oko-Sarnowska, Zofia; Wachowiak-Baszynska, Hanna; Krauze, Tomasz; Piskorski, Jaroslaw; Gwizdala, Adrian; Mitkowski, Przemyslaw; Guzik, Przemyslaw

    2013-01-01

    Aims Hypertrophic cardiomyopathy (HCM) is characterized by left ventricular hypertrophy and impaired diastolic and systolic function. Abnormal sympathetic–parasympathetic balance is a potential stimulus for left ventricular hypertrophy in HCM patients. β-Blockers are routinely used in HCM for their strong negative inotropic effect; however, these drugs also influence the sympathetic–parasympathetic balance. This study aimed to determine the autonomic control of the cardiovascular system and the autonomic effects of β-blockers in HCM patients treated or untreated with β-blockers. Methods Among 51 HCM outpatients (18–70 years old; 29 men) there were 19 individuals with no medication and 32 subjects treated with a β-blocker. Fourteen age- and gender-matched (23–70 years old; nine men) healthy volunteers were enrolled in the control group. Continuous, non-invasive finger blood pressure was recorded during supine rest for 30 min. Autonomic regulation of the cardiovascular system was measured by heart rate variability and spontaneous baroreflex function (cross-correlation sequence method). Results The mean pulse interval, time domain and spectral measures of heart rate variability and baroreflex sensitivity were comparable between HCM patients, treated or not with β-blockers, and the control group. However, the delay of the baroreflex was significantly longer in HCM patients who were not treated with β-blockers [2.0 (1.6–2.3) s] in comparison with HCM patients receiving β-blockers [1.4 (1.1–1.8) s; P = 0.0072] or control subjects [1.2 (0.8–1.8) s; P = 0.0025]. This delay did not differ between HCM patients treated with β-blockers and the control group. Conclusions Hypertrophic cardiomyopathy not treated with β-blockers is accompanied by prolonged baroreflex delay. The use of β-blockers normalizes this delay. PMID:23126403

  15. Increased infections with β-blocker use in ischemic stroke, a β2-receptor mediated process?

    PubMed

    Starr, Jordan B; Tirschwell, David L; Becker, Kyra J

    2017-03-03

    Strokes promote immunosuppression, partially from increased sympathetic activity. Altering sympathetic drive with β-blockers has variably been shown to improve stroke outcomes. This study adds to this literature using propensity score matching to limit confounding and by examining the effects of selective and non-selective β-blockers. Prospective data from acute ischemic stroke admissions at a single center from July 2010-June 2015 were analyzed. Outcomes included infection (urinary tract infection [UTI], pneumonia, or bacteremia), discharge modified Rankin Score (mRS), and in-hospital death. Any selective and non-selective β-blocker use during the first 3 days of admission were investigated with propensity score matching. A sensitivity analysis was also performed. This study included 1431 admissions. Any β-blocker use was associated with increased infections (16.4 vs. 10.7%, p = 0.030). Non-selective β-blocker use was associated with increased infections (18.9 vs. 9.7%, p = 0.005) and UTIs (13.0 vs. 5.5%, p = 0.009). Selective β-blocker use was not associated with infection. There were no associations between β-blocker use and in-hospital death or discharge mRS. In the sensitivity analysis, the association between non-selective β-blocker use and urinary tract infections persisted (12.5 vs. 4.2%, p = 0.044). No associations with death or mRS were found. Early β-blocker use after ischemic stroke may increase the risk of infection but did not change disability or mortality risk. The mechanism may be mediated by β2-adrenergic receptor antagonism given the different effects seen with selective versus non-selective β-blocker use.

  16. Uptitration of renin-angiotensin system blocker and beta-blocker therapy in patients hospitalized for heart failure with reduced versus preserved left ventricular ejection fractions.

    PubMed

    Verbrugge, Frederik H; Duchenne, Jürgen; Bertrand, Philippe B; Dupont, Matthias; Tang, W H Wilson; Mullens, Wilfried

    2013-12-15

    In ambulatory patients with heart failure (HF) and reduced ejection fraction (rEF), renin-angiotensin system (RAS) and β-blockers at guideline-recommended target dose reduce all-cause mortality and readmissions. Benefits in HF with preserved ejection fraction (pEF), as well as uptitration after a hospitalization, remain uncertain. This study assesses the impact of RAS- and β-blocker uptitrations in patients with HFrEF versus HFpEF during and immediately after a hospital admission. In consecutive patients (209 HFrEF with left ventricular ejection fraction <40% and 108 HFpEF with left ventricular ejection fraction ≥40%), RAS- and β-blocker dose changes were followed during 6 months after an index HF hospitalization. Patients with a RAS- and β-blocker dose increase of ≥10% of the recommended target dose were compared with patients without uptitration. Patients who received uptitration were significantly younger, with a higher heart rate and better renal function, and received spironolactone more often. Both RAS- and β-blocker uptitrations were associated with significant reductions in the composite end-point of all-cause mortality or HF readmissions in HFrEF (hazard ratio [HR] 0.36, 95% confidence interval [CI] 0.22 to 0.60 and HR 0.51, 95% CI 0.32 to 0.81, respectively). After correction for age, heart rate, blood pressure, renal function, and spironolactone use, this association remained significant for RAS blockers (HR 0.54, 95% CI 0.31 to 0.93, p = 0.027) but not for β-blockers (HR 0.65, 95% CI 0.39 to 1.09, p = 0.101). No benefit of RAS- or β-blocker uptitration was observed in HFpEF. In conclusion, uptitration of neurohumoral blockers after an HF hospitalization is more frequently performed in younger patients with low co-morbidity burden. RAS-blocker uptitration independently predicts clinical outcome in patients with HFrEF but not in those with HFpEF.

  17. Application of first-derivative, ratio derivative spectrophotometry, TLC-densitometry and spectrofluorimetry for the simultaneous determination of telmisartan and hydrochlorothiazide in pharmaceutical dosage forms and plasma.

    PubMed

    Bebawy, Lories I; Abbas, Samah S; Fattah, Laila A; Refaat, Heba H

    2005-10-01

    Four sensitive methods are described for the direct determination of telmisartan (TELM) and hydrochlorothiazide (HCT) in combined dosage forms without prior separation. The first method is a first derivative spectophotometry (1D) using a zero- crossing technique of measurement at 241.6 and 227.6 nm for TELM and HCT, respectively. The second method is the first derivative of ratio spectrophotometry (1DD) where the amplitudes were measured at 242.7 nm for TELM and 274.9 nm for HCT. The third method is based on TLC separation of the two drugs followed by the densitometric measurements of their spots at 295 and 225 nm for TELM and HCT, respectively. The separation was carried out on silica gel 60 F254 using butanol: ammonia 25% (8:2 v/v) as mobile phase. The fourth method is spectrofluorimetric determination of TELM, depending on measuring the native fluorescence of the drug in 1 M sodium hydroxide at lambda excitation 230 nm and emission at 365 nm. The proposed methods were applied successfully for the determination of the two drugs in bulk powder and in pharmaceutical formulations. The spectrofluorimetric method was utilized for the analysis of TELM in human plasma.

  18. Combination therapy with renin-angiotensin-aldosterone system inhibitor telmisartan and serine protease inhibitor camostat mesilate provides further renoprotection in a rat chronic kidney disease model.

    PubMed

    Narita, Yuki; Ueda, Miki; Uchimura, Kohei; Kakizoe, Yutaka; Miyasato, Yoshikazu; Mizumoto, Teruhiko; Morinaga, Jun; Hayata, Manabu; Nakagawa, Terumasa; Adachi, Masataka; Miyoshi, Taku; Sakai, Yoshiki; Kadowaki, Daisuke; Hirata, Sumio; Mukoyama, Masashi; Kitamura, Kenichiro

    2016-02-01

    We previously reported that camostat mesilate (CM) had renoprotective and antihypertensive effects in rat CKD models. In this study, we examined if CM has a distinct renoprotective effect from telmisartan (TE), a renin-angiotensin-aldosterone system (RAS) inhibitor, on the progression of CKD. We evaluated the effect of CM (400 mg/kg/day) and/or TE (10 mg/kg/day) on renal function, oxidative stress, renal fibrosis, and RAS components in the adenine-induced rat CKD model following 5-weeks treatment period. The combination therapy with CM and TE significantly decreased the adenine-induced increase in serum creatinine levels compared with each monotherapy, although all treatment groups showed similar reduction in blood pressure. Similarly, adenine-induced elevation in oxidative stress markers and renal fibrosis markers were significantly reduced by the combination therapy relative to each monotherapy. Furthermore, the effect of the combination therapy on plasma renin activity (PRA) and plasma aldosterone concentration (PAC) was similar to that of TE monotherapy, and CM had no effect on both PRA and PAC, suggesting that CM has a distinct pharmacological property from RAS inhibition. Our findings indicate that CM could be a candidate drug for an add-on therapy for CKD patients who had been treated with RAS inhibitors.

  19. Inhibition of Glutaminyl Cyclases alleviates CCL2-mediated inflammation of non-alcoholic fatty liver disease in mice.

    PubMed

    Cynis, Holger; Kehlen, Astrid; Haegele, Monique; Hoffmann, Torsten; Heiser, Ulrich; Fujii, Masato; Shibazaki, Yuichiro; Yoneyama, Hiroyuki; Schilling, Stephan; Demuth, Hans-Ulrich

    2013-06-01

    Inflammation is an integral part of non-alcoholic fatty liver disease (NAFLD), the most prevalent form of hepatic pathology found in the general population. In this context, recently we have examined the potential role of Glutaminyl Cyclases (QC and isoQC), and their inhibitors, in the maturation of chemokines, for example, monocyte chemoattractant protein 1 (MCP-1, CCL2), to generate their bioactive conformation. Catalysis by isoQC leads to the formation of an N-terminal pyroglutamate residue protecting CCL2 against degradation by aminopeptidases. This is of importance because truncated forms possess a reduced potential to attract immune cells. Since liver inflammation is characterized by the up-regulation of different chemokine pathways, and within this CCL2 is known to be a prominent example, we hypothesised that application of QC/isoQC inhibitors may alleviate liver inflammation by destabilizing CCL2. Therefore, we investigated the role of QC/isoQC inhibition, in comparison with the angiotensin receptor blocker Telmisartan, during development of pathology in a mouse model of non-alcoholic fatty liver disease. Application of a QC/isoQC inhibitor led to a significant reduction in circulating alanine aminotransferase and NAFLD activity score accompanied by an inhibitory effect on hepatocyte ballooning. Further analysis revealed a specific reduction of inflammation by decreasing the number of F4/80-positive macrophages, which is in agreement with the proposed CCL2-related mechanism of action of QC/isoQC inhibitors. Finally, QC/isoQC inhibitor application attenuated liver fibrosis as characterized by reduced collagen deposition in the liver parenchyma. Thus in conclusion, QC/isoQC inhibitors are a promising novel class of anti-non-alcoholic steatohepatitis drugs which have a comparable disease-modifying effect to that of Telmisartan, which is probably mediated via specific interference with a comparable monocyte/macrophage infiltration that occurs under inflammatory

  20. Regulation of intraocular pressure and pupil size by beta-blockers and epinephrine.

    PubMed

    Ohrström, A; Pandolfi, M

    1980-12-01

    The interaction of adrenergic beta-receptor blockers and epinephrine on intraocular pressure and pupil size was investigated in healthy volunteers. Oral (atenolol and propranolol) and local (timolol) beta-blockers were studied. The experiment was carried out under double-blind randomized crossover conditions. The results showed that the combination of oral beta-blockers with topical epinephrine had an additive hypotensive effect on IOP, while timolol and epinephrine eyedrops both reduced the IOP used alone, but combined had an antagonistic effect, resulting in the disappearance of the epinephrine-mediated IOP reduction.

  1. Comparative effects of telmisartan, sitagliptin and metformin alone or in combination on obesity, insulin resistance, and liver and pancreas remodelling in C57BL/6 mice fed on a very high-fat diet.

    PubMed

    Souza-Mello, Vanessa; Gregório, Bianca M; Cardoso-de-Lemos, Fernando S; de Carvalho, Laís; Aguila, Márcia B; Mandarim-de-Lacerda, Carlos A

    2010-06-08

    The aim of the present study was to evaluate the effects of monotherapies and combinations of drugs on insulin sensitivity, adipose tissue morphology, and pancreatic and hepatic remodelling in C57BL/6 mice fed on a very HF (high-fat) diet. Male C57BL/6 mice were fed on an HF (60% lipids) diet or SC (standard chow; 10% lipids) diet for 10 weeks, after which time the following drug treatments began: HF-T (HF diet treated with telmisartan; 5.2 mg x kg-1 of body weight x day-1), HF-S (HF diet treated with sitagliptin; 1.08 g x kg-1 of body weight.day-1), HF-M (HF diet treated with metformin; 310.0 mg x kg-1 of body weight x day-1), HF-TM (HF diet treated with telmisartan+metformin), HF-TS (HF diet treated with telmisartan+sitagliptin) and HF-SM (HF diet treated with sitagliptin+metformin). Treated groups also had free access to the HF diet, and treatments lasted for 6 weeks. Morphometry, stereological tools, immunostaining, ELISA, Western blot analysis and electron microscopy were used. The HF diet yielded an overweight phenotype, an increase in oral glucose intolerance, hyperinsulinaemia, hypertrophied islets and adipocytes, stage 2 steatosis (>33%), and reduced liver PPAR-alpha (peroxisome-proliferator-activated receptor-alpha) and GLUT-2 (glucose transporter-2) levels, concomitant with enhanced SREBP-1 (sterol-regulatory-element-binding protein-1) expression (P<0.0001). Conversely, all drug treatments resulted in significant weight loss, a reversal of insulin resistance, islet and adipocyte hypertrophy, and alleviated hepatic steatosis. Only the HF-T and HF-TS groups had body weights similar to the SC group at the end of the experiment, and the latter treatment reversed hepatic steatosis. Increased PPAR-alpha immunostaining in parallel with higher GLUT-2 and reduced SREBP-1 expression may explain the favourable hepatic outcomes. Restoration of adipocyte size was consistent with higher adiponectin levels and lower TNF-alpha (tumour necrosis factor-alpha) levels (P<0

  2. Safety and tolerability of beta-blockers: prejudices & reality.

    PubMed

    Erdmann, Erland

    2010-01-01

    Beta-blockers (BB) substantially improve survival in chronic heart failure and after myocardial infarction. However, concern about side-effects may deter clinicians from prescribing these life-saving drugs. In reality, absolute contraindications are rare. Only 3-5% of patients are intolerant because of hypotension or bradycardia. Data from randomized controlled trials and retrospective studies show that most patients eligible to receive BB tolerate them well. BB are not contraindicated in chronic obstructive pulmonary disease (COPD); in fact, these patients also benefit because of their high cardiovascular risk. In patients with COPD, as in the elderly, BB should be started at a low dose and uptitrated slowly. Monitoring of lung function during initiation is important, as undiagnosed coexistent asthma could be revealed. When patients are unaware of the drug in use, erectile dysfunction (ED) is reported no more often with BB than with any other drug prescribed for heart failure or hypertension. However, when patients are aware of the potential side-effects of BB, the resultant anxiety may cause ED. Patients should be reassured that BB prolong life and in the great majority are not the cause of ED, which may rather be related to the underlying disease (diabetes, hypertension, and atherosclerosis).

  3. Free radical destruction of beta-blockers in aqueous solution.

    PubMed

    Song, Weihua; Cooper, William J; Mezyk, Stephen P; Greaves, John; Peake, Barrie M

    2008-02-15

    Many pharmaceutical compounds and metabolites are currently found in surface and ground waters which indicates their ineffective removal by conventional water treatment technologies. Advanced oxidation/reduction processes (AO/ RPs) are alternatives to traditional water treatment, which utilize free radical reactions to directly degrade chemical contaminants. This study reports the absolute rate constants for reaction of three beta-blockers (atenolol, metoprolol, and propranolol) with the two major AO/RP radicals; the hydroxyl radical (*OH) and hydrated electron ((e-)aq). The bimolecular reaction rate constants for *OH are (7.05 +/- 0.27) x 10(9), (8.39 +/- 0.06) x 10(9), and (1.07 +/- 0.02) x 10(10), and for (e-)aq they are (5.91 +/- 0.21) x 10(8), (1.73 +/- 0.03) x 10(8), and (1.26 +/- 0.02) x 10(10), respectively. Transient spectra were observed for the intermediate radicals produced by hydroxyl radical reactions. In addition, preliminary degradation mechanisms and major products were elucidated using 60Co gamma-irradiation and LC-MS. These data are required for both evaluating the potential use of AO/RPs for the destruction of these compounds and for studies of their fate and transport in surface waters where radical chemistry may be important in assessing their lifetime.

  4. The PRoFESS trial: future impact on secondary stroke prevention.

    PubMed

    Diener, Hans-Christoph

    2007-09-01

    Patients with transient ischemic attack and ischemic stroke have a high risk of recurrent stroke and death. While aspirin is accepted as standard therapy in these patients, recent trials demonstrate that a combination of aspirin and extended-release dipyridamole or clopidogrel is superior to aspirin monotherapy. Blockade of the renin-angiotensin system with angiotensin-converting enzyme inhibitors or angiotensin-receptor blockers may also reduce recurrent stroke. The ongoing Prevention Regimen for Effectively Avoiding Second Strokes (PRoFESS) trial is designed to evaluate whether extended-release dipyridamole plus aspirin compared with clopidogrel, and whether telmisartan in addition to usual care, in individuals after a stroke, will reduce the risk of further strokes. PRoFESS is a multicenter, randomized, double-blind trial involving 695 sites from 35 countries or regions. The primary outcome for the trial is recurrent stroke, using a time-to-event analysis. Safety is evaluated by assessing the risk of major hemorrhagic and other serious adverse events. With over 20,000 patients randomized, and utilizing a 2 x 2 factorial design, PRoFESS is the largest stroke trial to investigate the prevention of recurrent stroke.

  5. Involvement of Renin-Angiotensin System in Retinopathy of Prematurity - A Possible Target for Therapeutic Intervention

    PubMed Central

    Nath, Madhu; Chandra, Parijat; Halder, Nabanita; Singh, Baskar; Deorari, Ashok Kumar; Kumar, Atul; Azad, Rajvardhan; Velpandian, Thirumurthy

    2016-01-01

    Objective Examining the Retinal Renin Angiotensin System (RRAS) in the ROP neonates and analyzing the possibility of modulating the RRAS to prevent the progression in Oxygen Induced Retinopathy (OIR) model. Method Vitreous of ROP patients (n = 44, median age 5.5 months) was quantified for RRAS components, VEGF, HIF-1α and compared with age matched control. The involvement of RRAS in ROP was tested in the rat model of OIR and compared with normoxia. Expressions of RAS components, VEGF and HIF-1α in retina were analyzed using qPCR and retinal structure and function was also analyzed. Effect of Angiotensin Converting Enzyme Inhibitor (ACEI) and Angiotensin Receptor Blocker (ARB) was evaluated and compared with Bevacizumab which served as a positive control. Drug penetration into retina was confirmed by liquid chromatography coupled ESI-tandem mass spectroscopy (LC-MS/MS). Results Multifold increase in the expression of RAS components in human vitreous and rat retina showed their involvement in ROP. ERG & fundus studies in OIR revealed the altered function of retina and were successfully prevented by ARB (telmisartan), ACEI (lisinopril) and bevacizumab. Retinal analysis revealed the presence of ACEI and ARB in their therapeutic levels. Conclusion This study for the first time demonstrates the upregulated level of RAS components in human ROP vitreous and further that the pharmacological intervention in RRAS can functionally and structurally preserve retina against the progression of ROP in the OIR model. PMID:28033392

  6. Modifiable lifestyle and social factors affect chronic kidney disease in high-risk individuals with type 2 diabetes mellitus.

    PubMed

    Dunkler, Daniela; Kohl, Maria; Heinze, Georg; Teo, Koon K; Rosengren, Annika; Pogue, Janice; Gao, Peggy; Gerstein, Hertzel; Yusuf, Salim; Oberbauer, Rainer; Mann, Johannes F E

    2015-04-01

    This observational study examined the association between modifiable lifestyle and social factors on the incidence and progression of early chronic kidney disease (CKD) among those with type 2 diabetes. All 6972 people from the Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial (ONTARGET) with diabetes but without macroalbuminuria were studied. CKD progression was defined as decline in GFR of more than 5% per year, progression to end-stage renal disease, microalbuminuria, or macroalbuminuria at 5.5 years. Lifestyle/social factors included tobacco and alcohol use, physical activity, stress, financial worries, the size of the social network and education. Adjustments were made for known risks such as age, diabetes duration, GFR, albuminuria, gender, body mass index, blood pressure, fasting plasma glucose, and angiotensin-converting enzyme inhibitors/angiotensin-receptor blockers use. Competing risk of death was considered. At study end, 31% developed CKD and 15% had died. The social network score (SNS) was a significant independent risk factor of CKD and death, reducing the risk by 11 and 22% when comparing the third to the first tertile of the SNS (odds ratios of CKD 0.89 and death 0.78). Education showed a significant association with CKD but stress and financial worries did not. Those with moderate alcohol consumption had a significantly decreased CKD risk compared with nonusers. Regular physical activity significantly decreased the risk of CKD. Thus, lifestyle is a determinant of kidney health in people at high cardiovascular risk with diabetes.

  7. Azilsartan, aliskiren, and combination antihypertensives utilizing renin-angiotensin-aldosterone system antagonists.

    PubMed

    Lanier, Gregg; Sankholkar, Kedar; Aronow, Wilbert S

    2014-01-01

    Health care providers managing hypertension (HTN) have a large selection of pharmacologic agents to choose from, including several different classes of drugs and many similar drugs within each class. Antagonism of the renin-angiotensin-aldosterone system has been shown to be very effective for HTN, especially in patients with cardiovascular disease, diabetes, and heart failure. Within this group, there have been 2 new agents recently introduced to the US market and approved by the Food and Drug Administration. It is important for the HTN specialist to be familiar with the merits of these 2 drugs: the angiotensin receptor blocker Edarbi (azilsartan) and the renin inhibitor Tekturna (aliskiren). Additionally, there have been several new, fixed-dose combination antihypertensives introduced to the market since 2006 that use a renin-angiotensin-aldosterone antagonist. Seven of these combine 2 drugs together in a single pill: Edarbyclor (azilsartan/chlorthalidone), Exforge (amlodipine/valsartan), Azor (olmesartan/amlodipine), Twynsta (amlodipine/telmisartan), Tekturna HCT [aliskiren/hydrochlorothiazide (HCTZ)], Valturna (aliskiren/valsartan), Tekamlo (aliskiren/amlodipine). Three triple-drug combination medications have also been introduced recently: Exforge HCT (amlodipine/valsartan/HCTZ), Tribenzor (olmesartan/amlodipine/HCTZ), and Amturnide (aliskiren/amlodipine/hydrocholorothiazide). This review will summarize the trial data and important pharmacologic merits of these 2 new renin-angiotensin-aldosterone antagonists and the advantages of initiating treatment with one of the new fixed-dose, combination drugs approved over the last 5 years.

  8. Beta-blockers in the treatment of neurological and psychiatric disorders.

    PubMed

    Peet, M; Yates, R A

    1981-09-01

    Beta-blockers, originally introduced into clinical practice for the treatment of cardiovascular disorders, are being increasingly advocated in the treatment of diverse neurological and psychiatric conditions. Thus, propranolol and certain other beta-blockers have been shown to be effective, and may be the drugs of choice, in the treatment of benign essential tremor and the prevention of recurrent migraine attacks. These drugs also have a useful role to play in the treatment of anxiety and alcohol withdrawal states, although beta-blockers have not come into general use in these conditions. The action of propranolol and related drugs in these neurological and psychiatric conditions is generally considered to be mediated by blockade of peripheral beta-adrenergic receptors, although other effects, either central or peripheral, may also be involved. The use of beta-blockers in the treatment of psychosis remains controversial. Current evidence does not support the use of propranolol in schizophrenia, but further studies in mania are warranted.

  9. The current status of beta blockers' use in the management of hypertension.

    PubMed

    Akbar, Shahid; Alorainy, Mohammad S

    2014-11-01

    The invention of beta (β)-blockers culminated in a new era in the treatment of cardiovascular diseases (CD), and changed the course of pharmacology research for years to come. Since the introduction of propranolol into clinical practice in 1964, β-blockers enjoyed a special place in the clinicians' armamentarium against CDs, especially for patients with ischemic heart diseases, and are still one of the most extensively used therapeutic drugs in both cardiac and non-cardiac ailments. Current uses of β-blockers in CDs include ischemic heart diseases, hypertension, cardiac arrhythmias, and heart failure. Other substantial non-cardiac uses include glaucoma, migraine, situational anxiety, benign essential tremors, and cardiac symptoms of thyrotoxicosis. This review covers some of the evolutionary changes of clinical uses of β-blockers, the rationale for their use, some recent controversies surrounding their use for treatment of hypertension, and advantages of newer additions to the group. 

  10. Modeling of the Binding of Peptide Blockers to Voltage-Gated Potassium Channels: Approaches and Evidence

    PubMed Central

    Novoseletsky, V. N.; Volyntseva, A. D.; Shaitan, K. V.; Kirpichnikov, M. P.; Feofanov, A. V.

    2016-01-01

    Modeling of the structure of voltage-gated potassium (KV) channels bound to peptide blockers aims to identify the key amino acid residues dictating affinity and provide insights into the toxin-channel interface. Computational approaches open up possibilities for in silico rational design of selective blockers, new molecular tools to study the cellular distribution and functional roles of potassium channels. It is anticipated that optimized blockers will advance the development of drugs that reduce over activation of potassium channels and attenuate the associated malfunction. Starting with an overview of the recent advances in computational simulation strategies to predict the bound state orientations of peptide pore blockers relative to KV-channels, we go on to review algorithms for the analysis of intermolecular interactions, and then take a look at the results of their application. PMID:27437138

  11. A meta-analysis of the effects of β-adrenergic blockers in chronic heart failure.

    PubMed

    Zhang, Xiaojian; Shen, Chengwu; Zhai, Shujun; Liu, Yukun; Yue, Wen-Wei; Han, Li

    2016-10-01

    Adrenergic β-blockers are drugs that bind to, but do not activate β-adrenergic receptors. Instead they block the actions of β-adrenergic agonists and are used for the treatment of various diseases such as cardiac arrhythmias, angina pectoris, myocardial infarction, hypertension, headache, migraines, stress, anxiety, prostate cancer, and heart failure. Several meta-analysis studies have shown that β-blockers improve the heart function and reduce the risks of cardiovascular events, rate of mortality, and sudden death through chronic heart failure (CHF) of patients. The present study identified results from recent meta-analyses of β-adrenergic blockers and their usefulness in CHF. Databases including Medline/Embase/Cochrane Central Register of Controlled Trials (CENTRAL), and PubMed were searched for the periods May, 1985 to March, 2011 and June, 2013 to August, 2015, and a number of studies identified. Results of those studies showed that use of β-blockers was associated with decreased sudden cardiac death in patients with heart failure. However, contradictory results have also been reported. The present meta-analysis aimed to determine the efficacy of β-blockers on mortality and morbidity in patients with heart failure. The results showed that mortality was significantly reduced by β-blocker treatment prior to the surgery of heart failure patients. The results from the meta-analysis studies showed that β-blocker treatment in heart failure patients correlated with a significant decrease in long-term mortality, even in patients that meet one or more exclusion criteria of the MERIT-HF study. In summary, the findings of the current meta-analysis revealed beneficial effects different β-blockers have on patients with heart failure or related heart disease.

  12. Effects of Beta-Blocker Withdrawal in Acute Decompensated Heart Failure

    PubMed Central

    Prins, Kurt W.; Neill, John M.; Tyler, John O.; Eckman, Peter M.; Duval, Sue

    2015-01-01

    OBJECTIVES This study sought to evaluate the effects of beta-blocker withdrawal in acute decompensated heart failure (ADHF). BACKGROUND Published reports showed trends for either no harm or increased risk of in-hospital mortality, short-term mortality, and rehospitalization rates in patients admitted for ADHF that discontinued beta-blockers; however, a comprehensive analysis has not been conducted. METHODS Relevant studies from January 2000 through January 2015 were identified in the PubMed, EMBASE, and COCHRANE electronic databases. Where appropriate data were available, weighted relative risks were estimated using random-effects meta-analysis techniques. RESULTS Five observational studies and 1 randomized clinical trial (n = 2,704 patients who continued beta-blocker therapy and n = 439 patients who discontinued beta-blocker therapy) that reported the short-term effects of beta-blocker withdrawal in ADHF were included in the analyses. In 2 studies, beta-blocker withdrawal significantly increased risk of in-hospital mortality (risk ratio: 3.72; 95% confidence interval [CI]: 1.51 to 9.14). Short-term mortality (relative risk: 1.61; 95% CI: 1.04 to 2.49; 4 studies) and combined short-term rehospitalization or death (relative risk: 1.59; 95% CI: 1.03 to 2.45; 4 studies) were also significantly increased. CONCLUSIONS Discontinuation of beta-blockers in patients admitted with ADHF was associated with significantly increased in-hospital mortality, short-term mortality, and the combined endpoint of short-term rehospitalization or mortality. These data suggest beta-blockers should be continued in ADHF patients if their clinical picture allows. PMID:26251094

  13. Dihydropyridine type calcium channel blocker-induced turbid dialysate in patients undergoing peritoneal dialysis.

    PubMed

    Yoshimoto, K; Saima, S; Nakamura, Y; Nakayama, M; Kubo, H; Kawaguchi, Y; Nishitani, H; Nakamura, Y; Yasui, A; Yokoyama, K; Kuriyama, S; Shirai, D; Kugiyama, A; Hayano, K; Fukui, H; Horigome, I; Amagasaki, Y; Tsubakihara, Y; Kamekawa, T; Ando, R; Tomura, S; Okamoto, R; Miwa, S; Koyama, T; Echizen, H

    1998-08-01

    We previously reported that manidipine, a new dihydropyridine type calcium channel blocker, produced chylous peritoneal dialysate being visually indistinguishable from infective peritonitis in 5 patients undergoing continuous ambulatory peritoneal dialysis (CAPD) [Yoshimoto et al. 1993]. To study whether such an adverse drug reaction would also be elicited by other commonly prescribed calcium channel blockers in CAPD patients, we have conducted postal inquiry to 15 collaborating hospitals and an institutional survey in International Medical Center of Japan as to the possible occurrence of calcium channel blocker-associated non-infective, turbid peritoneal dialysate in CAPD patients. Our diagnostic criteria for drug-induced turbidity of dialysate as a) it developed within 48 h after the administration of a newly introduced calcium channel blocker to the therapeutic regimen, b) absence of clinical symptoms of peritoneal inflammation (i.e., pyrexia, abdominal pain, nausea or vomiting), c) the fluid containing normal leukocyte counts and being negative for bacterial and fungal culture of the fluid, and d) it disappeared shortly after the withdrawal of the assumed causative agent. Results showed that 19 out of 251 CAPD patients given one of the calcium channel blockers developed non-infective turbid peritoneal dialysis that fulfilled all the above criteria. Four calcium channel blockers were suspected to be associated with the events: benidipine [2 out of 2 (100%) patients given the drug], manidipine [15 out of 36 (42%) patients], nisoldipine [1 out of 11 (9%) patients] and nifedipine [1 out of 159 (0.6%)] in descending order of frequency. None of the patients who received nicardipine, nilvadipine, nitrendipine, barnidipine and diltiazem (25, 7, 2, 1 and 8 patients, respectively) exhibited turbid dialysate. In conclusion, we consider that certain dihydropyridine type calcium channel blockers would cause turbid peritoneal dialysate being similar to that observed in

  14. Ziconotide: neuronal calcium channel blocker for treating severe chronic pain.

    PubMed

    Miljanich, G P

    2004-12-01

    Ziconotide (PRIALT) is a neuroactive peptide in the final stages of clinical development as a novel non-opioid treatment for severe chronic pain. It is the synthetic equivalent of omega-MVIIA, a component of the venom of the marine snail, Conus magus. The mechanism of action underlying ziconotide's therapeutic profile derives from its potent and selective blockade of neuronal N-type voltage-sensitive calcium channels (N-VSCCs). Direct blockade of N-VSCCs inhibits the activity of a subset of neurons, including pain-sensing primary nociceptors. This mechanism of action distinguishes ziconotide from all other analgesics, including opioid analgesics. In fact, ziconotide is potently anti-nociceptive in animal models of pain in which morphine exhibits poor anti-nociceptive activity. Moreover, in contrast to opiates, tolerance to ziconotide is not observed. Clinical studies of ziconotide in more than 2,000 patients reveal important correlations to ziconotide's non-clinical pharmacology. For example, ziconotide provides significant pain relief to severe chronic pain sufferers who have failed to obtain relief from opiate therapy and no evidence of tolerance to ziconotide is seen in these patients. Contingent on regulatory approval, ziconotide will be the first in a new class of neurological drugs: the N-type calcium channel blockers, or NCCBs. Its novel mechanism of action as a non-opioid analgesic suggests ziconotide has the potential to play a valuable role in treatment regimens for severe chronic pain. If approved for clinical use, ziconotide will further validate the neuroactive venom peptides as a source of new and useful medicines.

