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Sample records for bi-affinity alpha 1-adrenoceptor

  1. [Alpha1-adrenoceptor subtypes and alpha1-adrenoceptor antagonists].

    PubMed

    Muramatsu, Ikunobu; Suzuki, Fumiko; Tanaka, Takashi; Yamamoto, Hatsumi; Morishima, Shigeru

    2006-03-01

    Alpha(1)-adrenoceptors are widely distributed in the human body and play important physiologic roles. Three alpha(1)-adrenoceptor subtypes (alpha(1A), alpha(1B) and alpha(1D)) have been cloned and show different pharmacologic profiles. In addition, a putative alpha(1)-adrenoceptor (alpha(1L) subtype) has also been proposed. Recently, three drugs (tamsulosin, naftopidil, and silodosin) have been developed in Japan for the treatment of urinary obstruction in patients with benign prostatic hyperplasia. In this review, we describe recent alpha(1)-adrenoceptor subclassifications and the pharmacologic characteristics (subtype selectivity and clinical relevance) of alpha(1)-adrenoceptor antagonists. PMID:16518082

  2. Preclinical pharmacology of alpha1-adrenoceptor antagonists.

    PubMed

    Martin, D J

    1999-01-01

    The implication of a single adrenoceptor subtype in the contractility of prostatic and urethral smooth muscle cells led to the concept that drugs with selectivity for this subtype may exhibit functional uroselectivity. Comparison of the affinities of the alpha1-adrenoceptor antagonists revealed that few compounds show selectivity for one of the three cloned alpha1-adrenoceptor subtypes (alpha1a/A, alpha1b/B, alpha1d/D) whereas most of them had a similar affinity for the three subtypes. Moreover, data supporting a relationship between selectivity for the alpha1a/A-adrenoceptor subtype and functional uroselectivity are still lacking and recent data challenged the relevance of the selectivity for a given cloned alpha1-adrenoceptor subtype in predicting functional uroselectivity. In vivo data showed that alpha1-adrenoceptor antagonists without adrenoceptor subtype selectivity, like alfuzosin or to a minor extent doxazosin, showed functional uroselectivity whereas prazosin and terazosin were not shown to be uroselective. Compounds considered to be selective for the alpha1a/A-adrenoceptor, like tamsulosin or 5-Me-urapidil, did not show functional uroselectivity since they modified urethral and blood pressures in a manner which was not correlated to their selectivity for the cloned alpha1-adrenoceptor subtypes. Meanwhile, the identification in prostatic tissue, of a new sub-family of alpha1-adrenoceptors with low affinity for prazosin and denominated alpha1L gave rise to numerous studies. However, its functional role as well as the affinity of the known antagonists for this receptor subtype remains to be clarified. In conclusion, the existing alpha1-adrenoceptor antagonists have different pharmacological profiles in vivo which are yet not predictable from their receptor pharmacology based on the actual state of knowledge of the alpha1-adrenoceptor classification. PMID:10393471

  3. Quinazoline-derived alpha1-adrenoceptor antagonists induce prostate cancer cell apoptosis via an alpha1-adrenoceptor-independent action.

    PubMed

    Benning, Cynthia M; Kyprianou, Natasha

    2002-01-15

    Recent evidence suggests that the quinazoline-based alpha1-adrenoceptor antagonists, doxazosin and terazosin, exhibit a potent apoptotic effect against prostate tumor epithelial cells, whereas tamsulosin, a sulfonamide-based alpha1-adrenoceptor antagonist, was ineffective in inducing a similar apoptotic effect against prostate cells (Cancer Res., 60: 4550-4555, 2000). In this study, to identify the precise molecular mechanism underlying this apoptosis induction, we examined whether doxazosin and terazosin (both piperazinyl quinazolines) affect prostate growth via an alpha1-adrenoceptor-independent action. Transfection-mediated overexpression of alpha1-adrenoceptor in human prostate cancer cells, DU-145 (that lack alpha1-adrenoceptor), did not alter the ability of prostate cancer cells to undergo apoptosis in response to quinazolines. Significantly enough, there was no modification of the apoptotic threshold of the androgen-sensitive prostate cancer cells, LNCaP, to either quinazoline-based alpha1-agonist by androgens. Furthermore, human normal prostate epithelial cells exhibited a very low sensitivity to the apoptotic effects of doxazosin compared with that observed for the malignant prostate cells. These findings provide the first evidence that the apoptotic activity of the quinazoline-based alpha1-adrenoceptor antagonists (doxazosin and terazosin) against prostate cancer cells is independent of: (a) their capacity to antagonize alpha1-adrenoceptors; and (b) the hormone sensitivity status of the cells. This may have potential therapeutic significance in the use of quinazoline-based alpha1-adrenoceptor antagonists (already in clinical use for the treatment of hypertension and benign prostate hyperplasia) for the treatment of androgen-independent human prostate cancer. PMID:11809715

  4. Alpha1-adrenoceptors in the guinea pig thoracic aorta.

    PubMed

    Yamamoto, Y; Koike, K

    1999-01-01

    In the present study, we tried to determine which alpha1-adrenoceptor subtypes are involved in the guinea pig thoracic aorta by using in vitro functional analysis. In first, we tried to estimate the pA2 values of some key alpha1-adrenoceptor antagonists (prazosin, 5-methylurapidil, WB4101, BMY7378 and tamsulosin) against responses to norepinephrine in the thoracic aorta of guinea pigs. The concentration-response curves of norepinephrine were rightward shifted by the presence of prazosin, 5 methylurapidil, WB4101, BMY7378 and tamsulosin. The pA2 values for these antagonists against norepinephrine were 7.83, 7.78, 8.20, 5.73 and 9.57, respectively. In second, we tried to compare the estimated pA2 values obtained in the present study with reported pKi and pA2 values for cloned and native alpha1-adrenoceptor subtypes. In rabbit mesenteric artery, trigone, urethra, prostate and human lower urinary tract which were proposed to contain the putative alpha1L-adenoceptor, we obtained the good correlation for the pA2 values reported in these tissues with pA2 values estimated in guinea pig thoracic aorta. Moreover, regression lines were close to the line of identity. These results suggest that the alpha1-adenoceptors mediating contraction of guinea pig thoracic aorta are similar pharmacologically to the putative alpha1L-adenoceptor subtype in rabbit mesenteric artery, trigone, urethra, prostate and human lower urinary tract. As a final point, guinea pig thoracic aorta may be able to use as a tool to develop the new alpha1-adrenoceptor antagonist which is therapeutically advantageous in the treatment of urinary tract obstruction (e. g., in benign prostatic hyperplasia). PMID:10733154

  5. [beta]1-Adrenoceptor or [alpha]1-Adrenoceptor Activation Initiates Early Odor Preference Learning in Rat Pups: Support for the Mitral Cell/cAMP Model of Odor Preference Learning

    ERIC Educational Resources Information Center

    Harley, Carolyn W.; Darby-King, Andrea; McCann, Jennifer; McLean, John H.

    2006-01-01

    We proposed that mitral cell [beta]1-adrenoceptor activation mediates rat pup odor preference learning. Here we evaluate [beta]1-, [beta]2-, [alpha]1-, and [alpha]2-adrenoceptor agonists in such learning. The [beta]1-adrenoceptor agonist, dobutamine, and the [alpha]1-adrenoceptor agonist, phenylephrine, induced learning, and both exhibited an…

  6. Radioligand binding studies of alpha 1-adrenoceptor subtypes in rat heart.

    PubMed Central

    Michel, M. C.; Hanft, G.; Gross, G.

    1994-01-01

    1. In order to characterize the alpha 1-adrenoceptor subtypes mediating positive inotropic effects of adrenaline (in the presence of propranolol) in rat right ventricular strips and the Ca2+ sources used to elicit them, we have used radioligand binding to identify the alpha 1-adrenoceptor subtypes present in rat heart and the alpha 1-adrenoceptor affinity and subtype-selectivity of various pharmacological tools. 2. Amitryptiline, mianserin, trimipramine, oxaprotiline, clonidine, chloroethylclonidine, phenoxybenzamine, BE 2254 and 8-OH-DPAT competed for [3H]-prazosin binding in rat heart, vas deferens, liver, spleen, cerebral cortex and hippocampus but none of them displayed detectable alpha 1-adrenoceptor subtype-selectivity; nitrendipine did not compete for [3H]-prazosin binding in concentrations up to 5 mumol 1(-1). 3. The alpha 1 A-adrenoceptor-selective, 5-methyl-urapidil, (+)-niguldipine, and to a lesser extent (-)-niguldipine competed for [3H]-prazosin binding in rat heart, vas deferens, cerebral cortex and hippocampus with shallow and biphasic curves; analysis of these curves demonstrated that rat heart contains alpha 1A-and alpha 1B-adrenoceptors in a 20:80 ratio. 4. Treatment of rat right ventricular strips with 100 mumol l-1 chloroethylclonidine for 30 min at 30 degrees C followed by 60 min washout reduced the number of alpha 1-adrenoceptors, as assessed by [3H]-prazosin saturation experiments, by 74%. Treatment with 100 mumol l(-1) CdCl2 did not affect number or affinity of cardiac alpha 1-adrenoceptors and combined treatment with chlorethylclonidine and CdCl2 reduced alpha 1-adrenoceptor number by 90%.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:7911718

  7. Alpha(1) adrenoceptor subtype selectivity. 3D-QSAR models for a new class of alpha(1) adrenoceptor antagonists derived from the novel antipsychotic sertindole.

    PubMed

    Balle, Thomas; Andersen, Kim; Søby, Karina Krøjer; Liljefors, Tommy

    2003-06-01

    Receptor-binding affinities for the alpha(1) adrenoceptor subtypes alpha(1a), alpha(1b) and alpha(1d) for a series of 39 alpha(1) adrenoceptor antagonists derived from the antipsychotic sertindole are reported. The SAR of the compounds with respect to affinity for the alpha(1a), alpha(1b) and alpha(1d) adrenoceptor subtypes as well as affinity obtained by an alpha(1) assay (rat brain membranes) were investigated using a 3D-QSAR approach based on the GRID/GOLPE methodology. Good statistics (r(2)=0.91-0.96; q(2)=0.65-0.73) were obtained with the combination of the water (OH2) and methyl (C3) probes. The combination of steric repulsion and electrostatic attractions explain the affinities of the included molecules. The adrenergic alpha(1a) receptor seems to be more tolerant to large substituents in the area between the indole 5- and 6-positions compared to the adrenergic alpha(1b) and alpha(1d) receptor subtypes. There seems to be minor differences in the position of areas in the alpha(1b) receptor compared to alpha(1a) and alpha(1d) receptors where electrostatic interaction between the molecules and the receptor (OH2 probe) contribute to increased affinity. These observations may be used in the design of new subtype selective compounds. In addition, the model based on biological data from an alpha(1) assay (rat brain membranes) resembles the model for the alpha(1b) adrenoceptor subtype. PMID:12676239

  8. Induction of prostate apoptosis by alpha1-adrenoceptor antagonists: mechanistic significance of the quinazoline component.

    PubMed

    Anglin, I E; Glassman, D T; Kyprianou, N

    2002-01-01

    alpha(1)-Adrenoceptor antagonists, have been documented to induce apoptosis and reduce prostate tumor vascularity in benign and malignant prostate cells. The quinazoline based alpha(1)-antagonists, doxazosin and terazosin but not tamsulosin (a sulphonamide derivative) suppress prostate growth without affecting cell proliferation. These quinazoline-mediated apoptotic effects occur via an alpha(1)-adrenoceptor independent mechanism potentially involving activation of the TGF-beta signal transduction pathway. This review discusses the current knowledge of the action of quinazoline-derived alpha(1)-adrenoceptor antagonists in the benign and malignant prostate and their potential therapeutic use in the treatment of benign prostatic hyperplasia (BPH) and prostate cancer. Finally, a molecular pathway is proposed for their observed apoptotic function against prostate cells. Increased understanding of the action of these established and clinically accepted agents would provide a basis for the design of safe, effective therapeutic regimens in the treatment of prostatic diseases. PMID:12496995

  9. Role of alpha-1 adrenoceptor subtypes mediating constriction of the rabbit ear thermoregulatory microvasculature.

    PubMed

    Li, Z; Silver, W P; Koman, L A; Strandhoy, J W; Rosencrance, E; Gordon, S; Smith, T L

    2000-01-01

    An acute in vivo preparation of the microvasculature of the rabbit ear was used to evaluate the functional role of alpha1 (alpha1)-adrenoceptor subtypes in thermoregulatory microcirculation. The effect of alpha1-adrenoceptor subtype blockade on phenylephrine-induced vasoconstriction was assessed with the alpha1A, alpha1B, and alpha1D-adrenoceptor-selective antagonists 5-methyl-urapidil (10(-8) M), chloroethylclonidine (10(-5) M), and 8-[2-[4(2-methoxyphenyl)-1-piperazinyl]ethyl]-8-azaspirol[4.5]deca ne-7,9-dione dihydrochloride (BMY7378) (10(-6) M), respectively. The results demonstrated that pretreatment of the ear microvasculature with 5-methyl-urapidil or BMY7378 shifted the phenylephrine concentration-response curve rightward and significantly changed the log of the phenylephrine concentration, causing half-maximum stimulation (EC50) in arterioles (p < 0.05). BMY7378 shifted the phenylephrine concentration-response curve of the arteriovenous anastomoses about 100-fold rightward (p < 0.05). All three alpha1-adrenoceptor antagonists eliminated the vasoconstrictive effects of phenylephrine on venules. The results indicate that the ear microvasculature has a heterogenous distribution of alpha1-adrenoceptor subtypes. The alpha1A and alpha1D-adrenoceptor subtypes appear to have a greater influence on constrictive function in arterioles, whereas the alpha1D-adrenoceptor is the dominant constrictor of arteriovenous anastomoses. In general, the alpha1-adrenoceptor does not play a major vasoconstrictor role in venules. Chloroethylclonidine, an irreversible alpha1B-adrenoceptor antagonist, induced contractile responses in the ear microvasculature, probably due to its alpha2-adrenoceptor agonist effects. This study extended our understanding of the adrenergic receptor control mechanisms of a cutaneous thermoregulatory end organ characterized by two parallel perfusion circuits providing nutritional and thermoregulatory functions. PMID:10716292

  10. The use of alpha1-adrenoceptor antagonists in lower urinary tract symptoms: beyond benign prostatic hyperplasia.

    PubMed

    Nickel, J Curtis

    2003-09-01

    The first empirical use of alpha(1)-adrenoceptor antagonists in urology occurred about 25 years ago in patients with lower urinary tract symptoms (LUTS) suggestive of benign prostatic hyperplasia (BPH), or LUTS/BPH. Today, many randomized, controlled trials have provided evidence for the efficacy and tolerability of alpha(1)-adrenoceptor antagonists in LUTS/BPH, and they are the most frequently used initial treatment option for this cause of LUTS. For many years, alpha(1)-adrenoceptor antagonists have also been used empirically in other types of lower urinary tract dysfunction (LUTD), such as chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) and neurogenic LUTD (NLUTD). Several investigators have shown that alpha(1)-adrenoceptor antagonists may be useful in patients with CP/CPPS. This was recently confirmed by a 6-week, double-blind, placebo-controlled pilot study evaluating the efficacy and safety of tamsulosin in 58 CP/CPPS patients. Further well-designed and -powered research into the use of alpha(1)-adrenoceptor antagonists in patients with CP/CPPS is currently ongoing. Several small-scale predominantly open-label studies have suggested that alpha(1)-adrenoceptor antagonists may be of benefit in patients with NLUTD. Data from 2 recent large-scale studies with tamsulosin in patients with NLUTD caused by suprasacral spinal cord injury suggest that long-term tamsulosin treatment improves bladder storage and emptying and also reduces symptoms of autonomic dysreflexia. Tamsulosin has also shown promise in ameliorating (early) storage symptoms and urinary retention associated with transurethral microwave thermotherapy, external-beam radiotherapy, and brachytherapy. In BPH patients presenting with the ultimate form of LUTS-acute urinary retention-treatment with tamsulosin before catheter removal results in a higher success rate of catheter-free voiding. Finally, it seems that alpha(1)-adrenoceptor antagonists may reduce the occurrence of urinary retention

  11. Naftopidil, a novel alpha1-adrenoceptor antagonist, displays selective inhibition of canine prostatic pressure and high affinity binding to cloned human alpha1-adrenoceptors.