  15. Attenuation of thermal nociception and hyperalgesia by VR1 blockers

    PubMed Central

    García-Martínez, Carolina; Humet, Marc; Planells-Cases, Rosa; Gomis, Ana; Caprini, Marco; Viana, Felix; De la Peña, Elvira; Sanchez-Baeza, Francisco; Carbonell, Teresa; De Felipe, Carmen; Pérez-Payá, Enrique; Belmonte, Carlos; Messeguer, Angel; Ferrer-Montiel, Antonio

    2002-01-01

    Vanilloid receptor subunit 1 (VR1) appears to play a critical role in the transduction of noxious chemical and thermal stimuli by sensory nerve endings in peripheral tissues. Thus, VR1 antagonists are useful compounds to unravel the contribution of this receptor to pain perception, as well as to induce analgesia. We have used a combinatorial approach to identify new, nonpeptidic channel blockers of VR1. Screening of a library of trimers of N-alkylglycines resulted in the identification of two molecules referred to as DD161515 {N-[2-(2-(N-methylpyrrolidinyl)ethyl]glycyl]-[N-[2,4-dichlorophenethyl]glycyl]-N-(2,4-dichlorophenethyl)glycinamide} and DD191515 {[N-[3-(N,N-diethylamino)propyl]glycyl]-[N-[2,4-dichlorophenethyl]glycyl]-N-(2,4-dichlorophenethyl)glycinamide} that selectively block VR1 channel activity with micromolar efficacy, rivaling that characteristic of vanilloid-related inhibitors. These compounds appear to be noncompetitive VR1 antagonists that recognize a receptor site distinct from that of capsaicin. Intraperitoneal administration of both trialkylglycines into mice significantly attenuated thermal nociception as measured in the hot plate test. It is noteworthy that these compounds eliminated pain and neurogenic inflammation evoked by intradermal injection of capsaicin into the animal hindpaw, as well as the thermal hyperalgesia induced by tissue irritation with nitrogen mustard. In contrast, responses to mechanical stimuli were not modified by either compound. Modulation of sensory nerve fibers excitability appears to underlie the peptoid analgesic activity. Collectively, these results indicate that blockade of VR1 activity attenuates chemical and thermal nociception and hyperalgesia, supporting the tenet that this ionotropic receptor contributes to chemical and thermal sensitivity and pain perception in vivo. These trialkylglycine-based, noncompetitive VR1 antagonists may likely be developed into analgesics to treat inflammatory pain. PMID:11854530

  16. Angiotensin II Receptor Blocker Neprilysin Inhibitor (ARNI): New Avenues in Cardiovascular Therapy.

    PubMed

    Volpe, M; Tocci, G; Battistoni, A; Rubattu, S

    2015-09-01

    The burden of cardiovascular disease (CVD) is continuously and progressively raising worldwide. Essential hypertension is a major driver of cardiovascular events, including coronary artery disease, myocardial infarction, ischemic stroke and congestive heart failure. This latter may represent the final common pathway of different cardiovascular diseases, and it is often mediated by progressive uncontrolled hypertension. Despite solid advantages derived from effective and sustained blood pressure control, and the widespread availability of effective antihypertensive medications, the vast majority of the more than 1 billion hypertensive patients worldwide continue to have uncontrolled hypertension. Among various factors that may be involved, the abnormal activation of neurohormonal systems is one consistent feature throughout the continuum of cardiovascular diseases. These systems may initiate biologically meaningful "injury responses". However, their sustained chronic overactivity often may induce and maintain the progression from hypertension towards congestive heart failure. The renin-angiotensin-aldosteron system, the sympathetic nervous system and the endothelin system are major neurohormonal stressor systems that are not only able to elevate blood pressure levels by retaining water and sodium, but also to play a role in the pathophysiology of cardiovascular diseases. More recently, the angiotensin receptor neprilysin inhibitor (ARNI) represents a favourable approach to inhibit neutral endopeptidase (NEP) and suppress the RAAS via blockade of the AT1 receptors, without the increased risk of angioedema. LCZ696, the first-in-class ARNI, has already demonstrated BP lowering efficacy in patients with hypertension, in particular with respect to systolic blood pressure levels, improved cardiac biomarkers, cardiac remodelling and prognosis in patients with heart failure. This manuscript will briefly overview the main pathophysiological and therapeutic aspects of ARNI in

  17. Renin-angiotensin system blockers regulate the metabolism of isolated fat cells in vitro

    PubMed Central

    Caminhotto, R de O.; Sertié, R.A.L.; Andreotti, S.; Campaãa, A.B.; Lima, F.B.

    2016-01-01

    Due to the presence of the renin-angiotensin system (RAS) in tissues and its specific influence on white adipose tissue, fat cells are possible targets of pharmacological RAS blockers commonly used as anti-hypertensive drugs. In the present study, we investigated the effects of different RAS blockers on fat cell metabolism, more specifically on lipolysis, lipogenesis and oxidation of energy substrates. Isolated primary adipocytes were incubated with different RAS blockers (aliskiren, captopril and losartan) in vitro for 24 h and lipolysis, lipogenesis and glucose oxidation capacities were determined in dose-response assays to a β-adrenergic agonist and to insulin. Although no change was found in lipolytic capacity, the RAS blockers modulated lipogenesis and glucose oxidation in a different way. While captopril decreased insulin-stimulated lipogenesis (−19% of maximal response and −60% of insulin responsiveness) due to reduced glucose derived glycerol synthesis (−19% of maximal response and 64% of insulin responsiveness), aliskiren increased insulin-stimulated glucose oxidation (+49% of maximal response and +292% of insulin responsiveness) in fat cells. Our experiments demonstrate that RAS blockers can differentially induce metabolic alterations in adipocyte metabolism, characterized by a reduction in lipogenic responsiveness or an increase in glucose oxidation. The impact of RAS blockers on adipocyte metabolism may have beneficial implications on metabolic disorders during their therapeutic use in hypertensive patients. PMID:27487419

  18. Hypotension induced by the concomitant use of a calcium-channel blocker and clarithromycin

    PubMed Central

    Takeuchi, Sayako; Tsujimoto, Toshihide

    2017-01-01

    In the elderly, calcium-channel blockers are the first-line treatment for hypertension, and macrolides are commonly prescribed antibiotics. Here we report a 78-year-old man taking nifedipine, diltiazem and carvedilol who presented with persistent hypotension and bradycardia after clarithromycin was prescribed. He was diagnosed with drug-induced hypotension and treated with fluid resuscitation and vasoactive agents. His symptoms gradually improved. He was transferred out of the intensive care unit 3 days after hospitalisation. Combining calcium-channel blockers and clarithromycin can cause vasodilatory hypotension. The concomitant use of calcium-channel blockers and macrolide antibiotics increases the levels of calcium-channel blockers in the blood as they are metabolised by cytochrome P450 3A4 (CYP3A4), which is inhibited by macrolide antibiotics. Moreover, the addition of another calcium-channel blocker and a β blocker can lower cardiac output due to bradycardia and worsen hypotension. Therefore, it is important to consider drug interactions when the cause of hypotension is unknown. PMID:28069789

  19. Nebivolol versus other beta blockers in patients with hypertension and erectile dysfunction

    PubMed Central

    Sharp, Randall P.; Gales, Barry J.

    2017-01-01

    Erectile dysfunction (ED) impacts over 100 million men worldwide and occurs at a higher incidence in men with hypertension. Beta blockers are one of several antihypertensive drug classes associated with ED. Nebivolol is a beta blocker with vasodilating properties mediated through endothelial release of nitric oxide which facilitates penile erection. Thus, nebivolol may offer an advantage over other beta blockers in the patient with hypertension and ED. A literature search comparing nebivolol with other beta blockers identified four European studies of limited duration, with the longest study being 28 weeks. Survey scores for erectile function showed significant improvement in erectile function with nebivolol in two of the studies, while the other two studies showed erectile function did not significantly worsen with nebivolol as compared with other beta blocker agents. One study showed improved erectile function scores, possibly due to the presence of a Hawthorne effect. Based on this small sample of studies, nebivolol may be of use in the patient with or at risk of developing ED, when a practitioner specifically wants to use a beta blocker as add-on antihypertensive treatment. PMID:28203288

  20. Effects of captopril, telmisartan and bardoxolone methyl (CDDO-Me) in ischemia-reperfusion-induced acute kidney injury in rats: an experimental comparative study.

    PubMed

    Kocak, Cengiz; Kocak, Fatma Emel; Akcilar, Raziye; Bayat, Zeynep; Aras, Bekir; Metineren, Mehmet Huseyin; Yucel, Mehmet; Simsek, Hasan

    2016-02-01

    Renal ischemia-reperfusion (IR) injury is one of the most common causes of acute kidney injury. This study investigated the effects of captopril (CAP), telmisartan (TEL) and bardoxolone methyl (BM) in animals with renal IR injury. Adult male Wistar-Albino rats were divided into six groups: control, vehicle, IR, IR with CAP, IR with TEL and IR with BM. Before IR was induced, drugs were administered by oral gavage. After a 60-min ischemia and a 120-min reperfusion period, bilateral nephrectomies were performed. Serum urea, creatinine, neutrophil gelatinase-associated lipocalin (NGAL) levels, tissue total oxidant status (TOS), total antioxidant status (TAS), total thiol (TT), asymmetric dimethylarginine (ADMA) levels, superoxide dismutase (SOD) activity and glutathione peroxidase (GSH-Px) activity were measured. Tissue mRNA expression levels of peroxisome proliferator-activated receptor-ɣ (PPAR-ɣ), nuclear factor erythroid 2-related factor 2 (Nrf2) and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) were analyzed. In addition, renal tissues were evaluated histopathologically and immunohistochemically. All tested drugs reduced renal damage, apoptosis, urea, creatinine, NGAL, TOS, nitric oxide (NO) and ADMA levels, NF-κB, inducible nitric oxide synthase (iNOS) and endothelin-1 (ET-1) expressions (P < 0.001). All tested drugs increased SOD activity, GSH-Px activity, TAS levels, TT levels, endothelial nitric oxide synthase (eNOS) expression, dimethylarginine dimethylaminohydrolases (DDAHs) expression, Nrf2 expression and PPAR-ɣ expression (P < 0.001, P < 0.003). These results suggest that CAP, TEL and BM pretreatment could reduce renal IR injury via anti-inflammatory, antioxidant and anti-apoptotic effects.

  1. Roles of MgO release from polyethylene glycol 6000-based solid dispersions on microenvironmental pH, enhanced dissolution and reduced gastrointestinal damage of telmisartan.

    PubMed

    Tran, Phuong Ha-Lien; Tran, Thao Truong-Dinh; Lee, Seung Aeon; Nho, Vo Hong; Chi, Sang-Cheol; Lee, Beom-Jin

    2011-05-01

    The roles of magnesium oxide (MgO) release from solid dispersions (SDs) in simulated gastric fluid (SGF), simulated intestinal fluid (SIF) and water were investigated to elucidate the enhanced dissolution and reduced intestinal damages of telmisartan as a model drug. The polyethylene glycol 6000 (PEG 6000) was used to prepare the SDs. Three SDs were prepared: SD1 (PEG, MgO, TEL), SD2 (PEG 6000, TEL), SD3 (MgO, TEL). The physical mixture (PM) consisting of SD2 and MgO was also prepared. A binary SD without MgO (SD2) was also prepared for comparison in microenvironmental pH (pH(M)) modulation. The faster MgO released, the less control of pH(M) and the less enhanced dissolution of TEL were in consequences. SD3 increased dissolution in SIF and water (about 67%). Interestingly, ternary SD1 showed almost complete dissolution in all three media but dissolution of PM was the lowest due to the fast release of MgO and poor modulation of pH(M). MgO did not change the drug crystallinity but did have a strong molecular interaction with the drug. Additionally, the SD3-bearing tablet quickly increased pH(M) but then gradually decreased due to faster release of MgO while the SD1-bearing tablet gradually increased pH(M) at all fractional dimensions of the tablet by the MgO slowly released. The pH(M) of PM-bearing tablets was not varied as a function of time. Thus, the MgO-bearing SD1 also minimized gastrointestinal tissue damage caused by the model drug.

  2. Statin, Calcium Channel Blocker and Beta Blocker Therapy May Decrease the Incidence of Tuberculosis Infection in Elderly Taiwanese Patients with Type 2 Diabetes

    PubMed Central

    Lee, Mei-Yueh; Lin, Kun-Der; Hsu, Wei-Hao; Chang, Hsiu-Ling; Yang, Yi-Hsin; Hsiao, Pi-Jung; Shin, Shyi-Jang

    2015-01-01

    Background: It is well known that diabetes mellitus impairs immunity and therefore is an independent risk factor for tuberculosis. However, the influence of associated metabolic factors, such as hypertension, dyslipidemia and gout has yet to be confirmed. This study aimed to investigate whether the strong association between tuberculosis and diabetes mellitus is independent from the influence of hypertension and dyslipidemia, and its treatment in elderly Taiwanese patients. Methods: A total of 27,958 patients aged more than 65 years were identified from the National Health Insurance Research Database (NIHRD) in 1997 and were followed from 1998 to 2009. The demographic characteristics between the patients with and without diabetes were analyzed using the χ2 test. A total of 13,981 patients with type 2 diabetes were included in this study. Cox proportional hazard regression models were used to determine the independent effects of diabetes on the risk of tuberculosis. Results: After adjusting for age, sex, other co-morbidities and medications, calcium channel blocker, beta blocker and statin users had a lower independent association, with risk ratios of 0.76 (95% CI, 0.58–0.98), 0.72 (95% CI, 0.58–0.91) and 0.76 (95% CI, 0.60–0.97), respectively. Conclusion: Calcium channel blocker, beta blocker and statin therapy may decrease the incidence of tuberculosis infection in elderly Taiwanese patients with type 2 diabetes. PMID:25993300

  3. β blockers and mortality after myocardial infarction in patients without heart failure: multicentre prospective cohort study

    PubMed Central

    Riant, Elisabeth; Aissoui, Nadia; Soria, Angèle; Ducrocq, Gregory; Coste, Pierre; Cottin, Yves; Aupetit, Jean François; Bonnefoy, Eric; Blanchard, Didier; Cattan, Simon; Steg, Gabriel; Schiele, François; Ferrières, Jean; Juillière, Yves; Simon, Tabassome; Danchin, Nicolas

    2016-01-01

    Objective To assess the association between early and prolonged β blocker treatment and mortality after acute myocardial infarction. Design Multicentre prospective cohort study. Setting Nationwide French registry of Acute ST- and non-ST-elevation Myocardial Infarction (FAST-MI) (at 223 centres) at the end of 2005. Participants 2679 consecutive patients with acute myocardial infarction and without heart failure or left ventricular dysfunction. Main outcome measures Mortality was assessed at 30 days in relation to early use of β blockers (≤48 hours of admission), at one year in relation to discharge prescription, and at five years in relation to one year use. Results β blockers were used early in 77% (2050/2679) of patients, were prescribed at discharge in 80% (1783/2217), and were still being used in 89% (1230/1383) of those alive at one year. Thirty day mortality was lower in patients taking early β blockers (adjusted hazard ratio 0.46, 95% confidence interval 0.26 to 0.82), whereas the hazard ratio for one year mortality associated with β blockers at discharge was 0.77 (0.46 to 1.30). Persistence of β blockers at one year was not associated with lower five year mortality (hazard ratio 1.19, 0.65 to 2.18). In contrast, five year mortality was lower in patients continuing statins at one year (hazard ratio 0.42, 0.25 to 0.72) compared with those discontinuing statins. Propensity score and sensitivity analyses showed consistent results. Conclusions Early β blocker use was associated with reduced 30 day mortality in patients with acute myocardial infarction, and discontinuation of β blockers at one year was not associated with higher five year mortality. These findings question the utility of prolonged β blocker treatment after acute myocardial infarction in patients without heart failure or left ventricular dysfunction. Trial registration Clinical trials NCT00673036. PMID:27650822

  4. A beta-blocker, propranolol, decreases the efficacy from enzyme replacement therapy in Pompe disease

    PubMed Central

    Han, Sang-oh; Pope, Rand; Li, Songtao; Kishnani, Priya S.; Steet, Richard; Koeberl, Dwight D.

    2015-01-01

    Enzyme replacement therapy (ERT) with recombinant human acid α-glucosidase (rhGAA) fails to completely reverse muscle weakness in Pompe disease. β2-agonists enhanced ERT by increasing receptor-mediated uptake of rhGAA in skeletal muscles. Purpose To test the hypothesis that a β-blocker might reduce the efficacy of ERT, because the action of β-blockers opposes those of β2-agonists. Methods Mice with Pompe disease were treated with propranolol (a β-blocker) or clenbuterol in combination with ERT, or with ERT alone. Results Propranolol-treated mice had decreased weight gain (p<0.01), in comparison with clenbuterol-treated mice. Left ventricular mass was decreased (and comparable to wild-type) in ERT only and clenbuterol-treated groups of mice, and unchanged in propranolol-treated mice. GAA activity increased following either clenbuterol or propranolol in skeletal muscles. However, muscle glycogen was reduced only in clenbuterol-treated mice, not in propranolol-treated mice. Cell-based experiments confirmed that propranolol reduces uptake of rhGAA into Pompe fibroblasts and also demonstrated that the drug induces intracellular accumulation of glycoproteins at higher doses. Conclusion Propranolol, a commonly prescribed β-blocker, increased left ventricular mass and decreased glycogen clearance in skeletal muscle following ERT. β-blockers might therefore decrease the efficacy from ERT in patients with Pompe disease. PMID:26454691

  5. Effects of chloride channel blockers on hypoxic injury in rat proximal tubules.

    PubMed

    Reeves, W B

    1997-05-01

    These studies examined the pathways and consequences of chloride uptake into proximal tubule cells during in vitro hypoxia. The chloride channel blocker diphenylamine-2-carboxylate (DPC) markedly reduced the degree of hypoxia-induced membrane damage as measured by the release of lactate dehydrogenase (LDH). DPC reduced the release of LDH from hypoxic tubules from 38 +/- 2.7% to 16 +/- 1.7% after 30 minutes of hypoxia (P < 0.001, N = 16) and also reduced 36Cl- uptake by hypoxic tubules. The reduction in LDH release was not associated with better preservation of cell ATP content or with protection against hypoxia-induced DNA damage. Other Cl- channel blockers, such as niflumic acid, 5-nitro-2-(3-phenylpropylamino)-benzoate (NPPB) and 2-[(2-cyclopentyl-6,7-dichloro-2,3-dihyrdo-2-methyl-1-oxo-1H-in den-5-yl)oxy] acetic acid (IAA-94) provided even greater protection than DPC and were as effective as 2 mM glycine. The Cl- channel blockers appear to act late in the course of hypoxic injury since DNA damage, an early manifestation of injury, is not prevented by the blockers and since addition of the Cl- channel blocker after the hypoxic injury has begun reduces further membrane damage. These results support the conclusion that transport through Cl- channels contributes to hypoxic cell injury in proximal tubular cells.

  6. The safety of histamine 2 (H2) blockers in pregnancy: a meta-analysis.

    PubMed

    Gill, Simerpal Kaur; O'Brien, Lisa; Koren, Gideon

    2009-09-01

    Heartburn and acid reflux increase the severity of nausea and vomiting of pregnancy, and may lead to more serious medical conditions. The fetal safety of histamine 2 (H2) blockers, the most common antireflux medication, during pregnancy needs to be determined. The aim herein is to determine the fetal safety of H2 blockers during pregnancy through systematic review. All original research assessing the safety of H2 blockers in pregnancy was sought. Data included congenital malformations, spontaneous abortions, preterm delivery, and small for gestational age. A random-effects model combined results. With data from 2,398 exposed and 119,892 nonexposed to H2 blockers, overall odds ratio was 1.14 [0.89, 1.45]. Further analysis revealed no increased risks for spontaneous abortions, preterm delivery, and small for gestational age with odds ratios and 95% confidence intervals (CIs) of 0.62 [0.36-1.05], 1.17 [0.94, 1.147], and 0.28 [0.06, 1.22], respectively. H2 blockers can be used safely in pregnancy.

  7. Fluvial biofilms: A pertinent tool to assess beta-blockers toxicity.

    PubMed

    Bonnineau, Chloé; Guasch, Helena; Proia, Lorenzo; Ricart, Marta; Geiszinger, Anita; Romaní, Anna M; Sabater, Sergi

    2010-02-18

    Among increasingly used pharmaceutical products, beta-blockers have been commonly reported at low concentrations in rivers and littoral waters of Europe and North America. Little is known about the toxicity of these chemicals in freshwater ecosystems while their presence may lead to chronic pollution. Hence, in this study the acute toxicity of 3 beta-blockers: metoprolol, propranolol and atenolol on fluvial biofilms was assessed by using several biomarkers. Some were indicative of potential alterations in biofilm algae (photosynthetic efficiency), and others in biofilm bacteria (peptidase activity, bacterial mortality). Propranolol was the most toxic beta-blocker, mostly affecting the algal photosynthetic process. The exposure to 531microg/L of propranolol caused 85% of inhibition of photosynthesis after 24h. Metoprolol was particularly toxic for bacteria. Though estimated No-Effect Concentrations (NEC) were similar to environmental concentrations, higher concentrations of the toxic (503microg/L metoprolol) caused an increase of 50% in bacterial mortality. Atenolol was the least toxic of the three tested beta-blockers. Effects superior to 50% were only observed at very high concentration (707mg/L). Higher toxicity of metoprolol and propranolol might be due to better absorption within biofilms of these two chemicals. Since beta-blockers are mainly found in mixtures in rivers, their differential toxicity could have potential relevant consequences on the interactions between algae and bacteria within river biofilms.

  8. Effect of beta-blockers on psychomotor performance in normal volunteers.

    PubMed

    Betts, T A; Knight, R; Crowe, A; Blake, A; Harvey, P; Mortiboy, D

    1985-01-01

    The effects of beta-adrenergic receptor antagonists on psychometric tests including vehicle handling, choice reaction time, and kinetic visual acuity (KVA), are reviewed. The beta-blockers had little effect on the performance tests, with the unexplained but reproducible effect of enhanced KVA performance with atenolol. Although the beta-blockers had little effect on performance tests they were shown to have psychotropic effects in normal volunteers. The reasons for the conflicting evidence concerning the effect of these drugs on performance tests is discussed in relation to the present experiments and to variables that may influence response. It is concluded that one should use tests that are as independent as possible from potentially confounding variables. The use of evoked potentials in the electroencephalogram is one such test. A preliminary study is described in which the effects of beta-blockers were detected using visual evoked responses on the electroencephalogram.

  9. Combination monoamine oxidase inhibitor and beta-blocker treatment of migraine, with anxiety and depression.

    PubMed

    Merikangas, K R; Merikangas, J R

    1995-11-01

    This paper presents the results of a study comparing the effectiveness of a beta-adrenergic blocking agent, atenolol, a monoamine oxidase inhibitor (MAO-I), phenelzine, and the combination in treatment of 61 adults with migraine headache. The goals of the study are (1) to investigate the safety of concomitant treatment of migraine with beta-blockers and phenelzine, (2) to assess whether orthostatic hypertension and other side effects would be relieved, and (3) to compare the results of this open trial of phenelzine to those of a previous study using similar methods. Phenelzine was associated with a large decrease in the frequency and severity of migraine attacks. Anxiety and depression were also reduced by phenelzine both alone, and in combination with a beta-blocker. The results show that the combination of MAO-I's and beta-blockers can be administered safely, and can lead to the reduction in the side effects with either drug alone.

  10. Determination of Na channel blockers in paralytic shellfish toxins and pufferfish toxins with a tissue biosensor.

    PubMed

    Cheun, B S; Takagi, S; Hayashi, T; Nagashima, Y; Watanabe, E

    1998-06-01

    The biosensor consisted of a sodium electrode and covered with the frog bladder membrane within a flow cell was tested for the estimation of tetrodotoxin (TTX) and saxitoxin (STX). This sensor was applied to detect very low amounts of the Na+ channel blockers, STX and TTX, in different shellfishes and swellfishes. A good agreement was obtained between TTX activities determined by mouse assay and amounts of Na+ channel blockers estimated by frog membrane sensor. The lowest level of TTX (fg) that can be determined by frog membrane sensor does not cause human poisoning. The channel blockers in short-necked clam, which was assumed to be STX, were monitored by this sensor continuously every week for one year. It was discovered that the STX content increased from July until September and then decreased from October until March. The biosensor proposed here may be used for the estimation of STX and TTX conventionally in the future.

  11. Is carvedilol better than other beta-blockers for heart failure?

    PubMed

    Rain, Carmen; Rada, Gabriel

    2015-06-26

    There is wide consensus about the benefits of beta-blockers in systolic heart failure. However, it is not clear if one specific beta-blocker is superior to the others. Some guidelines favor three “evidence-based” beta-blockers (carvedilol, bisoprolol and metoprolol) that have proved to decrease mortality. Carvedilol might have different physiological properties, commonly referred as pleiotropic effects, but the clinical meaning of them is not clear. Searching in Epistemonikos database, which is maintained by screening 30 databases, we identified four systematic reviews including eight pertinent randomized controlled trials. We combined the evidence using meta-analysis and generated a summary of findings following the GRADE approach. We concluded there is little or no difference in hospitalization risk between carvedilol and bisoprolol or metoprolol, but carvedilol might decrease mortality compared to metoprolol or bisoprolol. It is uncertain whether nebivolol can be an alternative because the certainty of the evidence is very low.

  12. Unambiguous observation of blocked states reveals altered, blocker-induced, cardiac ryanodine receptor gating

    PubMed Central

    Mukherjee, Saptarshi; Thomas, N. Lowri; Williams, Alan J.

    2016-01-01

    The flow of ions through membrane channels is precisely regulated by gates. The architecture and function of these elements have been studied extensively, shedding light on the mechanisms underlying gating. Recent investigations have focused on ion occupancy of the channel’s selectivity filter and its ability to alter gating, with most studies involving prokaryotic K+ channels. Some studies used large quaternary ammonium blocker molecules to examine the effects of altered ionic flux on gating. However, the absence of blocking events that are visibly distinct from closing events in K+ channels makes unambiguous interpretation of data from single channel recordings difficult. In this study, the large K+ conductance of the RyR2 channel permits direct observation of blocking events as distinct subconductance states and for the first time demonstrates the differential effects of blocker molecules on channel gating. This experimental platform provides valuable insights into mechanisms of blocker-induced modulation of ion channel gating. PMID:27703263

  13. Design of fixed dose combination and physicochemical characterization of enteric-coated bilayer tablet with circadian rhythmic variations containing telmisartan and pravastatin sodium.

    PubMed

    Luo, Daoqi; Kim, Joo Hee; Park, Chulhun; Oh, Euichaul; Park, Jun-Bom; Cui, Jing-Hao; Cao, Qing-Ri; Lee, Beom-Jin

    2017-03-19

    The aim of this study was to investigate a fixed dose combination (FDC) of telmisartan (TEL) and pravastatin sodium (PRA) in enteric-coated bilayer tablets, which was designed for once-daily bedtime dose in order to match circadian rhythmic variations of hypertension and cholesterol synthesis and optimize the patient friendly dosing treatment. Due to the poor aqueous solubility of TEL, ternary solid dispersions (SD) consisting of TEL, polyethylene glycol 6000 (PEG 6000) and magnesium oxide (MgO) were designed to enhance its dissolution rate in intestinal fluid. MgO was added as an effective alkalizer to maintain the high microenvironmental pH of the saturated solution in the immediate vicinity of TEL particles because TEL is known to be ionizable but poorly soluble in intestinal fluid. In contrast, PRA is known to be very unstable in low pH conditions. In the SD system, TEL was present in an amorphous structure and formed an intermolecular hydrogen bonding with MgO, giving complete drug release without precipitation in intestinal fluid. In addition, the amount of hydrophilic carrier (PEG 6000) was also a factor. In the design of tablet formulation, the diluents and superdisintegrants could play a key role in release profiles. Then, to fulfill the unmet needs of the two model drugs and match circadian rhythmic variations of hypertension and cholesterol synthesis, enteric-coated bilayer tablet consisting of TEL SD and PRA was finally prepared using Acryl-EZE(®) as an enteric coating material. Prior to enteric coating, a seal coating layer (Opadry(®), 2% weight gains) was firstly introduced to separate the core bilayer tablet from the acidic enteric coating polymers to avoid premature degradation. Dissolution profiles of finished tablets revealed that enteric-coated bilayer tablets with 6% weight gains remained intact in acidic media (pH 1.0) for 2h and then released drugs completely within 45min after switching to the intestinal media (pH 6.8). It was observed that

  14. β-Blockers, heart disease and COPD: current controversies and uncertainties.

    PubMed

    Baker, Jillian G; Wilcox, Robert G

    2017-03-01

    Treating people with cardiovascular disease and COPD causes significant clinician anxiety. β-Blockers save lives in people with heart disease, specifically postinfarction and heart failure. COPD and heart disease frequently coexist and people with both disorders have particularly high cardiovascular mortality. There are concerns about giving β-blockers to people with concomitant COPD that include reduced basal lung function, diminished effectiveness of emergency β-agonist treatments, reduced benefit of long-acting β-agonist treatment and difficulty in discriminating between asthma and COPD. β-Blockers appear to reduce lung function in both the general population and those with COPD because they are poorly selective for cardiac β1-adrenoceptors over respiratory β2-adrenoceptors, and studies have shown that higher β-agonist doses are required to overcome the β-blockade. COPD and cardiovascular disease share similar environmental risks and both disease states have high adrenergic and inflammatory activation. β-Blockers may therefore be particularly helpful in reducing cardiovascular events in this high-risk group. They may reduce the background inflammatory state, and inhibit the tachycardia and hypertension associated with both the endogenous adrenaline and high-dose β-agonist treatment associated with acute exacerbations of COPD. Some studies have suggested no increased and, at times, reduced mortality in patients with COPD taking β-blockers for heart disease. However, these are all observational studies and there are no randomised controlled trials. Potential ways to improve this dilemma include the development of highly β1-selective β-blockers or the use of non-β-blocking heart rate reducing agents, such as ivabridine, if these are proven to be beneficial in randomised controlled trials.

  15. Are beta-blockers effective in heart failure with preserved ejection fraction?

    PubMed

    Alegría, Javier; Rada, Gabriel

    2016-11-02

    Beta-blockers constitute standard therapy for heart failure with reduced ejection. However, their role in patients with preserved ejection fraction is not clear. Searching in Epistemonikos database, which is maintained by screening multiple databases, we identified four systematic reviews covering 19 primary studies, including seven randomized trials answering the question of this summary. We combined the evidence using meta-analysis and generated a summary of findings table following the GRADE approach. We concluded the use of beta-blockers probably leads to little or no difference in the risk of death or hospitalization in patients with heart failure with preserved ejection fraction.

  16. Association of β-blocker therapy with long-term clinical outcomes in patients with coronary chronic total occlusion.

    PubMed

    Hwang, Jin Kyung; Yang, Jeong Hoon; Hwang, Ji-Won; Jang, Woo Jin; Song, Young Bin; Hahn, Joo-Yong; Choi, Jin-Ho; Lee, Sang Hoon; Gwon, Hyeon-Cheol; Choi, Seung-Hyuk

    2016-07-01

    There are limited data regarding the efficacy of β-blockers for secondary prevention in patients with coronary chronic total occlusion (CTO). Therefore, we investigated the association of β-blocker therapy with long-term clinical outcomes in CTO patients. From March 2003 to February 2012, a total of 2024 CTO patients treated with either medical therapy alone or revascularization were enrolled in the study. We assessed 1596 patients with stable ischemic heart disease and divided them into the β-blocker group (n = 932) and the no-β-blocker group (n = 664). The primary outcome was all-cause death. The median follow-up duration was 3.9 (interquartile range: 2.0-6.2) years. All-cause death occurred in 11.6% patients in the β-blocker group and 13.6% patients in the no-β-blocker group (hazard ratio [HR]: 0.81, 95% confidence interval [CI]: 0.61-1.08; P = 0.15). In the propensity score-matched population (570 pairs), all-cause death occurred in 12.3% patients in the β-blocker group and 12.8% patients in the no-β-blocker group (HR: 0.93, 95% CI: 0.67-1.29; P = 0.66). In subgroup analysis, β-blocker therapy was associated with better outcome, in terms of all-cause death, in patients with CTO of the left anterior descending coronary artery and Synergy Between PCI with Taxus and Cardiac Surgery (SYNTAX) score ≥23 (P for interaction = 0.01 and 0.02, respectively). In conclusion, β-blocker therapy was not associated with favorable long-term clinical outcomes in stable CTO patients, regardless of treatment strategy. However, β-blocker therapy might be beneficial in a highly selective group of CTO patients with a high ischemic burden.

  17. Blood Pressure in Early Autosomal Dominant Polycystic Kidney Disease

    PubMed Central

    Schrier, Robert W.; Abebe, Kaleab Z.; Perrone, Ronald D.; Torres, Vicente E.; Braun, William E.; Steinman, Theodore I.; Winklhofer, Franz T.; Brosnahan, Godela; Czarnecki, Peter G.; Hogan, Marie C.; Miskulin, Dana C.; Rahbari-Oskoui, Frederic F.; Grantham, Jared J.; Harris, Peter C.; Flessner, Michael F.; Bae, Kyongtae T.; Moore, Charity G.; Chapman, Arlene B.

    2015-01-01

    BACKGROUND Hypertension is common in autosomal dominant polycystic kidney disease (ADPKD) and is associated with increased total kidney volume, activation of the renin–angiotensin–aldosterone system, and progression of kidney disease. METHODS In this double-blind, placebo-controlled trial, we randomly assigned 558 hypertensive participants with ADPKD (15 to 49 years of age, with an estimated glomerular filtration rate [GFR] >60 ml per minute per 1.73 m2 of body-surface area) to either a standard blood-pressure target (120/70 to 130/80 mm Hg) or a low blood-pressure target (95/60 to 110/75 mm Hg) and to either an angiotensin-converting–enzyme inhibitor (lisinopril) plus an angiotensin-receptor blocker (telmisartan) or lisinopril plus placebo. The primary outcome was the annual percentage change in the total kidney volume. RESULTS The annual percentage increase in total kidney volume was significantly lower in the low-blood-pressure group than in the standard-blood-pressure group (5.6% vs. 6.6%, P = 0.006), without significant differences between the lisinopril–telmisartan group and the lisinopril–placebo group. The rate of change in estimated GFR was similar in the two medication groups, with a negative slope difference in the short term in the low-blood-pressure group as compared with the standard-blood-pressure group (P<0.001) and a marginally positive slope difference in the long term (P = 0.05). The left-ventricular-mass index decreased more in the low-blood-pressure group than in the standard-blood-pressure group (−1.17 vs. −0.57 g per square meter per year, P<0.001); urinary albumin excretion was reduced by 3.77% with the low-pressure target and increased by 2.43% with the standard target (P<0.001). Dizziness and light-headedness were more common in the low-blood-pressure group than in the standard-blood-pressure group (80.7% vs. 69.4%, P = 0.002). CONCLUSIONS In early ADPKD, the combination of lisinopril and telmisartan did not significantly

  18. Beta-1-Selective Beta-Blockers and Cognitive Functions in Patients With Coronary Artery Disease: A Cross-Sectional Study.

    PubMed

    Burkauskas, Julius; Noreikaite, Aurelija; Bunevicius, Adomas; Brozaitiene, Julija; Neverauskas, Julius; Mickuviene, Narseta; Bunevicius, Robertas

    2016-01-01

    The association between current beta-1-selective beta-blocker use and cognitive function was evaluated in 722 patients with coronary artery disease without dementia. Beta-1-selective beta-blocker use was associated with worse incidental learning independently of sociodemographic characteristics, clinical coronary artery disease severity, and depression/anxiety.

  19. Brain death provokes very acute alteration in myocardial morphology detected by echocardiography: preventive effect of beta-blockers.

    PubMed

    Ferrera, René; Hadour, Guylaine; Tamion, Fabienne; Henry, Jean-Paul; Mulder, Paul; Richard, Vincent; Thuillez, Christian; Ovize, Michel; Derumeaux, Geneviève

    2011-03-01

    Our objective was to evaluate immediate acute changes in myocardial function during the autonomic storm of brain death (BD). Wistar rats were divided into four groups (n = 8/group): controls without any treatment, β-blocker (Esmolol®, 10 mg/kg), calcium channel blocker (Diltiazem®, 10 mg/kg), or alpha-blocker (Prazosin®, 0.3 mg/kg). Treatments were administered intravenously 5 min before BD induction. Echocardiography (ATL-5000, 8 MHz) was performed to measure left ventricular (LV) dimensions and fractional shortening at baseline, during BD induction and 5 min and 15 min after BD. In controls, BD was immediately associated with an increase in wall thickness and a decrease in LV cavity dimension. This myocardial wall hypertrophy was completely prevented by β-blockers, but not with calcium- and alpha-blockers. Extensive myocardial interstitial edema was found in all groups, except in the β-blocker group. Myocardial wall hypertrophy was also prevented during a longer follow-up of 180 min after BD in β-blocker group as opposed to controls. In conclusion, BD is associated with an immediate and severe myocardial damage related to an important interstitial edema which is prevented by β-blockers.

  20. Systemic delivery of β-blockers via transdermal route for hypertension

    PubMed Central

    Ahad, Abdul; Al-Jenoobi, Fahad I.; Al-Mohizea, Abdullah M.; Akhtar, Naseem; Raish, Mohammad; Aqil, Mohd.

    2014-01-01

    Hypertension is the most common cardiovascular disease worldwide. Moreover, management of hypertension requires long-term treatment that may result in poor patient compliance with conventional dosage forms due to greater frequency of drug administration. Although there is availability of a plethora of therapeutically effective antihypertensive molecules, inadequate patient welfare is observed; this arguably presents an opportunity to deliver antihypertensive agents through a different route. Ever since the transdermal drug delivery came into existence, it has offered great advantages including non-invasiveness, prolonged therapeutic effect, reduced side effects, improved bioavailability, better patient compliance and easy termination of drug therapy. Attempts were made to develop the transdermal therapeutic system for various antihypertensive agents, including β-blockers, an important antihypertensive class. β-blockers are potent, highly effective in the management of hypertension and other heart ailments by blocking the effects of normal amounts of adrenaline in the heart and blood vessels. The shortcomings associated with β-blockers such as more frequent dose administration, extensive first pass metabolism and variable bioavailability, make them an ideal candidate for transdermal therapeutic systems. The present article gives a brief view of different β-blockers formulated as transdermal therapeutic system in detail to enhance the bioavailability as well as to improve patient compliance. Constant improvement in this field holds promise for the long-term success in technologically advanced transdermal dosage forms being commercialized sooner rather than later. PMID:26702253

  1. Systemic delivery of β-blockers via transdermal route for hypertension.

    PubMed

    Ahad, Abdul; Al-Jenoobi, Fahad I; Al-Mohizea, Abdullah M; Akhtar, Naseem; Raish, Mohammad; Aqil, Mohd

    2015-11-01

    Hypertension is the most common cardiovascular disease worldwide. Moreover, management of hypertension requires long-term treatment that may result in poor patient compliance with conventional dosage forms due to greater frequency of drug administration. Although there is availability of a plethora of therapeutically effective antihypertensive molecules, inadequate patient welfare is observed; this arguably presents an opportunity to deliver antihypertensive agents through a different route. Ever since the transdermal drug delivery came into existence, it has offered great advantages including non-invasiveness, prolonged therapeutic effect, reduced side effects, improved bioavailability, better patient compliance and easy termination of drug therapy. Attempts were made to develop the transdermal therapeutic system for various antihypertensive agents, including β-blockers, an important antihypertensive class. β-blockers are potent, highly effective in the management of hypertension and other heart ailments by blocking the effects of normal amounts of adrenaline in the heart and blood vessels. The shortcomings associated with β-blockers such as more frequent dose administration, extensive first pass metabolism and variable bioavailability, make them an ideal candidate for transdermal therapeutic systems. The present article gives a brief view of different β-blockers formulated as transdermal therapeutic system in detail to enhance the bioavailability as well as to improve patient compliance. Constant improvement in this field holds promise for the long-term success in technologically advanced transdermal dosage forms being commercialized sooner rather than later.

  2. Determination of nine beta-blockers in serum by micellar electrokinetic capillary chromatography.

    PubMed

    Lukkari, P; Nyman, T; Riekkola, M L

    1994-07-15

    beta-Adrenergic blocking agents are used for the treatment of angina pectoris, cardiac arrhythmia, hypertension, anxiety attacks, thyrotoxicosis, migraine and glaucoma. Owing to their sedative effect, they are also used as doping agents in sport. All beta-blockers have an alkanol amine side chain terminating in a secondary amino group in their structure. The pKa values vary from 9.2 to 9.8. Because some beta-blockers are hydrophilic and some lipophilic, simultaneous determination is difficult. In this work, a method based on micellar electrokinetic capillary chromatography (MECC) was developed for the separation and determination of beta-blockers in serum. The phosphate buffer 0.08 M (pH 6.7) solution contained 15 mM N-cetyl-N,N,N-trimethylammonium bromide. Nine parent beta-blockers could be separated in a single run and the concentrations determined by internal standard (ephedrine) method. The simple clean-up procedure consisted of enzyme hydrolysis (Helix pomatia), protein precipitation, and filtration through 0.5-microns PTFE membranes. The MECC method exhibited good repeatability and a linear range of 75-300 micrograms/ml. The method was successfully applied after concentration to the determination of propranolol in real samples.

  3. QSAR study on the antibacterial activity of some sulfa drugs: building blockers of Mannich bases.

    PubMed

    Mandloi, Dheeraj; Joshi, Sheela; Khadikar, Padmakar V; Khosla, Navita

    2005-01-17

    Sulfa drugs are building blockers of several types of Mannich bases. Consequently, the antibacterial activities of sulfa drugs are reported in this paper, which will help in explaining and understanding antibacterial activities of Mannich bases. Reported QSAR is carried out using distance-based topological indices and discussed critically on the basis of statistical parameters.

  4. Pharmacological, pharmacokinetic, and clinical properties of benidipine hydrochloride, a novel, long-acting calcium channel blocker.

    PubMed

    Yao, Kozo; Nagashima, Ken; Miki, Hiroyuki

    2006-04-01

    Benidipine is a dihydropyridine-derived calcium channel blocker developed in Japan, with several unique mechanisms of action, that is, triple calcium channels (L, N, and T) blocking action with a membrane approach. Benidipine has relatively high vascular selectivity and is expected to show protective effects on vascular endothelial cells. Renal protective effects of benidipine also have been shown in several basic and clinical studies. Moreover, anti-oxidative action and enhancing nitric oxide production have been noted with this drug, following its cardio-protective effects in patients with ischemic heart diseases. In fact, benidipine exerted a better prognostic effect than other calcium channel blockers in the therapy for patients with vasospastic angina. In addition, benidipine showed reliable antihypertensive, renoprotective effects if used in combination with angiotensin II type 1 receptor blockers (ARBs) when adequate anti-hypertensive effects are not achieved by ARBs alone, indicating that benidipine is an useful calcium channel blocker in combination therapy for hypertension. Benidipine was launched on the Japanese market 14 years ago, but few severe side effects have been reported, suggesting that this is a drug with established safety and long-acting pharmacological effects.

  5. Attenuation of malonate toxicity in primary mesencephalic cultures using the GABA transport blocker, NO-711.

    PubMed

    Stokes, A H; Bernard, L P; Nicklas, W J; Zeevalk, G D

    2001-04-01

    Cultured rat mesencephalic neurons were used to assess the effects of gamma-aminobutyric acid (GABA) transport blockers on toxicity caused by malonate, a reversible, competitive inhibitor of succinate dehydrogenase. Previous studies utilizing an ex vivo chick retinal preparation have shown that GABA release and cell swelling are early consequences of acute energy impairment and that GABA transport blockers attenuate this toxicity. The present results demonstrate that the nonsubstrate GABA transport blocker, NO-711 (1 nM-1 microM), dose-dependently protected cultured mesencephalic dopamine (DA) and GABA neurons from malonate-induced toxicity. Similar protection was demonstrated with nipecotic acid (1 mM) and SKF89976A (100 nM), substrate and nonsubstrate GABA transport blockers, respectively. These compounds by themselves produced no signs of toxicity, although nipecotic acid caused a long-term decrease in GABA uptake not associated with toxicity. Compounds which decrease intracellular reactive oxygen species (ROS) are protective in this model, but NO-711 did not prevent the rise in intracellular ROS induced by malonate, indicating its protective effects were downstream of ROS production. Supplementation of malonate treated cultures with the GABA(A) agonist, muscimol (10 microM), increased the toxicity toward the DA and GABA neuron populations. Antagonists at the GABA(A) and glycine receptors provided partial protection to both the GABA and DA neurons. These findings suggest that the GABA transporter, GABA(A), and/or glycine channels contribute to cell damage associated with energy impairment in this model.

  6. Nonadherence to beta blockers is a big issue with patients post-MI.

    PubMed

    2006-11-01

    Although healthcare organizations have made great strides in boosting prescribing rates for beta blockers in patients who have suffered a myocardial infarction, (MI) data show that patients are not reaping the full value from these life-saving drugs. The problem is poor medication compliance. Experts maintain that providers and healthcare organizations should now turn their attention to this pressing problem.

  7. Rigid body Brownian dynamics as a tool for studying ion channel blockers.

    PubMed

    Gordon, Dan; Chen, Rong; Ho, Junming; Coote, Michelle L; Chung, Shin-Ho

    2012-02-16

    Using a novel rigid body Brownian dynamics algorithm, we investigate how a spherically asymmetrical polyamine molecule, a branched analogue of spermine, interacts with the external vestibule of the voltage-gated potassium channel, Kv1.2. Simulations reveal that the blocker, with a charge of +4e, inserts one of its charged amine groups into the selectivity filter, while another forms a salt bridge with an aspartate residue located just outside the entrance of the pore. This binding mode mimics features of the binding of polypeptides such as the scorpion venom charybdotoxin to the channel. The potential of mean force constructed with Brownian dynamics is a reasonable match to that obtained from molecular dynamics simulations, with dissociation constants of 4.7 and 22 μM, respectively. The current-voltage relationships obtained with and without a blocker in the external reservoir show that the inward current is severely attenuated by the presence of the blocker, whereas the outward current is only moderately reduced. The computational molecular modeling technique we introduce here can provide detailed insights into ligand-channel interactions and can be used for rapidly screening potential blocker molecules.

  8. Pharmacodynamic models of various beta blockers: an explanation for the long duration of action of bopindolol.

    PubMed

    Grevel, J

    1986-01-01

    Models describing the time course of effects (pharmacodynamic models) of various beta blockers in man are used to explain the long duration of action of bopindolol. No matter what effect is used [reduction in exercise heart rate (RER) or isoproterenol dose ratio (DR)] human data show clearly that bopindolol is very potent compared to other beta blockers such as atenolol, metoprolol, pindolol, practolol, and propranolol. In pharmacokinetic terms, however, these drugs show no pronounced difference in their elimination half-life (ranging between 4 and 8 h). Also the site of action of the therapeutic effects (beta 1 receptors) is obviously identical for all beta blockers. Furthermore, there is no evidence to suggest that bopindolol (the prodrug) or hydrolyzed bopindolol (the active substance) is further metabolized to a slowly eliminated active metabolite. Thus, drug disposition provides no argument to explain the long-lasting effects of bopindolol as compared other beta blockers. The long duration of action of bopindolol seems to reflect an usually flat plasma concentration-response curve.

  9. [Influence of rifampicin on antihypertensive effects of dihydropiridine calcium-channel blockers in four elderly patients].

    PubMed

    Yoshimoto, H; Takahashi, M; Saima, S

    1996-09-01

    Rifamicin, an antituberculosis agent, is one of the most potent inducers of hepatic drug-oxidation enzymes. Rifampicin can reduce the efficacy of several therapeutically important drugs (including verapamil and diltiazem) by accelerating systemic elimination or by increasing hepatic first-pass metabolism. Because dihydropyridine calcium-channel blockers are mainly metabolized by the liver, rifampicin may also increase the extraction of these drugs and thereby reduce their antihypertensive effects. Here we report four possible cases of interaction between rifampicin and dihydropiridine calcium-channel blockers. Rifampicin was given to treat tuberculosis in four elderly hypertensive patients whose blood pressure was well-controlled by one or more dihydropiridine calcium-channel blockers (nisoldipine, nifedipine, or barnidipine and manidipine), shortly after the start of antituberculosis therapy, their blood pressures rose. Either much greater doses of dihydropyridines or additional antihypertensive agents had to be given to keep blood pressure under control. After withdrawal of rifampicin, blood pressure fell in all patients and the doses of the antihypertensive agents had to be reduced. These findings indicate that rifampicin may lessen the antihypertensive effects of dihydropiridine calcium-channel blockers.

  10. Beta-Blockers and the Kidney: Implications for Renal Function and Renin Release.

    ERIC Educational Resources Information Center

    Epstein, Murray; And Others

    1985-01-01

    Reviews and discusses current information on the human renal response as related to beta-blockers (antihypertension agents). Topic areas considered include cardioselectivity, renal hemodynamics, systemic hemodynamics, changes with acute and chronic administration, influence of dose, and others. Implications and an 11-item multiple-choice self-quiz…

  11. Playing with Performance: The Use and Abuse of Beta-Blockers in the Performing Arts

    ERIC Educational Resources Information Center

    Patston, Tim; Loughlan, Terence

    2014-01-01

    This article discusses the use of beta-blockers by performing artists, the reasons why they are taken, and the potential associated risks. We argue that there are high levels of usage within sectors of the professional performing arts community and that there may be high levels of risk in using these medications, particularly without medical…

  12. Dissociation of POMC Peptides after Self-Injury Predicts Responses To Centrally Acting Opiate Blockers.

    ERIC Educational Resources Information Center

    Sandman, Curt A.; Hetrick, William; Taylor, Derek V.; Chicz-DeMet, Aleksandra

    1997-01-01

    This study investigated whether blood plasma levels of pro-opiomelanocortin-derived (POMC) peptides, beta-endorphin-like activity, adrenocorticotrophic hormone, and adrenal cortisol immediately after self injurious behavior (SIB) episodes predicted subsequent response to an opiate blocker in 10 patients with mental retardation. Results suggest…

  13. Effect of β-Blockers on the Risk of Atrial Fibrillation in Patients with Acute Myocardial Infarction

    PubMed Central

    Pesaro, Antonio Eduardo; de Matos Soeiro, Alexandre; Serrano, Carlos Vicente; Giraldez, Roberto Rocha; Ladeira, Renata Teixeira; Nicolau, José Carlos

    2010-01-01

    INTRODUCTION: Oral β-blockers improve the prognosis of patients with acute myocardial infarction, while atrial fibrillation worsens the prognosis of this population. The reduction of atrial fibrillation incidence in patients treated with β-blockers could at least in part explain the benefits of this drug. OBJECTIVE: To investigate the effect of β-blockers on the incidence of atrial fibrillation in patients with acute myocardial infarction. METHODS: We analyzed 1401 patients with acute myocardial infarction and evaluated the occurrence or absence of atrial fibrillation, the use of oral β-blockers and mortality during the first 24 hours. RESULTS: a) The use of β-blockers was inversely correlated with the presence of atrial fibrillation (ρ = 0.004; OR = 0.54). b) Correlations with mortality were as follows: 31.5% in patients with atrial fibrillation, 9.2% in those without atrial fibrillation (ρ < 0.001; Odds Ratio = 4.52), and 17.5% in patients not treated with β-blockers and 6.7% in those who received the drug (ρ < 0.001; OR = 0.34). c) Adjusted Models: The presence of atrial fibrillation was independently correlated with mortality (OR = 2.48, ρ = 0.002). The use of β-blockers was inversely and independently correlated with mortality (OR = 0.53; ρ = 0.002). The patients who used β-blockers showed a lower risk of atrial fibrillation (OR = 0.59; ρ = 0.029) in the adjusted model. CONCLUSION: The presence of atrial fibrillation and the absence of oral β-blockers increased in-hospital mortality in patients with acute myocardial infarction. Oral β-blockers reduced the incidence of atrial fibrillation, which might be at least partially responsible for the drug’s benefit. PMID:20360916

  14. Epidemiology of cardioprotective pharmacological agent use in stable coronary heart disease

    PubMed Central

    Sharma, Krishna Kumar; Mathur, Mukul; Gupta, Rakesh; Guptha, Soneil; Roy, Sanjeeb; Khedar, R.S.; Gupta, Nishant; Gupta, Rajeev

    2013-01-01

    Objective To determine use of class and type of cardioprotective pharmacological agents in patients with stable coronary heart disease (CHD) we performed a prescription audit. Methods A cross sectional survey was conducted in major districts of Rajasthan in years 2008–09. We evaluated prescription for classes (anti-platelets, β-blockers, angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARB), calcium channel blockers (CCB) and statins) and specific pharmacological agents at clinics of physicians in tertiary (n = 18), secondary (n = 69) and primary care (n = 43). Descriptive statistics are reported. Results Prescriptions of 2290 stable CHD patients were audited. Anti-platelet use was in 2031 (88.7%), β-blockers 1494 (65.2%), ACE inhibitors 1196 (52.2%), ARBs 712 (31.1%), ACE inhibitors – ARB combinations 19 (0.8%), either ACE inhibitors or ARBs 1908 (83.3%), CCBs 1023 (44.7%), statins 1457 (63.6%) and other lipid lowering agents in 170 (7.4%). Among anti-platelets aspirin–clopidogrel combination was used in 88.5%. Top three molecules in β-blockers were atenolol (37.8%), metoprolol (26.4%) and carvedilol (11.9%); ACE inhibitors ramipril (42.1%), lisinopril (20.3%) and perindopril (10.9%); ARB's losartan (47.7%), valsartan (22.3%) and telmisartan (14.9%); CCBs amlodipine (46.7%), diltiazem (29.1%) and verapamil (9.5%) and statins were atorvastatin (49.8%), simvastatin (28.9%) and rosuvastatin (18.3%). Use of metoprolol, ramipril, valsartan, diltiazem and atorvastatin was more at tertiary care, and atenolol, lisinopril, losartan, amlodipine and simvasatin in primary care (p < 0.01). Conclusions There is low use of β-blockers, ACE inhibitors, ARBs and statins in stable CHD patients among physicians in Rajasthan. Significant differences in use of specific molecules at primary, secondary and tertiary healthcare are observed. PMID:23809376

  15. Mortality reduction with use of oral beta-blockers in patients with acute coronary syndrome

    PubMed Central

    de Matos Soeiro, Alexandre; de Barros e Silva, Pedro Gabriel Melo; de Castro Roque, Eduardo Alberto; Bossa, Aline Siqueira; Zullino, Cindel Nogueira; Simões, Sheila Aparecida; Okada, Mariana Yumi; de Carvalho Andreucci Torres Leal, Tatiana; de Almeida Soeiro, Maria Carolina Feres; Serrano, Carlos V.; Oliveira, Múcio Tavares

    2016-01-01

    OBJECTIVES: Recent studies have revealed a relationship between beta-blocker use and worse prognosis in acute coronary syndrome, mainly due to a higher incidence of cardiogenic shock. However, the relevance of this relationship in the reperfusion era is unknown. The aim of this study was to analyze the outcomes of patients with acute coronary syndrome that started oral beta-blockers within the first 24 hours of hospital admission (group I) compared to patients who did not use oral beta-blockers in this timeframe (group II). METHODS: This was an observational, retrospective and multicentric study with 2,553 patients (2,212 in group I and 341 in group II). Data regarding demographic characteristics, coronary treatment and medication use in the hospital were obtained. The primary endpoint was in-hospital all-cause mortality. The groups were compared by ANOVA and the chi-square test. Multivariate analysis was conducted by logistic regression and results were considered significant when p<0.05. RESULTS: Significant differences were observed between the groups in the use of angiotensin-converting enzyme inhibitors, enoxaparin, and statins; creatinine levels; ejection fraction; tabagism; age; and previous coronary artery bypass graft. Significant differences were also observed between the groups in mortality (2.67% vs 9.09%, OR=0.35, p=0.02) and major adverse cardiovascular events (11% vs 29.5%, OR=4.55, p=0.02). CONCLUSIONS: Patients with acute coronary syndrome who underwent early intervention with oral beta-blockers during the first 24 hours of hospital admission had a lower in-hospital death rate and experienced fewer major adverse cardiovascular events with no increase in cardiogenic shock or sustained ventricular arrhythmias compared to patients who did not receive oral beta-blockers within this timeframe. PMID:27982163

  16. β-Blockers Reduce Breast Cancer Recurrence and Breast Cancer Death: A Meta-Analysis.

    PubMed

    Childers, W Kurtis; Hollenbeak, Christopher S; Cheriyath, Pramil

    2015-12-01

    The normal physiologic stress mechanism, mediated by the sympathetic nervous system, causes a release of the neurotransmitters epinephrine and norepinephrine. Preclinical data have demonstrated an effect on tumor progression and metastasis via the sympathetic nervous system mediated primarily through the β-adrenergic receptor (β-AR) pathway. In vitro data have shown an increase in tumor growth, migration, tumor angiogenesis, and metastatic spread in breast cancer through activation of the β-AR. Retrospective cohort studies on the clinical outcomes of β-blockers in breast cancer outcomes showed no clear consensus. The purpose of this study was to perform a systematic review and meta-analysis of the effect of β-blockers on breast cancer outcomes. A systematic review was performed using the Cochrane library and PubMed. Publications between the dates of January 2010 and December 2013 were identified. Available hazard ratios (HRs) were extracted for breast cancer recurrence, breast cancer death, and all-cause mortality and pooled using a random effects meta-analysis. A total of 7 studies contained results for at least 1 of the outcomes of breast cancer recurrence, breast cancer death, or all-cause mortality in breast cancer patients receiving β-blockers. In the 5 studies that contained results for breast cancer recurrence, there was no statistically significant risk reduction (HR, 0.67; 95% confidence interval [CI], 0.39-1.13). Breast cancer death results were contained in 4 studies, which also suggested a significant reduction in risk (HR, 0.50; 95% CI, 0.32-0.80). Among the 4 studies that reported all-cause mortality, there was no significant effect of β-blockers on risk (HR, 1.02; 95% CI, 0.75-1.37). Results of this systematic review and meta-analysis suggest that the use of β-blockers significantly reduced risk of breast cancer death among women with breast cancer.

  17. Effect of subcutaneous administration of calcium channel blockers on nerve injury-induced hyperalgesia.

    PubMed

    White, D M; Cousins, M J

    1998-08-10

    Recent studies suggest that calcium contributes to peripheral neural mechanisms of hyperalgesia associated with nerve damage. In this animal behavioural study, we examined further the contribution of calcium in neuropathic pain by testing whether subcutaneous administration of either a calcium chelating agent or voltage-dependent calcium channel blockers attenuate nerve injury-induced hyperalgesia to mechanical stimulation. Studies were carried out in animals with partially ligated sciatic nerves, an established animal model of neuropathic pain. The nociceptive flexion reflex was quantified using an Ugo Basile Analgesymeter. Partial nerve injury induced a significant decrease in mechanical threshold compared to the sham operated controls. Daily subcutaneous injections of the calcium chelating agent, Quin 2 (20 microgram/2.5 microliter), significantly attenuated the nerve injury-induced hyperalgesia. Similarly, SNX-111, a N-type channel blocker, also significantly attenuated the nerve injury-induced hyperalgesia. SNX-230, a P and/or Q-type channel blocker, and nifedipine, a L-type channel blocker, had no effect on the hyperalgesia to mechanical stimulation. In control experiments, SNX-111 had no effect on mechanical thresholds when administered subcutaneously in either the hindpaw of normal animals or the back of the neck in nerve injury animals. This study shows that neuropathic pain involves a local calcium-dependent mechanism in the receptive field of intact neurons of an injured nerve, since it can be alleviated by subcutaneous injections of either a calcium chelating agent or SNX-111, a N-type calcium channel blocker. These agents may be effective, peripherally acting therapeutic agents for neuropathic pain.

  18. ß-adrenoceptor blockers increase cardiac sympathetic innervation by inhibiting autoreceptor suppression of axon growth.