    PubMed

    Takei, R; Ikegaki, I; Shibata, K; Tsujimoto, G; Asano, T

    1999-04-01

    The pharmacological profiles of the alpha1-adrenoceptor antagonists naftopidil, tamsulosin and prazosin were studied in an anesthetized dog model that allowed the simultaneous assessment of their antagonist potency against phenylephrine-mediated increases in prostatic pressure and mean blood pressure. The intravenous administration of each of these compounds dose-dependently inhibited phenylephrine-induced increases in prostatic pressure and mean blood pressure. To further assess the ability of the three compounds to inhibit phenylephrine-induced responses, the doses required to produce a 50% inhibition of the phenylephrine-induced increases in prostatic and mean blood pressure and the selectivity index obtained from the ratio of those two doses were determined for each test compound. Forty minutes after the intravenous administration of naftopidil, the selectivity index was 3.76, and those of tamsulosin and prazosin were 1.23 and 0.61, respectively. These findings demonstrated that naftopidil selectively inhibited the phenylephrine-induced increase in prostatic pressure compared with mean blood pressure in the anesthetized dog model. The selectivity of naftopidil for prostatic pressure was the most potent among the test compounds. In addition, using cloned human alpha1-adrenoceptor subtypes, naftopidil was selective for the alpha1d-adrenoceptor with approximately 3- and 17-fold higher affinity than for the alpha1a- and alpha1b-adrenoceptor subtypes, respectively. The selectivity of naftopidil for prostatic pressure may be attributable to its high binding affinity for alpha1a- and alpha1d-adrenoceptor subtypes. PMID:10361884

  12. Evaluation of the pharmacological selectivity profile of alpha 1 adrenoceptor antagonists at prostatic alpha 1 adrenoceptors: binding, functional and in vivo studies.

    PubMed Central

    Kenny, B. A.; Miller, A. M.; Williamson, I. J.; O'Connell, J.; Chalmers, D. H.; Naylor, A. M.

    1996-01-01

    1. The profile of a range of alpha 1 adrenoceptor antagonists was determined in vitro against cloned human alpha 1A, alpha 1B and alpha 1D adrenoceptors and against noradrenaline-mediated contractions of rat aorta and human prostate. The in vivo profile of compounds was determined in an anaesthetized dog model which allowed the simultaneous assessment of antagonist potency against phenylephrine-mediated increases in blood pressure and prostatic pressure. 2. The quinazoline antagonists, prazosin, doxazosin and alfuzosin displayed high affinity but were non selective for the three cloned human alpha 1 adrenoceptors. Indoramin and SNAP 1069 showed selectivity for alpha 1A and alpha 1B adrenoceptors relative to the alpha 1D subtype. Rec 15/2739, WB 4101, SL 89,0591, (+)- and (-)- tamsulosin showed selectivity for alpha 1A and alpha 1D adrenoceptors relative to the alpha 1B subtype. RS 17053 showed high affinity and selectivity for alpha 1A adrenoceptors (pKi 8.6) relative to alpha 1B (pKi = 7.3) and alpha 1D (pKi = 7.1) subtypes. 3. (+)-Tamsulosin, (-)-tamsulosin, SL 89,0591, Rec 15/2739, SNAP 1069 and RS 17053 appeared to act as competitive antagonists of noradrenaline-mediated contractions of rat aorta yielding pA2 affinity estimates which were similar to binding affinities at cloned human alpha 1D adrenoceptors. The following rank order was obtained: prazosin = (-)-tamsulosin > doxazosin > SL 89,0591 = (+)-tamsulosin > Rec 15/2739 > RS 17053 = SNAP 1069. 4. (-)-Tamsulosin was a very potent, insurmountable antagonist of noradrenaline-mediated contractions of human prostate, yielding an approximate pA2 estimate of 9.8 at 1 nM. The corresponding (+)-enantiomer was 30 fold weaker. SL 89,0591, SNAP 1069 and Rec 15/2739 yielded pA2 estimates which compared well with their alpha 1A binding affinities. The affinity estimate for prazosin on human prostate was lower than the corresponding binding affinity determined at alpha 1A adrenoceptors and RS 17053 was a very weak

  13. Comparison of guinea-pig, bovine and rat alpha 1-adrenoceptor subtypes.

    PubMed Central

    Büscher, R.; Heeks, C.; Taguchi, K.; Michel, M. C.

    1996-01-01

    1. To elucidate a possible role of species differences in the classification of alpha 1-adrenoceptor subtypes, we have characterized the alpha 1-adrenoceptors in guinea-pig spleen, kidney and cerebral cortex and in bovine cerebral cortex using concentration-dependent alkylation by chloroethylclonidine and competitive binding with 5-methlurapidil, methoxamine, (+)-niguldipine, noradrenaline, oxymetazoline, phentolamine, SDZ NVI-085, tamsulosin and (+)-tamsulosin. Rat liver alpha 1B-adrenoceptors were studied for comparison. Chloroethylclonidine-sensitivity and (+)-niguldipine affinity were also compared at cloned rat and bovine alpha 1a-adrenoceptors. 2. Chloroethylclonidine concentration-dependently inactivated alpha 1-adrenoceptors in all five tissues. While chloroethylclonidine inactivated almost all alpha 1-adrenoceptors in rat liver and guinea-pig kidney and brain, 20-30% of alpha 1-adrenoceptors in guinea-pig spleen and bovine brain were resistant to alkylation by 10 microM chloroethylclonidine. With regard to concentration-dependency guinea-pig kidney and brain were approximately 10 fold less sensitive than guinea-pig spleen or rat liver. 3. In rat liver, all drugs tested competed for [3H]-prazosin binding with steep and monophasic curves. Drug affinities were relatively low and resembled most closely those of cloned rat alpha 1b-adrenoceptors. 4. In guinea-pig spleen, all drugs tested competed for [3H]-prazosin binding with steep and monophasic curves. Drug affinities were relatively low and resembled most closely those of cloned rat alpha 1b-adrenoceptors. 5. In guinea-pig kidney most drugs tested competed for [3H]-prazosin binding with steep and monophasic curves and had relatively low drug affinities close to those of cloned rat alpha 1b- and alpha 1d-adrenoceptors. However, noradrenaline and tamsulosin had consistently biphasic competition curves recognizing 36-39% high and 61-64% low affinity sites. 6. In guinea-pig cerebral cortex, all drugs tested

  14. The stereospecificity of LY253352 for alpha 1-adrenoceptor binding sites in the brain and prostate.

    PubMed Central

    Lepor, H.; Baumann, M.; Shapiro, E.

    1988-01-01

    1. The stereospecificity of the enantiomers of LY253352, a potent and selective alpha 1-adrenoceptor antagonist, were studied in the human prostate and canine brain using radioligand receptor binding methods. 2. The mean equilibrium dissociation constant (KD) in the canine brain and human prostatic adenoma was 84.4 pM and 65.4 pM, respectively. 3. The alpha 1-adrenoceptor density in the canine brain was approximately eight fold greater than in the human prostatic adenoma. 4. The mean Ki values of (-)-LY253352 and (+)-LY253352 in the prostate were 0.19 nM and 5.79 nM, respectively. 5. The mean Ki values of (-)-LY253352 and (+)-LY253352 in the brain were 0.29 nM and 34.7 nM, respectively. 6. This study indicates that the stereochemical specificity of the optical isomers of LY253352 is a manifestation of differential affinities of the enantiomers for alpha 1-adrenoceptor binding sites. 7. The differential affinities of (+)-LY253352 in the brain and prostate are suggestive of subtle unique properties of adrenoceptor binding sites in these tissues. PMID:2851347

  15. Subtype selective alpha1-adrenoceptor antagonists for the treatment of benign prostatic hyperplasia.

    PubMed

    Forray; Noble

    1999-12-01

    Benign prostatic hyperplasia (BPH) is highly prevalent in the male population beyond the age of 60. Impairment of urinary flow due to prostate enlargement gives rise to symptoms of 'prostatism' that have a detrimental impact on the quality of life. The current trend in the management of symptomatic BPH favours pharmacotherapy as a first line option, while the number of surgical procedures being performed has experienced a steady decline during the last ten years. Among the pharmacological treatments, the use of alpha1-adrenoceptor blockers has demonstrated to be an effective treatment option for BPH. These agents reduce the adrenergic tone to the prostate and increase urinary flow, with a concomitant reduction of lower urinary tract symptoms. The alpha1-blockers currently approved include compounds such as alfuzosin, terazosin and doxazosin, originally developed for the treatment of hypertension, and more recently tamsulosin, an alpha1-subtype selective drug. The blockade of alpha1-adrenoceptors present in vascular smooth muscle is largely responsible for the most prominent side effects of current drugs, which can be severe and require patients dose titration. The limitation imposed by side effects naturally raises the possibility that complete blockade of prostatic alpha1 receptors is not attained at the maximum tolerated dose. The extensive efforts by the pharmaceutical industry towards the development of uroselective alpha1-blockers, is the subject of this review. Advances in the molecular cloning of genes encoding three alpha1-adrenoceptors led to the identification of the alpha1A-subtype as the predominant receptor responsible for the contraction of prostate smooth muscle. In preclinical animal models, selective alpha1A-antagonists have consistently been found to have minimal cardiovascular effects, thus providing a pharmacological rationale for uroselectivity. It has also become apparent, however, that uroselectivity can emerge in a poorly understood manner

  16. Prediction of alpha1-adrenoceptor occupancy in the human prostate from plasma concentrations of silodosin, tamsulosin and terazosin to treat urinary obstruction in benign prostatic hyperplasia.

    PubMed

    Yamada, Shizuo; Kato, Yasuhiro; Okura, Takashi; Kagawa, Yoshiyuki; Kawabe, Kazuki

    2007-07-01

    Alpha1-adrenoceptor antagonists are clinically useful for the improvement of urinary obstruction due to benign prostatic hyperplasia (BPH), and their therapeutic effects are mediated through the blockade of prostatic alpha(1)-adrenoceptors. The present study was undertaken to predict the magnitude and duration of alpha(1)-adrenoceptor occupancy in the human prostate after oral alpha(1)-adrenoceptor antagonists. Prostatic alpha(1)-adrenoceptor-binding parameters of silodosin were estimated by measuring specific [(3)H]prazosin binding in rat prostate after oral administration of this drug. The plasma concentration of silodosin after oral administration in rats and healthy volunteers was measured using a high-performance liquid chromatographic method. The alpha(1)-adrenoceptor-binding affinities (K(i)) of silodosin, tamsulosin, and terazosin in the human prostate and plasma concentrations of tamsulosin and terazosin were obtained from the literature. Using the alpha(1)-adrenoceptor binding parameters of silodosin in rat prostate, alpha(1)-adrenoceptor occupancy in the human prostate was estimated to be around 60-70% at 1-6 h after oral administration of silodosin at doses of 3.0, 8.1, and 16.1 micromol. Thereafter, the receptor occupancy was periodically decreased, to 24% (8.1 micromol) and 54% (16.1 micromol) 24 h later. A similar magnitude and time course of alpha(1)-adrenoceptor occupancy by silodosin in the human prostate were estimated using alpha(1)-adrenoceptor-binding affinities (K(i)) in the human prostate. Despite about two orders of differences in the plasma unbound concentrations after clinically effective oral dosages of silodosin, tamsulosin, and terazosin, there was a comparable magnitude of prostatic alpha(1)-adrenoceptor occupancy by these drugs. In conclusion, the prediction of alpha(1)-adrenoceptor occupancy in the human prostate by alpha(1)-adrenoceptor antagonists may provide the rationale for the optimum dosage regimen of these drugs in the

  17. (/sup 125/Iodo)BE 2254, a new radioligand for alpha 1-adrenoceptors

    SciTech Connect

    Engel, G.; Hoyer, D.

    1982-01-01

    (/sup 125/cIodo)2-(beta-(14-hydroxyphenyl)-ethyl-aminomethyl)-tetralone((/sup 125/Iodo)BE 2254 or IBE 2254), a new iodinated radioligand of high specific radioactivity (2175 Ci/mmol), was synthesized and used to characterize alpha 1-adrenoceptors in rat lung and cerebral cortex membranes. The binding constants of IBE 2254, using rat lung and cortex membranes, were Kd . 53 +/- 10 pM, Bmax . 53 +/- 8 fmol/mg; and Kd . 78 +/- 14 pM, Bmas . 210 +/- 26 fmol/mg, respectively (Kd . dissociation constant of IBE 2254 determined in saturation experiments). In equilibrium binding experiments with IBE 2254, at concentrations of the free ligand up to 1.2 nM, only one class of binding sites could be detected. In kinetic experiments, the association and dissociation rate constants were 2.3 X 10(9) M-1 min-1 and 0.10 min-1, respectively. In rat cerebral cortex membranes, alpha-adrenoceptor antagonists competed for IBE 2254 binding in the following order: prazosin greater than BE 2254 greater than WB 4101 greater than phentolamine greater than corynanthine greater than yohimbine greater than rauwolscine, indicating strongly that IBE 2254 binds to alpha 1-adrenoceptors. The calculated affinities of different alpha-adrenoceptor blocking agents from inhibition of IBE 2254 binding were nearly identical in rat lung and cerebral cortex. The low dissociation constant of the ligand together with its high specific radioactivity allows binding studies to be carried out with tissue samples where only small densities of alpha 1-adrenoceptors are present.

  18. The effects of SB 216469, an antagonist which discriminates between the alpha 1A-adrenoceptor and the human prostatic alpha 1-adrenoceptor.

    PubMed Central

    Chess-Williams, R.; Chapple, C. R.; Verfurth, F.; Noble, A. J.; Couldwell, C. J.; Michel, M. C.

    1996-01-01

    1. The affinity of the alpha 1-adrenoceptor antagonist SB 216469 (also known as REC 15/2739) has been determined at native and cloned alpha 1-adrenoceptor subtypes by radioligand binding and at functional alpha 1-adrenoceptor subtypes in isolated tissues. 2. In radioligand binding studies with [3H]-prazosin, SB 216469 had a high affinity at the alpha 1A-adrenoceptors of the rat cerebral cortex and kidney (9.5-9.8) but a lower affinity at the alpha 1B-adrenoceptors of the rat spleen and liver (7.7-8.2). 3. At cloned rat alpha 1-adrenoceptor subtypes transiently expressed in COS-1 cells and also at cloned human alpha 1-adrenoceptor subtypes stably transfected in Rat-1 cells, SB 216469 exhibited a high affinity at the alpha 1a-adrenoceptors (9.6-10.4) with a significantly lower affinity at the alpha 1b-adrenoceptor (8.0-8.4) and an intermediate affinity at the alpha 1d-adrenoceptor (8.7-9.2). 4. At functional alpha 1-adrenoceptors, SB 216469 had a similar pharmacological profile, with a high affinity at the alpha 1A-adrenoceptors of the rat vas deferens and anococcygeus muscle (pA2 = 9.5-10.0), a low affinity at the alpha 1B-adrenoceptors of the rat spleen (6.7) and guinea-pig aorta (8.0), and an intermediate affinity at the alpha 1D-adrenoceptors of the rat aorta (8.8). 5. Several recent studies have concluded that the alpha 1-adrenoceptor present in the human prostate has the pharmacological characteristics of the alpha 1A-adrenoceptor subtype. However, the affinity of SB 216469 at human prostatic alpha 1-adrenoceptors (pA2 = 8.1) determined in isolated tissue strips, was significantly lower than the values obtained at either the cloned alpha 1a-adrenoceptors (human, rat, bovine) or the native alpha 1A-adrenoceptors in radioligand binding and functional studies in the rat. 6. Our results with SB 216469, therefore, suggest that the alpha 1-adrenoceptor mediating contractile responses of the human prostate has properties which distinguish it from the cloned alpha 1a

  19. Selective action of two aporphines at alpha 1-adrenoceptors and potential-operated Ca2+ channels.

    PubMed

    Ivorra, M D; Chuliá, S; Lugnier, C; D'Ocon, M P

    1993-02-01

    Contractions evoked by noradrenaline (1 microM) or a depolarizing solution of 60 mM KCl were concentration dependently depressed by the aporphine alkaloids (S)-boldine and (R)-apomorphine in rat aorta. Both drugs had a greater inhibitory potency on the contraction elicited by noradrenaline. Dose-response curves for noradrenaline were shifted to the right in presence of (S)-boldine. (R)-Apomorphine acted by a complex mechanism at alpha 1-adrenoceptors and its inhibitory effect was irreversible. The conformational features of these alkaloids may explain their different behaviour at alpha 1-adrenoceptors. In Ca(2+)-free solution, the alkaloids inhibited the contraction evoked by noradrenaline but did not modify (apomorphine) or increase (boldine) the contractile response induced by caffeine. Both alkaloids interacted with [3H]prazosin binding and with the benzothiazepine binding site of the Ca2+ entry receptor complex but had no effect at the dihydropyridine binding site in the rat cerebral cortex. Both drugs showed some selectivity as inhibitors of [3H]prazosin binding as opposed to [3H]d-cis diltiazem binding. (R)-Apomorphine slightly inhibited one of the two forms of the Ca(2+)-independent, low Km cyclic AMP-phosphodiesterase (type IV), whereas it did not have a significant effect on the other phosphodiesterase forms. (S)-Boldine had negligible inhibitory effects on all phosphodiesterase forms. The present study provides evidence that (S)-boldine and (R)-apomorphine have interesting properties as Ca2+ entry blockers (through the benzothiazepine receptor site in the Ca2+ channel) and at alpha 1-adrenoceptors. PMID:8384112

  20. A comparison of the antagonistic activities of tamsulosin and terazosin against human vascular alpha1-adrenoceptors.

    PubMed

    Harada, K; Ohmori, M; Kitoh, Y; Sugimoto, K; Fujimura, A

    1999-07-01

    Tamsulosin, a selective alpha1A-adrenoceptor antagonist, and terazosin, a non-selective one, are effective for the treatment of urinary disturbance due to benign prostatic hypertrophy. In the present study, their alpha1-adrenoceptor-blocking effects on blood vessels, which may cause orthostatic hypotension, were investigated in 10 healthy males. After the subjects took orally 0.2 mg of tamsulosin, 1 mg of terazosin or a lactate capsule as the control in a randomized cross-over fashion, their finger tip vasoconstrictor response to cold stimulation and vasoconstrictor response of the dorsal hand vein to increasing doses of phenylephrine were examined. The finger tip vasoconstrictor response was significantly reduced and the infusion rate of phenylephrine producing a half-maximal constriction was significantly increased by terazosin, but tamsulosin had no significant effect on these parameters. These data suggest that the usual dose of tamsulosin exerts little alpha1-adrenoceptor-blocking activity on blood vessels, and orthostatic episodes might be mild, if any, during the treatment with tamsulosin. PMID:10461765

  1. (3H)bunazosin, a novel selective radioligand of alpha 1 adrenoceptors in human prostates

    SciTech Connect

    Yamada, S.; Suzuki, M.; Matsuoka, Y.; Kato, Y.; Kimura, R.; Maruyama, M.; Kawabe, K. )

    1991-09-01

    The binding properties of a new radioligand, (3H)bunazosin, were studied in membranes of human prostates with benign prostatic hypertrophy (BPH). Specific binding of (3H)bunazosin was saturable, reversible, and of high affinity (Kd = 0.55 {plus minus} 0.04 nM). The density of (3H)bunazosin binding sites (Bmax) was 676 {plus minus} 33 fmol/mg. protein. (3H)Bunazosin rapidly associated with its binding sites in membranes of human prostates and reached steady state by 20 min. at 25C. The rate constants for association and dissociation of (3H)bunazosin binding were calculated to be 0.11 {plus minus} 0.01/nM/min. and 0.05 {plus minus} 0.02/min. (n = 4), respectively. Seven alpha 1 adrenoceptor antagonists competed with (3H)bunazosin for the binding sites in the rank order: R-(-)-YM-12617 greater than prazosin greater than SGB-1534 greater than bunazosin greater than terazosin greater than naftopidil greater than urapidil. In parallel studies with (3H)bunazosin, the Kd and Bmax values for (3H)prazosin binding in human prostates were slightly lower. There was a similarity in the potency and rank order of seven alpha 1, adrenoceptor antagonists for the inhibition of (3H) bunazosin and (3H)prazosin binding in human prostates. The new (3H)bunazosin binding assay in human prostates is remarkable for its low degree of nonspecific binding as compared to (3H)prazosin, especially at high ligand concentrations. Thus, (3H)bunazosin may become a useful radioligand for the further analysis of the alph 1 adrenoceptor binding sites in human prostates.