    PubMed

    Clarke, Gwenaëlle L; Bhattacherjee, Aritra; Tague, Sarah E; Hasan, Wohaib; Smith, Peter G

    2010-09-15

    β-Adrenoceptor antagonists are used widely to reduce cardiovascular sympathetic tone, but withdrawal is accompanied by sympathetic hyperactivity. Receptor supersensitivity accounts for some but not all aspects of this withdrawal syndrome. Therefore, we investigated effects of β-blockers on sympathetic innervation. Rats received infusions of adrenergic receptor blockers or saline for 1 week. The nonselective β-blocker propranolol and the β(1)-antagonist metoprolol both increased myocardial sympathetic axon density. At 2 d after propranolol discontinuation, β-receptor sensitivity and responsiveness to isoproterenol were similar to controls. However, tyramine-induced mobilization of norepinephrine stores produced elevated ventricular contractility consistent with enhanced sympathetic neuroeffector properties. In addition, rats undergoing discontinuation showed exaggerated increases in mean arterial pressure in response to air puff or noise startle. In sympathetic neuronal cell cultures, both propranolol and metoprolol increased axon outgrowth but the β(2)-blocker ICI 118551 did not. Norepinephrine synthesis suppression by α-methyl-p-tyrosine also increased sprouting and concurrent dobutamine administration reduced it, confirming that locally synthesized norepinephrine inhibits outgrowth via β(1)-adrenoceptors. Immunohistochemistry revealed β(1)-adrenoceptor protein on sympathetic axon terminations. In rats with coronary artery ligation, propranolol reversed heart failure-induced ventricular myocardial sympathetic axon depletion, but did not affect infarct-associated sympathetic hyperinnervation. We conclude that sympathetic neurons possess β(1)-autoreceptors that negatively regulate axon outgrowth. Chronic β-adrenoceptor blockade disrupts this feedback system, leading to ventricular sympathetic axon proliferation and increased neuroeffector gain, which are likely to contribute to β-blocker withdrawal syndrome.

  19. Effects of β-blocker therapy on electrocardiographic and echocardiographic characteristics of left ventricular noncompaction.

    PubMed

    Li, Jin; Franke, Jennifer; Pribe-Wolferts, Regina; Meder, Benjamin; Ehlermann, Philipp; Mereles, Derliz; Andre, Florian; Abdelrazek, Mohamed Assem; Merten, Constanze; Schweizer, Patrick A; Becker, Rüdiger; Katus, Hugo A; Thomas, Dierk

    2015-03-01

    Left ventricular noncompaction (LVNC) is a cardiomyopathy with hypertrabeculation of the LV, often complicated by heart failure, arrhythmia and thromboembolic events. The features of LVNC are still incompletely characterized due to its late recognition as clinically relevant condition. The aims of this study were to describe echocardiographic and electrophysiologic characteristics of LVNC patients and to assess the effects of chronic β-blocker treatment. Study patients (n = 20; 42.5 [36.3; 52.5] years; 12 men) exhibited reduced LV ejection fraction (median LVEF = 32 %) and an increased LV mass of 210 g. Sinus rhythm was present in 19 patients, whereas one patient was in atrial fibrillation. Baseline heart rate was 77.5 beats per minute. Left bundle branch block was detected in five cases. In a subgroup of patients receiving β-blocker therapy (n = 17), LV mass was reduced from 226 [178; 306] g to 220 [169; 254] g (p = 0.007) at 13 ± 6 months follow-up. By contrast, a subgroup of three patients that were not treated with an anti-β-adrenergic agent showed LV mass increase from 180 [169; 197] g to 199 [185; 213] g (p = 0.023). LVEF and electrocardiographic parameters were not significantly modulated during chronic β-blocker treatment. There was no sustained symptomatic ventricular tachyarrhythmia, thromboembolic event or death in either group. In conclusion, this study reveals reduction of LV mass among LVNC patients during β-blocker therapy. Effects of β-blocker treatment in LVNC require validation in prospective controlled studies.

  20. Molecular Mechanism of Dihydropyridine Ca(2+) Channel Blockers in Pulmonary Hypertension.

    PubMed

    Yamamura, Aya

    2016-01-01

     Idiopathic pulmonary arterial hypertension (IPAH) is a progressive and fatal disease of unidentified pathogenesis. IPAH is pathologically characterized as sustained vasoconstriction and vascular remodeling of the pulmonary artery. In pulmonary arterial smooth muscle cells (PASMCs), an increase in cytosolic Ca(2+) concentration ([Ca(2+)]cyt) triggers vasoconstriction and stimulates cell proliferation leading to vascular remodeling. However, dihydropyridine-type voltage-dependent Ca(2+) channel blockers are only effective in very few patients with IPAH (<10%). It is unclear why dihydropyridine Ca(2+) channel blockers are not therapeutically effective in a majority of IPAH patients. We have previously shown that extracellular Ca(2+)-sensing receptor (CaSR) is upregulated in PASMCs from IPAH patients, and it contributes to enhanced [Ca(2+)]cyt responses and augmented cell proliferation. In this study, the effects of dihydropyridine Ca(2+) channel blockers on [Ca(2+)]cyt responses mediated by CaSR were examined in IPAH-PASMCs. Nifedipine (dihydropyridines) enhanced the CaSR-mediated increase in [Ca(2+)]cyt in IPAH-PASMCs, but not in PASMCs from normal subjects. Nicardipine (dihydropyridines) and Bay K 8644 (a dihydropyridine Ca(2+) channel activator) also augmented the CaSR-mediated [Ca(2+)]cyt increase in IPAH-PASMCs. In contrast, non-dihydropyridine Ca(2+) channel blockers such as diltiazem (benzothiazepines) and verapamil (phenylalkylamines) had no effect on the [Ca(2+)]cyt response in IPAH-PASMCs. Finally, in monocrotaline-induced pulmonary hypertensive rats, nifedipine caused further increase in right ventricular systolic pressure and thus right ventricular hypertrophy. In conclusion, dihydropyridine Ca(2+) channel blockers could exacerbate symptoms of pulmonary hypertension in IPAH patients with upregulated CaSR in PASMCs.

  1. High-affinity antibodies to the 1,4-dihydropyridine Ca2+-channel blockers

    SciTech Connect

    Campbell, K.P.; Sharp, A.; Strom, M.; Kahl, S.D.

    1986-05-01

    Antibodies with high affinity and specificity for the 1,4-dihydropyridine Ca2+-channel blockers have been produced in rabbits by immunization with dihydropyridine-protein conjugates. Anti-dihydropyridine antibodies were found to specifically bind (/sup 3/H)nitrendipine, (/sup 3/H)-nimodipine, (/sup 3/H)nisoldipine, and (/sup 3/H)PN 200-110 (all 1,4-dihydropyridine Ca2+-channel blockers) with high affinity, while (/sup 3/H)verapamil, (/sup 3/H)diltiazem, and (/sup 3/H)trifluoperazine were not recognized. The average dissociation constant of the (/sup 3/H)nitrendipine-antibody complex was 0.06 (+/- 0.02) X 10(-9) M for an antiserum studied in detail and ranged from 0.01 to 0.24 X 10(-9) M for all antisera. Inhibition of (/sup 3/H)nitrendipine binding was specific for the 1,4-dihydropyridine Ca2+-channel modifiers and the concentrations required for half-maximal inhibition ranged between 0.25 and 0.90 nM. Structurally unrelated Ca2+-channel blockers, calmodulin antagonists, inactive metabolites of nitrendipine, and UV-inactivated nisoldipine did not modify (/sup 3/H)nitrendipine binding to the anti-dihydropyridine antibodies. Dihydropyridines without a bulky substituent in the 4-position of the heterocycle were able to displace (/sup 3/H)nitrendipine binding, but the concentrations required for half-maximal inhibition were greater than 800 nM. In summary, anti-dihydropyridine antibodies have been shown to have high affinity and specificity for the 1,4-dihydropyridine Ca2+-channel blockers and to exhibit dihydropyridine binding properties similar to the membrane receptor for the 1,4-dihydropyridine Ca2+-channel blockers.

  2. Combination therapy of angiotensin II receptor blocker and calcium channel blocker exerts pleiotropic therapeutic effects in addition to blood pressure lowering: amlodipine and candesartan trial in Yokohama (ACTY).

    PubMed

    Maeda, Akinobu; Tamura, Kouichi; Kanaoka, Tomohiko; Ohsawa, Masato; Haku, Sona; Azushima, Kengo; Dejima, Toru; Wakui, Hiromichi; Yanagi, Mai; Okano, Yasuko; Fujikawa, Tetsuya; Toya, Yoshiyuki; Mizushima, Shunsaku; Tochikubo, Osamu; Umemura, Satoshi

    2012-01-01

    Recent guidelines recommend combination antihypertensive therapy to achieve the target blood pressure (BP) and to suppress target organ damage. This study aimed to examine the beneficial effects of combination therapy with candesartan and amlodipine on BP control and markers of target organ function in Japanese essential hypertensive patients (N = 20) who did not achieve the target BP level during the monotherapy period with either candesartan or amlodipine. After the monotherapy period, for patients already being treated with amlodipine, a once-daily 8 mg dose of candesartan was added on during the combination therapy period (angiotensin II receptor blocker [ARB] add-on group, N = 10), and a once-daily 5 mg dose of amlodipine was added on for those already being treated with candesartan (calcium channel blocker [CCB] add-on group, N = 10). Combination therapy with candesartan and amlodipine for 12 weeks significantly decreased clinic and home systolic blood pressure (SBP) and diastolic blood pressure (DBP). In addition, the combination therapy was able to significantly reduce urine albumin excretion without decrease in estimated glomerular filtration ratio and resulted in significant improvements in brachial-ankle pulse wave velocity, central SBP, and insulin sensitivity. Furthermore, the CCB add-on group showed a significantly greater decrease in clinic and home DBP than the ARB add-on group. The calcium channel blocker add-on group also exhibited better improvements in vascular functional parameters than the ARB add-on group. These results suggest that combination therapy with candesartan and amlodipine is an efficient therapeutic strategy for hypertension with pleiotropic benefits.

  3. Alpha blockers for treatment of ureteric stones: systematic review and meta-analysis

    PubMed Central

    Canales, Benjamin K; Rogers, Mary A M; Sukumar, Shyam; Yan, Phyllis; Kuntz, Gretchen M; Dahm, Philipp

    2016-01-01

    Objective To investigate the efficacy and safety of alpha blockers in the treatment of patients with ureteric stones. Design Systematic review and meta-analysis. Data sources Cochrane Central Register of Controlled Trials, Web of Science, Embase, LILACS, and Medline databases and scientific meeting abstracts to July 2016. Review methods Randomized controlled trials of alpha blockers compared with placebo or control for treatment of ureteric stones were eligible.Two team members independently extracted data from each included study. The primary outcome was the proportion of patients who passed their stone. Secondary outcomes were the time to passage; the number of pain episodes; and the proportions of patients who underwent surgery, required admission to hospital, and experienced an adverse event. Pooled risk ratios and 95% confidence intervals were calculated for the primary outcome with profile likelihood random effects models. Cochrane Collaboration’s tool for assessing risk of bias and the GRADE approach were used to evaluate the quality of evidence and summarize conclusions. Results 55 randomized controlled trials were included. There was moderate quality evidence that alpha blockers facilitate passage of ureteric stones (risk ratio 1.49, 95% confidence interval 1.39 to 1.61). Based on a priori subgroup analysis, there seemed to be no benefit to treatment with alpha blocker among patients with smaller ureteric stones (1.19, 1.00 to 1.48). Patients with larger stones treated with an alpha blocker, however, had a 57% higher risk of stone passage compared with controls (1.57, 1.17 to 2.27). The effect of alpha blockers was independent of stone location (1.48 (1.05 to 2.10) for upper or middle stones; 1.49 (1.38 to 1.63) for lower stones). Compared with controls, patients who received alpha blockers had significantly shorter times to stone passage (mean difference −3.79 days, −4.45 to −3.14; moderate quality evidence), fewer episodes of pain (−0

  4. The effect of quorum-sensing blockers on the formation of marine microbial communities and larval attachment.

    PubMed

    Dobretsov, Sergey; Dahms, Hans-Uwe; Yili, Huang; Wahl, Martin; Qian, Pei-Yuan

    2007-05-01

    We studied the effect of the quorum-sensing (QS) blockers 5-hydroxy-3[(1R)-1-hydroxypropyl]-4-methylfuran-2(5H)-one (FUR1), (5R)-3,4-dihydroxy-5-[(1S)-1,2-dihydroxyethyl]furan-2(5H)-one (FUR2) and triclosan (TRI) on the formation of bacterial biofilms, and the effect of these biofilms on the larval attachment of the polychaete Hydroides elegans and the bryozoan Bugula neritina. 14-day-old subtidal biofilms were harvested from artificial substrata and were allowed to develop in the laboratory with and without QS blockers. QS blockers inhibited the production of violacein by the QS reporter strain Chromobacterium violaceum CV026 and did not affect the metabolic activity of bacteria in multispecies biofilms. At a concentration of 10(-3) M all three tested compounds inhibited the establishment of microbial communities, but at one of 10(-4) M only FUR2 inhibited establishment. The tested QS blockers caused changes in bacterial density and bacterial community structure, as revealed by terminal restriction fragment length polymorphism and FISH. The groups most affected by QS blockers were Alphaproteobacteria, Gammaproteobacteria and the Cytophagales. Larvae of H. elegans and B. neritina avoided settling on biofilms that had developed in the presence of QS blockers. Our results suggest that QS blockers directly control the formation of multi-species biofilms, and indirectly - by means of biofilm properties - affect larval attachment on these modified biofilms.

  5. Protective effects of beta-blockers against 2,2'-azobis(2-amidinopropane)-dihydrochloride-induced damage.

    PubMed

    Miura, T; Muraoka, S; Ogiso, T

    1995-06-30

    The protective effects of beta-blockers against 2,2'-azobis(2- amidinopropane)-dihydrochloride (AAPH)-induced damage were investigated. With the exception of pindolol, none of the beta-blockers tested inhibited arachidonate peroxidation induced by AAPH in the absence of iron. In contrast, ADP-Fe(3+)- and NADPH-dependent microsomal lipid peroxidation was inhibited by all the beta-blockers tested, although the inhibitory effects of atenolol and metoprolol were very slight. Oxidation of tryptophan residues in bovine serum albumin (BSA) induced by AAPH was strongly inhibited by pindolol and propranolol but not by atenolol or metoprolol. All the beta-blockers tested, however, inhibited AAPH-induced carbonyl formation of BSA. Furthermore, all the beta-blockers tested also strongly inhibited the deoxyribose degradation induced by AAPH, suggesting that these agents act as hydroxyl radical scavengers to inhibit carbonyl formation. DNA strand scission was induced by AAPH in the absence or presence of O2. Only pindolol strongly inhibited the DNA damage in the absence of O2. In the presence of O2, however, all the beta-blockers tested effectively prevented the DNA damage. These results suggested that the hydroxyl radicals produced from AAPH damaged DNA and, that beta-blockers might act as hydroxyl radical scavengers to protect DNA against the AAPH-induced oxidative damage.

  6. Efficacy of beta-blocker therapy in symptomatic athletes with exercise-induced intra-ventricular gradients

    PubMed Central

    2010-01-01

    Background Upright exercise stress echocardiography (SE) induces significant intraventricular gradient (IVG) and systolic anterior motion (SAM) in a large proportion of symptomatic athletes, who may therefore benefit from a negative inotropic therapy. The purpose of the present study was to assess the effect of chronic oral β blocker therapy on the occurrence of exercise-induced IVG and mitral valve SAM, in symptomatic athletes. Methods We enrolled 35 symptomatic athletes (age = 23 ± 11 years) with IVG (>30 mmHg) during SE off therapy. All repeated SE on chronic oral beta-blocker therapy (atenolol up to 50 mg, bisoprolol up to 10 mg, or metoprolol up to 100 mg daily according to physician-driven choice). Results On therapy, there was during SE a reduction in IVG (35 off vs 17 on beta blocker, p < 0.01), decrease of IVG (102 ± 34 mmHg off vs 69 ± 24 mmHg on beta blocker, p < 0.01), peak heart rate (178 ± 15 bpm off vs 157 ± 9 bpm on beta blocker), SAM (24 off vs 9 on beta blocker, p < 0.001), symptoms during SE (17 off vs 2 on beta blocker p < 0.001), ST segment depression (13 off vs 2 on beta blocker, p < 0.001). Conclusions In athletes with positive screening on medical evaluation for sports practice and IVG on exertion, treatment with oral beta blockers improved symptoms in the large majority of patients. Symptomatic benefit was mirrored by objective evidence of improvement of echocardiographic signs of obstruction (IVG and SAM) and reduction of ischemia-like electrocardiographic changes. PMID:20813061

  7. In silico screening for agonists and blockers of the β2 adrenergic receptor: implications of inactive and activated state structures

    PubMed Central

    Costanzi, Stefano; Vilar, Santiago

    2011-01-01

    Ten crystal structures of the β2 adrenergic receptor (β2AR) have been published, reflecting different signaling states. Here, through controlled docking experiments, we examined the implications of using inactive or activated structures on the in silico screening for agonists and blockers of the receptor. Specifically, we targeted the crystal structures solved in complex with carazolol (2RH1), the neutral antagonist alprenalol (3NYA), the irreversible agonist FAUC50 (3PDS) and the full agonist BI-167017 (3P0G). Our results indicate that activated structures favor agonists over blockers while inactive structures favor blockers over agonists. This tendency is more marked for activated than for inactive structures. Additionally, agonists tend to receive more favorable docking scores when docked at activated rather than inactive structures, while blockers do the opposite. Hence, the difference between the docking scores attained with an activated and an inactive structure is an excellent means for the classification of ligands into agonists and blockers, as we determined through receiver operating characteristic (ROC) curves and linear discriminant analysis (LDA). With respect to virtual screening, all structures prioritized well agonists and blockers over non-binders. However, inactive structures worked better for blockers and activated structures worked better for agonists. Notably, the combination of individual docking experiments through receptor ensemble docking (RED) resulted in an excellent performance in the retrieval of both agonists and blockers. Finally, we demonstrated that the induced fit docking of agonists is a viable way of modifying an inactive crystal structure and bias it towards the in silico recognition of agonists rather than blockers. PMID:22170280

  8. Effects of aspirin plus extended-release dipyridamole versus clopidogrel and telmisartan on disability and cognitive function after recurrent stroke in patients with ischaemic stroke in the Prevention Regimen for Effectively Avoiding Second Strokes (PRoFESS) trial: a double-blind, active and placebo-controlled study

    PubMed Central

    Diener, Hans-Christoph; Sacco, Ralph L; Yusuf, Salim; Cotton, Daniel; Ôunpuu, Stephanie; Lawton, William A; Palesch, Yuko; Martin, Reneé H; Albers, Gregory W; Bath, Philip; Bornstein, Natan; Chan, Bernard P L; Chen, Sien-Tsong; Cunha, Luis; Dahlöf, Björn; Keyser, Jacques De; Donnan, Geoffrey A; Estol, Conrado; Gorelick, Philip; Gu, Vivian; Hermansson, Karin; Hilbrich, Lutz; Kaste, Markku; Lu, Chuanzhen; Machnig, Thomas; Pais, Prem; Roberts, Robin; Skvortsova, Veronika; Teal, Philip; Toni, Danilo; VanderMaelen, Cam; Voigt, Thor; Weber, Michael; Yoon, Byung-Woo

    2009-01-01

    Summary Background The treatment of ischaemic stroke with neuroprotective drugs has been unsuccessful, and whether these compounds can be used to reduce disability after recurrent stroke is unknown. The putative neuroprotective effects of antiplatelet compounds and the angiotensin II receptor antagonist telmisartan were investigated in the Prevention Regimen for Effectively Avoiding Second Strokes (PRoFESS) trial. Methods Patients who had had an ischaemic stroke were randomly assigned in a two by two factorial design to receive either 25 mg aspirin (ASA) and 200 mg extended-release dipyridamole (ER-DP) twice a day or 75 mg clopidogrel once a day, and either 80 mg telmisartan or placebo once per day. The predefined endpoints for this substudy were disability after a recurrent stroke, assessed with the modified Rankin scale (mRS) and Barthel index at 3 months, and cognitive function, assessed with the mini-mental state examination (MMSE) score at 4 weeks after randomisation and at the penultimate visit. Analysis was by intention to treat. The study was registered with ClinicalTrials.gov, number NTC00153062. Findings 20 332 patients (mean age 66 years) were randomised and followed-up for a median of 2·4 years. Recurrent strokes occurred in 916 (9%) patients randomly assigned to ASA with ER-DP and 898 (9%) patients randomly assigned to clopidogrel; 880 (9%) patients randomly assigned to telmisartan and 934 (9%) patients given placebo had recurrent strokes. mRS scores were not statistically different in patients with recurrent stroke who were treated with ASA and ER-DP versus clopidogrel (p=0·38), or with telmisartan versus placebo (p=0·61). There was no significant difference in the proportion of patients with recurrent stroke with a good outcome, as measured with the Barthel index, across all treatment groups. Additionally, there was no significant difference in the median MMSE scores, the percentage of patients with an MMSE score of 24 points or less, the

  9. Current use of beta blockers in patients with reactive airway disease who are hospitalized with acute coronary syndromes.

    PubMed

    Olenchock, Benjamin A; Fonarow, Gregg G; Pan, Wenqin; Hernandez, Adrian; Cannon, Christopher P

    2009-02-01

    Beta blockers have a proven benefit in the management of patients with acute coronary syndromes (ACS) and for secondary prevention of coronary events. Current guidelines list such reactive airway diseases (RADs) such as asthma and chronic obstructive pulmonary disease as relative contraindications to beta-blocker use. However, the co-morbid burden of RAD and coronary heart disease is substantial, and data suggest that the treatment benefit of beta blockers is shared by patients with RAD. The Get with the Guidelines (GWTG) database was used to evaluate use of beta blockers within 24 hours of admission and at discharge in patients with ACS with (n = 12,967) and without (n = 81,140) a history of RAD. Data were collected in 435 hospitals between January 2000 and September 2006. A multivariable logistic regression model was used to determine predictors of beta-blocker treatment. In patients with no RAD history, beta-blocker prescription rates were 78.3% at admission and 88.7% at discharge; in patients with a RAD history, rates were 65.6% at admission and 77.2% at discharge. Compared with patients with no history of RAD, patients with a history of RAD were 42% less likely (odds ratio 0.58, confidence interval 0.54 to 0.62, p <0.0001) to receive a beta blocker upon admission and 55% less likely (odds ratio 0.45, confidence interval 0.41 to 0.48, p <0.0001) to receive a beta blocker at discharge in multivariable analysis. Among all other clinical factors, RAD history was the most significant predictor of likelihood of not receiving a beta blocker at admission or discharge. Receipt of beta blockers within 24 hours after admission was associated with a lower in-hospital mortality rate for patients with RAD (odds ratio = 0.52, p <0.001) and for patients without RAD (odds ratio = 0.38, p <0.001). Careful assessment of beta-blocker safety and RAD severity by physicians is needed to improve beta-blocker prescription rates in this large group of patients with ACS.

  10. The combination of OLmesartan and a CAlcium channel blocker (azelnidipine) or candesartan and a calcium channel blocker (amlodipine) in type 2 diabetic hypertensive patients: the OLCA study.

    PubMed

    Daikuhara, Hiroyuki; Kikuchi, Fumi; Ishida, Toshihiko

    2012-10-01

    Angiotensin II receptor blockers (ARB) are often co-administered with a calcium channel blocker (CCB) for treating hypertension. In this open-label randomised study, untreated diabetic hypertensive patients were randomised to receive either olmesartan 20 mg/day or candesartan 8 mg/day for 12 weeks. Patients with blood pressure exceeding 130/80 mm Hg received add-on 16 mg/day azelnidipine to ongoing olmesartan (OL group) or 5 mg/day amlodipine to ongoing candesartan (CA group) for 24 weeks. Home-measured and clinic-measured blood pressure decreased in both groups. Fasting blood glucose, haemoglobin A1c (HbA1c) and urinary albumin levels decreased significantly in the OL group but not in the CA group. In conclusion, this study revealed clinically relevant differences between two combinations of an ARB+CCB in diabetic hypertensive patients. Olmesartan and azelnidipine had a more persistent early morning antihypertensive effect and produced greater decreases in heart rate, fasting blood glucose and HbA1c (National Glycohemoglobin Standardization Program values) levels, and microalbuminuria than did candesartan and amlodipine.

  11. Characterization of in vivo and in vitro electrophysiological and antiarrhythmic effects of a novel IKACh blocker, NIP-151: a comparison with an IKr-blocker dofetilide.

    PubMed

    Hashimoto, Norio; Yamashita, Toru; Tsuruzoe, Nobutomo

    2008-02-01

    We investigated the electrophysiological and antiarrhythmic effects of a novel antiarrhythmic agent, NIP-151, and compared these effects with those of an IKr-blocker dofetilide. NIP-151 potently inhibited acetylcholine-activated K current (IKACh) with an IC50, with 1.6 nM in HEK293 cells expressing the GIRK1/4 channel, but it had little effect on IKr (IC50 = 57.6 microM). NIP-151 dose-dependently terminated AF both in vagal nerve stimulation-induced AF (at 5 and 15 microg/kg per minute) and aconitine-induced AF (at 30 and 100 microg/kg) models. This compound significantly prolonged the atrial effective refractory period (ERP), but it had no significant effects on ventricular ERP. There were no significant changes on electrocardiographic variables with NIP-151 (up to 1,000 microg/kg per minute) administration. In contrast, dofetilide had little effect in either AF model, even though this compound potently prolonged atrial ERP. Dofetilide also significantly prolonged ventricular ERP and the QT interval in anesthetized dogs, which are related to proarrhythmic risk. In conclusion, a novel antiarrhythmic agent NIP-151, which potently blocked IKACh, was highly effective in the two types of canine AF models with an atrial-specific ERP-prolonging profile. Therefore, NIP-151 might be useful for the treatment of AF with lower risk of proarrhythmia, compared with IKr blockers.

  12. Perioperative beta-blockers for preventing surgery-related mortality and morbidity.

    PubMed

    Bolton, Nerys

    2016-03-01

    For many patients any type of surgical invention can increase their stress response which can make the body vulnerable to untoward outcomes. An extreme consequence of the stress response is death with other responses including heart attacks and stroke, to impacting on the patients' postoperative reviver such as their psychological status and pain recovery. Therefore there is a need to consider the attenuation of the perioperative stress response through the use of drugs such as beta-blockers. These drugs have been shown to reduce the heart rate and lower the patients' blood pressure. Although this is a desired result in trying to eliminate the effects of the stress response it can also have the opposite effect on reducing the patients' blood pressure and pulse to a point where the patients suffers ill effects such as stroke or death. Therefore it is vital to understand the influence of beta-blockers and their ability to influence perioperative cardiovascular morbidity and mortality.

  13. Differential Metabolic Effects of Beta-Blockers: an Updated Systematic Review of Nebivolol.

    PubMed

    Marketou, Maria; Gupta, Yashaswi; Jain, Shashank; Vardas, Panos

    2017-03-01

    Blood pressure management in hypertensive patients with metabolic abnormalities is challenging, since many of the antihypertensive drugs adversely affect metabolism. Besides effective control of blood pressure in patients with hypertension, third-generation beta-blockers such as nebivolol offer additional benefits for central hemodynamics and neutral or beneficial effects on metabolism. Emerging clinical data suggest that nebivolol also has similar effects on metabolism in obese hypertensive and hypertensive diabetic patients. The present article will provide a systematic analysis of the pathophysiological links among hypertension, insulin resistance, and metabolic syndrome. We will also summarize the available clinical evidence regarding the metabolic effects of beta-blockers in hypertensive patients, with an emphasis on nebivolol. Nebivolol exerts neutral or beneficial effects on insulin sensitivity and lipid metabolism in hypertensive patients, owing to its nitric oxide-mediated vasodilatory and antioxidative properties. Thus, nebivolol could be a favorable therapeutic option for the treatment of hypertension in patients with impaired glucose and lipid metabolism.

  14. Evolution of β-blockers: from anti-anginal drugs to ligand-directed signalling.

    PubMed

    Baker, Jillian G; Hill, Stephen J; Summers, Roger J

    2011-04-01

    Sir James Black developed β-blockers, one of the most useful groups of drugs in use today. Not only are they being used for their original purpose to treat angina and cardiac arrhythmias, but they are also effective therapeutics for hypertension, cardiac failure, glaucoma, migraine and anxiety. Recent studies suggest that they might also prove useful in diseases as diverse as osteoporosis, cancer and malaria. They have also provided some of the most useful tools for pharmacological research that have underpinned the development of concepts such as receptor subtype selectivity, agonism and inverse agonism, and ligand-directed signalling bias. This article examines how β-blockers have evolved and indicates how they might be used in the future.

  15. 2-Ethynylbenzenealkanamines: a new class of calcium entry blockers with potential antihypertensive and antianginal properties

    SciTech Connect

    Brannan, M.D.; Carson, J.R.; Gill, A.; Keely, S.L.; Flaim, S.F.; Sit, S.P.; Damiano, B.P.; Carmosin, R.R.J.; Gleason, M.M.; Ludovici, D.W.; Pitis, P.M.

    1986-03-05

    2-Ethynylbenzenealkanamines represent a newly discovered class of calcium channel blockers in that they inhibited KCl-stimulated /sup 45/Ca influx and isometric tension development in isolated vascular smooth muscle and prolonged AV-nodal conduction time in canine hearts. Testing revealed optimal activity in the following structure where R1 is aryl, R2 and R4 are methyl, R3 is aralkyl and X is methoxy: compounds in this group lowered arterial pressures in conscious spontaneously hypertensive rats and renal hypertensive dogs following either oral or parenteral administration, and thus are potential antihypertensive agents. These compounds also caused coronary vasodilation at concentrations which did not affect rate or force of contraction in the isolated, perfused guinea pig heart preparation, they increased coronary blood flow and decreased coronary vascular resistance in the anesthetized canine, and thus are potential antianginal agents. In summary, 2-ethynylbenzenealkanamines represent a new class of calcium entry blockers which have potential antihypertensive and antianginal properties.

  16. Pharmacological correction of obesity-induced autophagy arrest using calcium channel blockers

    PubMed Central

    Park, Hwan-Woo; Park, Haeli; Semple, Ian A.; Jang, Insook; Ro, Seung-Hyun; Kim, Myungjin; Cazares, Victor A.; Stuenkel, Edward L.; Kim, Jung-Jae; Kim, Jeong Sig; Lee, Jun Hee

    2014-01-01

    Autophagy deregulation during obesity contributes to the pathogenesis of diverse metabolic disorders. However, without understanding the molecular mechanism of obesity interference in autophagy, development of therapeutic strategies for correcting such defects in obese individuals is challenging. Here we show that chronic increase of cytosolic calcium concentration in hepatocytes upon obesity and lipotoxicity attenuates autophagic flux by preventing the fusion between autophagosomes and lysosomes. As a pharmacological approach to restore cytosolic calcium homeostasis in vivo, we administered the clinically approved calcium channel blocker verapamil to obese mice. Such treatment successfully increases autophagosome-lysosome fusion in liver, preventing accumulation of protein inclusions and lipid droplets and suppressing inflammation and insulin resistance. As calcium channel blockers have been safely used in clinics for the treatment of hypertension for more than thirty years, our results suggest they may be a safe therapeutic option for restoring autophagic flux and treating metabolic pathologies in obese patients. PMID:25189398

  17. Should we add beta-blockers to band ligation for secondary prophylaxis of variceal bleeding?

    PubMed

    Cotoras, Petre; Faúndez, Jorge; Candia, Roberto

    2017-02-23

    Cirrhotic patients who have had an episode of bleeding from gastroesophageal varices are at high risk of rebleeding, despite treatment with endoscopic variceal ligation. Adding beta-blockers could reduce this risk, but it is associated with adverse effects. Searching in Epistemonikos database, which is maintained by screening multiple databases, we identified seven systematic reviews including 21 randomized controlled trials addressing the question of this article. We extracted data, combined the evidence using meta-analysis and generated a summary of findings following the GRADE approach. We concluded the addition of beta-blockers to endoscopic variceal ligation as secondary prophylaxis of variceal bleeding reduces the risk of rebleeding, but probably does not lead to any difference in terms of mortality. Even though it is associated to frequent adverse effects, these would be mild and generally do not lead to discontinuation of treatment.

  18. Comparison of Alpha Blockers in Treatment of Premature Ejaculation: A Pilot Clinical Trial

    PubMed Central

    Akin, Yigit; Gulmez, Hakan; Ates, Mutlu; Bozkurt, Aliseydi; Nuhoglu, Baris

    2013-01-01

    Background: Premature ejaculation (PE) is the most common sexual disorder in men and studies reported prevalence up to 30% (1, 2). PE is not a life-threatening medical condition but it influences the quality of life (QoL). Objectives: The aim of this study was to compare the efficiency, and safety of alpha blocker drugs in the treatment of patients with premature ejaculation (PE). Additionally we investigated the quality of life (QoL) in patients with PE who were treated with alpha blocker drugs. Materials and Methods: This study was a pilot clinical trial. Prospectively documented 108 patients with PE were treated and were followed-up in urology outpatient clinic. All patients were divided into 5 groups according to used alpha blocker agents which were determined by simple randomization. Silodosin 4mg (Group 1, n = 21), tamsulosin hydrochloride 0.4mg (Group 2, n = 23), alfuzosin 10mg (Group 3, n = 22), terazosin 5mg (Group 4, n = 21), doksazosin mesylate 4mg (Group5, n = 21), were used for treatment. The demographic parameters of patients, pre and post treatment intravaginal ejaculation latency time (IELT), PE Profile (PEP), and QoL index were recorded and evaluated. Effectiveness of treatment was evaluated by measuring IELT. Additionally, side effects of drugs were recorded. P < 0.05 was considered statistically significant. Results: All alpha blocker drugs were statistically effective for preventing PE. Notably, silodosin seemed to be more effective for preventing PE than other alpha blockers (P < 0.05). However all alpha blockers provided development in QoL scores, silodosin was a little better than other drugs in statistical analyses. Furthermore statistical increase in IELT and decrease in PEP were provided more in Group 1 than other groups (P < 0.05). Conclusions: Silodosin seems to be able to even more prevent PE. Silodosin may provide development in QoL than other alpha blocker agents. Additionally, lower systemic adverse events and more effectivity are

  19. The use of vasopressin in the setting of recalcitrant hypotension due to calcium channel blocker overdose.

    PubMed

    Kanagarajan, Karthikeyan; Marraffa, Jeanna M; Bouchard, Nicole C; Krishnan, Padmanabhan; Hoffman, Robert S; Stork, Christine M

    2007-01-01

    Treatment of hypotension caused by calcium channel blocker overdose (CCB) remains a challenge. We describe the successful use of vasopressin in two patients with massive CCB overdoses in whom hypotension was unresponsive to calcium, glucagon, insulin, and conventional vasopressor therapies. While various modes of treatments have been used to treat the hypotension of CCB overdose, this is the first report to our knowledge of the successful use of vasopressin in this clinical setting.

  20. Pineal perfusion with calcium channel blockers inhibits differently daytime and nighttime melatonin production in rat.

    PubMed

    Zhao, Z Y; Touitou, Y

    1994-05-01

    In a previous study we have shown that the response of perifused pineal glands to calcium was different according to the circadian stage at which the glands were removed. This difference may be explained by circadian changes in calcium channel function. Therefore in the present study we documented the effects of calcium channel blockers in perifused rat pineal glands removed in the middle of the light and dark spans (7 and 19 HALO (hours after light onset), in a L/D 12:12 regimen). Moreover, we have studied the effect of calcium channel blockers on adrenergically stimulated pineal glands removed 7 HALO. Inorganic (Co2+ and Cd2+) and organic (nifedipine and diltiazem) calcium channel blockers at 10(-4) mol/l all significantly reduced melatonin production and this inhibition was more effective with the glands removed 7 HALO. In a concentration of 10(-)5 mol/l, only Cd2+ and diltiazem reduced melatonin production significantly in pineal glands removed 7 HALO. Verapamil at 10(-4) and 10(-5) mol/l showed no significant effect on melatonin production in glands removed both during the light and dark spans. Mn2+ at 10(-4) mol/l (but not at 10[-5] mol/l) appeared to stimulate melatonin production in glands removed both during the light and the dark (significant increase only with glands removed during the dark). Cobalt showed an immediate short inhibitory effect on both isoproterenol and norepinephrine-stimulated melatonin release, whereas nifedipine showed a significant inhibition only on isoproterenol-stimulated melatonin release. These results strongly suggest a circadian stage dependence of the pineal gland response to some calcium channel blockers and the involvement of calcium in the release of melatonin from pinealocytes.

  1. Indistinguishable Synaptic Pharmacodynamics of the N-Methyl-d-Aspartate Receptor Channel Blockers Memantine and Ketamine

    PubMed Central

    Emnett, Christine M.; Eisenman, Lawrence N.; Taylor, Amanda M.; Izumi, Yukitoshi; Zorumski, Charles F.

    2013-01-01

    Memantine and ketamine, voltage- and activation-dependent channel blockers of N-methyl-d-aspartate (NMDA) receptors (NMDARs), have enjoyed a recent resurgence in clinical interest. Steady-state pharmacodynamic differences between these blockers have been reported, but it is unclear whether the compounds differentially affect dynamic physiologic signaling. In this study, we explored nonequilibrium conditions relevant to synaptic transmission in hippocampal networks in dissociated culture and hippocampal slices. Equimolar memantine and ketamine had indistinguishable effects on the following measures: steady-state NMDA currents, NMDAR excitatory postsynaptic current (EPSC) decay kinetics, progressive EPSC inhibition during repetitive stimulation, and extrasynaptic NMDAR inhibition. Therapeutic drug efficacy and tolerability of memantine have been attributed to fast kinetics and strong voltage dependence. However, pulse depolarization in drug presence revealed a surprisingly slow and similar time course of equilibration for the two compounds, although memantine produced a more prominent fast component (62% versus 48%) of re-equilibration. Simulations predicted that low gating efficacy underlies the slow voltage–dependent relief from block. This prediction was empirically supported by faster voltage-dependent blocker re-equilibration with several experimental manipulations of gating efficacy. Excitatory postsynaptic potential–like voltage commands produced drug differences only with large, prolonged depolarizations unlikely to be attained physiologically. In fact, we found no difference between drugs on measures of spontaneous network activity or acute effects on plasticity in hippocampal slices. Despite indistinguishable synaptic pharmacodynamics, ketamine provided significantly greater neuroprotection from damage induced by oxygen glucose deprivation, consistent with the idea that under extreme depolarizing conditions, the biophysical difference between drugs

  2. Long-term effect of β-blocker in ST-segment elevation myocardial infarction in patients with preserved left ventricular systolic function: a propensity analysis.

    PubMed

    Konishi, Hirokazu; Miyauchi, Katsumi; Kasai, Takatoshi; Tsuboi, Shuta; Ogita, Manabu; Naito, Ryo; Nishizaki, Yuji; Okai, Iwao; Tamura, Hiroshi; Okazaki, Shinya; Isoda, Kikuo; Daida, Hiroyuki

    2016-04-01

    The current guidelines for acute myocardial infarction (AMI) recommended that β-blocker should be used in patients with decreased left ventricular (LV) systolic function for long-term period. However, the effect of β-blocker in AMI patients with preserved LV systolic function is uncertain. We sought to assess the long-term effect of β-blocker in AMI patients with preserved LV systolic function. During the follow-up period (1997-2011), total 3508 patients were performed percutaneous coronary intervention (PCI). Of these patients, 424 AMI patients with preserved LV systolic function [ejection fraction (EF) > 40 %] were analyzed. Median follow-up period was 4.7 years. Then, patients were divided into two groups (β-blocker group 197 patients and no-β-blocker group 227 patients). However, there are substantial differences in baseline characteristics between two groups. Therefore, we calculated propensity score to match the patients in β-blocker and no-β-blocker groups. After post-match patients (N = 206, 103 matched pair), β-blocker therapy significantly reduced cardiac death compared with no-β-blocker [hazard ratio (HR) 0.40, p = 0.04], whereas β-blocker therapy was not associated with major adverse cardiac events (MACE) and all-cause death. β-Blocker is an effective treatment for AMI patients who underwent PCI with preserved LV systolic function.

  3. Ca sup 2+ channel blockers interact with. alpha. sub 2 -adrenergic receptors in rabbit ileum

    SciTech Connect

    Homaidan, F.R.; Donowitz, M.; Wicks, J.; Cusolito, S.; El Sabban, M.E.; Weiland, G.A.; Sharp, G.W.G. Tufts Univ. School of Medicine and New England Medical Center Hospital, Boston, MA )

    1988-04-01

    An interaction between Ca{sup 2+} channel blockers and {alpha}{sub 2}-adrenergic receptors has been demonstrated in rabbit ileum by studying the effect of clonidine on active electrolyte transport, under short-circuited conditions, in the presence and absence of several Ca{sup 2+} channel blocking agents. Clonidine, verapamil, diltiazem, cadmium, and nitrendipine all decrease short-circuit current and stimulate NaCl absorption to different extents with clonidine having the largest effect. Exposure to verapamil, diltiazem, and cadmium inhibited the effects of clonidine on transport, whereas nitrendipine had no such effect. Verapamil, diltiazem, and cadmium, but not nitrendipine, also decreased the specific binding of ({sup 3}H){alpha}{sub 2}-adrenergic agents to a preparation of ileal basolateral membranes explaining the observed decrease in the transport effects of clonidine. The effective concentrations of the Ca{sup 2+} channel blockers that inhibited the effects of clonidine on transport were fairly similar to the concentrations needed to inhibit its specific binding. The displacement of clonidine by calcium channel blockers is ascribed to a nonspecific effect of these agents, although the possibility that their effects are exerted via their binding to the calcium channels is not excluded.

  4. Persistent current blockers of voltage-gated sodium channels: a clinical opportunity for controlling metastatic disease.

    PubMed

    Djamgoz, Mustafa B A; Onkal, Rustem

    2013-01-01

    A range of experimental and clinical data suggests strongly (i) that metastatic progression in carcinomas is accompanied (maybe even preceded) by upregulation of functional voltage-gated sodium channels (VGSCs) and (ii) that VGSC activity enhances cancer cell invasiveness. First, this review outlines the available in vitro and in vivo evidence for the VGSC expression and its proposed pathophysiological role. Second, we question the mechanism(s) whereby VGSC activity can induce such a cancer-promoting effect. We advance the hypothesis that it is the hypoxia-sensitive persistent component of the VGSC current (INaP) that is central to the phenomenon. Indeed, blockers of INaP are very effective in suppressing cancer cell invasiveness in vitro. Based upon these data, UK and international patent applications have been filed which describe the use of INaP blockers, like ranolazine ("Ranexa") and riluzole ("Rilutex"), as anti-metastatic agents. Importantly, since these drugs are already in clinical use, against conditions like cardiac angina and amyotrophic lateral scelerosis, there are no issues of dosage, unacceptable side effects or long-term use. Thus, INaP blockers have the potential to turn cancer into a chronic condition.

  5. Interrupting autocrine ligand-receptor binding: comparison between receptor blockers and ligand decoys.

    PubMed Central

    Forsten, K E; Lauffenburger, D A

    1992-01-01

    Stimulation of cell behavioral functions by ligand/receptor binding can be accomplished in autocrine fashion, where cells secrete ligand capable of binding to receptors on their own surfaces. This proximal secretion of autocrine ligands near the surface receptors on the secreting cell suggests that control of these systems by inhibitors of receptor/ligand binding may be more difficult than for systems involving exogenous ligands. Hence, it is of interest to predict the conditions under which successful inhibition of cell receptor binding by the autocrine ligand can be expected. Previous theoretical work using a compartmentalized model for autocrine cells has elucidated the conditions under which addition of solution decoys for the autocrine ligand can interrupt cell receptor/ligand binding via competitive binding of the secreted molecules (Forsten, K. E., and D. A. Lauffenburger. 1992. Biophys. J. 61:1-12.) We now apply a similar modeling approach to examine the addition of solution blockers targeted against the cell receptor. Comparison of the two alternative inhibition strategies reveals that a significantly lower concentration of receptor blockers, compared to ligand decoys, will obtain a high degree of inhibition. The more direct interruption scheme characteristic of the receptor blockers may make them a preferred strategy when feasible. PMID:1330038

  6. How Administration of the Beta-Blocker Propranolol Before Extinction can Prevent the Return of Fear.

    PubMed

    Kroes, Marijn C W; Tona, Klodiana-Daphne; den Ouden, Hanneke E M; Vogel, Susanne; van Wingen, Guido A; Fernández, Guillén

    2016-05-01

    Combining beta-blockers with exposure therapy has been advocated to reduce fear, yet experimental studies combining beta-blockers with memory reactivation have had contradictory results. We explored how beta-blockade might affect the course of safety learning and the subsequent return of fear in a double-blind placebo-controlled functional magnetic resonance imaging study in humans (N=46). A single dose of propranolol before extinction learning caused a loss of conditioned fear responses, and prevented the subsequent return of fear and decreased explicit memory for the fearful events in the absence of drug. Fear-related neural responses were persistently attenuated in the dorsal medial prefrontal cortex (dmPFC), increased in the hippocampus 24 h later, and correlated with individual behavioral indices of fear. Prediction error-related responses in the ventral striatum persisted during beta-blockade. We suggest that this pattern of results is most consistent with a model where beta-blockade can prevent the return of fear by (i) reducing retrieval of fear memory, via the dmPFC and (ii) increasing contextual safety learning, via the hippocampus. Our findings suggest that retrieval of fear memory and contextual safety learning form potential mnemonic target mechanisms to optimize exposure-based therapy with beta-blockers.

  7. Obesity and beta-blockers: influence of body fat on their kinetics and cardiovascular effects.

    PubMed

    Galletti, F; Fasano, M L; Ferrara, L A; Groppi, A; Montagna, M; Mancini, M

    1989-03-01

    Beta-blockers are among the most widely used antihypertensive drugs. They differ from each other in regard to several factors such as: beta-agonist activity, beta 1-selectivity and solubility. Aim of this work was to evaluate the influence of obesity on the kinetics and the antihypertensive effect of two Beta-blockers with different solubility such as: the water-soluble, atenolol and the liposoluble, metoprolol. The study was carried out according to an open randomized cross-over design. Eight obese hypertensive patients, after a two week washout period, were randomly allocated to a four week treatment. After a two week intermediate washout period, each patient switched to the other treatment for an additional four week period. On the first and the last day of each treatment the subjects were hospitalized to collect blood samples for the assay of the two drugs and to measure cardiovascular parameters. Obesity does not exert any effect on the kinetics of the water-soluble beta-blocker, atenolol, while markedly interferes with that of the liposoluble, without any apparent influence on its anti-hypertensive effect. These findings extend to obese hypertensives the concept that the plasma concentrations of beta-blocking agents are not reliable predictors of their therapeutic effect.

  8. A potent 1,4-dihydropyridine L-type calcium channel blocker, benidipine, promotes osteoblast differentiation.

    PubMed

    Nishiya, Y; Kosaka, N; Uchii, M; Sugimoto, S

    2002-01-01

    During their differentiation, osteoblasts sequentially express type I collagen, alkaline phosphatase (ALP), and osteocalcin, and then undergo mineral deposition. Among dihydropyridine-type calcium channel blockers, only benidipine stimulated ALP activity of osteoblastic cells derived from neonatal mouse calvaria. To identify the molecular target of benidipine and elucidate the mechanism of action of the drug in osteoblasts, the mouse osteoblastic cell line MC3T3-E1 was used. Benidipine prompted ALP activity and ALP transcription induced by ascorbic acid, and mineral deposition by ascorbic acid and b-glycerophosphate. Benidipine, however, did not change collagen accumulation. MC3T3-E1 cells expressed the L-type Ca channel a1C subunit throughout the differentiation process, and Ca influx by potassium ions and Bay K 8644, an agonist, was strongly attenuated by benidipine. Each one of three structurally different classes of Ca channel blockers, nifedipine, verapamil, and diltiazem stimulated ALP activity, although at much higher concentrations of ca. 100 nM than benidipine, 1 pM. These results suggest that benidipine directly exerts its effect on osteoblasts and promotes osteoblast differentiation after the step of collagen accumulation by blocking the L-type Ca channel. Since benidipine blocked Ca influx more potently than the three other Ca channel blockers, the unique and potent osteoblast differentiating ability of benidipine may be due to its high affinity for Ca channel together with its high membrane retaining ability, as has been previously reported.

  9. Scatter correction for cone-beam computed tomography using moving blocker strips

    NASA Astrophysics Data System (ADS)

    Wang, Jing; Mao, Weihua; Solberg, Timothy

    2011-03-01

    One well-recognized challenge of cone-beam computed tomography (CBCT) is the presence of scatter contamination within the projection images. Scatter degrades the CBCT image quality by decreasing the contrast, introducing shading artifacts and leading to inaccuracies in the reconstructed CT number. We propose a blocker-based approach to simultaneously estimate scatter signal and reconstruct the complete volume within the field of view (FOV) from a single CBCT scan. A physical strip attenuator (i.e., "blocker"), consists of lead strips, is inserted between the x-ray source and the patient. The blocker moves back and forth along z-axis during the gantry rotation. The two-dimensional (2D) scatter fluence is estimated by interpolating the signal from the blocked regions. A modified Feldkamp-Davis-Kress (FDK) algorithm and an iterative reconstruction based on the constraint optimization are used to reconstruct CBCT images from un-blocked projection data after the scatter signal is subtracted. An experimental study is performed to evaluate the performance of the proposed scatter correction scheme. The scatter-induced shading/cupping artifacts are substantially reduced in CBCT using the proposed strategy. In the experimental study using a CatPhan©600 phantom, CT number errors in the selected regions of interest are reduced from 256 to less than 20. The proposed method allows us to simultaneously estimate the scatter signal in projection data, reduce the imaging dose and obtain complete volumetric information within the FOV.

  10. An N-methyl-d-aspartate receptor channel blocker with neuroprotective activity

    PubMed Central

    Tai, Kwok-Keung; Blondelle, Sylvie E.; Ostresh, John M.; Houghten, Richard A.; Montal, Mauricio

    2001-01-01

    Excitotoxicity, resulting from sustained activation of glutamate receptors of the N-methyl-d-aspartate (NMDA) subtype, is considered to play a causative role in the etiology of ischemic stroke and several neurodegenerative diseases. The NMDA receptor is therefore a target for the development of neuroprotective agents. Here, we identify an N-benzylated triamine (denoted as NBTA) as a highly selective and potent NMDA-receptor channel blocker selected by screening a reduced dipeptidomimetic synthetic combinatorial library. NBTA blocks recombinant NMDA receptors expressed in Xenopus laevis oocytes with a mean IC50 of 80 nM; in contrast, it does not block GluR1, a glutamate receptor of the non-NMDA subtype. The blocking activity of NBTA on NMDA receptors exhibits the characteristics of an open-channel blocker: (i) no competition with agonists, (ii) voltage dependence, and (iii) use dependence. Significantly, NBTA protects rodent hippocampal neurons from NMDA receptor, but not kainate receptor-mediated excitotoxic cell death, in agreement with its selective action on the corresponding recombinant receptors. Mutagenesis data indicate that the N site, a key asparagine on the M2 transmembrane segment of the NR1 subunit, is the main determinant of the blocker action. The results highlight the potential of this compound as a neuroprotectant. PMID:11248110

  11. beta-adrenergic receptor gene polymorphisms and beta-blocker treatment outcomes in hypertension.

    PubMed

    Pacanowski, M A; Gong, Y; Cooper-Dehoff, R M; Schork, N J; Shriver, M D; Langaee, T Y; Pepine, C J; Johnson, J A

    2008-12-01

    Numerous studies have demonstrated that beta(1)- and beta(2)-adrenergic receptor gene (ADRB1 and ADRB2) variants influence cardiovascular risk and beta-blocker responses in hypertension and heart failure. We evaluated the relationship between ADRB1 and ADRB2 haplotypes, cardiovascular risk (death, nonfatal myocardial infarction (MI), and nonfatal stroke), and atenolol-based vs. verapamil sustained-release (SR)-based antihypertensive therapy in 5,895 coronary artery disease (CAD) patients. After an average of 2.8 years, death rates were higher in patients carrying the ADRB1 Ser49-Arg389 haplotype (hazard ratio (HR) 3.66, 95% confidence interval (95% CI) 1.68-7.99). This mortality risk was significant in patients randomly assigned to verapamil SR (HR 8.58, 95% CI 2.06-35.8) but not atenolol (HR 2.31, 95% CI 0.82-6.55), suggesting a protective role for the beta-blocker. ADRB2 haplotype associations were divergent within the treatment groups but did not remain significant after adjustment for multiple comparisons. ADRB1 haplotype variation is associated with mortality risk, and beta-blockers may be preferred in subgroups of patients defined by ADRB1 or ADRB2 polymorphisms.

  12. α-Blockers for the Treatment of Chronic Prostatitis/Chronic Pelvic Pain Syndrome: An Update on Current Clinical Evidence

    PubMed Central

    Nickel, J. Curtis; Touma, Naji

    2012-01-01

    The pathogenesis of chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) is multifactorial, making its treatment difficult. Multimodal therapy including α-adrenergic antagonists (α-blockers), anti-inflammatory agents, and other pain treatments may provide optimal management for CP/CPPS. Although α-blockers are the most prescribed drugs for patients with CP/CPPS, not all studies support their efficacy. A recent meta-analysis of small trials suggested that treatment with α-blockers, possibly in combination with antibacterial agents, is efficacious in relieving symptoms. Third-generation α1A blockers (silodosin, tamsulosin) may provide efficacy as well as reduced cardiovascular side effects. Future research should aim to identify potential biomarkers associated with treatment response. PMID:23526487

  13. An Analysis of Beta-Blocker Administration Pre-and Post-Traumatic Brain Injury with Subanalyses for Head Injury Severity and Myocardial Injury.

    PubMed

    Edavettal, Mathew; Gross, Brian W; Rittenhouse, Katelyn; Alzate, James; Rogers, Amelia; Estrella, Lisa; Miller, Jo Ann; Rogers, Frederick B

    2016-12-01

    A growing body of literature indicates that beta-blocker administration after traumatic brain injury (TBI) is cerebroprotective, limiting secondary injury; however, the effects of preinjury beta blocker status remain poorly understood. We sought to characterize the effects of pre- and postinjury beta-blocker administration on mortality with subanalyses accounting for head injury severity and myocardial injury. In a Level II trauma center, all admissions of patients ≥18 years with a head Abbreviated Injury Scale Score ≥2, Glasgow Coma Scale ≤13 from May 2011 to May 2013 were queried. Demographic, injury-specific, and outcome variables were analyzed using univariate analyses. Subsequent multivariate analyses were conducted to determine adjusted odds of mortality for beta-blocker usage controlling for age, Injury Severity Score, head Abbreviated Injury Scale, arrival Glasgow Coma Scale, ventilator use, and intensive care unit stay. A total of 214 trauma admissions met inclusion criteria: 112 patients had neither pre- nor postinjury beta-blocker usage, 46 patients had preinjury beta-blocker usage, and 94 patients had postinjury beta-blocker usage. Both unadjusted and adjusted odds ratios of preinjury beta-blocker were insignificant with respect to mortality. However, postinjury in-hospital administration of beta blockers was found to significantly in the decrease of mortality in both univariate (P = 0.002) and multivariate analyses (P = 0.001). Our data indicate that beta-blocker administration post-TBI in hospital reduces odds of mortality; however, preinjury beta-blocker usage does not. Additionally, myocardial injury is a useful indicator for beta-blocker administration post-TBI. Further research into which beta blockers confer the best benefits as well as the optimal period of beta-blocker administration post-TBI is recommended.

  14. Beta Blockers Suppress Dextrose-Induced Endoplasmic Reticulum Stress, Oxidative Stress, and Apoptosis in Human Coronary Artery Endothelial Cells.

    PubMed

    Haas, Michael J; Kurban, William; Shah, Harshit; Onstead-Haas, Luisa; Mooradian, Arshag D

    Beta blockers are known to have favorable effects on endothelial function partly because of their capacity to reduce oxidative stress. To determine whether beta blockers can also prevent dextrose-induced endoplasmic reticulum (ER) stress in addition to their antioxidative effects, human coronary artery endothelial cells and hepatocyte-derived HepG2 cells were treated with 27.5 mM dextrose for 24 hours in the presence of carvedilol (a lipophilic beta blockers with alpha blocking activity), propranolol (a lipophilic nonselective beta blockers), and atenolol (a water-soluble selective beta blockers), and ER stress, oxidative, stress and cell death were measured. ER stress was measured using the placental alkaline phosphatase assay and Western blot analysis of glucose regulated protein 78, c-Jun-N-terminal kinase (JNK), phospho-JNK, eukaryotic initiating factor 2α (eIF2α), and phospho-eIF2α and measurement of X-box binding protein 1 (XBP1) mRNA splicing using reverse transcriptase-polymerase chain reaction. Superoxide (SO) generation was measured using the superoxide-reactive probe 2-methyl-6-(4-methoxyphenyl)-3,7-dihydroimidazo[1,2-A]pyrazin-3-one hydrochloride (MCLA) chemiluminescence. Cell viability was measured by propidium iodide staining method. The ER stress, SO production, and cell death induced by 27.5 mM dextrose were inhibited by all 3 beta blockers tested. The antioxidative and ER stress reducing effects of beta blockers were also observed in HepG2 cells. The salutary effects of beta blockers on endothelial cells in reducing both ER stress and oxidative stress may contribute to the cardioprotective effects of these agents.

  15. Anthracene based compounds as new L-type Ca2+ channel blockers: design, synthesis, and full biological profile.

    PubMed

    Bova, Sergio; Saponara, Simona; Rampa, Angela; Gobbi, Silvia; Cima, Lorenzo; Fusi, Fabio; Sgaragli, Giampietro; Cavalli, Maurizio; de los Rios, Cristobal; Striessnig, Jörg; Bisi, Alessandra

    2009-03-12

    L-Type Ca(2+) channels (LTCCs) play a key role in the regulation of vascular smooth muscle contraction, and substances that interfere with their function (Ca(2+) channel blockers) are widely used in the therapy of hypertension. Here, we report anthracene-maleimide derivatives as new LTCC blockers. Among these, 3, lacking intracellular effects, was investigated in more detail. The results show that 3 binds preferentially to inactivated LTCCs, directly interacting with the pore-forming subunit of the channel.

  16. Impact of alpha- and beta-adrenergic receptor blockers on fractional flow reserve and index of microvascular resistance.

    PubMed

    Barbato, Emanuele; Sarno, Giovanna; Berza, Catalina Trana; Di Gioia, Giuseppe; Bartunek, Jozef; Vanderheyden, Marc; Di Serafino, Luigi; Wijns, William; Trimarco, Bruno; De Bruyne, Bernard

    2014-12-01

    We investigated the effect of β- and α-adrenergic blockers on fractional flow reserve (FFR) and index of microvascular resistance (IMR). In 43 patients (pts) with intermediate stenoses, we measured FFR and IMR before and after nonselective β-blocker propranolol (30 μg/kg, n = 20) and selective β1-blocker metoprolol (40 μg/kg, n = 23) IC; (b) In additional 21 pts after percutaneous coronary intervention (PCI), FFR and IMR were measured before and after α-blocker phentolamine (3 mg) IC. Neither propranolol nor metoprolol changed values of FFR and IMR. Phentolamine slightly decreased FFR (from 0.88 ± 0.05 to 0.87 ± 0.06, p = 0.025) but did not change IMR. FFR decreased from >0.80 to ≤0.80 in 3 pts (14%), but in none, the value decreased to <0.75. β-blockers do not affect FFR and IMR in intermediate stenoses. After PCI, a mild decrease in FFR occurs after α-blockers, though of limited clinical impact.

  17. Comparative effect of angiotensin II type I receptor blockers and calcium channel blockers on laboratory parameters in hypertensive patients with type 2 diabetes

    PubMed Central

    2012-01-01

    Background Both angiotensin II type I receptor blockers (ARBs) and calcium channel blockers (CCBs) are widely used antihypertensive drugs. Many clinical studies have demonstrated and compared the organ-protection effects and adverse events of these drugs. However, few large-scale studies have focused on the effect of these drugs as monotherapy on laboratory parameters. We evaluated and compared the effects of ARB and CCB monotherapy on clinical laboratory parameters in patients with concomitant hypertension and type 2 diabetes mellitus. Methods We used data from the Clinical Data Warehouse of Nihon University School of Medicine obtained between Nov 1, 2004 and July 31, 2011, to identify cohorts of new ARB users (n = 601) and propensity-score matched new CCB users (n = 601), with concomitant mild to moderate hypertension and type 2 diabetes mellitus. We used a multivariate-adjusted regression model to adjust for differences between ARB and CCB users, and compared laboratory parameters including serum levels of triglyceride (TG), total cholesterol (TC), non-fasting blood glucose, hemoglobin A1c (HbA1c), sodium, potassium, creatinine, alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamyltransferase (GGT), hemoglobin and hematocrit, and white blood cell (WBC), red blood cell (RBC) and platelet (PLT) counts up to 12 months after the start of ARB or CCB monotherapy. Results We found a significant reduction of serum TC, HbA1c, hemoglobin and hematocrit and RBC count and a significant increase of serum potassium in ARB users, and a reduction of serum TC and hemoglobin in CCB users, from the baseline period to the exposure period. The reductions of RBC count, hemoglobin and hematocrit in ARB users were significantly greater than those in CCB users. The increase of serum potassium in ARB users was significantly greater than that in CCB users. Conclusions Our study suggested that hematological adverse effects and electrolyte imbalance are

  18. Telmisartan and amlodipine single-pill combinations vs amlodipine monotherapy for superior blood pressure lowering and improved tolerability in patients with uncontrolled hypertension: results of the TEAMSTA-5 study.

    PubMed

    Neldam, Steen; Lang, Margreet; Jones, Russell

    2011-07-01

    An 8-week, randomized, double-blind, controlled study with single-pill combinations of telmisartan 40 mg or 80 mg/amlodipine 5 mg (T40/A5 or T80/A5) vs monotherapy with amlodipine 5 mg or 10 mg (A10) in 1097 patients with uncontrolled hypertension (diastolic blood pressure [BP] ≥ 90 mm Hg). T40/A5 and T80/A5 resulted in significantly greater (P<.0001) reductions in seated trough systolic/diastolic BP vs A5 (-7.4 mm Hg/-3.6 mm Hg; -8.8 mm Hg/-4.9 mm Hg) and a significantly greater (P<.001) proportion of patients achieving systolic/diastolic BP goal rate (60.0%/56.7%; 65.7%/63.8%) vs A5 (39.2%/42.0%). Superior BP reductions were also seen with T40-T80/A5 vs A10, with BP goal rates at least as high as with A10; however, there was significantly more peripheral edema with A10 (27.2% vs 4.3% for pooled T40-T80/A5; P<.0001). Switching patients with uncontrolled BP to a single-pill combination of T40/A5 or T80/A5 is a better treatment option than up-titration to full-dose monotherapy with A10.