  2. RBx 6198: a novel alpha1-adrenoceptor antagonist for the treatment of benign prostatic hyperplasia.

    PubMed

    Nanda, Kamna; Naruganahalli, Krishna S; Gupta, Suman; Malhotra, Shivani; Tiwari, Atul; Hegde, Laxminarayan G; Jain, Sanjay; Sinha, Neelima; Gupta, Jung B; Chugh, Anita; Anand, Nitya; Ray, Abhijit

    2009-04-01

    The present study, investigates the effect of RBx 6198, 2-{3-[4-(2-Isopropoxy-phenyl)-piperazin-1-yl]-propyl}-3a, 4, 7, 7a-tetrahydro-isoindole-1, 3,-dione, a novel alpha(1)-adrenoceptor antagonist, in both in vitro and in vivo test systems. RBx 6198 is a potent (nanomolar affinity) alpha(1A)-adrenoceptor antagonist with demonstrable uroselectivity in anaesthesized dog model. In radioligand binding studies using human recombinant receptors, RBx 6198 exhibited high selectivity (approximately 50 fold) for the alpha(1A)-adrenoceptor subtype as compared to alpha(1B)-adrenoceptor subtype. In order to assess tissue selectivity, the antagonistic effect of RBx 6198 on the phenylephrine induced contractile response of isolated rat prostate, spleen and aorta was characterized. RBx 6198 was 8 fold more potent in inhibiting phenylephrine-evoked contractions of isolated tissues compared to tamsulosin. However, the compound was non-selective for alpha(1A) vs. alpha(1D)-adrenoceptor like tamsulosin. In anaesthetized beagle dogs RBx 6198 suppressed the intraurethral pressure response to phenylephrine to a greater extent than the mean arterial pressure response thereby demonstrating uroselectivity consistent with in vitro binding and functional data. RBx 6198 was 6.4 fold more uroselective as compared to tamsulosin after i.v. route dose administration. Taken together all results from preclinical studies, it is suggested that RBx 6198 is a novel alpha(1)-adrenoceptor antagonist that exhibited improved pharmacological profile over tamsulosin in both in vitro and in vivo. PMID:19239913

  3. Analysis of the activity of alpha 1-adrenoceptor antagonists in rat aorta.

    PubMed Central

    Van der Graaf, P. H.; Shankley, N. P.; Black, J. W.

    1996-01-01

    1. In this study, the effect of seven alpha 1-adrenoceptor antagonists (tamsulosin, phentolamine, prazosin, WB-4101, 5-methylurapidil, spiperone and HV723) have been examined on the contractile response to noradrenaline (NA) and phenylephrine (PE) in rat isolated aorta. 2. NA and PE, when administered using a cumulative dosing schedule, both produced concentration-dependent contraction of aortic rings. It was possible to fit the individual concentration-effect (E/[A]) curve data to the Hill equation to provide estimates of the curve midpoint location (p[A]50 = 7.74 +/- 0.10 and 7.14 +/- 0.18), midpoint slope (nH = 0.82 +/- 0.03 and 0.99 +/- 0.10) and upper asymptote (alpha = 3.2 +/- 0.3 and 3.1 +/- 0.2 g) parameters for NA and PE, respectively. However, the Hill equation provided a better fit to the E/[A] curve data obtained with another contractile agent, 5-hydroxytryptamine (5-HT) (p[A50] = 6.09 +/- 0.08, nH = 1.49 +/- 0.09, alpha = 2.6 +/- 0.3 g), as judged by calculation of the mean sum of squares of the differences between the observed and predicted values. 3. All of the antagonists investigated produced concentration-dependent inhibition of the contractile responses of the aorta to NA and PE. Although no significant effects on the upper asymptotes of the E/[A] curves of any of the antagonists tested were detected, only tamsulosin and 5-methylurapidil did not have a significant effect on the slope (nH) of the NA and PE E/[A] curves. The other antagonists produced significant steepening of the curves obtained with NA and/or PE. 4. Notwithstanding the fact that one of the basic criteria for simple competitive antagonism at a single receptor class was not always satisfied, the individual log [A]50 values estimated in the absence and presence of antagonist within each experiment were fitted to the competitive model. The Schild plot slope parameters for the antagonism of NA and PE by phentolamine and HV723 were found to be significantly less than unity. The Schild

  4. [Alpha1-adrenoceptor subtype selectivity and organ specificity of silodosin (KMD-3213)].

    PubMed

    Tatemichi, Satoshi; Kobayashi, Kumi; Maezawa, Ayaka; Kobayashi, Mamoru; Yamazaki, Yoshinobu; Shibata, Nobuo

    2006-03-01

    The selectivity of silodosin (KMD-3213), an antagonist of alpha(1)-adrenoceptor (AR), to the subtypes (alpha(1A)-, alpha(1B)- and alpha(1D)-ARs) was examined by a receptor-binding study and a functional pharmacological study, and we compared its subtype-selectivity with those of other alpha(1)-AR antagonists. In the receptor-binding study, a replacement experiment using [(3)H]-prazosin was conducted using the membrane fraction of mouse-derived LM (tk-) cells in which each of three human alpha(1)-AR subtypes was expressed. In the functional pharmacological study, the following isolated tissues were used as representative organs with high distribution densities of alpha(1)-AR subtypes (alpha(1A)-AR: rabbit prostate, urethra and bladder trigone; alpha(1B)-AR: rat spleen; alpha(1D)-AR: rat thoracic aorta). Using the Magnus method, we studied the inhibitory effect of silodosin on noradrenaline-induced contraction, and compared it with those of tamsulosin hydrochloride, naftopidil and prazosin hydrochloride. Silodosin showed higher selectivity for the alpha(1A)-AR subtype than tamsulosin hydrochloride, naftopidil or prazosin hydrochloride (affinity was highest for tamsulosin hydrochloride, followed by silodosin, prazosin hydrochloride and naftopidil in that order). Silodosin strongly antagonized noradrenaline-induced contractions in rabbit lower urinary tract tissues (including prostate, urethra and bladder trigone, with pA(2) or pKb values of 9.60, 8.71 and 9.35, respectively). On the other hand, the pA(2) values for antagonism of noradrenaline-induced contractions in rat isolated spleen and rat isolated thoracic aorta were 7.15 and 7.88, respectively. Selectivity for lower urinary tract was higher for silodosin than for the other alpha(1)-AR antagonists. Our data suggest that silodosin has a high selectivity for the alpha(1A)-AR subtype and for the lower urinary tract. PMID:16518085

  5. Renal vasodilatation by dopexamine and fenoldopam due to alpha 1-adrenoceptor blockade.

    PubMed Central

    Martin, S. W.; Broadley, K. J.

    1995-01-01

    1. The renal vascular responses of the rat isolated perfused kidney to the dopamine D1-receptor agonists, dopexamine and fenoldopam, were examined. 2. Both kidneys were perfused in situ at constant flow rate (11 ml min-1) with Krebs-bicarbonate solution at 37 degrees C. The perfusion pressure was monitored and to enable vasodilator responses to be measured, the resting perfusion pressure was raised by infusing noradrenaline (6 x 10(-9) M). 3. Dose-related vasodilator responses to bolus doses of dopexamine and fenoldopam were obtained. However, these were not antagonized by the D1-receptor antagonist, SCH 23390, indicating that D1-receptors were not involved. 4. Bolus doses of the alpha 1-adrenoceptor antagonist, prazosin, caused similar dose-related vasodilator responses indicating the possibility that alpha 1-adrenoceptor blocking properties of dopexamine and fenoldopam were responsible for the vasodilatation. 5. alpha-Adrenoceptor blockade by dopexamine and fenoldopam was confirmed by the parallel displacement of dose-response curves for the vasopressor responses to noradrenaline. pA2 values were determined by Schild analysis for dopexamine, fenoldopam and prazosin antagonism of noradrenaline in the presence of neuronal (cocaine, 10(-5) M) and extraneuronal uptake blockade (metanephrine, 10(-5) M). The values were 6.23, 6.02 and 8.91, respectively. Schild plot slopes of unity were obtained for dopexamine and fenoldopam indicating competitive antagonism. A slope of greater than unity for prazosin may be explained by the lack of equilibrium conditions associated with bolus doses of noradrenaline, the responses of which are affected more by the high affinity antagonist, prazosin, than the two lower affinity antagonists.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:7670737

  6. Binding and functional characterization of alpha1-adrenoceptor subtypes in the rat prostate.

    PubMed

    Hiraoka, Y; Ohmura, T; Oshita, M; Watanabe, Y; Morikawa, K; Nagata, O; Kato, H; Taniguchi, T; Muramatsu, I

    1999-01-29

    The alpha1-adrenoceptor subtypes of rat prostate were characterized in binding and functional experiments. In binding experiments, [3H]tamsulosin bound to a single class of binding sites with an affinity (pKD) of 10.79+/-0.04 and Bmax of 87+/-2 fmol mg(-1) protein. This binding was inhibited by prazosin, 2-(2,6-dimethoxy-phenoxyethyl)-aminomethyl-1,4-benzodioxane hydrochloride (WB4101), 5-methylurapidil, alpha-ethyl-3,4,5,-trimethoxy-alpha-(3-((2-(2-methoxyphenoxy)ethyl)-amin o)-propyl)benzeneacetonitrile fumarate (HV723) and oxymetazoline with high efficacy, resulting in a good correlation with the binding characteristics of cloned alpha1a but not alpha1b and alpha1d-adrenoceptor subtypes. In functional studies, noradrenaline and oxymetazoline produced concentration-dependent contractions. These contractions were antagonized by tamsulosin, prazosin, WB4101 and 5-methylurapidil with an efficacy lower than that exhibited by these agents for inhibition of [3H]tamsulosin binding. The relationship between receptor occupancy and contractile amplitude revealed the presence of receptor reserve for noradrenaline, but the contraction induced by oxymetazoline was not in parallel with receptor occupation and developed after predicted receptor saturation. From these results, it is suggested that alpha1A-adrenoceptors are the dominant subtype in the rat prostate which can be detected with [3H]tamsulosin, but that the functional subtype mediating adrenergic contractions has the characteristics of the alpha1L-adrenoceptor subtype, having a lower affinity for prazosin and some other drugs than the alpha1A-adrenoceptor subtype. PMID:10064160

  7. Suppression of human prostate cancer cell growth by alpha1-adrenoceptor antagonists doxazosin and terazosin via induction of apoptosis.

    PubMed

    Kyprianou, N; Benning, C M

    2000-08-15

    Recent evidence from our laboratory has demonstrated that alpha1-adrenoceptor antagonists doxazosin and terazosin induced apoptosis in prostate epithelial and smooth muscle cells in patients with benign prostatic hypertrophy (BPH; J. Urol., 159: 1810-1815, 1998; J. Urol., 161: 2002-2007, 1999). In this study, we investigated the biological action of three alpha1-adrenoceptor antagonists, doxazosin, terazosin, and tamsulosin, against prostate cancer cell growth. The antigrowth effect of the three alpha1-adrenoceptor antagonists was examined in two human prostate cancer cell lines, PC-3 and DU-145, and a prostate smooth muscle cell primary culture, SMC-1, on the basis of: (a) cell viability assay; (b) rate of DNA synthesis; and (c) induction of apoptosis. Our results indicate that treatment of prostate cancer cells with doxazosin or terazosin results in a significant loss of cell viability, via induction of apoptosis in a dose-dependent manner, whereas tamsulosin had no effect on prostate cell growth. Neither doxazosin nor terazosin exerted a significant effect on the rate of cell proliferation in prostate cancer cells. Exposure to phenoxybenzamine, an irreversible inhibitor of alpha1-adrenoceptors, does not abrogate the apoptotic effect of doxazosin or terazosin against human prostate cancer or smooth muscle cells. This suggests that the apoptotic activity of doxazosin and terazosin against prostate cells is independent of their capacity to antagonize alpha1-adrenoceptors. Furthermore, an in vivo efficacy trial demonstrated that doxazosin administration (at tolerated pharmacologically relevant doses) in SCID mice bearing PC-3 prostate cancer xenografts resulted in a significant inhibition of tumor growth. These findings demonstrate the ability of doxazosin and terazosin (but not tamsulosin) to suppress prostate cancer cell growth in vitro and in vivo by inducing apoptosis without affecting cell proliferation. This evidence provides the rationale for targeting both

  8. Possible dopaminergic stimulation of locus coeruleus alpha1-adrenoceptors involved in behavioral activation.

    PubMed

    Lin, Yan; Quartermain, David; Dunn, Adrian J; Weinshenker, David; Stone, Eric A

    2008-07-01

    alpha(1)-Adrenoceptors of the locus coeruleus (LC) have been implicated in behavioral activation in novel surroundings, but the endogenous agonist that activates these receptors has not been established. In addition to the canonical activation of alpha(1)-receptors by norepinephrine (NE), there is evidence that dopamine (DA) may also activate certain brain alpha(1)-receptors. This study examined the contribution of DA to exploratory activity in a novel cage by determining the effect of infusion of various dopaminergic and adrenergic drugs into the mouse LC. It was found that the D2/D3 agonist, quinpirole, which selectively blocks the release of CNS DA, produced a dose-dependent and virtually complete abolition of exploration and all movement in the novel cage test. The quinpirole-induced inactivity was significantly attenuated by coinfusion of DA but not by the D1 agonist, SKF38390. Furthermore, the DA attenuation of quinpirole inactivity was blocked by coinfusion of the alpha(1)-adrenergic receptor antagonist, terazosin, but not by the D1 receptor antagonist, SCH23390. LC infusions of either quinpirole or terazosin also produced profound inactivity in DA-beta-hydroxylase knockout (Dbh -/-) mice that lack NE, indicating that their behavioral effects were not due to an alteration of the release or action of LC NE. Measurement of endogenous DA, NE, and 5HT and their metabolites in the LC during exposure to the novel cage indicated an increase in the turnover of DA and NE but not 5HT. These results indicate that DA is a candidate as an endogenous agonist for behaviorally activating LC alpha(1)-receptors and may play a role in the activation of this nucleus by novel surroundings. PMID:18435418

  9. Functional studies on alpha 1-adrenoceptor subtypes mediating inotropic effects in rat right ventricle.

    PubMed Central

    Michel, M. C.; Hanft, G.; Gross, G.