  19. Use of non-selective β-blockers is associated with decreased tumor proliferative indices in early stage breast cancer.

    PubMed

    Montoya, Alexa; Amaya, Clarissa N; Belmont, Andres; Diab, Nabih; Trevino, Richard; Villanueva, Geri; Rains, Steven; Sanchez, Luis A; Badri, Nabeel; Otoukesh, Salman; Khammanivong, Ali; Liss, Danielle; Baca, Sarah T; Aguilera, Renato J; Dickerson, Erin B; Torabi, Alireza; Dwivedi, Alok K; Abbas, Aamer; Chambers, Karinn; Bryan, Brad A; Nahleh, Zeina

    2017-01-24

    Previous studies suggest beta-adrenergic receptor (β-AR) antagonists (β-blockers) decrease breast cancer progression, tumor metastasis, and patient mortality; however the mechanism for this is unknown. Immunohistochemical analysis of normal and malignant breast tissue revealed overexpression of β1-AR and β3-AR in breast cancer. A retrospective cross-sectional study of 404 breast cancer patients was performed to determine the effect of β-blocker usage on tumor proliferation. Our analysis revealed that non-selective β-blockers, but not selective β-blockers, reduced tumor proliferation by 66% (p < 0.0001) in early stage breast cancer compared to non-users. We tested the efficacy of propranolol on an early stage breast cancer patient, and quantified the tumor proliferative index before and after treatment, revealing a propranolol-mediated 23% reduction (p = 0.02) in Ki67 positive tumor cells over a three-week period. The anti-proliferative effects of β-blockers were measured in a panel of breast cancer lines, demonstrating that mammary epithelial cells were resistant to propranolol, and that most breast cancer cell lines displayed dose dependent viability decreases following treatment. Selective β-blockers alone or in combination were not as effective as propranolol at reducing breast cancer cell proliferation. Molecular analysis revealed that propranolol treatment of the SK-BR-3 breast cancer line, which showed high sensitivity to beta blockade, led to a reduction in Ki67 protein expression, decreased phosphorylation of the mitogenic signaling regulators p44/42 MAPK, p38 MAPK, JNK, and CREB, increased phosphorylation of the cell survival/apoptosis regulators AKT, p53, and GSK3β. In conclusion, use of non-selective β-blockers in patients with early stage breast cancer may lead to decreased tumor proliferation.

  20. Use of non-selective β-blockers is associated with decreased tumor proliferative indices in early stage breast cancer

    PubMed Central

    Diab, Nabih; Trevino, Richard; Villanueva, Geri; Rains, Steven; Sanchez, Luis A.; Badri, Nabeel; Otoukesh, Salman; Khammanivong, Ali; Liss, Danielle; Baca, Sarah T.; Aguilera, Renato J.; Dickerson, Erin B.; Torabi, Alireza; Dwivedi, Alok K.; Abbas, Aamer; Chambers, Karinn; Bryan, Brad A.; Nahleh, Zeina

    2017-01-01

    Previous studies suggest beta-adrenergic receptor (β-AR) antagonists (β-blockers) decrease breast cancer progression, tumor metastasis, and patient mortality; however the mechanism for this is unknown. Immunohistochemical analysis of normal and malignant breast tissue revealed overexpression of β1-AR and β3-AR in breast cancer. A retrospective cross-sectional study of 404 breast cancer patients was performed to determine the effect of β-blocker usage on tumor proliferation. Our analysis revealed that non-selective β-blockers, but not selective β-blockers, reduced tumor proliferation by 66% (p < 0.0001) in early stage breast cancer compared to non-users. We tested the efficacy of propranolol on an early stage breast cancer patient, and quantified the tumor proliferative index before and after treatment, revealing a propranolol-mediated 23% reduction (p = 0.02) in Ki67 positive tumor cells over a three-week period. The anti-proliferative effects of β-blockers were measured in a panel of breast cancer lines, demonstrating that mammary epithelial cells were resistant to propranolol, and that most breast cancer cell lines displayed dose dependent viability decreases following treatment. Selective β-blockers alone or in combination were not as effective as propranolol at reducing breast cancer cell proliferation. Molecular analysis revealed that propranolol treatment of the SK-BR-3 breast cancer line, which showed high sensitivity to beta blockade, led to a reduction in Ki67 protein expression, decreased phosphorylation of the mitogenic signaling regulators p44/42 MAPK, p38 MAPK, JNK, and CREB, increased phosphorylation of the cell survival/apoptosis regulators AKT, p53, and GSK3β. In conclusion, use of non-selective β-blockers in patients with early stage breast cancer may lead to decreased tumor proliferation. PMID:28031536

  1. Incidence of medication error associated with the use of beta-blockers in Pakistan.

    PubMed

    Nesar, Shagufta; Shoaib, Muhammad Harris; Yousuf, Rabia Ismail; Rahim, Najia; Muhammad, Iyad Naeem

    2014-05-01

    Medication errors (ME) are human errors, which are very frequent in cardiovascular patients and result in patient morbidity and mortality. This study was focused to evaluate the quality of prescriptions and to emphasize the placement of clinical pharmacist in health care team. This study was carried out in different outpatient settings of (in) Karachi, Pakistan. The study period was June 2011 till June 2012. Retrospective data was analyzed for the outpatients' prescription of beta blocker drugs. During the study, prescriptions (n=450) were collected from different outpatient settings of (in) Karachi, Pakistan. Prescription containing beta-blockers were analyzed for the essential elements to be mentioned in prescription. Drug-drug interactions were identified by the Micromedex.2.0 Drug-Reax database and severity of medication error was determined by NCCMERP Index. A total of 1627 medication errors were identified in 450 prescriptions. The most frequent error was not mentioning the patient's weight (95%), followed by missing diagnosis (79.4%) and drug-drug interactions (69.5%). Twenty-two prescriptions were placed in the most severe category I (4.88%). Average number of drugs per prescription was 4.76. Significant difference was observed (χ(2)=52.418, p<0.05) using SPSS 19 for those prescription orders having more than 5 drugs with Beta-blockers. This indicates that the errors in prescription such as drug-drug interactions, wrong dose etc. was significantly increased with the number of drugs per prescription. Results showed that medication errors are very frequent in prescription written in outpatient setting of various hospitals and clinics in Karachi. This shows that the irrational prescribing is a common practice in developing countries. Placement of skilled pharmacist in the health care system is the only solution for avoidance of these medication related problems.

  2. Pro-survival function of MEF2 in cardiomyocytes is enhanced by β-blockers

    PubMed Central

    Hashemi, S; Salma, J; Wales, S; McDermott, JC

    2015-01-01

    β1-Adrenergic receptor (β1-AR) stimulation increases apoptosis in cardiomyocytes through activation of cAMP/protein kinase A (PKA) signaling. The myocyte enhancer factor 2 (MEF2) proteins function as important regulators of myocardial gene expression. Previously, we reported that PKA signaling directly represses MEF2 activity. We determined whether (a) MEF2 has a pro-survival function in cardiomyocytes, and (b) whether β-adrenergic/PKA signaling modulates MEF2 function in cardiomyocytes. Initially, we observed that siRNA-mediated gene silencing of MEF2 induces cardiomyocyte apoptosis as indicated by flow cytometry. β1-AR activation by isoproterenol represses MEF2 activity and promotes apoptosis in cultured neonatal cardiomyocytes. Importantly, β1-AR mediated apoptosis was abrogated in cardiomyocytes expressing a PKA-resistant form of MEF2D (S121/190A). We also observed that a β1-blocker, Atenolol, antagonizes isoproterenol-induced apoptosis while concomitantly enhancing MEF2 transcriptional activity. β-AR stimulation modulated MEF2 cellular localization in cardiomyocytes and this effect was reversed by β-blocker treatment. Furthermore, Kruppel-like factor 6, a MEF2 target gene in the heart, functions as a downstream pro-survival factor in cardiomyocytes. Collectively, these data indicate that (a) MEF2 has an important pro-survival role in cardiomyocytes, and (b) β-adrenergic signaling antagonizes the pro-survival function of MEF2 in cardiomyocytes and β-blockers promote it. These observations have important clinical implications that may contribute to novel strategies for preventing cardiomyocyte apoptosis associated with heart pathology. PMID:27551452

  3. Enantiomeric selectivity in adsorption of chiral β-blockers on sludge.

    PubMed

    Sanganyado, Edmond; Fu, Qiuguo; Gan, Jay

    2016-07-01

    Adsorption of weakly basic compounds by sludge is poorly understood, although it has important implications on the distribution and fate of such micropollutants in wastewater effluent and sludge. Additionally, many of these compounds are chiral, and it is likely that their interactions with sludge is stereoselective and that the process may be further modified by surfactants that coexist in these systems. Adsorption of (R) and (S)-enantiomers of five commonly used β-blockers, i.e., acebutolol, atenolol, metoprolol, pindolol and propranolol, on sludge was characterized through batch experiments. Stereoselectivity in adsorption increased with decreases in hydrophobicity of the β-blockers. The enantiomeric fraction (EF) of the amount of acebutolol, atenolol and metoprolol sorbed on sludge were 0.27, 0.55 and 0.32, respectively. Thus, Kd values of the (S)-enantiomers of acebutolol and metoprolol were approximately twice that of the (R)-enantiomer, that is, 109 ± 11 and 57 ± 8 L/kg compared to 52 ± 13 and 22 ± 8 L/kg, respectively. There was no statistically significant difference in Kd values of the enantiomers of pindolol and propranolol, suggesting stereoselectivity in adsorption was likely driven by specific polar interactions rather than hydrophobic interactions. The EF value of atenolol decreased from 0.55 ± 0.03 to 0.44 ± 0.04 after modifying the sludge with Triton X 100. These results suggested that surfactants altered adsorption of β-blockers to sludge, likely by forming ion pair complexes that promote hydrophobic interactions with the solid surfaces.

  4. Effect of RAAS blockers on adverse clinical outcomes in high CVD risk subjects with atrial fibrillation

    PubMed Central

    Chaugai, Sandip; Sherpa, Lhamo Yanchang; Sepehry, Amir A.; Arima, Hisatomi; Wang, Dao Wen

    2016-01-01

    Abstract Recent studies have demonstrated that atrial fibrillation significantly increases the risk of adverse clinical outcomes in high cardiovascular disease risk subjects. Application of renin–angiotensin–aldosterone system blockers for prevention of recurrence of atrial fibrillation and adverse clinical outcomes in subjects with atrial fibrillation is a theoretically appealing concept. However, results of clinical trials evaluating the effect of renin–angiotensin–aldosterone blockers on adverse clinical outcomes in high cardiovascular disease risk subjects with atrial fibrillation remain inconclusive. A pooled study of 6 randomized controlled trials assessing the efficacy of renin–angiotensin–aldosterone blockers on subjects with atrial fibrillation was performed. A total of 6 randomized controlled trials enrolled a total of 53,510 patients followed for 1 to 5 years. RAAS blockade therapy was associated with 14% reduction in the incidence of heart failure (OR: 0.86, [95%CI: 0.76– 0.97], P=0.018) and 17% reduction in the incidence of CVE (OR: 0.83, [95%CI: 0.70–0.99], P = 0.038). The corresponding decline in absolute risk against heart failure (ARR: 1.4%, [95%CI: 0.2–2.6%], P = 0.018) and CVE (ARR: 3.5%, [95%CI: 0.0–6.9%], P = 0.045) in the AF group was much higher than the non-AF group for heart failure (ARR: 0.4%, [95%CI: 0.0–0.7%], P = 0.057) and CVE (ARR: 1.6%, [95%CI: –0.1% to 3.3%], P = 0.071). No significant effect was noted on all-cause or cardiovascular mortality, stroke, or myocardial infarction. This study suggests that RAAS blockade offers protection against heart failure and cardiovascular events in high cardiovascular disease risk subjects with atrial fibrillation. PMID:27368043

  5. SU-E-I-08: Investigation of Deconvolution Methods for Blocker-Based CBCT Scatter Estimation

    SciTech Connect

    Zhao, C; Jin, M; Ouyang, L; Wang, J

    2015-06-15

    Purpose: To investigate whether deconvolution methods can improve the scatter estimation under different blurring and noise conditions for blocker-based scatter correction methods for cone-beam X-ray computed tomography (CBCT). Methods: An “ideal” projection image with scatter was first simulated for blocker-based CBCT data acquisition by assuming no blurring effect and no noise. The ideal image was then convolved with long-tail point spread functions (PSF) with different widths to mimic the blurring effect from the finite focal spot and detector response. Different levels of noise were also added. Three deconvolution Methods: 1) inverse filtering; 2) Wiener; and 3) Richardson-Lucy, were used to recover the scatter signal in the blocked region. The root mean square error (RMSE) of estimated scatter serves as a quantitative measure for the performance of different methods under different blurring and noise conditions. Results: Due to the blurring effect, the scatter signal in the blocked region is contaminated by the primary signal in the unblocked region. The direct use of the signal in the blocked region to estimate scatter (“direct method”) leads to large RMSE values, which increase with the increased width of PSF and increased noise. The inverse filtering is very sensitive to noise and practically useless. The Wiener and Richardson-Lucy deconvolution methods significantly improve scatter estimation compared to the direct method. For a typical medium PSF and medium noise condition, both methods (∼20 RMSE) can achieve 4-fold improvement over the direct method (∼80 RMSE). The Wiener method deals better with large noise and Richardson-Lucy works better on wide PSF. Conclusion: We investigated several deconvolution methods to recover the scatter signal in the blocked region for blocker-based scatter correction for CBCT. Our simulation results demonstrate that Wiener and Richardson-Lucy deconvolution can significantly improve the scatter estimation

  6. Acrolein-mediated conduction loss is partially restored by K+ channel blockers

    PubMed Central

    Yan, Rui; Page, Jessica C.

    2015-01-01

    Acrolein-mediated myelin damage is thought to be a critical mechanism leading to conduction failure following neurotrauma and neurodegenerative diseases. The exposure and activation of juxtaparanodal voltage-gated K+ channels due to myelin damage leads to conduction block, and K+ channel blockers have long been studied as a means for restoring axonal conduction in spinal cord injury (SCI) and multiple sclerosis (MS). In this study, we have found that 100 μM K+ channel blockers 4-aminopyridine-3-methanol (4-AP-3-MeOH), and to a lesser degree 4-aminopyridine (4-AP), can significantly restore compound action potential (CAP) conduction in spinal cord tissue following acrolein-mediated myelin damage using a well-established ex vivo SCI model. In addition, 4-AP-3-MeOH can effectively restore CAP conduction in acrolein-damaged axons with a range of concentrations from 0.1 to 100 μM. We have also shown that while both compounds at 100 μM showed no preference of small- and large-caliber axons when restoring CAP conduction, 4-AP-3-MeOH, unlike 4-AP, is able to augment CAP amplitude while causing little change in axonal responsiveness measured in refractory periods and response to repetitive stimuli. In a prior study, we show that 4-AP-3-MeOH was able to functionally rescue mechanically injured axons. In this investigation, we conclude that 4-AP-3-MeOH is an effective K+ channel blocker in restoring axonal conduction following both primary (physical) and secondary (chemical) insults. These findings also suggest that 4-AP-3-MeOH is a viable alternative of 4-AP for treating myelin damage and improving function following central nervous system trauma and neurodegenerative diseases. PMID:26581866

  7. Calcium channel blockers in the management of hypertension in the elderly.

    PubMed

    Caballero-Gonzalez, Francisco J

    2015-01-01

    The aging population is rapidly increasing, and is mainly due to medical advances and the control of chronic diseases, with a real worldwide increase in the elderly population. Special emphasis has been placed on the management of hypertension in the geriatric patient, since its long-term benefits have been shown to prevent both cerebral and cardiac infarctions. Calcium channel blockers have been shown to be effective in this condition in the elderly. Their success depends on their mechanism of action, as well as on the physiological changes observed, and on the aging process itself, which include cardiac hypertrophy, calcification of cardiac valves, and a decrease in the excitation-conduction system. There is thickening of the tunica intima of the arteries, and the production of nitric oxide at cellular level decreases with age, along with an increase in endothelin 1, which leads to vascular endothelium dysfunction. In the kidneys, there is a decrease in prostacyclin, endothelial hyperpolarization factor, as well as the Klotho anti-aging protein, which leads to an increase in blood pressure. Calcium channel blocker drugs have been shown to be effective in any age group for the management of hypertension, and are safe in the elderly patients. These drugs block L-type calcium channels, with the long-acting or latest generation dihydropyridines being the most effective of this group. Several studies, including SYST-EUR2, NORDIL, and STOP-2, have demonstrated the effectiveness of these drugs in the geriatric patient. The prescribing of long-acting calcium channel blocker drugs in a single dose is the most recommended. The safety in the use of this drug group has been demonstrated in the treatment of hypertension in the elderly patient, with a level of effectiveness similar to other widely used drugs.

  8. Electrically enhanced microextraction for highly selective transport of three β-blocker drugs.

    PubMed

    Seidi, Shahram; Yamini, Yadollah; Rezazadeh, Maryam

    2011-12-15

    Facilitated transport of three β-blocker drugs including atenolol (ATE), betaxolol (BET) and propranolol (PRO) was investigated under electrical field across a supported liquid membrane (SLM) using phosphoric acid derivatives as selective ion carriers, dissolved in 2-nitro phenyl octyl ether (NPOE). In the presence of di-(2-ethylhexyl) phosphate (DEHP) and tris-(2-ethylhexyl) phosphate (TEHP) in the membrane phase, the three β-blockers showed completely different transport behaviors which enabled highly selective separation of the drugs. Each β-blocker migrated from 3 mL of sample solutions, through a thin layer of specific organic solvent immobilized in the pores of a porous hollow fiber, and into a 15 μL acidic aqueous acceptor solution present inside the lumen of the fiber. The influences of fundamental parameters affecting the transport of target drugs including type of ion carrier for selective separation of each drug and its concentration in the membrane phase, extraction voltage, time of transport, pH of donor and acceptor phases, stirring speed of donor phase and salt effect were studied and optimized. After microextraction process, the extracts were analyzed by high-performance liquid chromatography with ultraviolet detection. Under optimal conditions, ATE was selectively extracted from different saliva samples with recovery of 37%, which corresponded to preconcentration factor of 74. A good linearity was achieved for calibration curve with a coefficient of determination higher than 0.997. Limits of detection and intra-day precision (n=3) were less than 2 μg L(-1) and 8.8%, respectively.

  9. Novel blockers of hyperpolarization-activated current with isoform selectivity in recombinant cells and native tissue.

    PubMed

    Del Lungo, Martina; Melchiorre, Michele; Guandalini, Luca; Sartiani, Laura; Mugelli, Alessandro; Koncz, Istvan; Szel, Tamas; Varro, Andras; Romanelli, Maria Novella; Cerbai, Elisabetta

    2012-05-01

    BACKGROUND AND PURPOSE Selective hyperpolarization activated, cyclic nucleotide-gated channel (HCN) blockers represent an important therapeutic goal due to the wide distribution and multiple functions of these proteins, representing the molecular correlate of f- and h-current (I(f) or I(h) ). Recently, new compounds able to block differentially the homomeric HCN isoforms expressed in HEK293 have been synthesized. In the present work, the electrophysiological and pharmacological properties of these new HCN blockers were characterized and their activities evaluated on native channels. EXPERIMENTAL APPROACH HEK293 cells expressing mHCN1, mHCN2 and hHCN4 isoforms were used to verify channel blockade. Selected compounds were tested on native guinea pig sinoatrial node cells and neurons from mouse dorsal root ganglion (DRG) by patch-clamp recordings and on dog Purkinje fibres by intracellular recordings. KEY RESULTS In HEK293 cells, EC18 was found to be significantly selective for HCN4 and MEL57A for HCN1 at physiological membrane potential. When tested on guinea pig sinoatrial node cells, EC18 (10 µM) maintained its activity, reducing I(f) by 67% at -120 mV, while MEL57A (3 µM) reduced I(f) by 18%. In contrast, in mouse DRG neurons, only MEL57A (30 and 100 µM) significantly reduced I(h) by 60% at -80 mV. In dog cardiac Purkinje fibres, EC18, but not MEL57A, reduced the amplitude and slowed the slope of the spontaneous diastolic depolarization. CONCLUSIONS Our results have identified novel and highly selective HCN isoform blockers, EC18 and MEL57A; the selectivity found in recombinant system was maintained in various tissues expressing different HCN isoforms.

  10. Comparative effects of sodium channel blockers in short term rat whole embryo culture

    SciTech Connect

    Nilsson, Mats F; Sköld, Anna-Carin; Ericson, Ann-Christin; Annas, Anita; Villar, Rodrigo Palma; Cebers, Gvido; Hellmold, Heike; Gustafson, Anne-Lee; Webster, William S

    2013-10-15

    This study was undertaken to examine the effect on the rat embryonic heart of two experimental drugs (AZA and AZB) which are known to block the sodium channel Nav1.5, the hERG potassium channel and the L-type calcium channel. The sodium channel blockers bupivacaine, lidocaine, and the L-type calcium channel blocker nifedipine were used as reference substances. The experimental model was the gestational day (GD) 13 rat embryo cultured in vitro. In this model the embryonic heart activity can be directly observed, recorded and analyzed using computer assisted image analysis as it responds to the addition of test drugs. The effect on the heart was studied for a range of concentrations and for a duration up to 3 h. The results showed that AZA and AZB caused a concentration-dependent bradycardia of the embryonic heart and at high concentrations heart block. These effects were reversible on washout. In terms of potency to cause bradycardia the compounds were ranked AZB > bupivacaine > AZA > lidocaine > nifedipine. Comparison with results from previous studies with more specific ion channel blockers suggests that the primary effect of AZA and AZB was sodium channel blockage. The study shows that the short-term rat whole embryo culture (WEC) is a suitable system to detect substances hazardous to the embryonic heart. - Highlights: • Study of the effect of sodium channel blocking drugs on embryonic heart function • We used a modified method rat whole embryo culture with image analysis. • The drugs tested caused a concentration dependent bradycardia and heart block. • The effect of drugs acting on multiple ion channels is difficult to predict. • This method may be used to detect cardiotoxicity in prenatal development.

  11. Ozonation of reverse osmosis concentrate: kinetics and efficiency of beta blocker oxidation.

    PubMed

    Benner, Jessica; Salhi, Elisabeth; Ternes, Thomas; von Gunten, Urs

    2008-06-01

    Reverse osmosis (RO) concentrate samples were obtained from a RO-membrane system that uses effluents of wastewater treatment plants (WWTP) as feed water for the production of drinking water. A number of different pharmaceuticals (e.g. antibiotics, contrast media, beta blockers) were found in the WWTP effluent as well as in the RO-concentrate. Overall, a concentration factor (feed:concentrate) of approximately 3-4 was measured. Beta blockers (acebutolol, atenolol, bisoprolol, celiprolol, metoprolol, propranolol, timolol) were found in the range of low ng/L to low microg/L. Because metoprolol and propranolol are classified as potentially toxic to aquatic organisms and all beta blocker molecules have moieties, which are reactive towards ozone (amine groups, activated aromatic rings), it was tested whether ozonation can be applied for their mitigation. Rate constants for the reaction of acebutolol, atenolol, metoprolol and propranolol with ozone and OH radicals were determined. At pH 7 acebutolol, atenolol and metoprolol react with ozone with an apparent second-order rate constant k(O)(3) of about 2,000 M(-1)s(-1), whereas propranolol reacts with approximately 10(5)M(-1)s(-1). The rate constants for the reaction of the selected compounds with OH radicals were determined to be 0.5-1.0 x 10(10)M(-1)s(-1). Experiments with RO concentrate showed that an ozone dose of only 5mg/L resulted in a quantitative removal of propranolol in 0.8s and 10mg O(3)/L oxidized 70% of metoprolol in only 1.2s. Tests with chlorinated and non-chlorinated WWTP effluent showed an increase of ozone stability but a decrease of hydroxyl radical exposure in the samples after chlorination. This may shift the oxidation processes towards direct ozone reactions and favor the degradation of compounds with high k(O)(3).

  12. A real-time screening assay for GIRK1/4 channel blockers.

    PubMed

    Walsh, Kenneth B

    2010-12-01

    The cardiac acetylcholine-activated K(+) channel (I(K,Ach)) represents a novel target for drug therapy in the treatment of atrial fibrillation (AF). This channel is a member of the G-protein-coupled inward rectifier K(+) (GIRK) channel superfamily and is composed of the GIRK1/4 (Kir3.1 and Kir3.4) subunits. The goal of this study was to develop a cell-based screening assay for identifying new blockers of the GIRK1/4 channel. The mouse atrial HL-1 cell line, expressing the GIRK1/4 channel, was plated in 96-well plate format, loaded with the fluorescent membrane potential-sensitive dye bis-(1,3-dibutylbarbituric acid) trimethine oxonol (DiBAC(4)(3)) and measured using a fluorescent imaging plate reader (FLIPR). Application of the muscarinic agonist carbachol to the cells caused a rapid, time-dependent decrease in the fluorescent signal, indicative of K(+) efflux through the GIRK1/4 channel (carbachol vs. control solution, Z' factor = 0.5-0.6). The GIRK1/4 channel fluorescent signal was blocked by BaCl(2) and enhanced by increasing the driving force for K(+) across the cell membrane. To test the utility of the assay for screening GIRK1/4 channel blockers, cells were treated with a small compound library of Na(+) and K(+) channel modulators. Analogues of amiloride and propafenone were identified as channel blockers at concentrations less than 1 µM. Thus, the GIRK1/4 channel assay may be used in the development of new and selective agents for treating AF.

  13. Experts Consensus Recommendations for the Management of Calcium Channel Blocker Poisoning in Adults

    PubMed Central

    Anseeuw, Kurt; Cantrell, Frank Lee; Gilchrist, Ian C.; Hantson, Philippe; Bailey, Benoit; Lavergne, Valéry; Gosselin, Sophie; Kerns, William; Laliberté, Martin; Lavonas, Eric J.; Juurlink, David N.; Muscedere, John; Yang, Chen-Chang; Sinuff, Tasnim; Rieder, Michael; Mégarbane, Bruno

    2017-01-01

    Objective: To provide a management approach for adults with calcium channel blocker poisoning. Data Sources, Study Selection, and Data Extraction: Following the Appraisal of Guidelines for Research & Evaluation II instrument, initial voting statements were constructed based on summaries outlining the evidence, risks, and benefits. Data Synthesis: We recommend 1) for asymptomatic patients, observation and consideration of decontamination following a potentially toxic calcium channel blocker ingestion (1D); 2) as first-line therapies (prioritized based on desired effect), IV calcium (1D), high-dose insulin therapy (1D–2D), and norepinephrine and/or epinephrine (1D). We also suggest dobutamine or epinephrine in the presence of cardiogenic shock (2D) and atropine in the presence of symptomatic bradycardia or conduction disturbance (2D); 3) in patients refractory to the first-line treatments, we suggest incremental doses of high-dose insulin therapy if myocardial dysfunction is present (2D), IV lipid-emulsion therapy (2D), and using a pacemaker in the presence of unstable bradycardia or high-grade arteriovenous block without significant alteration in cardiac inotropism (2D); 4) in patients with refractory shock or who are periarrest, we recommend incremental doses of high-dose insulin (1D) and IV lipid-emulsion therapy (1D) if not already tried. We suggest venoarterial extracorporeal membrane oxygenation, if available, when refractory shock has a significant cardiogenic component (2D), and using pacemaker in the presence of unstable bradycardia or high-grade arteriovenous block in the absence of myocardial dysfunction (2D) if not already tried; 5) in patients with cardiac arrest, we recommend IV calcium in addition to the standard advanced cardiac life-support (1D), lipid-emulsion therapy (1D), and we suggest venoarterial extracorporeal membrane oxygenation if available (2D). Conclusion: We offer recommendations for the stepwise management of calcium channel blocker

  14. Acrolein-mediated conduction loss is partially restored by K⁺ channel blockers.

    PubMed

    Yan, Rui; Page, Jessica C; Shi, Riyi

    2016-02-01

    Acrolein-mediated myelin damage is thought to be a critical mechanism leading to conduction failure following neurotrauma and neurodegenerative diseases. The exposure and activation of juxtaparanodal voltage-gated K(+) channels due to myelin damage leads to conduction block, and K(+) channel blockers have long been studied as a means for restoring axonal conduction in spinal cord injury (SCI) and multiple sclerosis (MS). In this study, we have found that 100 μM K(+) channel blockers 4-aminopyridine-3-methanol (4-AP-3-MeOH), and to a lesser degree 4-aminopyridine (4-AP), can significantly restore compound action potential (CAP) conduction in spinal cord tissue following acrolein-mediated myelin damage using a well-established ex vivo SCI model. In addition, 4-AP-3-MeOH can effectively restore CAP conduction in acrolein-damaged axons with a range of concentrations from 0.1 to 100 μM. We have also shown that while both compounds at 100 μM showed no preference of small- and large-caliber axons when restoring CAP conduction, 4-AP-3-MeOH, unlike 4-AP, is able to augment CAP amplitude while causing little change in axonal responsiveness measured in refractory periods and response to repetitive stimuli. In a prior study, we show that 4-AP-3-MeOH was able to functionally rescue mechanically injured axons. In this investigation, we conclude that 4-AP-3-MeOH is an effective K(+) channel blocker in restoring axonal conduction following both primary (physical) and secondary (chemical) insults. These findings also suggest that 4-AP-3-MeOH is a viable alternative of 4-AP for treating myelin damage and improving function following central nervous system trauma and neurodegenerative diseases.

  15. Global chemical reactivity parameters for several chiral beta-blockers from the Density Functional Theory viewpoint

    PubMed Central

    TALMACIU, MONA MARIA; BODOKI, EDE; OPREAN, RADU

    2016-01-01

    Background and aim Beta-adrenergic antagonists have been established as first line treatment in the medical management of hypertension, acute coronary syndrome and other cardiovascular diseases, as well as for the prevention of initial episodes of gastrointestinal bleeding in patients with cirrhosis and esophageal varices, glaucoma, and have recently become the main form of treatment of infantile hemangiomas. The aim of the present study is to calculate for 14 beta-blockers several quantum chemical descriptors in order to interpret various molecular properties such as electronic structure, conformation, reactivity, in the interest of determining how such descriptors could have an impact on our understanding of the experimental observations and describing various aspects of chemical binding of beta-blockers in terms of these descriptors. Methods The 2D chemical structures of the beta-blockers (14 molecules with one stereogenic center) were cleaned in 3D, their geometry was preoptimized using the software MOPAC2012, by PM6 method, and then further refined using standard settings in MOE; HOMO and LUMO descriptors were calculated using semi-empirical molecular orbital methods AM1, MNDO and PM3, for the lowest energy conformers and the quantum chemical descriptors (HLG, electronegativity, chemical potential, hardness and softness, electrophilicity) were then calculated. Results According to HOMO-LUMO gap and the chemical hardness the most stable compounds are alprenolol, bisoprolol and esmolol. The softness values calculated for the study molecules revolve around 0.100. Propranolol, sotalol and timolol have among the highest electrophilicity index of the studied beta-blocker molecules. Results obtained from calculations showed that acebutolol, atenolol, timolol and sotalol have the highest values for the electronegativity index. Conclusions The future aim is to determine whether it is possible to find a valid correlation between these descriptors and the physicochemical

  16. Development of a highly cardioselective ultra short-acting beta-blocker, ONO-1101.

    PubMed

    Iguchi, S; Iwamura, H; Nishizaki, M; Hayashi, A; Senokuchi, K; Kobayashi, K; Sakaki, K; Hachiya, K; Ichioka, Y; Kawamura, M

    1992-06-01

    A novel, highly cardioselective ultra short-acting beta-blocker, ONO-1101, has been developed for application in the emergency treatment of tachycardia and better control of heart rate in surgery. This agent is approximately nine times more potent in beta-blocking activity in vivo and eight times more cardioselective in vitro than esmolol. This beta-blocking drug has a short duration of activity, enabling rapid recovery after cessation of administration if side effects occur. It can be used safely in patients suffering from acute heart disease and represents a major therapeutic advance in the treatment of heart disease.