    1994-01-01

    1. We have studied the alpha 1-adrenoceptor subtypes mediating inotropic effects of adrenaline in rat right ventricle and the Ca2+ sources used to elicit these effects. alpha 1A-Adrenoceptor-mediated contractile effects in rat vas deferens were studied for comparison in some cases. 2. Treatment with chloroethylclonidine did not affect the maximal beta-adrenoceptor-mediated inotropic effects in rat right ventricle or the maximal alpha 1A-adrenoceptor-mediated contractile effects in rat vas deferens; it did not alter the potency of isoprenaline in the ventricle and reduced the potency of the alpha-adrenoceptor antagonists in vas deferens only slightly. Treatment of right ventricular strips with CdCl2 markedly reduced resting tension and enhanced maximal inotropic effects of isoprenaline but did not affect its potency. 3. Inactivation of cardiac alpha 1B-adrenoceptors by treatment with chloroethylclonidine slightly enhanced the maximal inotropic effects of the full agonist, adrenaline and of several partial agonists. 4. Schild analysis of inhibition experiments with the alpha 1A-adrenoceptor-selective antagonists, 5-methyl-urapidil and (+/-)-tamsulosin, demonstrated that adrenaline causes its inotropic effects mainly via the alpha 1B-adrenoceptor subtype. Schild analysis of 5-methyl-urapidil inhibition experiments in chloroethylclonidine-treated ventricles indicated that only alpha 1A-adrenoceptors mediate the inotropic effects of adrenaline following inactivation of the alpha 1B-adrenoceptors. 5. In control ventricles the organic Ca2+ entry blocker, nitrendipine and treatment with the inorganic Ca2+ entry blocker, CdCl2 did not reduce inotropic effects of adrenaline whereas ryanodine treatment inhibited them. In contrast, nitrendipine and CdCl2 treatment had major inhibitory effects in chloroethylclonidine-treated but lacked inhibitory effects in phenoxybenzamine-treated ventricular strips. 6. We conclude that inotropic effects of adrenaline in rat heart are mediated

  10. Alpha-1 adrenoceptors in brown adipose tissue of lean and ob/ob mice

    SciTech Connect

    Behrens-Zaror, G.; Himms-Hagen, J.

    1986-03-01

    Obese (ob/ob) mice have a low capacity to increase thyroxine 5'-deiodinase (T4 5'-D) in brown adipose tissue (BAT) when exposed to cold. This effect is mediated by alpha-1 (A-1) adrenoceptors. The authors objective was to find out whether BAT of the ob/ob mouse has normal A-1 receptors. Saturation analysis of binding of (3H)-WB4101 at 0.05 nM to 10 ..mu..M to crude membrane preparations (100,000 g pellets from Polytron homogenates) using the LIGAND program of Munson and Rodbard, showed two populations of binding sites in BAT of lean (+/+, 11-15 wk old) mice. Acute exposure (12 h, 14/sup 0/C) or acclimation to cold (3 wk, 14/sup 0/C) did not alter affinity or concentration of sites. Displacement with yohimbine and prazosin indicated binding of WB4101 to A-1 receptors. Very young (5 wk) lean (+/.) and obese mice had similar affinity constants (lean 0.13 +/- 0.043 and 34.2 +/- 14.9; obese, 0.12 +/- 0.028 and 20.9 +/- 5.48 nM) and concentrations (lean 22.4 +/- 3.8 and 647 +/- 137; obese, 28.6 +/- 4.6 and 547 +/- 105 fmol/mg protein) of sites. Old (1 yr) mice had high affinity sites similar to those in younger animals (KD lean 0.19 +/- 0.028, obese, 0.25 +/- 0.075; Bmax lean, 60.2 +/- 12.1; obese, 63.1 +/- 13.5 fmol/mg protein). The authors conclude that the ob/ob mouse has normal high affinity A-1 receptors in BAT. Anomalous properties of low affinity binding in old ob/ob mice could not be characterized because of high nonspecific binding. BAT of the ob/ob mouse does not lack A-1 receptors but may have a post-receptor alteration in the A-1 adrenoceptor-mediated response.

  11. Induction of apoptosis in the prostate by alpha1-adrenoceptor antagonists: a novel effect of "old" drugs.

    PubMed

    Kyprianou, N; Jacobs, S C

    2000-08-01

    Advances in our understanding of the integrated functions governing prostate cell proliferation and cell death imply that effective therapies for prostate neoplasia should not only be molecularly targeted, but should be customized to take into account the delicate balance of opposing growth influences. Evidence from studies on the dynamics of prostate growth in benign prostatic hyperplasia (BPH) and prostate cancer established that disruption of the molecular mechanisms that regulate apoptosis and cell proliferation among the stroma and epithelial cell populations may underlie the neoplastic development that characterizes the aging gland. Our own efforts have been focused on investigating whether a1-adrenoceptor antagonists clinically used for the relief of the obstructive symptoms associated with BPH affect prostate pathophysiology via mechanisms other than smooth muscle contraction. Such efforts led to the identification of a novel effect of two alpha1-adrenoceptor antagonists, doxazosin and terazosin. More recent in vitro experiments examined the potential anti-tumor action of three clinically used alpha1-adrenoceptor antagonists--doxazosin, terazosin and tamsulosin--against prostate cancer cell growth. These findings demonstrate the ability of doxazosin and terazosin, but not tamsulosin, to suppress prostate growth by inducing apoptosis among the epithelial cells in the benign and malignant prostate. Thus, evidence indicates that rather than just causing pure relaxation of the smooth muscle, certain alpha1-blockers can also affect the dynamics of prostate growth by changing the balance between prostate cell proliferation and apoptosis at the expense of the proliferative process. PMID:12084321

  12. Role of receptor reserve in the inhibition of alpha-1 adrenoceptor-mediated pressor responses by calcium antagonists in the pithed rat.

    PubMed

    Jim, K F; Macia, R A; Matthews, W D

    1986-07-01

    The effect of the calcium channel antagonists nifedipine and FR 34235 on the vasopressor response to alpha-1 adrenoceptor stimulation in the pithed normotensive rat was investigated. The maximal pressor response elicited by the full alpha-1 adrenoceptor agonist SK&F l-89748 was slightly but significantly reduced by 1-mg/kg doses of nifedipine (21 +/- 2%) and FR 34235 (34 +/- 4%). In comparison, the maximal pressor response to alpha-1 adrenoceptor stimulation by the partial alpha-1 agonist SK&F 88444 was markedly inhibited by nifedipine (51 +/- 1%) and FR 34235 (65 +/- 3%). Partial inactivation of the postsynaptic alpha-1 adrenoceptors with phenoxybenzamine (0.1 mg/kg) resulted in a maximal increase in diastolic pressure to alpha-1 adrenoceptor activation by SK&F l-89748 less than that induced by SK&F 88444. After phenoxybenzamine treatment, nifedipine and FR 34235 produced even greater reductions in the maximal vasopressor response to alpha-1 adrenoceptor stimulation by SK&F l-89748 (77 +/- 8 and 85 +/- 1%, respectively). Moreover, an inverse linear correlation (r = 1.00) was observed between the sensitivity of the maximal vasopressor response to nifedipine and FR 34235 and the magnitude of the maximal pressor response. The data suggest that the sensitivity of the alpha-1 adrenoceptor-mediated pressor response to inhibition by calcium antagonists in the pithed rat is inversely related to the magnitude of the pressor response, and they are consistent with the notion that the presence of "spare" alpha-1 adrenoceptors may determine the sensitivity of the pressor response to calcium antagonists. PMID:3014124

  13. Alpha 1-adrenoceptors and calcium sources in adrenergic neurogenic contractions of rat vas deferens.

    PubMed Central

    Bültmann, R.; Kurz, A. K.; Starke, K.

    1994-01-01

    1. The involvement of alpha 1-adrenoceptor subtypes in adrenergic neurogenic contractions of different type was studied in epididymal and prostatic portions of the rat vas deferens. 2. The adrenergic component of neurogenic contractions was isolated by suramin (300 microM). Twitch-like and tonic contractions were elicited by appropriate pulse patterns of electrical field stimulation, and contractions relying on intracellular calcium mobilization and calcium entry were isolated by means of nifedipine (10 microM) and ryanodine (20 microM), respectively. Increasing concentrations of 2-(2,6-dimethoxyphenoxyethyl)aminomethyl-1,4-benzodioxane (WB 4101), alpha-ethyl-3,4,5-trimethoxy-alpha-(3-((2-(2-methoxyphenoxy)ethyl)- amino)-propyl)benzeneacetonitrile (HV 723), prazosin and 5-methylurapidil progressively, monophasically and with potency decreasing in that order reduced and finally abolished all types of contraction, with one exception: concentration-effect curves of 5-methylurapidil in epididymal segments in the presence of ryanodine levelled off at about 75% inhibition. In the presence of both nifedipine (10 microM) and ryanodine (20 microM), contractions were abolished. 3. Contractions elicited by exogenous noradrenaline were also studied in the presence of either nifedipine 10 microM (prostatic segments) or ryanodine 20 microM (epididymal segments). Increasing concentrations of tamsulosin, WB 4101, benoxathian, HV 723, prazosin, 5-methylurapidil and urapidil progressively, monophasically and with potency decreasing in that order reduced and eventually abolished both kinds of contraction, with two exceptions: in epididymal segments in the presence of ryanodine, the concentration-effect curve of 5-methylurapidil was biphasic and the curve of urapidil levelled off at only partial inhibition. 4. In slices prepared from the prostatic end and preincubated with [3H]-noradrenaline, WB 4101, HV 723, prazosin and 5-methylurapidil, at the highest concentrations tested against

  14. Synthesis, alpha-adrenoceptors affinity and alpha 1-adrenoceptor antagonistic properties of some 1,4-substituted piperazine derivatives.

    PubMed

    Marona, H; Kubacka, M; Filipek, B; Siwek, A; Dybała, M; Szneler, E; Pociecha, T; Gunia, A; Waszkielewicz, A M

    2011-10-01

    A series of different 1,4-substituted piperazine derivatives (1-11) was synthesized. It comprised 1-(substituted-phenoxyalkyl)-4-(2-methoxyphenyl)piperazine derivatives (1-5); 1,4-bis(substituted-phenoxyethyl)piperazine derivatives (6-8) and 1-(substituted-phenoxy)-3-(substituted-phenoxyalkylpiperazin-1-yl)propan-2-ol derivatives (9-11). All compounds were evaluated for affinity toward alpha 1- and alpha 2-receptors by radioligand binding assays on rat cerebral cortex using [3H]prazosin and [3H]clonidine as specific radioligand, respectively. Furthermore alpha 1-antagonistic properties were checked for most promising compounds (1-5 and 10) by means of inhibition of phenylephrine induced contraction in isolated rat aorta. Antagonistic potency stayed in agreement with radioligand binding results. The most active compounds (1-5) displaced [3H]prazosin from cortical binding sites in low nanomolar range (Ki = 2.1-13.1 nM). Compound 10 showed slightly lower affinity for alpha 1-adrenoceptor (Ki = 781 nM). Compounds 2-5 displayed the strongest antagonistic activity with pA2 values ranging from 8.441 to 8.807. Compound 1 gave a pA2 value of 7.868, while compound 10 showed the weakest antagonistic potency, giving a pA2 value of 6.374. 1-[3-(2-Chloro-6-methylphenoxy)propyl]-4-(2-methoxyphenyl)piperazine hydrochloride (5) showed the best alpha 1- affinity properties with a Ki(alpha 1) value of 2.1 nM and it was 61.05 fold more selective toward alpha 1 than alpha 2-receptors. The best properties showed 1-[3-(2,6-dimethylphenoxy)propyl]-4-(2-methoxyphenyl)piperazine hydrochloride (4) with a Ki(alpha 1) value of 2.4 nM, a 142.13 fold better selectivity to alpha 1 - over alpha 2-adrenoceptors and the best antagonistic potency (pA2 = 8.807). It is worth to emphasized that all most promising compounds possessed an 1-(o-methoxyphenyl)piperazine moiety which probably plays an important role in the affinity to alpha-adrenoceptors. PMID:22026152

  15. The effect of S-(+)-boldine on the alpha 1-adrenoceptor of the guinea-pig aorta.

    PubMed Central

    Chuliá, S.; Moreau, J.; Naline, E.; Noguera, M. A.; Ivorra, M. D.; D'Ocón, M. P.; Advenier, C.

    1996-01-01

    1. The cardiovascular activity of S-(+)-boldine, an aporphine alkaloid structurally related to papaverine, was determined. The work includes functional studies on guinea-pig isolated aorta contracted with noradrenaline, caffeine, KCl or Ca2+, and on guinea-pig trachea contracted with acetylcholine or histamine. 2. S-(+)-boldine inhibited in a concentration-dependent manner the contractile response evoked by noradrenaline (10 microM) in guinea-pig aorta (IC50 = 1.4 +/- 0.2 microM) while the KCl depolarizing solution (60 mM)- or the Ca2+ (1 mM)-induced contractions were only partially affected by boldine up to 300 microM. In contrast, papaverine relaxed noradrenaline (NA), KCl or Ca2+ induced contractions showing similar IC50 values in all cases. S-(+)-boldine had a greater potency on the contraction elicited by NA whereas papaverine acted in a non-selective manner. 3. S-(+)-boldine was found to be an alpha 1-adrenoceptor blocking agent in guinea-pig aorta as revealed by its competitive antagonism of noradrenaline-induced vasoconstriction (pA2 = 5.64 +/- 0.08), and its potency was compared with that of prazosin (pA2 = 8.56 +/- 0.24), a known potent alpha 1-adrenoceptor antagonist. In contrast, papaverine caused rightward shifts of the NA concentration-response curves with depression of maximal response indicating that it acts as a non-competitive antagonist. 4. Contraction of guinea-pig aorta induced by caffeine (60 mM) in a Ca(2+)-containing Krebs solution was not affected by a 60 min incubation period with different doses of S-(+)-boldine (1-300 microM). Papaverine inhibited partially this caffeine-induced contraction at the maximal dose used (100 microM). 5. Inositol phosphates formation induced by noradrenaline (10 microM) in guinea-pig thoracic aorta was inhibited by S-(+)-boldine (30 microM) but not by papaverine (10 microM). 6. Contractions of guinea-pig trachea caused by acetylcholine (100 microM) or histamine (10 microM) were not modified by S-(+)-boldine (0

  16. Alpha 1-adrenoceptors mediating contraction in arteries of normotensive and spontaneously hypertensive rats are of the alpha 1D or alpha 1A subtypes.

    PubMed

    Villalobos-Molina, R; Ibarra, M

    1996-03-18

    Alpha 1-Adrenoceptor subtypes mediating contraction in carotid, aorta, mesenteric and caudal arteries from both Wistar Kyoto (WKY) normotensive and spontaneously hypertensive (SHR) rats were investigated by using the alpha 1A-adrenoceptor agonist methoxamine and antagonized with selective, competitive antagonists WB-4101, 5-methyl urapidil or BMY 7378 (8-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-8-azaspiro(4,5)decane -7,9-dione dihydrochloride). Isometric tension changes were recorded after methoxamine addition to the arterial rings, and the effects of the antagonists determined. All the antagonists shifted to the right the concentration-response curve to methoxamine. pA2 values indicate that all arteries but caudal express the alpha 1D-adrenoceptor subtype, since BMY 7378 values were high in these arteries. Due to the high pA2 values for 5-methyl urapidil and WB-4101 and the low values for BMY 7378 we conclude that the tail artery expresses the alpha 1A and not the alpha 1B subtype. No differences were found between both strains of rats, suggesting that hypertension does not modify the alpha 1-adrenoceptors in conductance arteries. PMID:8846824

  17. In vivo studies on the effects of alpha1-adrenoceptor antagonists on pupil diameter and urethral tone in rabbits.

    PubMed

    Michel, Martin C; Okutsu, Hiroko; Noguchi, Yukiko; Suzuki, Masanori; Ohtake, Akiyoshi; Yuyama, Hironori; Yanai-Inamura, Hiroko; Ukai, Masashi; Watanabe, Mai; Someya, Akiyoshi; Sasamata, Masao

    2006-02-01

    Alpha1-adrenoceptors mediate contraction of iris dilator smooth muscle and hence pupil dilatation. We compared the ability of i.v. bolus injections of alfuzosin, doxazosin, naftopidil, prazosin, tamsulosin and terazosin to antagonise phenylephrine-induced mydriasis relative to their potency for inhibiting phenylephrine-induced elevations of intraurethral pressure (IUP) in rabbits. Moreover, we compared the ability of these drugs to induce miosis in conscious rabbits in the absence of phenylephrine. All antagonists inhibited the effects of phenylephrine on pupil size and IUP, and the ratio of the respective ED50 values was close to unity in all cases. The doses required to induce statistically significant miosis in the absence of phenylephrine were 30- to 100-fold higher than those inhibiting phenylephrine-induced mydriasis for all antagonists, except for naftopidil. Moreover, the miotic effects of all alpha1-adrenoceptor antagonists were fully reversible within 8 h. We conclude that alfuzosin, doxazosin, naftopidil, prazosin, tamsulosin and terazosin inhibit phenylephrine-induced mydriasis in the same dose range as they inhibit elevations in IUP. Higher doses of all antagonists are required to induce miosis in the absence of an exogenous agonist, and such miosis is always reversible within hours. PMID:16489448

  18. Alpha1-Adrenoceptor Antagonists Improve Memory by Activating N-methyl-D-Aspartate-Induced Ion Currents in the Rat Hippocampus

    PubMed Central

    Ko, Il Gyu; Kim, Sung Eun; Shin, Mal Soon; Kang, Yeon Ho; Cho, Jung Wan; Shin, Key Moon; Kim, Chang Ju; Lim, Baek Vin

    2015-01-01

    Purpose: Alpha1 (α1)-adrenoceptor antagonists are widely used to treat lower urinary tract symptoms. These drugs not only act on peripheral tissues, but also cross the blood-brain barrier and affect the central nervous system. Therefore, α1-adrenoceptor antagonists may enhance brain functions. In the present study, we investigated the effects of tamsulosin, an α1-adrenoceptor antagonist, on short-term memory, as well as spatial learning and memory, in rats. Methods: The step-down avoidance test was used to evaluate short-term memory, and an eight-arm radial maze test was used to evaluate spatial learning and memory. TUNEL (terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling) staining was performed in order to evaluate the effect of tamsulosin on apoptosis in the hippocampal dentate gyrus. Patch clamp recordings were used to evaluate the effect of tamsulosin on ionotropic glutamate receptors, such as N-methyl-D-aspartate (NMDA), amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA), and kainate receptors, in hippocampal CA1 neurons. Results: Tamsulosin treatment improved short-term memory, as well as spatial learning and memory, without altering apoptosis. The amplitudes of NMDA-induced ion currents were dose-dependently increased by tamsulosin. However, the amplitudes of AMPA- and kainate-induced ion currents were not affected by tamsulosin. Conclusions: Tamsulosin enhanced memory function by activating NMDA receptor-mediated ion currents in the hippocampus without initiating apoptosis. The present study suggests the possibility of using tamsulosin to enhance memory under normal conditions, in addition to its use in treating overactive bladder. PMID:26739177

  19. Effect of JTH-601, a novel alpha1-adrenoceptor antagonist, on the function of lower urinary tract and blood pressure.

    PubMed

    Suzuki, Y; Kanada, A; Okaya, Y; Aisaka, K; Muramatsu, I

    1999-06-25

    In the present study, we investigated the effect of JTH-601 (3-{N-[2-(4-hydroxy-2-isopropyl-5-methylphenoxy)ethyl]-N-methylaminomethyl}-4-methoxy-2,5,6-trimethylphenol hemifumarate), a novel alpha1-adrenoceptor antagonist, in vitro and in vivo. JTH-601 (10(-9)-3 x 10(-8) M) competitively antagonized phenylephrine-induced contraction in lower urinary tract tissues (prostate, urethra and bladder trigon) in a concentration-dependent manner. The mean pA2 values for JTH-601 were 8.59+/-0.14, 8.74+/-0.09 and 8.77+/-0.11 for prostate, urethra and bladder trigon, respectively. In anesthetized rabbits, intraduodenal administration of JTH-601 (0.3-3 mg/kg), prazosin (0.03-0.3 mg/kg) and tamsulosin (0.03-0.3 mg/kg) dose dependently inhibited the phenylephrine-induced increase in urethral pressure for 3 h. Although these drugs also decreased mean blood pressure, JTH-601 was less potent than prazosin or tamsulosin. In conscious rabbits, administered JTH-601 (0.01-1 mg/kg, i.v.) had a tendency to augment orthostatic hypotension, but dose dependency was not evident. Prazosin (0.01-1 mg/kg) and tamsulosin (0.001-1 mg/kg) dose dependently augmented orthostatic hypotension. These results indicate that JTH-601 antagonized alpha1-adrenoceptor-mediated contractile responses more potently than prazosin or tamsulosin in rabbit lower urinary tract both in vitro and in vivo. JTH-601 is therefore expected to be effective in the treatment of urinary outlet obstruction in benign prostatic hypertrophy. PMID:10422795

  20. Analysis of the effects of alpha 1-adrenoceptor antagonists on noradrenaline-mediated contraction of rat small mesenteric artery.

    PubMed Central

    Van der Graaf, P. H.; Shankley, N. P.; Black, J. W.

    1996-01-01

    1. In this study, we examined the interaction between noradrenaline (NA) and phenylephrine (PE) with seven antagonists (prazosin, tamsulosin, phentolamine, WB-4101, 5-methylurapidil, spiperone and HV 723) in an attempt to characterize the alpha 1-adrenoceptor population of the rat isolated small mesenteric artery (SMA) preparation. 2. Six of the seven antagonists investigated produced concentration-dependent, parallel, rightward shift of the NA concentration-effect (E/[A]) curves. The exception was tamsulosin, which produced significant decrease of the upper asymptote. In the case of 5-methylurapidil and HV723, the Schild plot slope parameters were not significantly different from unity over the range of concentrations used. However, the Schild plot slopes obtained for the other antagonists were all significantly greater than unity, inconsistent with expectations for simple competitive antagonism. 3. HV723, prazosin and tamsulosin were also tested using PE as an agonist. All three antagonists produced concentration-dependent, parallel, rightward shifts of the PE curves and Schild analysis yielded slope parameters not significantly different from unity. The pKB estimates obtained for tamsulosin and prazosin were not significantly different from the pA2 values obtained when NA was used as agonist. In the case of HV723, the 95% confidence intervals for the pKB values yielded with NA and PE did not overlap (pKB = 8.80-9.13 and 8.15-8.77 for NA and PE, respectively). 4. In the absence of evidence to indicate that the steep Schild plots were due to failure to satisfy the basic criteria for quantitative analysis in a one-receptor system, we considered the possibility that the complexity was caused by an action of NA at inhibitory D1 receptors. The selective D1 receptor antagonists, SCH-23390 (10 nM), had no significant effect on the NA E/[A] control curve, but the apparent potency of 100 nM prazosin was reduced by approximately 3.5 fold. 5. This study indicates that the

  1. In vivo binding in rat brain and radiopharmaceutical preparation of radioiodinated HEAT, an alpha-1 adrenoceptor ligand

    SciTech Connect

    Couch, M.W.; Greer, D.M.; Thonoor, C.M.; Williams, C.M.

    1988-03-01

    In vivo binding of (/sup 125/I)-2-(beta-(3-iodo-4-hydroxyphenyl)ethylaminomethyl tetralone) ((/sup 125/I)HEAT) to alpha-1 adrenoceptors in the rat brain was determined over 4 hr. Uptake in the thalamus and frontal cortex was approximately 0.1% injected dose per gram tissue. Thalamus/cerebellum ratios of 10:1 and frontal cortex/cerebellum ratios of 5:1 were found at 4 hr. Pretreatment with prazosin, an alpha-1 antagonist, completely inhibited the accumulation of (/sup 125/I)HEAT in thalamus and frontal cortex; yet uptake of radioactivity was not significantly affected by antagonists and agonists for other receptors classes (propranolol, beta-1; apomorphine, D-1; spiperone, D-2). Binding of (/sup 125/I)HEAT is saturable. At 4 hr, (/sup 125/I)HEAT or (/sup 123/I)HEAT was shown to be the only radioactive material in rat thalamus and frontal cortex. Iodine-123 HEAT and (/sup 125/I)HEAT were synthesized as radiopharmaceuticals within 3 hr in 99% radiochemical purity.

  2. Effects of alpha1-adrenoceptor antagonists on agonist and tilt-induced changes in blood pressure: relationships to uroselectivity.

    PubMed

    Hieble, J P; Kolpak, D C; McCafferty, G P; Ruffolo, R R; Testa, R; Leonardi, A

    1999-05-28

    We evaluated the uroselectivity of a series of alpha1-adrenoceptor antagonists by comparing their potency against phenylephrine-induced increases in urethral perfusion pressure and diastolic blood pressure in the anesthetized rabbit and pithed rat. In the rabbit, Rec 15/2739 (N-[3-[4-(2-methoxyphenyl)-1-piperazinyl]propyl]-3-methyl-4-oxo-2-phenyl -4H-1-benzopyran-8-carboxamide) as well as analogs with a chlorine substituent on the methoxyphenyl ring (Rec 15/2869) or this substituent combined with the replacement of the phenyl substituent on the pyran ring by cyclohexyl (Rec 15/3011) were 2-6-fold more potent against the urethral vs. vascular response to phenylephrine. Rec 15/2841 (N-[3-[4-(2-methoxyphenyl)-1-piperazinyl]propyl]-3-methyl-4-oxo-2-cyc lohexy-4H-1-benzopyran-8-carboxamide) was only 1.5-fold more potent against the urethral response. SL 89.0591 and tamsulosin also showed selectivity for the urethral response (2-2.5-fold), while the quinazolines produced equipotent blockade of urethral and vascular responses (selectivity ratio = 0.9-1.1). The urethral selectivities of Rec 15/2739 and its derivatives were confirmed by evaluation of the response to tilt in sedated, hypovolemic rabbits. Phenylephrine challenge assays did not show any of the antagonists, with the exception of terazosin at 300 microg kg(-1), to be uroselective in the rat (selectivity ratios = 0.2-1.5); potentiation of tilt-induced hypotension in the anesthetized rat showed substantial differences from the rabbit, with Rec 15/2739, but not Rec 15/3011 and Rec 15/2841 showing orthostatic effects equivalent to that observed for prazosin. Hence, Rec 15/2739 was uroselective in the rabbit, but not in the rat, while two of its close structural analogs were highly uroselective in both species. An assay for orthostatic activity in the conscious rat yielded different results, showing prazosin and terazosin, but not Rec 15/2739, to cause a reversal of the pressor response to tilt. Hence, the apparent

  3. Antagonistic effects of selective alpha1-adrenoceptor antagonists MDL73005EF and tamsulosin and partial agonists clonidine and tizanidine in rat thoracic aorta and rabbit iliac artery.

    PubMed

    Satoh, M; Enomoto, K; Koike, K

    2001-01-01

    The antagonistic effects of MDL73005EF and tamsulosin and partial agonists clonidine and tizanidine at rat thoracic aorta and rabbit iliac artery alpha1-adrenoceptors were investigated in this study. Selective alpha1-adrenoceptor antagonists MDL73005EF and tamsulosin dose-dependently shifted the concentration-response curves for noradrenaline to the right. Schild plots of the results obtained from the inhibition by MDL73005EF (pA2 8.30 +/- 0.04) and tamsulosin (pA2 10.51 +/- 0.06) of noradrenaline yielded a straight line with a slope of unity in rat thoracic aorta. The slopes of Schild plots obtained from the inhibition by MDL73005EF and tamsulosin of noradrenaline were significantly different from unity in rabbit iliac artery. Schild plots of the results obtained from the inhibition by clonidine and tizanidine of noradrenaline yielded a straight line with a slope of unity in rat thoracic aorta (pA2 7.08 +/- 0.04 and 7.32 +/- 0.04, respectively). These results suggest that alpha1D-adrenoceptors play a significant role in the alpha1-adrenoceptor-agonist-induced contraction of rat thoracic aorta and rabbit iliac artery, and that clonidine and tizanidine interact with the alpha1D-adrenoceptor subtype as competitive antagonists in rat thoracic aorta. PMID:11206183

  4. Quinazoline-based alpha 1-adrenoceptor antagonists induce prostate cancer cell apoptosis via TGF-beta signalling and I kappa B alpha induction.

    PubMed

    Partin, J V; Anglin, I E; Kyprianou, N

    2003-05-19

    Previous studies documented the ability of quinazoline-based alpha1-adrenoceptor antagonists to induce apoptosis in prostate cancer cells via an alpha 1-adrenoceptor-independent mechanism. In this study we investigated the molecular events initiating this apoptotic effect. Since transforming growth factor-beta 1 (TGF-beta 1) mediates prostate epithelial cell apoptosis, we hypothesised that the activation of the TGF-beta 1 pathway underlies the quinazoline-based apoptotic effect in prostate cancer cells. Treatment of the androgen-independent human prostate cancer cells PC-3 with doxazosin resulted in a strong caspase-3 activation within 24 h, whereas tamsulosin, a sulphonamide-based alpha 1-adrenoceptor antagonist, had no significant apoptotic effect against prostate cancer cells. To identify the molecular components involved in this quinazoline-mediated apoptosis, cDNA microarray analysis of PC-3 prostate cancer cells treated with doxazosin (3 h) was performed. Induced expression of several genes was observed including p21(WAF-1) and I kappa B alpha (inhibitor of NF-kappa B alpha). Relative quantitative reverse transcription-polymerase chain reaction analysis revealed induction of several TGF-beta1 signalling effectors: Induction of mRNA for Smad4 and the TGF-beta1-regulated apoptosis-inducing transcription factor TGF-beta1-inducible early gene (TIEG1) was detected within the first 6 h of doxazosin treatment. Upregulation of I kappa B alpha at both the mRNA and protein level was also detected after 6 h of treatment. Furthermore, doxazosin resulted in a considerable elevation in Smad4 and TIEG protein expression (6 h). A 'latent' increase in TGF-beta mRNA expression was detected after 48 h of treatment. These findings suggest that the quinazoline-based doxazosin mediates prostate cancer apoptosis by initially inducing the expression of TGF-beta1 signalling effectors and subsequently I kappa B alpha. The present study provides an initial insight into the molecular

  5. Pharmacological analysis of the novel, selective alpha1-adrenoceptor antagonist, KMD-3213, and its suitability as a tritiated radioligand.

    PubMed

    Murata, S; Taniguchi, T; Muramatsu, I

    1999-05-01

    Pharmacological profiles of tritiated KMD-3213, a new antagonist of alpha1-adrenoceptor (AR), were examined in recombinant and native alpha1-AR, and compared with those of prazosin (PZ) and tamsulosin (YM-617). In saturation experiments, [3H]-KMD (10-2000 pM) showed high affinity for alpha1a-AR (pK(D) = 10.5). However, no significant binding to alpha1b-AR and insufficient/unsaturated binding to alpha1d-AR were observed at concentrations up to 2000 pM. In contrast, [3H]-PZ and [3H]-YM bound to all subtypes with high affinity (pK(D)>9). In competition experiments, KMD-3213 also had higher affinity for alpha1a-AR than for other two subtypes; pKi = 10.4, 8.1 and 8.6 for alpha1a-, alpha1b- and alpha1d-AR, respectively. [3H]-KMD also bound to the native alpha1A-AR (rat submaxillary gland) with high affinity, but not to alpha1B-AR (rat liver). In rat kidney which expresses alpha1A- and alpha1B-AR, [3H]-KMD and [3H]-PZ bound to a single high-affinity site (pK(D) = 10.8 and 10.1, respectively) with distinct amount of binding sites (Bmax = 159 and 267 fmol mg(-1) protein, respectively). [3H]-PZ binding sites consisted of low- and high-affinity sites for KMD-3213 (pKi = 7.6 and 10.7, respectively), for WB4101 (pK = 8.1 and 10.0) and for YM-617 (pKi = 8.7 and 10.8). The proportion of the high affinity site was approximately 60% in these drugs which was compatible to the ratio between Bmax of [3H]-KMD and [3H]-PZ. [3H]-KMD binding sites consisted of a single site for these drugs with affinities which were similar to those of the high affinity sites in [3H]-PZ binding. In functional experiments, KMD-3213 antagonized the contractile responses to NS-49 or noradrenaline (NA) with higher affinity in functional alpha1A- (rat caudal artery, pA2= 10.0 against NS-49) and alpha1L-AR (dog mesenteric artery, pA2 = 9.9 against NA) than in alpha1B- (dog carotid artery, pA2 = 7.7 against NA) and alpha1D-AR (rat thoracic aorta, pA2 = 8.3 against NA). These results confirm the alpha1A

  6. In vivo study on the effects of alpha1-adrenoceptor antagonists on intraurethral pressure in the prostatic urethra and intraluminal pressure in the vas deferens in male dogs.

    PubMed

    Noguchi, Yukiko; Ohtake, Akiyoshi; Suzuki, Masanori; Sasamata, Masao

    2008-02-01

    Alpha-adrenoceptor antagonists are used worldwide for the treatment of voiding dysfunction associated with benign prostatic hyperplasia. Recently, abnormal ejaculation, an adverse effect associated with their use, has attracted attention. Here, we simultaneously investigated the effects of alpha(1)-adrenoceptor antagonists on intraurethral pressure in the prostatic urethra and intraluminal pressure in the vas deferens in anesthetized male dogs, and compared their tissue selectivity. Phenylephrine, an alpha(1)-adrenoceptor agonist, induced simultaneous increases in intraurethral and intraluminal pressure. Alfuzosin, naftopidil, prazosin, silodosin and tamsulosin dose-dependently inhibited both responses. Comparison of ED(50) values in both tissues showed that silodosin had the highest selectivity for the vas deferens (7.5-fold), followed by naftopidil (4.3-fold), alfuzosin (3.8-fold), tamsulosin (2.6-fold) and prazosin (2.5-fold). These results suggest that alpha(1)-adrenoceptor antagonists inhibit contraction of not only the urethra but also the vas deferens in a dose-dependent fashion, and that their high tissue selectivity for the vas deferens over the urethra may contribute to the incidence of abnormal ejaculation. PMID:18078926

  7. Effects of alpha1-adrenoceptor antagonist (tamsulosin) on incident of ejaculation and semen quality in the goat.

    PubMed

    Kimsakulvech, S; Suttiyotin, P; Pinyopummin, A

    2015-04-01

    Male temporary contraception is occasionally required in some animals. Alpha1-adrenoceptor antagonist (tamsulosin) can cause ejaculation disorder. Two sets of Latin square were applied to six male goats to received either normal saline, dimethylsulphoxide or tamsulosin (179.8 nmol kg(-1) ) at 1-week interval. Semen collection and libido scoring were undertaken at 3, 6 and 24 h post-injection. For ejaculated semen, its quality was evaluated. Physiological measurements including body temperature, respiration and heart rates were measured before injection and at 30 min before semen collection. The results showed that libido score and physiological changes were not affected by treatments and time periods. Anejaculation was observed in 11 (91.7%), 5 (41.7%) and 1 (8.3%) males at 3, 6 and 24 h post-tamsulosin injection respectively. The incidence returned to normal when compared with control groups at 24 h. The percentages of motile and live spermatozoa at 6 h post-tamsulosin injection were significantly lower (P < 0.05) than that of normal saline group. At 24 h post-injection, there were no significant differences of all semen parameters among treatments. This study demonstrated that tamsulosin had temporary effects on ejaculation and semen quality without reducing sex desire and physiological functions in male goats. PMID:24684217

  8. Evidence for two mechanisms of depolarization associated with alpha 1-adrenoceptor activation in the rat anococcygeus muscle.