  17. Synthesis and biological evaluation of oxazole derivatives as T-type calcium channel blockers.

    PubMed

    Lee, Jie Eun; Koh, Hun Yeong; Seo, Seon Hee; Baek, Yi Yeon; Rhim, Hyewhon; Cho, Yong Seo; Choo, Hyunah; Pae, Ae Nim

    2010-07-15

    T-type calcium channel is one of therapeutic targets for the treatment of cardiovascular diseases and neuropathic pain. In this study, as a part of our ongoing efforts to develop potent T-type calcium channel blockers, we designed oxazole derivatives substituted with arylpiperazinylalkylamines. The oxazoles were synthesized in a convenient convergent synthetic method, and biologically evaluated against alpha(1G) (Ca(V)3.1) T-type calcium channel. Among total 41 oxazole compounds synthesized, the most active one was the compound 10-35 with an IC(50) value of 0.65 microM, which is comparable with that of mibefradil.

  18. PRISMA-combined α-blockers and antimuscarinics for ureteral stent-related symptoms

    PubMed Central

    Zhang, Yu-ming; Chu, Pei; Wang, Wen-jin

    2017-01-01

    Abstract Background: As a monotherpay, a-blockers and anti-muscarinics are both efficacy for ureteral stent-related symptoms (SRS). The aim of the study was to systematically evaluate their efficacy of a combination therapy for SRS. Methods: Relevant studies investigating α-blockers and/or anti-muscarinics for SRS were identified though searching online databases including PubMed, EMBASE, Cochrane Library, and other sources up to March 2016. The RevMan software was used for data analysis, and senesitivity analysis and inverted funnel plot were also adopted. Results: Seven randomized controlled trials (RCTs) and 1 prospective controlled trial including 545 patients were selected. Compared with α-blockers, the combination group achieved significant improvements in total International Prostate Symptom Score (IPSS) [–3.93 (2.89, 4.96), P < 0.00001], obstructive subscore [–1.29 (0.68, 1.89), P < 0.0001], irritative subscore [–2.93 (2.18, 3.68), P < 0.00001], and quality of life score [–0.99 (0.42, 1.55), P < 0.001]. Compared with antimuscarinics, there were also significant differences in total IPSS [–3.49 (2.43, 4.55), P < 0.00001], obstructive subscore [–1.40 (0.78, 2.01), P < 0.00001], irritative subscore [–2.10 (1.30, 2.90), P < 0.00001], and quality of life score [–1.18 (0.58, 1.80), P < 0.001] in favor of combination group. No significant difference was found in the visual analog pain score and the urinary symptoms score in Ureteral Stent Symptom Questionnaire (USSQ). No significant difference in complications was found. Conclusions: Current analysis shows significant advantages of combination therapy compared with monotherapy of α-blockers or antimuscarinics alone mainly based on IPSS. More RCTs adopting validated USSQ as outcome measures are warranted to support the finding. PMID:28207522

  19. Management of beta-adrenergic blocker and calcium channel antagonist toxicity.

    PubMed

    Kerns, William

    2007-05-01

    State-of-the-art therapy for beta-adrenergic receptor blocker and calcium channel antagonist toxicity is reviewed in the light of new insights into drug-induced shock. A brief discussion of pathophysiology, including cardiac, hemodynamic, and metabolic effects of cardiac drug toxicity, provides a foundation for understanding the basis of therapy. The major focus of this review is a critical evaluation of antidotal use of calcium, glucagon, catecholamines, insulin-euglycemia, and other novel therapies based on investigational studies and cumulative clinical experience.

  20. Intraoperative Extracorporeal Carbon Dioxide Removal During Apneic Oxygenation with an EZ-Blocker in Tracheal Surgery.

    PubMed

    Rispoli, Marco; Nespoli, Moana Rossella; Mattiacci, Dario Maria; Esposito, Marianna; Corcione, Antonio; Buono, Salvatore

    2016-06-01

    Tracheal surgery requires continued innovation to manage the anesthetic during an open airway phase. A common approach is apneic oxygenation with continuous oxygen flow, but the lack of effective ventilation causes hypercapnia, with respiratory acidosis. We used extracorporeal carbon dioxide removal for intraoperative decapneization during apneic oxygenation in a 64-year-old woman who was scheduled for tracheal surgery because of tracheal stenosis caused by long-term intubation. Our findings demonstrate that even after 40 minutes of total apnea, using an EZ-blocker for oxygenation and external decapneization, hemodynamic and gas exchange variables never demonstrated any dangerous alterations.

  1. Two functionally distinct subsites for the binding of internal blockers to the pore of voltage-activated K+ channels

    PubMed Central

    Baukrowitz, Thomas; Yellen, Gary

    1996-01-01

    Many blockers of Na+ and K+ channels act by blocking the pore from the intracellular side. For Shaker K+ channels, such intracellular blockers vary in their functional effect on slow (C-type) inactivation: Some blockers interfere with C-type inactivation, whereas others do not. These functional differences can be explained by supposing that there are two overlapping “subsites” for blocker binding, only one of which inhibits C-type inactivation through an allosteric effect. We find that the ability to bind to these subsites depends on specific structural characteristics of the blockers, and correlates with the effect of mutations in two distinct regions of the channel protein. These interactions are important because they affect the ability of blockers to produce use-dependent inhibition. PMID:8917595

  2. Influence of the previous use of β-blockers on the early clinical course of acute coronary syndromes.

    PubMed

    Garcia-Rubira, Juan Carlos; Almendro-Delia, Manuel; Calvo-Taracido, Manuel; Blanco-Ponce, Emilia; Bastos-Amador, Pablo; Reina-Toral, Antonio; Calvo-Jambrina, Roman; Cruz-Fernández, José Maria; Garcia-Alcántara, Angel; Hidalgo-Urbano, Rafael

    2015-10-01

    Recent studies have recently questioned the current role of β-blockers in myocardial infarction. Our purpose is to analyze the influence of the previous use of β-blockers on the early course of patients admitted because of acute coronary syndrome (ACS). We analyzed the data of 37.359 patients included in the ARIAM-Andalucia Registry. Of them, 7759 (20.8%) were previously receiving β-blockers. BB patients were older, more often female, had more risk factors and vascular disease, and less often had an ST-elevation myocardial infarction. In the unadjusted analysis, BB patients less often had ventricular fibrillation or atrioventricular block, and more often a Killip classification >1, and no difference of in-hospital mortality (5.7 vs 5.6%). After logistic regression analysis and propensity score matching, no differences in complications or mortality (odds ratio 0.997, 95% confidence interval 0.882-1.128) were found in relationship to previous β-blockers. In conclusion, we find that the previous administration of β-blockers is not an independent predictor of the early prognosis of ACS.

  3. Effects of beta-adrenergic blockers with different ancillary properties on lipid peroxidation in hyperthyroid rat cardiac muscle.

    PubMed

    Asayama, K; Dobashi, K; Hayashibe, H; Kato, K

    1989-10-01

    To determine whether beta-blockade protects rat heart against thyroxine (T4)-induced accelelation of lipid peroxidation, in vivo effects of 3 beta-blockers with different ancillary properties on the mitochondrial oxidative enzyme, antioxidant enzymes and lipid peroxide were investigated. The rats were rendered hyperthyroid by adding T4 to their drinking water for 3 weeks and were treated simultaneously with either carteolol (a blocker with partial agonist activity; 30 mg/kg/day), atenolol (50 mg/kg/day) or arotinolol (a blocker with weak alpha-blocking action; 50 mg/kg/day). The T4-induced tachycardia was alleviated completely by either atenolol or arotinolol, but only partially by carteolol. Cytochrome c oxidase activity in the heart muscle was increased by T4 with a parallel increase in manganese (mitochondrial) superoxide dismutase. Atenolol, but neither carteolol nor arotinolol, suppressed this increase. Similarly, the T4-induced acceleration of lipid peroxidation was suppressed by atenolol alone. Glutathione peroxidase was markedly decreased, and both copper zinc (cytosolic) superoxide dismutase and catalase were also decreased or tended to be decreased by T4. The levels of these 3 enzymes were only minimally affected by the beta-blocker treatments. These results suggest that beta-blockade suppresses mitochondrial hypermetabolism and protects heart muscle against oxidative stress in hyperthyroidism, and that the ancillary properties of beta-blockers such as partial agonist activity and alpha-blocking action negate the protection.

  4. Blue blocker glasses impede the capacity of bright light to suppress melatonin production.

    PubMed

    Sasseville, Alexandre; Paquet, Nathalie; Sévigny, Jean; Hébert, Marc

    2006-08-01

    Blocking morning light exposure with dark goggles can contribute to the adjustment to night work but these glasses are incompatible with driving. Recently, it was discovered that the biological clock is most sensitive to short wavelengths (blue light). Therefore, we tested the hypothesis that cutting the blue portion of the light spectrum with orange lens glasses (blue blockers) would prevent the light-induced melatonin suppression, a test broadly used as an indirect assessment of the circadian clock sensitivity. Fourteen normal subjects were exposed at night to a 60 min bright light pulse (1300 lx behind filters) between 01:00 and 02:00 hr while wearing orange lens glasses (experimental condition) or grey lens glasses (control condition). The amount of salivary melatonin change observed during the light pulse was compared with a melatonin baseline obtained the night before. Although both glasses transmitted the same illuminance (1300 lx) but at an irradiance 25% higher for the orange lens (408 microW/cm2) compared with the grey lens (327 microW/cm2), a non-significant increase of 6% (95% CI, -20% to 9%) was observed with the orange lens whereas a significant (P < 0.05) reduction of 46% (95% CI, 35-57%) was observed with the grey lens. Blue blockers represent an elegant means to prevent the light-induced melatonin suppression. Further studies are needed to show that these glasses, which are suitable for driving, could facilitate adaptation to night work.

  5. Bean amylase inhibitor and other carbohydrate absorption blockers: effects on diabesity and general health.

    PubMed

    Preuss, Harry G

    2009-06-01

    Many believe that excessive intake of refined carbohydrates (CHO) plays a major role in the development of obesity/overweight, type 2 diabetes mellitus and insulin resistance, a collection of events commonly referred to as "diabesity," and have sought natural means to overcome these linked perturbations. As a first approach, planned diets with low portions of refined CHO have become popular. However, these diets do not satisfy everyone; and many are concerned over replacing CHO with more fats. As a second option, addition of soluble fiber to the diet can slow absorption of refined CHO, i.e., lower the glycemic index of foods and overcome or at least ameliorate many of the adverse reactions resulting from increased refined CHO ingestion. Unfortunately, the general public does not favor diets high in fiber content, and various fibers can lead to gastrointestinal problems such as gas and diarrhea. A third choice to favorably influence CHO absorption is to use natural dietary supplements that block or slow CHO absorption in the gastrointestinal tract via inhibiting enzymes necessary for CHO absorption -amylase and alpha-glucosidases. Although a number of natural supplements with anti-amylase activity have been recognized, the most studied and favored one is white kidney bean extract. Animal and human studies clearly show that this agent works in vivo and has clinical utility. This paper reviews many aspects of diabesity and the use of "carb blockers" to prevent and ameliorate the situation. In many respects, carb blockers mimic the beneficial effects of fibers.

  6. Comparison of annual cost between brand and generic ocular beta-adrenergic blockers.

    PubMed

    Ikeda, Hiroaki; Tsukamoto, Hidetoshi; Sawa, Akihiro; Sugimoto, Ayako; Mishima, Hiromu; Kihira, Kenji

    2005-05-01

    We conducted a study of the annual cost of various ophthalmic products used in Japan for treating glaucoma including six of brands and generic ocular beta-adrenergic blockers (38 products). The total number of drops in one bottle of each solution was counted drop by drop. The cost per drop was calculated by dividing the government-controlled standard prices by the total number of drops in one bottle. The annual cost of ophthalmic solution was calculated by multiplying the cost per drop by the number of drops typically used per day. The total number of drops of the ophthalmic solutions in one bottle ranged from 108 to 168. The yearly cost of the beta-adrenergic blockers studied ranged widely, from yen 5392 to yen 27236. Differences in the total number of drops and the usage effect on the annual cost of ophthalmic solutions were found. The annual cost depended on not only the price of the products but also on the total number of drops in one bottle and the usage. Annual cost data may be helpful in selecting ophthalmic products for treating glaucoma in Japan.

  7. Non-additive interactions between mitochondrial complex IV blockers and hypoxia in rat carotid body responses

    PubMed Central

    Donnelly, David F; Kim, Insook; Mulligan, Eileen M; Carroll, John L

    2013-01-01

    The metabolic hypothesis of carotid body chemoreceptor hypoxia transduction proposes an impairment of ATP production as the signal for activation. We hypothesized that mitochondrial complex IV blockers and hypoxia would act synergistically in exciting afferent nerve activity. Following a pretreatment with low dosage sodium cyanide (10-20μM), the hypoxia-induced nerve response was significantly reduced along with hypoxia-induced catecholamine release. However, in isolated glomus cells, the intracellular calcium response was enhanced as initially predicted. This suggests a cyanide-mediated impairment in the step between the glomus cell intracellular calcium rise and neurotransmitter release from secretory vesicles. Administration of a PKC blocker largely reversed the inhibitory actions of cyanide on the neural response. We conclude that the expected synergism between cyanide and hypoxia occurs at the level of glomus cell intracellular calcium but not at downstream steps due to a PKC-dependent inhibition of secretion. This suggests that at least one regulatory step beyond the glomus cell calcium response may modulate the magnitude of chemoreceptor responsiveness. PMID:24096081

  8. Effects of calcium channel blockers on cloned cardiac K+ channels IKr and IKs.

    PubMed

    Chouabe, C; Drici, M D; Romey, G; Barhanin, J

    2000-01-01

    Cloned HERG and KvLQT1-IsK K+ channels have been expressed in mammalian cells and assayed as a target for calcium channel blockers. These channels generate the rapid and slow components of the cardiac delayed rectifier K+ current, and mutations can affect them that lead to long QT syndromes. HERG is blocked by bepridil (EC50 = 0.55 microM), verapamil (EC50 = 0.83 microM) and mibefradil (EC50 = 1.43 microM), whereas nitrendipine and diltiazem have negligible effects. Steady-state activation and inactivation parameters are shifted to more negative values in the presence of the blockers. Similarly, KvLQT1-IsK is inhibited by bepridil (EC50 = 10.0 microM) and mibefradil (EC50 = 11.8 microM), whilst being insensitive to nitrendipine, diltiazem or verapamil. This work may help to understand the mechanisms of action of verapamil in certain ventricular tachycardias as well as some of the deleterious adverse cardiac events associated with bepridil and mibefradil.

  9. Chiral Recognition Mechanisms of four β-Blockers by HPLC with Amylose Chiral Stationary Phase

    PubMed Central

    Wang, Dongmei; Li, Fang; Jiang, Zhen; Yu, Li; Guo, Xingjie

    2014-01-01

    The high performance liquid chromatography (HPLC) enantioseparation of four β-blocking agents metoprolol, bisoprolol, propranolol and atenolol was performed on amylose tris-(3,5-dimethylphenylcarbamate) chiral stationary phase using n-hexane-ethanol-diethylamine (DEA) as the mobile phase and related chiral recognition mechanisms were discussed. Enantiomeric separation of the four β-blockers was a result of more than one type of interaction between solutes and CSP. Besides hydrogen bonding, there was another type interaction that was independent of solvent polarity and responsible for enantiomeric selectivity, such as - interactions. Both the groups close to the chiral centers and the substituent groups on the phenyl rings, which were far away from the chiral centers, could contribute to the good separation. The separations of the four β-blocker enantiomers were all enthalpy driven process. In the range of 293–308K (20–35 ℃), as the temperature increased, the retention as well as the resolution decreased. The molecular size rather than concentration of the alcohol modifiers affected the resolution and retention. PMID:25237340

  10. [Treatment of arrhythmia in coronary patients and hypertensives with beta blockers and Depasan retard].

    PubMed

    Kandziora, J

    1981-05-14

    In the ambulatory of an internal specialist a number of patients suffering from angina pectoris or hypertonia together with arrhythmic troubles received an initial treatment with beta-blockers over a period of 21 days. In cases in which arrhythmia persisted after this initial period the treatment was continued for another 21 days with the addition of Depasan retard in function of a second medicament. This combined treatment in form of an open study was extended to a total number of 50 patients presenting ventricular extrasystolia in 45 cases and in 5 cases absolute arrhythmia in addition to the main disease. Treatment with Depasan retard showed good or satisfactory results in 39 out of 45 patients suffering from ventricular extrasystoles, whilst no effect could be obtained in the 5 cases with absolute arrhythmia. No signs of incompatibility or unwanted interactions were observed in the course of this open study. Based on these results it can be concluded that Depasan retard should be recommended in those cases where on account of persistent arrhythmical troubles and especially extrasystoles, during a treatment with beta-blockers in patients suffering from angina pectoris or hypertonia, and additional treatment with anti-arrhythmical medicaments appears to be indicated.

  11. Inhibition of purified lysosomal phospholipase A1 by beta-adrenoceptor blockers.

    PubMed

    Pappu, A S; Yazaki, P J; Hostetler, K Y

    1985-02-15

    Inhibition of rat liver lysosomal phospholipases is one of the main events that leads to accumulation of tissue phospholipids during drug-induced phospholipidosis. Drug inhibition of lysosomal phospholipase A may occur by direct effects of drugs on the enzyme (or substrate) or by drug-induced increases in intralysosomal pH. Although beta-adrenoceptor blockers have not been reported to cause lipid storage, they do inhibit lysosomal phospholipase A. To investigate the structural requirements for drug inhibition, we studied the effects of six beta-adrenoceptor blockers on purified rat liver lysosomal phospholipase A1. The agents studied include: propranolol, timolol, metoprolol, practolol, atenolol and the combined alpha and beta adrenoceptor blocking agent, labetalol. The drugs varied by two logs in their abilities to inhibit phospholipase A1 activity. The relative inhibitory potencies were propranolol greater than labetalol much greater than timolol greater than metoprolol much greater than practolol greater than atenolol. Our studies identify drug hydrophobicity as a key determinant for phospholipase A1 inhibition. A strong negative correlation was noted between the octanol/water partition coefficients and IC50 for phospholipase inhibition (r = -0.91). The ability of propranolol to inhibit phospholipase A1 was identical for the d, l and the d and l stereoisomers.

  12. Characterization of Novel Cannabinoid Based T-Type Calcium Channel Blockers with Analgesic Effects

    PubMed Central

    2015-01-01

    Low-voltage-activated (T-type) calcium channels are important regulators of the transmission of nociceptive information in the primary afferent pathway and finding ligands that modulate these channels is a key focus of the drug discovery field. Recently, we characterized a set of novel compounds with mixed cannabinoid receptor/T-type channel blocking activity and examined their analgesic effects in animal models of pain. Here, we have built on these previous findings and synthesized a new series of small organic compounds. We then screened them using whole-cell voltage clamp techniques to identify the most potent T-type calcium channel inhibitors. The two most potent blockers (compounds 9 and 10) were then characterized using radioligand binding assays to determine their affinity for CB1 and CB2 receptors. The structure–activity relationship and optimization studies have led to the discovery of a new T-type calcium channel blocker, compound 9. Compound 9 was efficacious in mediating analgesia in mouse models of acute inflammatory pain and in reducing tactile allodynia in the partial nerve ligation model. This compound was shown to be ineffective in Cav3.2 T-type calcium channel null mice at therapeutically relevant concentrations, and it caused no significant motor deficits in open field tests. Taken together, our data reveal a novel class of compounds whose physiological and therapeutic actions are mediated through block of Cav3.2 calcium channels. PMID:25314588

  13. Differential effects of K(+) channel blockers on frequency-dependent action potential broadening in supraoptic neurons.

    PubMed

    Hlubek, M D; Cobbett, P

    2000-09-15

    Recordings were made from magnocellular neuroendocrine cells dissociated from the supraoptic nucleus of the adult guinea pig to determine the role of voltage gated K(+) channels in controlling the duration of action potentials and in mediating frequency-dependent action potential broadening exhibited by these neurons. The K(+) channel blockers charybdotoxin (ChTx), tetraethylammonium (TEA), and 4-aminopyridine (4-AP) increased the duration of individual action potentials indicating that multiple types of K(+) channel are important in controlling action potential duration. The effect of these K(+) channel blockers was almost completely reversed by simultaneous blockade of voltage gated Ca(2+) channels with Cd(2+). Frequency-dependent action potential broadening was exhibited by these neurons during trains of action potentials elicited by membrane depolarizing current pulses presented at 10 Hz but not at 1 Hz. 4-AP but not ChTx or TEA inhibited frequency-dependent action potential broadening indicating that frequency-dependent action potential broadening is dependent on increasing steady-state inactivation of A-type K(+) channels (which are blocked by 4-AP). A model of differential contributions of voltage gated K(+) channels and voltage gated Ca(2+) channels to frequency-dependent action potential broadening, in which an increase of Ca(2+) current during each successive action potential is permitted as a result of the increasing steady-state inactivation of A-type K(+) channels, is presented.

  14. Simultaneous determination of beta-blockers in human plasma using liquid chromatography-tandem mass spectrometry.

    PubMed

    Umezawa, Hironobu; Lee, Xiao-Pen; Arima, Yoshiko; Hasegawa, Chika; Izawa, Hikaru; Kumazawa, Takeshi; Sato, Keizo

    2008-07-01

    A detailed procedure for the analysis of four beta-blockers, acebutolol, labetalol, metoprolol and propranolol, in human plasma by high-performance liquid chromatography (LC)-tandem mass spectrometry (MS-MS) using an MSpak GF column, which enables direct injection of crude plasma samples, is presented. Protein and/or macromolecule matrix compounds were eluted first from the column, while the drugs were retained on the polymer stationary phase of the MSpak GF column. The analytes retained on the column were then eluted into an acetonitrile-rich mobile phase using a gradient separation technique. All drugs showed base peak ions due to [M + H]+ ions by LC-MS with positive ion electrospray ionization, and the product ions were produced from each [M + H]+ ion by LC-MS-MS. Quantification was performed by selected reaction monitoring. The recoveries of the four beta-blockers spiked into plasma were 73.5-89.9%. The regression equations for all compounds showed excellent linearity in the range 10-1000 ng/mL of plasma, with the exception of propranolol (10-800 ng/mL). The limits of detection and quantification for each drug were 1-3 and 10 ng/mL, respectively, of plasma. The intra- and inter-day coefficients of variation for all drugs in plasma were not greater than 10.9%.

  15. Substituted Indazoles as Nav1.7 Blockers for the Treatment of Pain.

    PubMed

    Frost, Jennifer M; DeGoey, David A; Shi, Lei; Gum, Rebecca J; Fricano, Meagan M; Lundgaard, Greta L; El-Kouhen, Odile F; Hsieh, Gin C; Neelands, Torben; Matulenko, Mark A; Daanen, Jerome F; Pai, Madhavi; Ghoreishi-Haack, Nayereh; Zhan, Cenchen; Zhang, Xu-Feng; Kort, Michael E

    2016-04-14

    The genetic validation for the role of the Nav1.7 voltage-gated ion channel in pain signaling pathways makes it an appealing target for the potential development of new pain drugs. The utility of nonselective Nav blockers is often limited due to adverse cardiovascular and CNS side effects. We sought more selective Nav1.7 blockers with oral activity, improved selectivity, and good druglike properties. The work described herein focused on a series of 3- and 4-substituted indazoles. SAR studies of 3-substituted indazoles yielded analog 7 which demonstrated good in vitro and in vivo activity but poor rat pharmacokinetics. Optimization of 4-substituted indazoles yielded two compounds, 27 and 48, that exhibited good in vitro and in vivo activity with improved rat pharmacokinetic profiles. Both 27 and 48 demonstrated robust activity in the acute rat monoiodoacetate-induced osteoarthritis model of pain, and subchronic dosing of 48 showed a shift to a lower EC50 over 7 days.

  16. Acute effect of calcium blocker on renal hemodynamics in diabetic spontaneously hypertensive rat.

    PubMed

    Kaizu, K; Ling, Q Y; Uriu, K; Ikeda, M; Eto, S

    1995-01-01

    This study was done to examine the acute effect of a calcium channel blocker on renal hemodynamics in the diabetic spontaneously hypertensive rat (SHR). Streptozotocin was used to induce diabetes, and barnidipine (B) was used as a calcium blocker. Renal blood flow (RBF) and glomerular filtration rate (GFR) were measured by a clearance method with paraaminohypurate (PAH) and inulin, respectively. Rats were divided into two groups: nondiabetic SHR, N-SHR; diabetic SHR, DM-SHR. B increased RBF in N-SHR (7.44 +/- 1.99 versus 8.50 +/- 1.97 mL/min/g.kw) while there was no change in DM-SHR. B reduced renovascular resistance (RVR) in DM-SHR and N-SHR. B increased GFR in N-SHR (1.15 +/- 0.24 versus 1.34 +/- 0.25 mL/min/g.kw), in spite of no changes in DM-SHR. B did not modify filtration fraction (FF) in both groups. These results indicate (1) in SHR, B exerts beneficial effects on hypertensive renal damage by reducing mean arterial pressure (MAP), RVR, RBF, and GFR; (2) in diabetic SHR, B is less effective in restoring renal hyperfiltration in spite of reducing RVR.

  17. Calcium channel blockers as potential therapeutics for obesity-associated autophagy defects and fatty liver pathologies.

    PubMed

    Park, Hwan-Woo; Lee, Jun Hee

    2014-01-01

    Nonalcoholic fatty liver disease (NAFLD), typically associated with overnutrition and obesity, is one of the most common liver diseases both in the US and worldwide. During obesity and NAFLD, lipotoxic injuries to hepatocytes can provoke formation of protein inclusions consisting of SQSTM1/p62 and ubiquitinated proteins. It has been suggested that autophagy deregulation during obesity contributes to protein inclusion formation and progression of other liver pathologies including insulin resistance, steatohepatitis, and hepatocellular carcinoma. To examine how lipotoxicity and obesity affect autophagy, we established an in vitro system where cultured HepG2 cells exhibit prominent accumulation of SQSTM1 and ubiquitinated proteins in insoluble inclusion bodies upon treatment with saturated fatty acids. Using this system and a mouse model of obesity, we have determined that obesity induces chronic elevation of cytosolic calcium levels in hepatocytes, which interferes with the fusion between autophagosomes and lysosomes. Intriguingly, pharmacological inhibition of calcium channels using the FDA-approved drug verapamil successfully restores autophagic flux and suppresses protein inclusions, not only in HepG2 cells but also in mouse liver. Verapamil also reduces hepatic lipid droplet accumulation, insulin resistance and steatohepatitis, suggesting that calcium channel blockers can be used for correction of general NAFLD pathologies. Indeed, there have been a number of clinical observations in which beneficial effects of calcium channel blockers against obesity-associated metabolic pathologies are observed in humans and animal models.

  18. Predictors of response to TNF blockers in patients with polyarticular psoriatic arthritis.

    PubMed

    Carvalho, Pedro David; Duarte, Cátia; Vieira-Sousa, Elsa; Cunha-Miranda, Luís; Avila-Ribeiro, Pedro; Santos, Helena; Bernardes, Miguel; Santos, Maria José; Cerqueira, Marcos; Mateus, Margarida; Nero, Patrícia; Águeda, Ana; Silva, José António Pereira da; Machado, Pedro

    2017-01-01

    Psoriatic arthritis (PsA) is a chronic inflammatory rheumatic disease with a broad clinical spectrum. PsA can affect the axial skeleton, peripheral joints, entheses, synovial sheaths of tendons, skin, nails and extra-articular organs. Tumour necrosis factor alpha blockers (TNF blockers) were a breakthrough development in the treatment of PsA. Identifying predictors of response to biological therapies in patients with PsA is of utmost importance, especially in view of the costs and potential side effects of these agents. The aims of the present study were to determine baseline predictive factors of response to biological therapies, at 3 and 6 months, in PsA patients with polyarticular involvement (with or without axial involvement). Data were collected from the Rheumatic Diseases Portuguese Register (Reuma.pt). Eligible patients had to be anti-TNF-naive at baseline and to have at least 3 months of follow-up after the beginning of TNF blocker therapy. Only patients with information on at least one of the response measures (at 3 or 6 months of follow-up) were included in the analysis. Univariable logistic regression analysis of potential baseline predictors of European League Against Rheumatism (EULAR) good clinical response, EULAR good/moderate response, 28-joint Disease Activity Score with three variables including the erythrocyte sedimentation rate (DAS28-3V-ESR) remission and Health Assessment Questionnaire (HAQ) response were performed. Multivariable logistic regression using a forward selection procedure was used until the best-fit model was obtained, taking confounding effects into account. A total of 180 patients were eligible for the study (mean age 52 years, 54% women). In multivariable analysis at 3 months, females were less likely to attain a good EULAR response [OR=0.082 (95% CI=0.024, 0.278)], a DAS28-3V-ESR remission [OR=0.083 (95% CI=0.017, 0.416)], a moderate or good EULAR response [OR=0.091 (95% CI=0.011, 0.091)] and a HAQ response [OR=0.074 (95% CI

  19. The potential anticancer effect of beta-blockers and the genetic variations involved in the interindividual difference.

    PubMed

    He, Ruo-Hui; He, Yi-Jing; Tang, Yong-Jun; Zhou, Hong-Hao; McLeod, Howard L; Liu, Jie

    2016-01-01

    β-ARs are extensively spread in different tissues of our body, which could be activated by neurotransmitters norepinephrine and epinephrine to mediate physiological function and abnormal states including cancer. Recently, β-AR blockers could have significant implications in cancer therapy. But the precise molecular mechanisms are far from being fully understood. Through identifying the β-AR system signal pathways relevant to cancer, we can understand the mechanisms of β-blockers used for cancer treatment. What's more, retrospective clinical data made β-blockers jump out of the traditional field of cardiovascular disease and strengthened our confidence in cancer therapy. At last, genetic studies of β-adrenergic system offered crucial genes to analyze the effects of polymorphisms on cancer susceptibility, therapy response and prognosis of cancer patients.