    PubMed

    Byrne, N G; Large, W A

    1985-11-01

    Membrane potential responses in the rat isolated anococcygeus to bath-applied noradrenaline and field stimulation have been investigated by use of intracellular microelectrode and combined extracellular electrical and mechanical (sucrose gap) recording techniques. Intracellular recordings were made usually from tissues immobilized with hypertonic Krebs solution. Bath-application of noradrenaline produced depolarizations which consisted of two components; an initial 'fast' phase which peaked within 1-2 s and which was followed by a 'slow' sustained depolarization. Both components were concentration-dependent. Noradrenaline could also evoke oscillations in membrane potential which, unlike the 'fast' component of depolarization, were prevented by conditioning hyperpolarization of the membrane and were evoked by direct membrane depolarization with externally applied current pulses. Thus, the oscillations are voltage-dependent phenomena. Replacement of the external NaCl of the Krebs solution with an equimolar amount of Na benzenesulphonate abolished the noradrenaline-evoked 'fast' depolarization while the 'slow' phase was unaffected. This suggests that two mechanisms of depolarization are activated in this muscle by the bath-application of noradrenaline. The adrenergic excitatory junction potential was also abolished in Na benzenesulphonate. Prazosin reduced both the 'fast' and 'slow' components of depolarization produced by noradrenaline indicating their mediation by alpha 1-adrenoceptors. The membrane potential (-29 mV) at the maximum amplitude of the 'fast' depolarization was similar to the equilibrium potential (-27 mV) for the depolarization evoked by ionophoretically applied noradrenaline and which was obtained by extrapolation from the relationship between amplitude of the ionophoretic response and membrane potential displacement in the partition chamber. These results suggest that the 'fast' depolarization and the ionophoretic response are due to an increased

  9. Ranolazine enhances nicardipine-induced relaxation of alpha1-adrenoceptor-mediated contraction on isolated rabbit aorta.

    PubMed

    Malavaki, Christina; Hatziefthimiou, Apostolia; Daskalopoulou, Stella S; Stefanidis, Ioannis; Karatzaferi, Christina; Aidonidis, Isaac

    2015-04-01

    Ranolazine (RAN) and nicardipine (NIC) have been studied for their vasorelaxing effects but the combination of these agents against adrenergic vasoconstriction has not been tested. The present study aimed at investigating the vasorelaxing effect by the combination of the two agents on alpha1-adrenoceptor-mediated contraction on isolated rabbit aorta. Aortic rings were mounted for isometric tension recording in organ baths containing Krebs-Henseleit solution. Concentration-response curves of RAN (10(-9) to 10(-4) M), NIC (10(-1) to 10(-5) M), and RAN + NIC (3 x 10(-6) M) were obtained in a cumulative manner using phenylephrine (PE, 2 x 10(-6) M) as constrictor agent. The effective concentration (EC)50 values for RAN and NIC were 6.5 x 10(-6) M and 1.4 x 10(-5) M, respectively. The treatment of PE-precontracted aortic rings with either RAN or NIC up to 65 min revealed that both agents displayed a biphasic pattern of initial rising and late sustained phases of relaxation. At 35 min of incubation, RAN and NIC induced relaxation by 23 +/- 3% and 14 +/- 4%, respectively (N = 7, P=NS, RAN vs. NIC); their combination resulted in a 34 +/- 4% relaxation (N=7; P < 0.01, RAN + NIC vs. NIC). At 65 min the effect of NIC prevailed and tended to be closer to the values of the combination treatment (P < 0.01, RAN + NIC vs. RAN). The results indicate that RAN at therapeutic concentrations exerts a significant additive vasorelaxing effect when combined with NIC in rabbit aorta. PMID:26148375

  10. Comparative study on pharmacokinetics and in vivo alpha1-adrenoceptor binding of [3H]tamsulosin and [3H]prazosin in rats.

    PubMed

    Ohkura, T; Yamada, S; Deguchi, Y; Kimura, R

    1999-04-01

    The plasma concentration, total radioactivity and in vivo alpha1-adrenoceptor binding in rat tissues after intravenous (i.v.) injection of [3H]tamsulosin were measured and they were compared with those obtained after the injection of [3H]prazosin. The plasma concentration of [3H]tamsulosin was consistently higher than that of [3H]prazosin, with 1.4 times greater areas under the curve (AUC(0-infinity)) of plasma concentration. As there was a significantly lower value of apparent volume of central compartment (Vd(c)) and distribution volume at steady state (Vd(ss)) for [3H]tamsulosin than [3H]prazosin with little difference in elimination rate constant (beta), the higher concentration of [3H]tamsulosin in plasma might be associated mainly with the smaller volume of distribution. The ratio of total radioactivity in tissues to the plasma unbound concentration of [3H]tamsulosin after i.v. injection of the ligand was consistently lower than that of [3H]prazosin. These observations suggest that [3H]tamsulosin is distributed in rat tissues in a more limited manner than [3H]prazosin. A significantly lower level of in vivo specific binding of [3H]tamsulosin than [3H]prazosin was observed in the spleen, heart and liver. Further, the apparent dissociation constant (Kd) and maximal number of binding sites (Bmax) for in vivo specific [3H]tamsulosin binding were considerably lower than those for [3H]prazosin binding. Therefore, these findings suggest that [3H]tamsulosin labels preferentially a subpopulation of the alpha1-adrenoceptor sites in rat tissues labeled by [3H]prazosin. In conclusion, the present study has shown that there is a significant difference in the pharmacokinetics and in vivo alpha1-adrenoceptor binding characteristics between tamsulosin and prazosin. PMID:10328564

  11. In vitro alpha1-adrenoceptor pharmacology of Ro 70-0004 and RS-100329, novel alpha1A-adrenoceptor selective antagonists.

    PubMed

    Williams, T J; Blue, D R; Daniels, D V; Davis, B; Elworthy, T; Gever, J R; Kava, M S; Morgans, D; Padilla, F; Tassa, S; Vimont, R L; Chapple, C R; Chess-Williams, R; Eglen, R M; Clarke, D E; Ford, A P

    1999-05-01

    It has been hypothesized that in patients with benign prostatic hyperplasia, selective antagonism of the alpha1A-adrenoceptor-mediated contraction of lower urinary tract tissues may, via a selective relief of outlet obstruction, lead to an improvement in symptoms. The present study describes the alpha1-adrenoceptor (alpha1-AR) subtype selectivities of two novel alpha1-AR antagonists, Ro 70-0004 (aka RS-100975) and a structurally-related compound RS-100329, and compares them with those of prazosin and tamsulosin. Radioligand binding and second-messenger studies in intact CHO-K1 cells expressing human cloned alpha1A-, alpha1B- and alpha1D-AR showed nanomolar affinity and significant alpha1A-AR subtype selectivity for both Ro 70-0004 (pKi 8.9: 60 and 50 fold selectivity) and RS-100329 (pKi 9.6: 126 and 50 fold selectivity) over the alpha1B- and alpha1D-AR subtypes respectively. In contrast, prazosin and tamsulosin showed little subtype selectivity. Noradrenaline-induced contractions of human lower urinary tract (LUT) tissues or rabbit bladder neck were competitively antagonized by Ro 70-0004 (pA2 8.8 and 8.9), RS-100329 (pA2 9.2 and 9.2), tamsulosin (pA2 10.4 and 9.8) and prazosin (pA2 8.7 and 8.3 respectively). Affinity estimates for tamsulosin and prazosin in antagonizing alpha1-AR-mediated contractions of human renal artery (HRA) and rat aorta (RA) were similar to those observed in LUT tissues, whereas Ro 70-0004 and RS-100329 were approximately 100 fold less potent (pA2 values of 6.8/6.8 and 7.3/7.9 in HRA/RA respectively). The alpha1A-AR subtype selectivity of Ro 70-0004 and RS-100329, demonstrated in both cloned and native systems, should allow for an evaluation of the clinical utility of a 'uroselective' agent for the treatment of symptoms associated with benign prostatic hyperplasia. PMID:10369480

  12. Alpha 1-Adrenoceptor Blocker May Improve Not Only Voiding But Also Storage Lower Urinary Tract Symptoms Caused by 125I Brachytherapy for Prostate Cancer

    PubMed Central

    Aoki, Yoshitaka; Ito, Hideaki; Miwa, Yoshiji; Akino, Hironobu; Shioura, Hiroki; Kimura, Hirohiko; Yokoyama, Osamu

    2014-01-01

    Purpose. To assess changes in lower urinary tract symptoms (LUTS) within 1 year after brachytherapy in patients receiving alpha 1-adrenoceptor antagonists. Methods. We retrospectively evaluated 116 patients who underwent 125I prostate brachytherapy in our institute. Seventy-one patients were treated with a combination of external beam radiation therapy and brachytherapy. Alpha 1-adrenoceptor antagonists were prescribed to all patients after brachytherapy. International Prostate Symptom Score (IPSS) forms and postvoid residual urine volume were recorded at all follow-up visits. Results. Forty-nine patients were given tamsulosin hydrochloride, 32 were given silodosin hydrochloride, and 35 were given naftopidil for up to 6 months after seed implantation. Patients given tamsulosin or naftopidil tended to show a higher peak IPSS and slower recovery to baseline values than those given silodosin. The patients given naftopidil showed an insufficient recovery in storage symptoms in naftopidil group in comparison with tamsulosin group at 3 months and with silodosin group at 6 and 9 months. Conclusions. In the management of LUT after brachytherapy, silodosin may provide a more favorable improvement. Silodosin and tamsulosin may have an advantage in improving not only voiding but also storage lower urinary tract symptoms after brachytherapy. PMID:25006516

  13. Modulation of intracellular Ca2+ via L-type calcium channels in heart cells by the autoantibody directed against the second extracellular loop of the alpha1-adrenoceptors.

    PubMed

    Bkaily, Ghassan; El-Bizri, Nesrine; Bui, Michel; Sukarieh, Rami; Jacques, Danielle; Fu, Michael L X

    2003-03-01

    The effects of methoxamine, a selective alpha1-adrenergic receptor agonist, and the autoantibody directed against the second extracellular loop of alpha1-adrenoceptors were studied on intracellular free Ca2+ levels using confocal microscopy and ionic currents using the whole-cell patch clamp technique in single cells of 10-day-old embryonic chick and 20-week-old fetal human hearts. We observed that like methoxamine, the autoantibody directed against the second extracellular loop of alpha1-adrenoreceptors significantly increased the L-type calcium current (I(Ca(L))) but had no effect on the T-type calcium current (I(Ca(T))), the delayed outward potassium current, or the fast sodium current. This effect of the autoantibody was prevented by a prestimulation of the receptors with methoxamine and vice versa. Moreover, treating the cells with prazosin, a selective alpha1-adrenergic receptor antagonist blocked the methoxamine and the autoantibody-induced increase in I(Ca(L)), respectively. In absence of prazosin, both methoxamine and the autoantibody showed a substantial enhancement in the frequency of cell contraction and that of the concomitant cytosolic and nuclear free Ca2+ variations. The subsequent addition of nifedipine, a specific L-type Ca2+ channel blocker, reversed not only the methoxamine or the autoantibody-induced effect but also completely abolished cell contraction. These results demonstrated that functional alpha1-adrenoceptors exist in both 10-day-old embryonic chick and 20-week-old human fetal hearts and that the autoantibody directed against the second extracellular loop of this type of receptors plays an important role in stimulating their activity via activation of L-type calcium channels. This loop seems to have a functional significance by being the target of alpha1-receptor agonists like methoxamine. PMID:12733822

  14. In vitro studies of release of adenine nucleotides and adenosine from rat vascular endothelium in response to alpha 1-adrenoceptor stimulation.

    PubMed Central

    Shinozuka, K; Hashimoto, M; Masumura, S; Bjur, R A; Westfall, D P; Hattori, K

    1994-01-01

    1. Noradrenaline-induced release of endogenous adenine nucleotides (ATP, ADP, AMP) and adenosine from both rat caudal artery and thoracic aorta was characterized, using high-performance liquid chromatography with fluorescence detection. 2. Noradrenaline, in a concentration-dependent manner, increased the overflow of ATP and its metabolites from the caudal artery. The noradrenaline-induced release of adenine nucleotides and adenosine from the caudal artery was abolished by bunazosin, an alpha 1-adrenoceptor antagonist, but not by idazoxan, an alpha 2-adrenoceptor antagonist. Clonidine, an alpha 2-adrenoceptor agonist, contracted caudal artery smooth muscle but did not induce release of adenine nucleotides or adenosine. 3. Noradrenaline also significantly increased the overflow of ATP and its metabolites from the thoracic aorta in the rat; however, the amount of adenine nucleotides and adenosine released from the aorta was considerably less than that released from the caudal artery. 4. Noradrenaline significantly increased the overflow of ATP and its metabolites from cultured endothelial cells from the thoracic aorta and caudal artery. The amount released from the cultured endothelial cells from the thoracic aorta and caudal artery. The amount released from the cultured endothelial cells from the aorta was also much less than that from cultured endothelial cells from the caudal artery. In cultured smooth muscle cells from the caudal artery, a significant release of ATP or its metabolites was not observed. 5. These results suggest that there are vascular endothelial cells that are able to release ATP by an alpha 1-adrenoceptor-mediated mechanism, but that these cells are not homogeneously distributed in the vasculature. PMID:7889273

  15. Correlation between mRNA levels and functional role of alpha1-adrenoceptor subtypes in arteries: evidence of alpha1L as a functional isoform of the alpha1A-adrenoceptor.

    PubMed

    Martí, Daniel; Miquel, Raquel; Ziani, Khalid; Gisbert, Regina; Ivorra, M Dolores; Anselmi, Elsa; Moreno, Lucrecia; Villagrasa, Victoria; Barettino, Domingo; D'Ocon, Pilar

    2005-11-01

    The mRNA levels for the three alpha1-adrenoceptor subtypes, alpha1A, alpha1B, and alpha1D, were quantified by real-time RT-PCR in arteries from Wistar rats. The alpha1D-adrenoceptor was prominent in both aorta (79.0%) and mesenteric artery (68.7%), alpha1A predominated in tail (61.7%) and small mesenteric artery (73.3%), and both alpha1A- and alpha1D-subtypes were expressed at similar levels in iliac artery. The mRNA levels of the alpha1B-subtype were a minority in all vessels (1.7-11.1%). Concentration-response curves of contraction in response to phenylephrine or relaxation in response to alpha1-adrenoceptor antagonists on maximal sustained contraction induced by phenylephrine were constructed from control vessels and vessels pretreated with 100 micromol/l chloroethylclonidine (CEC) for 30 min. The significant decrease in the phenylephrine potency observed after CEC treatment together with the inhibitory potency displayed by 8-{2-[4-(2-methoxyphenyl)-1-piperazinyl]-8-azaspiro (4,5) decane-7-dionedihydrochloride} (BMY-7378, an alpha1D-adrenoceptor antagonist) confirm the relevant role of alpha1D-adrenoceptors in aorta and iliac and proximal mesenteric arteries. The potency of 5-methylurapidil (an alpha1A-adrenoceptor antagonist) and the changes in the potency of both BMY-7378 and 5-methylurapidil after CEC treatment provided evidence of a mixed population of alpha1A- and alpha1D-adrenoceptors in iliac and distal mesenteric arteries. The low potency of prazosin (pIC50 < 9) as well as the high 5-methylurapidil potency in tail and small mesenteric arteries suggest the main role of alpha1A/alpha1L-adrenoceptors with minor participation of the alpha1D-subtype. The mRNA levels and CEC treatment corroborated this pattern and confirmed that the alpha1L-adrenoceptor could be a functional isoform of the alpha1A-subtype. PMID:15951348

  16. PKC regulates alpha(1)-adrenoceptor-mediated contractions and baseline Ca(2+) sensitivity in the uterine arteries of nonpregnant and pregnant sheep acclimatized to high altitude hypoxia.

    PubMed

    Xiao, Daliao; Huang, Xiaohui; Longo, Lawrence D; Zhang, Lubo

    2010-01-01

    Chronic hypoxia has a profound effect on uterine artery adaptation to pregnancy. The present studies tested the hypothesis that pregnant kinase C (PKC) differentially regulates alpha(1)-adrenoceptor-mediated contractions and Ca(2+) sensitivity in the uterine arteries of nonpregnant and pregnant sheep acclimatized to high altitude hypoxia. Uterine arteries were isolated from nonpregnant (NPUA) and near-term pregnant (PUA) ewes maintained at high altitude (3801 m, Pao(2) approximately 60 torr) for 110 days. Phorbol 12,13-dibutyrate (PDBu) decreased phenylephrine-induced contractions in PUA but not in NPUA, which was partly inhibited by the PKC inhibitor GF109203X. Additionally, GF109203X shifted the concentration-response curve of phenylephrine-induced contractions to the right in PUA. In beta-escin-permeabilized arteries, Ca(2+)-induced increases in 20-kDa myosin light chain phosphorylation (MLC(20)-P) were similar in NPUA and PUA. However, Ca(2+) produced a concentration-dependent increase in the ratio of tension to MLC(20)-P in PUA, as compared with NPUA. PKC inhibition decreased Ca(2+)-induced contractions in both NPUA and PUA. PDBu induced contractions of PUA in the absence of changes in MLC(20)-P, which was not affected by PD098059. There was a significant increase in the basal activity of PKCvarepsilon in PUA, but not in NPUA, in hypoxic sheep, as compared with normoxic animals. The results demonstrate that the inhibitory effect of PKC on alpha(1)-adrenoceptor-mediated contractions of uterine arteries is preserved in pregnant sheep at high altitude. However, the PKC-mediated thin-filament regulatory pathway is upregulated, resulting in increased baseline Ca(2+) sensitivity in the uterine artery during pregnancy at high altitude. PMID:20586600

  17. Rapid Eye Movement Sleep Deprivation Induces Neuronal Apoptosis by Noradrenaline Acting on Alpha1 Adrenoceptor and by Triggering Mitochondrial Intrinsic Pathway

    PubMed Central

    Somarajan, Bindu I.; Khanday, Mudasir A.; Mallick, Birendra N.

    2016-01-01

    Many neurodegenerative disorders are associated with rapid eye movement sleep (REMS) loss; however, the mechanism was unknown. As REMS loss elevates noradrenaline (NA) level in the brain as well as induces neuronal apoptosis and degeneration, in this study, we have delineated the intracellular molecular pathway involved in REMS deprivation (REMSD)-associated NA-induced neuronal apoptosis. Rats were REMS deprived for 6 days by the classical flower pot method; suitable controls were conducted and the effects on apoptosis markers evaluated. Further, the role of NA was studied by one, intraperitoneal (i.p.) injection of NA-ergic alpha1 adrenoceptor antagonist prazosin (PRZ) and two, by downregulation of NA synthesis in locus coeruleus (LC) neurons by local microinjection of tyrosine hydroxylase siRNA (TH-siRNA). Immunoblot estimates showed that the expressions of proapoptotic proteins viz. Bcl2-associated death promoter protein, apoptotic protease activating factor-1 (Apaf-1), cytochrome c, caspase9, caspase3 were elevated in the REMS-deprived rat brains, while caspase8 level remained unaffected; PRZ treatment did not allow elevation of these proapoptotic factors. Further, REMSD increased cytochrome c expression, which was prevented if the NA synthesis from the LC neurons was blocked by microinjection of TH-siRNA in vivo into the LC during REMSD in freely moving normal rats. Mitochondrial damage was re-confirmed by transmission electron microscopy, which showed distinctly swollen mitochondria with disintegrated cristae, chromosomal condensation, and clumping along the nuclear membrane, and all these changes were prevented in PRZ-treated rats. Combining findings of this study along with earlier reports, we propose that upon REMSD NA level increases in the brain as the LC, NA-ergic REM-OFF neurons do not cease firing and TH is upregulated in those neurons. This elevated NA acting on alpha1 adrenoceptors damages mitochondria causing release of cytochrome c to activate

  18. Rapid Eye Movement Sleep Deprivation Induces Neuronal Apoptosis by Noradrenaline Acting on Alpha1 Adrenoceptor and by Triggering Mitochondrial Intrinsic Pathway.

    PubMed

    Somarajan, Bindu I; Khanday, Mudasir A; Mallick, Birendra N

    2016-01-01

    Many neurodegenerative disorders are associated with rapid eye movement sleep (REMS) loss; however, the mechanism was unknown. As REMS loss elevates noradrenaline (NA) level in the brain as well as induces neuronal apoptosis and degeneration, in this study, we have delineated the intracellular molecular pathway involved in REMS deprivation (REMSD)-associated NA-induced neuronal apoptosis. Rats were REMS deprived for 6 days by the classical flower pot method; suitable controls were conducted and the effects on apoptosis markers evaluated. Further, the role of NA was studied by one, intraperitoneal (i.p.) injection of NA-ergic alpha1 adrenoceptor antagonist prazosin (PRZ) and two, by downregulation of NA synthesis in locus coeruleus (LC) neurons by local microinjection of tyrosine hydroxylase siRNA (TH-siRNA). Immunoblot estimates showed that the expressions of proapoptotic proteins viz. Bcl2-associated death promoter protein, apoptotic protease activating factor-1 (Apaf-1), cytochrome c, caspase9, caspase3 were elevated in the REMS-deprived rat brains, while caspase8 level remained unaffected; PRZ treatment did not allow elevation of these proapoptotic factors. Further, REMSD increased cytochrome c expression, which was prevented if the NA synthesis from the LC neurons was blocked by microinjection of TH-siRNA in vivo into the LC during REMSD in freely moving normal rats. Mitochondrial damage was re-confirmed by transmission electron microscopy, which showed distinctly swollen mitochondria with disintegrated cristae, chromosomal condensation, and clumping along the nuclear membrane, and all these changes were prevented in PRZ-treated rats. Combining findings of this study along with earlier reports, we propose that upon REMSD NA level increases in the brain as the LC, NA-ergic REM-OFF neurons do not cease firing and TH is upregulated in those neurons. This elevated NA acting on alpha1 adrenoceptors damages mitochondria causing release of cytochrome c to activate

  19. Enhancement by neuropeptide Y (NPY) of the dihydropyridine-sensitive component of the response to alpha 1-adrenoceptor stimulation in rat isolated mesenteric arterioles.

    PubMed Central

    Andriantsitohaina, R.; Stoclet, J. C.

    1990-01-01

    1. The mechanism by which neuropeptide Y (NPY) potentiates the vasoconstriction induced by alpha 1-adrenoceptor agonists was investigated in 3rd generation mesenteric arterioles of the rat. 2. At a maximally active concentration, nitrendipine (10(-6) M) displaced to the right the concentration-response curves to noradrenaline (pD2 decreased from 6.2 +/- 0.06 to 5.7 +/- 0.03) and phenylephrine (pD2 decreased from 5.6 +/- 0.03 to 5.3 +/- 0.03). Diltiazem (10(-5) M) also shifted to the right the concentration-response curve to phenylephrine (pD2 decreased from 6.0 +/- 0.06 to 5.5 +/- 0.04). In addition, the maximal response to phenylephrine was significantly decreased in the presence of either nitrendipine or diltiazem. 3. In the absence of a calcium channel blocking agent, NPY (100 nM) produced a leftward shift of the concentration-response curves to noradrenaline (pD2 increased from 6.2 +/- 0.06 to 6.5 +/- 0.05) and phenylephrine (pD2 increased from 5.6 +/- 0.03 to 6.0 +/- 0.06 and from 6.0 +/- 0.06 to 6.3 +/- 0.11). In the presence of either nitrendipine (10(-6) M) or diltiazem (10(-5) M), NPY (100 nM) did not alter the concentration-response curves to either noradrenaline or phenylephrine. 4. NPY was added to arterioles brought to the same level of tension (40% of the maximal contraction) either by phenylephrine alone (1.5 x 10(-6) M) or by a higher concentration of phenylephrine (3 x 10(-6) M) followed by the addition of prazosin (1.3 x 10(-9) M; a concentration at which it partially blocks alpha 1-adrenoceptors).(ABSTRACT TRUNCATED AT 250 WORDS) PMID:1970270

  20. Relationship between phosphatidylinositol (PI) turnover and Ca/sup 2 +/ utilization induced by. cap alpha. /sub 1/-adrenoceptor stimulation in rat aorta

    SciTech Connect

    Chiu, A.T.; P.B.M.W.M. Timmermans

    1986-03-05

    The authors have recently demonstrated that stimulation of ..cap alpha../sub 1/-adrenoceptors in rat aorta can activate two distinct processes of Ca/sup 2 +/ utilization for contraction. Sgd 101/75 (indanidine) was found to exclusively facilitate an influx of extracellular Ca/sup 2 +/ which was sensitive to nifedipine inhibition, whereas norepinephrine (NE) elicited both influx and intracellular release of Ca/sup 2 +/. The latter process was insensitive to nifedipine. In this study, the causal relationship between ..cap alpha../sub 1/-receptor activation and the mediatory responses, such as PI turnover has been evaluated. NE (1 x 10/sup -5/ M) maximally induced a /sup 45/Ca/sup 2 +/ efflux and also maximally increased the accumulation of /sup 3/H-inositol-1-PO/sub 4/ (IP) in the presence of 10 mM LiCl in a time-dependent fashion (0-60 min). This accumulation reached 1000% over control at 60 min of stimulation which could be abolished by 10/sup -6/ M prazosin and partially by 10/sup -6/ M yohimbine, while it was unaffected by nifedipine. Potassium depolarization as well as Sgd 101/75 (1 x 10/sup -5/ M) only slightly invoked IP production. However, the effect of NE on IP formation was antagonized by Sgd 101/75. These results support the concept that PI turnover mediates primarily the process of intracellular Ca/sup 2 +/ release subsequent to ..cap alpha../sub 1/-receptor activation in rat aorta.

  1. Regulation of renal artery smooth muscle tone by alpha1-adrenoceptors: role of voltage-gated calcium channels and intracellular calcium stores.

    PubMed

    Eckert, R E; Karsten, A J; Utz, J; Ziegler, M

    2000-04-01

    The ischemia induced vasospasm of the renal arterial blood vessels mediated by alpha1-adrenoceptors is of importance for the loss of kidney function. This is based on reduced perfusion of the kidney cortex occurring in kidney transplant and organ preserving surgery. The present study considered the intracellular mechanism of the norepinephrine (NE) induced renal artery vasospasm by using swine renal artery smooth muscle ring. Norepinephrine and phenylephrine (PE) induced dose-dependent and fully reversible isometric contractions with a threshold concentration of 10 nM (n = 7) and 10 nM (n = 4), and an EC50 of 0.3 microM and 1 microM, respectively. The receptor was identified as alpha1A-subtype. The contraction was completely inhibited by verapamil (IC50 = 1.51 microM; n = 11) and diltiazem (IC50 = 9.49 microM; n = 8) and 85% by nifedipine (IC50 = 0.13 microM; n = 21). Blockade of the intracellular inositol- 1,4,5-trisphosphate (IP3)-sensitive Ca2+ store by thapsigargin (1 microM, n = 7) or suppression of Ca2+ release from the intracellular Ca2+-sensitive Ca2+ store by ryanodine (100 microM, n = 4) inhibited the PE induced contraction by 39.5% and 47.6%, respectively. The results suggest a key role of voltage-dependent Ca2+ channels and intracellular Ca2+ stores in the alpha1A-adrenoceptor induced contraction of the renal artery. PMID:10850635

  2. Multiple actions of glaucine on cyclic nucleotide phosphodiesterases, alpha 1-adrenoceptor and benzothiazepine binding site at the calcium channel.

    PubMed

    Ivorra, M D; Lugnier, C; Schott, C; Catret, M; Noguera, M A; Anselmi, E; D'Ocon, P

    1992-06-01

    1. In the present study, the properties of glaucine (an aporphine structurally related to papaverine) were compared with those of papaverine, diltiazem, nifedipine and prazosin. The work includes functional studies on rat isolated aorta contracted with noradrenaline, caffeine or KCl, and a determination of the affinity of glaucine at calcium channel binding sites of alpha-adrenoceptors, by use of [3H]-(+)-cis-diltiazem, [3H]-nitrendipine and [3H]-prazosin binding to cerebral cortical membranes. The effects of glaucine on the different molecular forms of cyclic nucleotide phosphodiesterases (PDE) isolated from bovine aorta were also determined. 2. Contraction evoked by noradrenaline (1 microM) or depolarizing solution (60 mM KCl) were inhibited in a concentration-dependent manner by all the compounds tested. As expected, prazosin showed a greater selectivity of action on NA-induced contraction, whereas nifedipine and diltiazem appeared more potent on KCl-induced contraction. Glaucine had a greater potency on the contraction elicited by noradrenaline whereas papaverine acted non specifically. 3. In Ca(2+)-free solution, prazosin (0.1 microM) and glaucine (0.1 mM) inhibited the contraction evoked by NA; diltiazem (0.1 mM) diminished this contraction whereas nifedipine (1 microM) had no effect. Preincubation of tissues with glaucine, diltiazem, nifedipine and prazosin did not modify the contractile response induced by caffeine. In contrast, papaverine (0.1 mM) significantly inhibited the contractions evoked by NA or caffeine in Ca(2+)-free medium. 4. Glaucine and papaverine show affinity at the [3H]-prazosin binding site and at the benzothiazepine binding site of the Ca(2+)-channel receptor complex, but have no effect at the dihydropyridine binding site in rat cerebral cortex. Glaucine exerts some selectivity as an inhibitor of [3H]-prazosin binding as opposed to [3H]-(+ )-cis-diltiazem binding while papaverine appears to have approximately equal affinity in this

  3. Multiple actions of glaucine on cyclic nucleotide phosphodiesterases, alpha 1-adrenoceptor and benzothiazepine binding site at the calcium channel.

    PubMed Central

    Ivorra, M. D.; Lugnier, C.; Schott, C.; Catret, M.; Noguera, M. A.; Anselmi, E.; D'Ocon, P.

    1992-01-01

    1. In the present study, the properties of glaucine (an aporphine structurally related to papaverine) were compared with those of papaverine, diltiazem, nifedipine and prazosin. The work includes functional studies on rat isolated aorta contracted with noradrenaline, caffeine or KCl, and a determination of the affinity of glaucine at calcium channel binding sites of alpha-adrenoceptors, by use of [3H]-(+)-cis-diltiazem, [3H]-nitrendipine and [3H]-prazosin binding to cerebral cortical membranes. The effects of glaucine on the different molecular forms of cyclic nucleotide phosphodiesterases (PDE) isolated from bovine aorta were also determined. 2. Contraction evoked by noradrenaline (1 microM) or depolarizing solution (60 mM KCl) were inhibited in a concentration-dependent manner by all the compounds tested. As expected, prazosin showed a greater selectivity of action on NA-induced contraction, whereas nifedipine and diltiazem appeared more potent on KCl-induced contraction. Glaucine had a greater potency on the contraction elicited by noradrenaline whereas papaverine acted non specifically. 3. In Ca(2+)-free solution, prazosin (0.1 microM) and glaucine (0.1 mM) inhibited the contraction evoked by NA; diltiazem (0.1 mM) diminished this contraction whereas nifedipine (1 microM) had no effect. Preincubation of tissues with glaucine, diltiazem, nifedipine and prazosin did not modify the contractile response induced by caffeine. In contrast, papaverine (0.1 mM) significantly inhibited the contractions evoked by NA or caffeine in Ca(2+)-free medium. 4. Glaucine and papaverine show affinity at the [3H]-prazosin binding site and at the benzothiazepine binding site of the Ca(2+)-channel receptor complex, but have no effect at the dihydropyridine binding site in rat cerebral cortex.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:1327380

  4. Attenuation of KATP channel-opener induced shortening of repolarization time by alpha 1-adrenoceptor antagonist during ischemia in canine heart.

    PubMed

    Tanabe, T; Aikawa, M; Deguchi, Y; Yoshioka, K; Handa, S

    2000-06-01

    The purpose of the study was to determine whether a new KATP channel opener, Y 26763 (Y), can influence the electrophysiological properties in the ischemic myocardium as well as to determine whether the blunting effect of the alpha 1-adrenoceptor antagonist bunazosin (BN) on an ischemia-induced shortening of repolarization time can be related to the KATP channel activity. The anterior descending branch of the left coronary artery was ligated four times for 5 minutes, separated by 15 minutes of reperfusion (stages 1-4) to test the dose-dependent effect of drugs on repolarization. Dogs received either vehicle (n = 9), Y (0.4, 2.0, and 4.0 micrograms/kg at stages 2, 3, and 4, respectively, with 0.4 microgram/kg/min drip infusion at each of stages 2-4, n = 7), BN (0.1 mg at each of stages 2-4, n = 8), or a combination of these two drugs (BN + Y, the same dose of BN and Y in groups BN and Y, respectively, n = 9). Drugs were administered into the left atrium. The monophasic action potential (MAP) and regional electrograms were recorded. The MAP90 and the duration of the slow deflections (DSD) of the regional electrogram were used as markers of repolarization. The Vmax of the MAP and the rapid deflections (DRD) of the regional electrogram were used as markers of conduction. Y augmented an ischemia-induced shortening of MAP90 and DSD in proportion to an increase in the dose given and the plasma concentration (P < .05-.01), especially at the epicardial site. BN and BN + Y blunted the ischemia-related shortening of MAP90 and DSD, causing a reduction in repolarization time dispersion between the ischemic and normal zones. There were no significant changes in the Vmax or DRD in the ischemic zone between periods before and after an increase in each drug dose in the four groups. None of the seven dogs developed ventricular tachycardia (VT)/ventricular fibrillation (VF) in the Y group, whereas two of the eight dogs in the BN group, three of the nine dogs in the BN + Y group, and

  5. Comparison of relaxation responses of cavernous and trigonal smooth muscles from rabbits by alpha1-adrenoceptor antagonists; prazosin, terazosin, doxazosin, and tamsulosin.