  20. Inhibition of collagen synthesis by select calcium and sodium channel blockers can be mitigated by ascorbic acid and ascorbyl palmitate.

    PubMed

    Ivanov, Vadim; Ivanova, Svetlana; Kalinovsky, Tatiana; Niedzwiecki, Aleksandra; Rath, Matthias

    2016-01-01

    Calcium, sodium and potassium channel blockers are widely prescribed medications for a variety of health problems, most frequently for cardiac arrhythmias, hypertension, angina pectoris and other disorders. However, chronic application of channel blockers is associated with numerous side effects, including worsening cardiac pathology. For example, nifedipine, a calcium-channel blocker was found to be associated with increased mortality and increased risk for myocardial infarction. In addition to the side effects mentioned above by different channel blockers, these drugs can cause arterial wall damage, thereby contributing to vascular wall structure destabilization and promoting events facilitating rupture of plaques. Collagen synthesis is regulated by ascorbic acid, which is also essential for its optimum structure as a cofactor in lysine and proline hydroxylation, a precondition for optimum crosslinking of collagen and elastin. Therefore, the main objective in this study was to evaluate effects of various types of channel blockers on intracellular accumulation and cellular functions of ascorbate, specifically in relation to formation and extracellular deposition of major collagen types relevant for vascular function. Effects of select Na- and Ca- channel blockers on collagen synthesis and deposition were evaluated in cultured human dermal fibroblasts and aortic smooth muscle cells by immunoassay. All channel blockers tested demonstrated inhibitory effects on collagen type I deposition to the ECM by fibroblasts, each to a different degree. Ascorbic acid significantly increased collagen I ECM deposition. Nifedipine (50 µM), a representative of channel blockers tested, significantly reduced ascorbic acid and ascorbyl palmitate-dependent ECM deposition of collagen type l and collagen type lV by cultured aortic smooth muscle cells. In addition, nifedipine (50 µM) significantly reduced ascorbate-dependent collagen type l and type lV synthesis by cultured aortic smooth

  1. Inhibition of collagen synthesis by select calcium and sodium channel blockers can be mitigated by ascorbic acid and ascorbyl palmitate

    PubMed Central

    Ivanov, Vadim; Ivanova, Svetlana; Kalinovsky, Tatiana; Niedzwiecki, Aleksandra; Rath, Matthias

    2016-01-01

    Calcium, sodium and potassium channel blockers are widely prescribed medications for a variety of health problems, most frequently for cardiac arrhythmias, hypertension, angina pectoris and other disorders. However, chronic application of channel blockers is associated with numerous side effects, including worsening cardiac pathology. For example, nifedipine, a calcium-channel blocker was found to be associated with increased mortality and increased risk for myocardial infarction. In addition to the side effects mentioned above by different channel blockers, these drugs can cause arterial wall damage, thereby contributing to vascular wall structure destabilization and promoting events facilitating rupture of plaques. Collagen synthesis is regulated by ascorbic acid, which is also essential for its optimum structure as a cofactor in lysine and proline hydroxylation, a precondition for optimum crosslinking of collagen and elastin. Therefore, the main objective in this study was to evaluate effects of various types of channel blockers on intracellular accumulation and cellular functions of ascorbate, specifically in relation to formation and extracellular deposition of major collagen types relevant for vascular function. Effects of select Na- and Ca- channel blockers on collagen synthesis and deposition were evaluated in cultured human dermal fibroblasts and aortic smooth muscle cells by immunoassay. All channel blockers tested demonstrated inhibitory effects on collagen type I deposition to the ECM by fibroblasts, each to a different degree. Ascorbic acid significantly increased collagen I ECM deposition. Nifedipine (50 µM), a representative of channel blockers tested, significantly reduced ascorbic acid and ascorbyl palmitate-dependent ECM deposition of collagen type l and collagen type lV by cultured aortic smooth muscle cells. In addition, nifedipine (50 µM) significantly reduced ascorbate-dependent collagen type l and type lV synthesis by cultured aortic smooth

  2. Effects of different alpha-1 adrenoceptor blockers on proximal urethral function using in vivo isovolumetric pressure changes.

    PubMed

    Yamaguchi, Takanori; Nagano, Masashi; Osada, Yukio

    2005-10-01

    The effects of different alpha-1 adrenoceptor blockers on the urethra and the cardiovascular system were evaluated using an in vivo isovolumetric intra-urethral pressure model in New Zealand white rabbits. The urethra of anesthetized male rabbits was cannulated through the bladder and secured at the vesico-urethral junction. The distal side of urethra under the pubic bone was also closed to allow measurement of the intra-urethral pressure. Both the intra-urethral pressure and the femoral arterial pressure were monitored. The effects of five different alpha-1 adrenoceptor blockers on the increases in both the intra-urethral pressure and blood pressure induced by phenylephrine were then examined. The inhibition rate of the alpha-1 adrenoceptor blockers prazosin, bunazosin, terazosin, alfuzosin and tamsulosin on the increase in intra-urethral pressure caused as a result of contraction by phenylephrine was 87.5 +/- 4.5% (mean +/- S.E.), 88.0 +/- 7.2%, 86.2 +/- 6.2%, 81.4 +/- 4.8% and 92.5 +/- 5.0% respectively. The potency ranking of these alpha-1 adrenoceptor blockers was tamsulosin > bunazosin > prazosin > terazosin > alfuzosin. Their inhibition rate of the arterial pressure increase induced by phenylephrine was 81.9 +/- 5.0%, 86.2 +/- 5.9%, 76.0 +/- 6.0%, 63.6 +/- 5.7% and 58.0 +/- 5.2% respectively, with a potency ranking of bunazosin > prazosin > terazosin > alfuzosin > tamsulosin. We therefore conclude that the alpha-1 adrenoceptor blockers bunazosin and prazosin have a more potent action on both the urethra and the vascular system. However, tamsulosin and alfuzosin displayed a marked blockade of the increased urethral pressure induced by phenylephrine, with much less of a blockade of arterial pressure. In the present study, tamsulosin has been shown to be the most sensitive and powerful of the alpha-1 adrenoceptor blockers on urethral smooth muscle.

  3. CNS-related (side-)effects of beta-blockers with special reference to mechanisms of action.

    PubMed

    Koella, W P

    1985-01-01

    beta-Adrenoreceptor antagonists are liable to produce behavioural side-effects such as drowsiness, fatigue, lethargy, sleep disorders, nightmares, depressive moods, and hallucinations. These undesirable actions indicate that beta-blockers affect not only peripheral autonomic activity but also some central nervous mechanisms. In experimental animals beta-blockers have been found to reduce spontaneous motor activity, to counteract isolation-, lesion-, stimulation- and amphetamine-induced hyperactivity, and to produce slow-wave and paradoxical sleep disturbances. Furthermore, central effects such as tranquilizing influences are used for the treatment of conditions such as anxiety. Several different mechanisms of action could be responsible for these CNS effects: Centrally mediated specific actions on centrally located beta-adrenergic receptors, known to exist downstream from, and at the terminals of, 'vigilance-enhancing' central noradrenergic pathways. Centrally mediated specific actions on centrally located receptors of the non-adrenergic type; an affinity of some beta-blockers towards 5-HT-receptors is well documented. Centrally mediated non-specific actions on centrally located neurones, owing to the membrane-stabilizing effects of beta-blockers. Peripherally mediated actions whereby beta-blockers induce changes in the autonomic activity in the periphery, which are relayed to the CNS to induce changes in activity of a variety of central systems. It can be assumed that with any one of the beta-blockers all these mechanisms come into play, yet with varying degrees depending on characteristics of the drugs such as lipophilicity and hydrophilicity, the ratio of antagonist versus (partial) agonist properties, affinity to 'alien' receptor sites, strength of membrane-stabilizing activity, stereospecific affinity, and potency.

  4. T Cell Subset and Stimulation Strength-Dependent Modulation of T Cell Activation by Kv1.3 Blockers

    PubMed Central

    Fung-Leung, Wai-Ping; Edwards, Wilson; Liu, Yi; Ngo, Karen; Angsana, Julianty; Castro, Glenda; Wu, Nancy; Liu, Xuejun; Swanson, Ronald V.; Wickenden, Alan D.

    2017-01-01

    Kv1.3 is a voltage-gated potassium channel expressed on T cells that plays an important role in T cell activation. Previous studies have shown that blocking Kv1.3 channels in human T cells during activation results in reduced calcium entry, cytokine production, and proliferation. The aim of the present study was to further explore the effects of Kv1.3 blockers on the response of different human T cell subsets under various stimulation conditions. Our studies show that, unlike the immune suppressor cyclosporine A, the inhibitory effect of Kv1.3 blockers was partial and stimulation strength dependent, with reduced inhibitory efficacy on T cells under strengthened anti-CD3/CD28 stimulations. T cell responses to allergens including house dust mites and ragweed were partially reduced by Kv1.3 blockers. The effect of Kv1.3 inhibition was dependent on T cell subsets, with stronger effects on CCR7- effector memory compared to CCR7+ central memory CD4 T cells. Calcium entry studies also revealed a population of CD4 T cells resistant to Kv1.3 blockade. Activation of CD4 T cells was accompanied with an increase in Kv1.3 currents but Kv1.3 transcripts were found to be reduced, suggesting a posttranscriptional mechanism in the regulation of Kv1.3 activities. In summary, Kv1.3 blockers inhibit T cell activation in a manner that is highly dependent on the T cell identity and stimulation strength, These findings suggest that Kv1.3 blockers inhibit T cells in a unique, conditional manner, further refining our understanding of the therapeutic potential of Kv1.3 blockers. PMID:28107393

  5. Impact of oral beta-blocker therapy on mortality after primary percutaneous coronary intervention for Killip class 1 myocardial infarction.

    PubMed

    Hioki, Hirofumi; Motoki, Hirohiko; Izawa, Atsushi; Kashima, Yuichirou; Miura, Takashi; Ebisawa, Souichirou; Tomita, Takeshi; Miyashita, Yusuke; Koyama, Jun; Ikeda, Uichi

    2016-05-01

    The use of beta-blockers therapy has been recommended to reduce mortality in patients with left ventricular dysfunction after acute myocardial infarction (AMI). Primary percutaneous coronary intervention (PCI), which has become the mainstay of treatment for AMI, is associated with a lower mortality than fibrinolysis. The benefits of beta-blockers after primary PCI in AMI patients without pump failure are unclear. We hypothesized that oral beta-blocker therapy after primary PCI might reduce the mortality in AMI patients without pump failure. The assessment of lipophilic vs. hydrophilic statin therapy in acute myocardial infarction (ALPS-AMI) study was a multi-center study that enrolled 508 AMI patients to compare the efficacy of hydrophilic and lipophilic statins in secondary prevention after myocardial infarction. We prospectively tracked cardiovascular events for 3 years in 444 ALPS-AMI patients (median age 66 years; 18.2 % women) who had Killip class 1 on admission and were discharged alive. The primary endpoint was all-cause mortality. The 3-year follow-up was completed in 413 patients (93.0 %). During this follow-up, 21 patients (4.7 %) died. In Kaplan-Meier analysis, patients on beta-blockers had a significantly lower incidence of all-cause mortality (2.7 vs. 7.3 %, log-rank p = 0.025). After adjusting for the calculated propensity score for using beta-blockers, their use remained an independent predictor of all-cause mortality (hazard ratio 0.309; 95 % confidence interval 0.116-0.824; p = 0.019). In the statin era, the use of beta-blocker therapy after primary PCI is associated with lower mortality in AMI patients with Killip class 1 on admission.

  6. ACT‐ONE ‐ ACTION at last on cancer cachexia by adapting a novel action beta‐blocker

    PubMed Central

    Laviano, Alessandro

    2016-01-01

    Abstract Novel action beta‐blockers combine many different pharmacological effects. The espindolol exhibits effects through β and central 5‐HT1α receptors to demonstrate pro‐anabolic, anti‐catabolic, and appetite‐stimulating actions. In the ACT‐ONE trial, espindolol reversed weight loss and improved handgrip strength in patients with cachexia due to non‐small cell lung cancer or colorectal cancer. With this trial, another frontier of cachexia management is in sight. Nonetheless, more efficacy and safety data is needed before new therapeutic indications for novel action beta‐blockers can be endorsed. PMID:27625919

  7. Binding modes of noncompetitive GABA-channel blockers revisited using engineered affinity-labeling reactions combined with new docking studies.

    PubMed

    Charon, Sébastien; Taly, Antoine; Rodrigo, Jordi; Perret, Philippe; Goeldner, Maurice

    2011-04-13

    The binding modes of noncompetitive GABA(A)-channel blockers were re-examined taking into account the recent description of the 3D structure of prokaryotic pentameric ligand-gated ion channels, which provided access to new mammalian or insect GABA receptor models, emphasizing their transmembrane portion. Two putative binding modes were deciphered for this class of compounds, including the insecticide fipronil, located nearby either the intra- or the extracellular part of the membrane, respectively. These results are in full agreement with previously described affinity-labeling reactions performed with GABA(A) noncompetitive blockers (Perret et al. J. Biol. Chem.1999, 274, 25350-25354).

  8. ACT-ONE - ACTION at last on cancer cachexia by adapting a novel action beta-blocker.

    PubMed

    Lainscak, Mitja; Laviano, Alessandro

    2016-09-01

    Novel action beta-blockers combine many different pharmacological effects. The espindolol exhibits effects through β and central 5-HT1α receptors to demonstrate pro-anabolic, anti-catabolic, and appetite-stimulating actions. In the ACT-ONE trial, espindolol reversed weight loss and improved handgrip strength in patients with cachexia due to non-small cell lung cancer or colorectal cancer. With this trial, another frontier of cachexia management is in sight. Nonetheless, more efficacy and safety data is needed before new therapeutic indications for novel action beta-blockers can be endorsed.

  9. [Effect of calcium channel blockers on developing nervous syndrome of high pressure and nitrogen narcosis in mice].

    PubMed

    Sledkov, A I

    1997-01-01

    In the experiments conducted on mice which prior to compression in a heliox environment have been injected the blockers of various types of calcium channels (flunarezine, verapramil and nifedipine) as well as bemethyl (actoprotector) and oxymethacye (antioxidant) there escaped detection of noticeable effect of these drugs on developing the high pressure nervous syndrome (HPNS). On exposure to the hyperbaric nitrogen-oxygen environment verapromil (phenylalkulamine blocker of L-type calcium channels) had a protection effect with respect to a convulsive component of the nitrogen narcosis.

  10. Heart rate recovery improvement in patients following acute myocardial infarction: exercise training, β-blocker therapy or both.

    PubMed

    Medeiros, Wladimir M; de Luca, Fabio A; de Figueredo Júnior, Alcides R; Mendes, Felipe A R; Gun, Carlos

    2017-04-12

    Heart rate recovery (HRR) is a strong mortality predictor. Exercise training (ET) and β-blocker therapy have significant impact on the HRR of patients following myocardial infarction (MI). However, the combination of ET and β-blocker therapy, as well as its effectiveness in patients with a more compromised HRR (≤12 bpm), has been under-studied. Male patients (n = 64) post-MI were divided: Training + β-blocker (n = 19), Training (n = 15), β-blocker (n = 11) and Control (n = 19). Participants performed an ergometric test before and after 3 months of intervention. HRR was obtained during 5 min of recovery and corrected by the cardiac reserve (HRRcorrCR ). Compared to pre-intervention, HRRcorrCR was significantly increased during the 1st and 2nd minutes of recovery in the Training + β-blocker group (70·5% and 37·5%, respectively; P<0·05). A significant improvement, lasting from the 1st to the 4th minute of recovery, was also observed in the Training group (47%, 50%, 25% and 8·7%, respectively; P<0·05). In contrast, the β-blocker group showed a reduction in HRRcorrCR during the 2nd and 3rd minutes of recovery (-21·2% and -16·3%, respectively; P<0·05). In addition, interventions involving ET (Training + βb, Training) were significantly more effective in patients with a pre-intervention HRR ≤ 12 bpm than for patients with HRR > 12 bpm. Combination of β-blocker therapy with ET does not compromise the effect of training and instead promotes HRR and aerobic capacity improvement. In addition, this combination is particularly beneficial for individuals presenting with a more compromised HRR. However, chronic administration of β-blocker therapy alone did not promote improvement in HRR or aerobic capacity.

  11. Otilonium: a potent blocker of neuronal nicotinic ACh receptors in bovine chromaffin cells.

    PubMed Central

    Gandía, L.; Villarroya, M.; Lara, B.; Olmos, V.; Gilabert, J. A.; López, M. G.; Martínez-Sierra, R.; Borges, R.; García, A. G.

    1996-01-01

    1. Otilonium, a clinically useful spasmolytic, behaves as a potent blocker of neuronal nicotinic acetylcholine receptors (AChR) as well as a mild wide-spectrum Ca2+ channel blocker in bovine adrenal chromaffin cells. 2. 45Ca2+ uptake into chromaffin cells stimulated with high K+ (70 mM, 1 min) was blocked by otilonium with an IC50 of 7.6 microM. The drug inhibited the 45Ca2+ uptake stimulated by the nicotinic AChR agonist, dimethylphenylpiperazinium (DMPP) with a 79 fold higher potency (IC50 = 0.096 microM). 3. Whole-cell Ba2+ currents (IBa) through Ca2+ channels of voltage-clamped chromaffin cells were blocked by otilonium with an IC50 of 6.4 microM, very close to that of K(+)-evoked 45Ca2+ uptake. Blockade developed in 10-20 s, almost as a single step and was rapidly and almost fully reversible. 4. Whole-cell nicotinic AChR-mediated currents (250 ms pulses of 100 microM DMPP) applied at 30 s intervals were blocked by otilonium in a concentration-dependent manner, showing an IC50 of 0.36 microM. Blockade was induced in a step-wise manner. Wash out of otilonium allowed a slow recovery of the current, also in discrete steps. 5. In experiments with recordings in the same cells of whole-cell IDMPP, Na+ currents (INa) and Ca2+ currents (ICa), 1 microM otilonium blocked 87% IDMPP, 7% INa and 13% ICa. 6. Otilonium inhibited the K(+)-evoked catecholamine secretory response of superfused bovine chromaffin cells with an IC50 of 10 microM, very close to the IC50 for blockade of K(+)-induced 45Ca2+ uptake and IBa. 7. Otilonium inhibited the secretory responses induced by 10 s pulses of 50 microM DMPP with an IC50 of 7.4 nM. Hexamethonium blocked the DMPP-evoked responses with an IC50 of 29.8 microM, 4,000 fold higher than that of otilonium. 8. In conclusion, otilonium is a potent blocker of nicotinic AChR-mediated responses. The drugs also blocked various subtypes of neuronal voltage-dependent Ca2+ channels at a considerably lower potency. Na+ channels were unaffected by

  12. Angiotensin receptor subtype mediated physiologies and behaviors: New discoveries and clinical targets

    PubMed Central

    Wright, John W.; Yamamoto, Brent J.; Harding, Joseph W.

    2008-01-01

    The renin–angiotensin system (RAS) mediates several classic physiologies including body water and electrolyte homeostasis, blood pressure, cyclicity of reproductive hormones and sexual behaviors, and the regulation of pituitary gland hormones. These functions appear to be mediated by the angiotensin II (AngII)/AT1 receptor subtype system. More recently, the angiotensin IV (AngIV)/AT4 receptor subtype system has been implicated in cognitive processing, cerebroprotection, local blood flow, stress, anxiety and depression. There is accumulating evidence to suggest an inhibitory influence by AngII acting at the AT1 subtype, and a facilitory role by AngIV acting at the AT4 subtype, on neuronal firing rate, long-term potentiation, associative and spatial learning, and memory. This review initially describes the biochemical pathways that permit synthesis and degradation of active angiotensin peptides and three receptor subtypes (AT1, AT2 and AT4) thus far characterized. There is vigorous debate concerning the identity of the most recently discovered receptor subtype, AT4. Descriptions of classic and novel physiologies and behaviors controlled by the RAS are presented. This review concludes with a consideration of the emerging therapeutic applications suggested by these newly discovered functions of the RAS. PMID:18160199

  13. Anteroposterior distribution of AT(1) angiotensin receptors in caudal brainstem cardiovascular regulatory centers of the rat.

    PubMed

    Bourassa, Erick A; Sved, Alan F; Speth, Robert C

    2010-01-08

    Angiotensin II acts on Ang II type 1 (AT(1)) receptors in areas of the caudal brainstem involved in cardiovascular regulation. In particular, activation of AT(1) receptors in the rostral ventrolateral medulla (RVLM) has been suggested to contribute to hypertension. However, the characteristics of AT(1) receptors in the RVLM of rat, the species in which the most experimental work has been done, are not well documented. This study evaluated AT(1) receptor binding along a 2.7-mm length of rat medulla, which included the full extent of the RVLM and the caudal ventrolateral medulla (CVLM). Sections of medulla from female rats cut on a cryostat were incubated with five concentrations of (125)I-sarcosine(1), isoleucine(8) angiotensin II to assess the density (B(max)) and dissociation constant (K(D)) of the receptors for the radioligand. The dorsomedial medulla (DMM) displayed a high density of AT(1) binding (1207+/-100 fmol/g), which peaked at 0.4 mm rostral to the calamus scriptorius (approximately 14 mm caudal to Bregma). The RVLM and CVLM displayed significantly lower (p<0.01) densities of AT(1) binding, 278+/-38 and 379+/-64 fmol/g, respectively. However, the dissociation constants were significantly lower (i.e., higher affinity) in RVLM and CVLM (164+/-38 and 178+/-27 pM, respectively,) than in DMM (328+/-12 pM, p<0.01 and p<0.05, respectively). These results provide an anatomical and pharmacological framework for future studies on the role in cardiovascular regulation of AT(1) receptors in the caudal brainstem.

  14. Properly timed exposure to central ANG II prevents behavioral sensitization and changes in angiotensin receptor expression

    PubMed Central

    Santollo, Jessica; Whalen, Philip E.; Speth, Robert C.; Clark, Stewart D.

    2014-01-01

    Previous studies show that the angiotensin type 1 receptor (AT1R) is susceptible to rapid desensitization, but that more chronic treatments that stimulate ANG II lead to sensitization of several responses. It is unclear, however, if the processes of desensitization and sensitization interact. To test for differences in AT1R expression associated with single or repeated injections of ANG II, we measured AT1R mRNA in nuclei that control fluid intake of rats given ANG II either in a single injection or divided into three injections spaced 20 min apart. Rats given a single injection of ANG II had more AT1R mRNA in the subfornical organ (SFO) and the periventricular tissue surrounding the anteroventral third ventricle (AV3V) than did controls. The effect was not observed, however, when the same cumulative dose of ANG II was divided into multiple injections. Behavioral tests found that single daily injections of ANG II sensitized the dipsogenic response to ANG II, but a daily regimen of four injections did not cause sensitization. Analysis of 125I-Sar1-ANG II binding revealed a paradoxical decrease in binding in the caudal AV3V and dorsal median preoptic nucleus after 5 days of single daily injections of ANG II; however, this effect was absent in rats treated for 5 days with four daily ANG II injections. Taken together, these data suggest that a desensitizing treatment regimen prevents behavior- and receptor-level effects of repeated daily ANG II. PMID:25354729

  15. Estrogen effects on angiotensin receptors are modulated by pituitary in female rats

    SciTech Connect

    Douglas, J.G.

    1987-01-01

    The present studies were designed to test the hypothesis that changes in angiotensin II (ANG II) receptors might modulate the layered target tissue responsiveness accompanying estradiol administration. Estradiol was infused continuously in oophorectomized female rats. Aldosterone was also infused in control and experimental animals to avoid estrogen-induced changes in renin and ANG II. ANG II binding constants were determined in radioreceptor assays. Estradiol increased binding site concentration in adrenal glomerulosa by 76% and decreased binding sites of uterine myometrium and glomeruli by 45 and 24%, respectively. There was an accompanying increase in the affinity of ANG II binding to adrenal glomerulosa and uterine myometrium. Because estrogen is a potent stimulus of prolactin release from the pituitary of rodents, studies were also designed to test the hypothesis that prolactin may mediate some or all of the estrogen-induced effects observed. Hypophysectomy abolished estradiol stimulation of prolactin release and most ANG II receptor changes. Prolactin administration to pituitary intact rats was associated with a 50% increase in receptor density of adrenal glomerulosa simulating estradiol administration. However, the changes in glomeruli and uterine myometrium were opposite in that both tissues also increased receptor density, suggesting that prolactin was not the sole mediator of the estrogen-induced receptor changes. In conclusion, regulation of ANG II receptors in a number of diverse target tissues by estradiol is complex with contributions from estrogens and pituitary factors, which include but do not exclusively involve prolactin.

  16. Angiotensin receptors and β-catenin regulate brain endothelial integrity in malaria

    PubMed Central

    Basu-Roy, Upal; Ty, Maureen; Alique, Matilde; Fernandez-Arias, Cristina; Movila, Alexandru; Gomes, Pollyanna; Edagha, Innocent; Wassmer, Samuel C.; Walther, Thomas

    2016-01-01

    Cerebral malaria is characterized by cytoadhesion of Plasmodium falciparum–infected red blood cells (Pf-iRBCs) to endothelial cells in the brain, disruption of the blood-brain barrier, and cerebral microhemorrhages. No available antimalarial drugs specifically target the endothelial disruptions underlying this complication, which is responsible for the majority of malaria-associated deaths. Here, we have demonstrated that ruptured Pf-iRBCs induce activation of β-catenin, leading to disruption of inter–endothelial cell junctions in human brain microvascular endothelial cells (HBMECs). Inhibition of β-catenin–induced TCF/LEF transcription in the nucleus of HBMECs prevented the disruption of endothelial junctions, confirming that β-catenin is a key mediator of P. falciparum adverse effects on endothelial integrity. Blockade of the angiotensin II type 1 receptor (AT1) or stimulation of the type 2 receptor (AT2) abrogated Pf-iRBC–induced activation of β-catenin and prevented the disruption of HBMEC monolayers. In a mouse model of cerebral malaria, modulation of angiotensin II receptors produced similar effects, leading to protection against cerebral malaria, reduced cerebral hemorrhages, and increased survival. In contrast, AT2-deficient mice were more susceptible to cerebral malaria. The interrelation of the β-catenin and the angiotensin II signaling pathways opens immediate host-targeted therapeutic possibilities for cerebral malaria and other diseases in which brain endothelial integrity is compromised. PMID:27643439

  17. Expression of AT1 and AT2 angiotensin receptors in astrocytomas is associated with poor prognosis

    PubMed Central

    Arrieta, O; Pineda-Olvera, B; Guevara-Salazar, P; Hernández-Pedro, N; Morales-Espinosa, D; Cerón-Lizarraga, T L; González-De la Rosa, C H; Rembao, D; Segura-Pacheco, B; Sotelo, J

    2008-01-01

    Astrocytomas develop intense vascular proliferation, essential for tumour growth and invasiveness. Angiotensin II (ANGII) was initially described as a vasoconstrictor; recent studies have shown its participation in cellular proliferation, vascularisation, and apoptosis. We conducted a prospective study to evaluate the expression of ANGII receptors – AT1 and AT2 – and their relationship with prognosis. We studied 133 tumours from patients with diagnosis of astrocytoma who underwent surgery from 1997 to 2002. AT1 and AT2 were expressed in 52 and 44% of the tumours, respectively, when determined by both reverse transcriptase–polymerase chain reaction and immunohistochemistry. Ten per cent of low-grade astrocytomas were positive for AT1, whereas grade III and IV astrocytomas were positive in 67% (P<0.001). AT2 receptors were positive in 17% of low-grade astrocytomas and in 53% of high-grade astrocytomas (P=0.01). AT1-positive tumours showed higher cellular proliferation and vascular density. Patients with AT1-positive tumours had a lower survival rate than those with AT1-negative (P<0.001). No association to survival was found for AT2 in the multivariate analysis. Expression of AT1 and AT2 is associated with high grade of malignancy, increased cellular proliferation, and angiogenesis, and is thus related to poor prognosis. These findings suggest that ANGII receptors might be potential therapeutic targets for high-grade astrocytomas. PMID:18594540

  18. Beta-blockers in the environment: part I. Mobility and hydrolysis study.

    PubMed

    Maszkowska, Joanna; Stolte, Stefan; Kumirska, Jolanta; Łukaszewicz, Paulina; Mioduszewska, Katarzyna; Puckowski, Alan; Caban, Magda; Wagil, Marta; Stepnowski, Piotr; Białk-Bielińska, Anna

    2014-09-15

    Beta-blockers (BB) are one of the most widely used pharmaceuticals whose presence in different environmental compartments has already been proven in concentrations of even up to a few μg L(-1). However, our knowledge of their fate in the environment is still scarce. To obtain a better understanding on the environmental behavior of three selected BB comprehensive laboratory experiments assessing their mobility and hydrolytic stability has been conducted. Propranolol, metoprolol and nadolol--the most commonly consumed and detected in environmental samples--were selected as representatives of this group of pharmaceuticals. The objectives of our research were: (i) evaluation of the sorption potential and an explanation of the sorption mechanisms of these compounds onto soil and clay mineral (kaolinite); and (ii) investigation of the hydrolytic stability of these BB according to OECD 111. This comprehensive study supports the Environmental Risk Assessment of these pharmaceuticals.

  19. Cadmium and calcium uptake in the mollusc donax rugosus and effect of a calcium channel blocker

    SciTech Connect

    Sidoumou, Z.; Gnassia-Barelli, M.; Romeo, M.

    1997-02-01

    Donax rugosus, a common bivalve mollusc in the coastal waters of Mauritania, has been studied for trace metal concentrations as a function of sampling site (from South of Mauritania to the North of this country) and of season. In this paper, the uptake of cadmium was experimentally studied in the different organs of D. rugosus. Since metals such as cadmium, copper and mercury may alter calcium homeostasis, calcium uptake was also studied in the animals treated with cadmium. Since calcium is taken up through specific channels, it appears that metals inhibit Ca uptake by interacting with these channels in the plasma membrane. Cadmium and calcium have very similar atomic radii, thus cadmium may be taken up through the calcium channels, particularly through voltage-dependent channels. The uptake of cadmium and calcium by D. Rugosus was therefore also studied in the presence of the calcium channel blocker verapamil. 13 refs., 3 figs., 1 tab.

  20. Antioxidant effect of T-type calcium channel blockers in gastric injury.

    PubMed

    Bilici, Dilek; Banoğlu, Z Nur; Kiziltunç, Ahmet; Avci, Bahattin; Ciftçioğlu, Akif; Bilici, Sefa

    2002-04-01

    It is known that calcium ion has an important role in the cellular function. For this reason, calcium channel blockers may have a protective action against gastric injury which is induced by various stimuli. In this study, the influence of mibefradil on ethanol-induced gastric injury was investigated in rats. Mibefradil was given at a dose 50 mg/kg intraperitoneally 30 min before administration of 1 ml absolute ethanol given by gavage. We compared this effect of mibefradil with that of omeprazol. Ethanol-induced mucosal damage was evaluated using three different approaches: analysis of biochemical parameters and pathologic and macroscopic investigation. It was found that pretreatment with mibefradil significantly reduced ethanol-induced macroscopic, pathologic, and biochemical changes in the gastric mucosa. In conclusion, it is speculated that this findings may prove important in the development of new and improved therapies for the treatment and prevention of gastric ulcers in humans.