    PubMed

    Seo, K K; Lee, M Y; Lim, S W; Kim, S C

    1999-02-01

    Alpha1a-adrenergic receptor (AR) primarily mediates the contraction of the prostatic and cavernous smooth muscles. Among clinically available alpha1-AR antagonists for the medical management of benign prostatic hyperplasia (BPH), tamsulosin has a modest selectivity for alpha1A- and alpha1D- over alpha1B-ARs. To compare the effects of various alpha1-AR antagonists on relaxation responses of cavernous and trigonal smooth muscles, isometric tension studies with relatively selective (tamsulosin) and non-selective (prazosin, doxazosin, and terazosin) alpha1A-AR antagonists, were conducted in the cavernous and trigonal muscle strips of rabbits (n=10 each). Tamsulosin had the strongest inhibitory effect on contraction of trigonal smooth muscle among the various alpha1-AR antagonists, and the inhibitory activities of prazosin, doxazosin, and terazosin were not statistically different. All alpha1-AR antagonists caused concentration-dependent relaxation of the cavernous muscle strips. Tamsulosin was shown to have greater potency than prazosin (more than 100-fold), doxazosin (more than 1000-fold), and terazosin (more than 1000-fold), in relaxation of cavernous smooth muscle. In conclusion, tamsulosin might be the most effective drug among the four commonly used alpha1-AR antagonists for the medical management of BPH. Tamsulosin might be a potential substitute for phentolamine in combination with vasoactive agents as an intracavernous injection therapy for patients with erectile dysfunction. PMID:10102527

  6. Effects of polymorphisms in beta1-adrenoceptor and alpha-subunit of G protein on heart rate and blood pressure during exercise test. The Finnish Cardiovascular Study.

    PubMed

    Nieminen, Tuomo; Lehtimäki, Terho; Laiho, Jarno; Rontu, Riikka; Niemelä, Kari; Kööbi, Tiit; Lehtinen, Rami; Viik, Jari; Turjanmaa, Väinö; Kähönen, Mika

    2006-02-01

    We tested whether the Arg389Gly and Ser49Gly polymorphisms of the beta1-adrenergic receptor gene ADRB1 and the T393C polymorphism of the G protein alpha-subunit gene GNAS1 modulate heart rate (HR) and blood pressure responses during an exercise stress test. The study population comprised 890 participants (563 men and 327 women, mean age 58.1 +/- 12.6 yr) of the Finnish Cardiovascular Study. Their HR, systolic (SAP), and diastolic arterial pressures (DAP) at rest, during exercise, and 4 min after the test were measured and analyzed by repeated-measurement ANOVA (RANOVA). Genotypes were detected by TaqMan 5' nuclease assay. In all subjects, and in men and women separately, the T393C of GNAS1 was the only polymorphism with genotype x time interaction in HR over the three study phases (P = 0.04, RANOVA). None of the polymorphisms presented genotype x time interaction in SAP or DAP responses (P > 0.10, RANOVA). In all subjects at rest, the Ser49Gly polymorphism of ADRB1 tended (P = 0.06, ANOVA) to differentiate HR. Arg389Gly polymorphism of ADRB1 affected maximal SAP during exercise (P = 0.04, ANOVA) and the change in SAP from rest to maximal (P = 0.03, ANOVA). Arg389 homozygotes, particularly men, were less likely to have ventricular extrasystoles during the exercise (odds ratio = 0.68, 95% confidence interval = 0.51-0.91, P = 0.009, and odds ratio = 0.60, 95% confidence interval = 0.42-0.86, P = 0.006, respectively) than did Gly389 carriers. In conclusion, polymorphisms examined appear to have modulatory effects on hemodynamics in a clinical exercise test setting. However, the effects in absolute numbers were minor and clinically possibly insignificant. PMID:16210433

  7. The effect of urapidil, an alpha-1 adrenoceptor antagonist and a 5-HT1A agonist, on the vascular tone of the porcine coronary and pulmonary arteries, the rat aorta and the human pulmonary artery.

    PubMed

    Bopp, Claire; Auger, Cyril; Diemunsch, Pierre; Schini-Kerth, Valérie

    2016-05-15

    Urapidil (Eupressyl(®)) an antihypertensive drug acting as an α1 antagonist and a 5-HT1A agonist, may be of special interest in the treatment of hypertension associated with preeclamptic toxaemia and hypoxia-induced pulmonary arterial vasoconstriction. However, the effect of urapidil on vascular tone has been poorly investigated. Vascular reactivity was evaluated using pulmonary and coronary arteries from 36 pigs, aortae from 22 rats and 9 human pulmonary artery samples suspended in organ chambers. Concentration-relaxation curves either to urapidil, 5-HT, or the 5-HT1A receptor agonist 8-OH-DPAT were constructed after pre-contraction of rings. Pig pulmonary and coronary artery rings were contracted with U46619, a thromboxane mimetic, rat aortic rings with either endothelin-1 or phenylephrine, and human pulmonary artery rings with U46619 or phenylephrine. Urapidil markedly inhibited phenylephrine-induced contractions in rat aortic rings with and without endothelium with a more pronounced effect observed in rings without endothelium. Both 5-HT and 8-OH-DPAT failed to induce relaxation in rat aortic rings with an intact endothelium. 5-HT, but not urapidil and 8-OH-DPAT, induced a concentration-dependent relaxation in the porcine coronary and pulmonary artery rings with an intact endothelium (P<0.05). 5-HT and phenylephrine but not urapidil caused concentration-dependent contractions in human pulmonary artery rings. The present findings, while confirming that urapidil is a potent inhibitor of α1-adrenoceptor-induced contraction, do not support the role of 5-HT1A receptor activation in the control of the vascular tone of the different types of arteries tested in response to urapidil. In addition, they indicate that urapidil seems to preferentially target arteries with endothelial dysfunction. PMID:26957055

  8. α1-Adrenoceptors are required for normal male sexual function

    PubMed Central

    Sanbe, A; Tanaka, Y; Fujiwara, Y; Tsumura, H; Yamauchi, J; Cotecchia, S; Koike, K; Tsujimoto, G; Tanoue, A

    2007-01-01

    Background and purpose: α1-Adrenoceptor antagonists are extensively used in the treatment of hypertension and lower urinary tract symptoms associated with benign prostatic hyperplasia. Among the side effects, ejaculatory dysfunction occurs more frequently with drugs that are relatively selective for α1A-adrenoceptors compared with other drugs of this class. This suggests that α1A-adrenoceptors may contribute to ejaculation. However, this has not been studied at the molecular level. Experimental approach: The physiological contribution of each α1-adrenoceptor subtype was characterized using α1-adrenoceptor subtype-selective knockout (KO) mice (α1A-, α1B- and α1D-AR KO mice) since the subtype-specific drugs available are only moderately selective. We analysed the role of α1-adrenoceptors in the blood pressure and vascular response as well as ejaculation by determining these variables in α1-adrenoceptor subtype-selective KO mice and in mice with all their α1-adrenoceptor subtypes deleted (α1-AR triple-KO mice). Key results: The pregnancy rate was reduced by 50% in α1A-adrenoceptor KO mice, and this reduction was dramatically enhanced in α1-adrenoceptor triple-KO mice. Contractile tension of the vas deferens in response to noradrenaline was markedly decreased in α1A-adrenoceptor KO mice, and this contraction was completely abolished in α1-adrenoceptor triple-KO mice. This attenuation of contractility was also observed in the electrically stimulated vas deferens. Conclusions and implications: These results demonstrate that α1-adrenoceptors, particularly α1A-adrenoceptors, are required for normal contractility of the vas deferens and consequent sperm ejaculation as well as having a function in fertility. PMID:17603545

  9. Phenotype pharmacology of lower urinary tract α1-adrenoceptors

    PubMed Central

    Nishimune, A; Yoshiki, H; Uwada, J; Anisuzzaman, ASM; Umada, H; Muramatsu, I

    2012-01-01

    α1-Adrenoceptors are involved in numerous physiological functions, including micturition. However, the pharmacological profile of the α1-adrenoceptor subtypes remains controversial. Here, we review the literature regarding α1-adrenoceptors in the lower urinary tract from the standpoint of α1L phenotype pharmacology. Among three α1-adrenoceptor subtypes (α1A, α1B and α1D), α1a-adrenoceptor mRNA is the most abundantly transcribed in the prostate, urethra and bladder neck of many species, including humans. In prostate homogenates or membrane preparations, α1A-adrenoceptors with high affinity for prazosin have been detected as radioligand binding sites. Functional α1-adrenoceptors in the prostate, urethra and bladder neck have low affinity for prazosin, suggesting the presence of an atypical α1-adrenoceptor phenotype (designated as α1L). The α1L-adrenoceptor occurs as a distinct binding entity from the α1A-adrenoceptor in intact segments of variety of tissues including prostate. Both the α1L- and α1A-adrenoceptors are specifically absent from Adra1A (α1a) gene-knockout mice. Transfection of α1a-adrenoceptor cDNA predominantly expresses α1A-phenotype in several cultured cell lines. However, in CHO cells, such transfection expresses α1L- and α1A-phenotypes. Under intact cell conditions, the α1L-phenotype is predominant when co-expressed with the receptor interacting protein, CRELD1α. In summary, recent pharmacological studies reveal that two distinct α1-adrenoceptor phenotypes (α1A and α1L) originate from a single Adra1A (α1a-adrenoceptor) gene, but adrenergic contractions in the lower urinary tract are predominantly mediated via the α1L-adrenoceptor. From the standpoint of phenotype pharmacology, it is likely that phenotype-based subtypes such as the α1L-adrenoceptor will become new targets for drug development and pharmacotherapy. LINKED ARTICLE This article is commented on by Ventura, pp. 1223–1225 of this issue. To view this commentary

  10. Synthesis and α1-adrenoceptor antagonist activity of tamsulosin analogues.

    PubMed

    Sagratini, Gianni; Angeli, Piero; Buccioni, Michela; Gulini, Ugo; Marucci, Gabriella; Melchiorre, Carlo; Poggesi, Elena; Giardinà, Dario

    2010-12-01

    Tamsulosin (-)-1 is the most utilized α(1)-adrenoceptor antagonist in the benign prostatic hyperplasia therapy owing to its uroselective antagonism and capability in relieving both obstructive and irritative lower urinary tract symptoms. Here we report the synthesis and pharmacological study of the homochiral (-)-1 analogues (-)-2-(-)-5, bearing definite modifications in the 2-substituted phenoxyethylamino group in order to evaluate their influence on the affinity profile for α(1)-adrenoceptor subtypes. The benzyl analogue (-)-3, displaying a preferential antagonist profile for α1A-than α1D-and α1B-adrenoceptors, and a 12-fold higher potency at α1A-adrenoceptors with respect to the α1B subtype, may have improved uroselectivity compared to (-)-1. PMID:20934789

  11. Negative cooperativity across β1-adrenoceptor homodimers provides insights into the nature of the secondary low-affinity CGP 12177 β1-adrenoceptor binding conformation.

    PubMed

    Gherbi, Karolina; May, Lauren T; Baker, Jillian G; Briddon, Stephen J; Hill, Stephen J

    2015-07-01

    At the β1-adrenoceptor, CGP 12177 potently antagonizes agonist responses at the primary high-affinity catecholamine conformation while also exerting agonist effects of its own through a secondary low-affinity conformation. A recent mutagenesis study identified transmembrane region (TM)4 of the β1-adrenoceptor as key for this low-affinity conformation. Others suggested that TM4 has a role in β1-adrenoceptor oligomerization. Here, assessment of the dissociation rate of a fluorescent analog of CGP 12177 [bordifluoropyrromethane-tetramethylrhodamine-(±)CGP 12177 (BODIPY-TMR-CGP)] at the human β1-adrenoceptor expressed in Chinese hamster ovary cells revealed negative cooperative interactions between 2 distinct β1-adrenoceptor conformations. The dissociation rate of 3 nM BODIPY-TMR-CGP was 0.09 ± 0.01 min(-1) in the absence of competitor ligands, and this was enhanced 2.2- and 2.1-fold in the presence of 1 µM CGP 12177 and 1 µM propranolol, respectively. These effects on the BODIPY-TMR-CGP dissociation rate were markedly enhanced in β1-adrenoceptor homodimers constrained by bimolecular fluorescence complementation (9.8- and 9.9-fold for 1 µM CGP 12177 and 1 µM propranolol, respectively) and abolished in β1-adrenoceptors containing TM4 mutations vital for the second conformation pharmacology. This study suggests that negative cooperativity across a β1-adrenoceptor homodimer may be responsible for generating the low-affinity pharmacology of the secondary β1-adrenoceptor conformation. PMID:25837585

  12. Up-regulation of cutaneous α1-adrenoceptors after a burn.

    PubMed

    Drummond, Peter D; Dawson, Linda F; Finch, Philip M; Drummond, Eleanor S; Wood, Fiona M; Fear, Mark W

    2015-09-01

    Stimulation of α1-adrenoceptors evokes inflammatory cytokine production, boosts neurogenic inflammation and pain, and influences cellular migration and proliferation. As expression of α1-adrenoceptors increases on dermal nerves and keratinocytes after peripheral nerve injury, the aim of this study was to determine whether another form of tissue injury (a cutaneous burn) triggered a similar response. In particular, changes in expression of α1-adrenoceptors were investigated on dermal nerve fibres, keratinocytes and fibroblast-like cells using immunohistochemistry 2-12 weeks after a full thickness burn in Wistar rats. Within two weeks of the burn, local increases in α1-adrenoceptor expression were seen in the re-forming epidermis, in dense bands of spindle-shaped cells in the upper dermis (putatively infiltrating immune cells and fibroblasts), and on nerve fibres in the deep dermis. In addition, nerve fibre density increased approximately three-fold in the deep dermis, and this response persisted for several more weeks. In contrast, α1-adrenoceptor labelled cells and staining intensity in the upper dermis decreased contralateral to the burn, as did nerve fibre density in the deep dermis. These findings suggest that inflammatory mediators and/or growth factors at the site of a burn trigger the synthesis of α1-adrenoceptors on resident epidermal cells and nerve fibres, and an influx of α1-adrenoceptor labelled cells. The heightened expression of α1-adrenoceptors in injured tissue could shape inflammatory and wound healing responses. PMID:25630693

  13. Regression of Intracranial Meningioma during Treatment with α1-Adrenoceptor Blocker

    PubMed Central

    Hoegestoel, Einar August; Berg-Johnsen, Jon

    2016-01-01

    Background Regression of meningioma has been reported after hemorrhage or hormonal withdrawal. Here, we report a case of an incidentally diagnosed meningioma that regressed in association with α1-adrenoceptor antagonist. Case report A 59-year old male patient with an incidentally diagnosed lateral sphenoid wing meningioma was followed with serial magnetic resonance imaging. The tumor with a maximum diameter of 43 mm showed progressive regression, and after 3 years the size was reduced to 22% of the initial volume. During follow-up the patient was treated with an α1-adrenoceptor antagonist (tamsulosin) for benign prostatic hyperplasia. Possible mechanisms are discussed, including our main hypothesis of reduced mitogenic effects through phospholipase C-signal transduction. Conclusion This is the first report of regression of an incidentally diagnosed meningioma associated with α1-adrenoceptor antagonist treatment. PMID:27175325

  14. Regression of Intracranial Meningioma during Treatment with α1-Adrenoceptor Blocker.

    PubMed

    Hoegestoel, Einar August; Berg-Johnsen, Jon

    2016-03-01

    Background Regression of meningioma has been reported after hemorrhage or hormonal withdrawal. Here, we report a case of an incidentally diagnosed meningioma that regressed in association with α1-adrenoceptor antagonist. Case report A 59-year old male patient with an incidentally diagnosed lateral sphenoid wing meningioma was followed with serial magnetic resonance imaging. The tumor with a maximum diameter of 43 mm showed progressive regression, and after 3 years the size was reduced to 22% of the initial volume. During follow-up the patient was treated with an α1-adrenoceptor antagonist (tamsulosin) for benign prostatic hyperplasia. Possible mechanisms are discussed, including our main hypothesis of reduced mitogenic effects through phospholipase C-signal transduction. Conclusion This is the first report of regression of an incidentally diagnosed meningioma associated with α1-adrenoceptor antagonist treatment. PMID:27175325

  15. Insights into cardio-oncology: Polypharmacology of quinazoline-based α1-adrenoceptor antagonists

    PubMed Central

    Patanè, Salvatore

    2015-01-01

    New uses of cardiovascular drugs with proven experience are emerging, including for treating cancer. Quinazoline is a compound made up of two fused six member simple aromatic rings, benzene and pyrimidine rings, with several biological effects. Cardiologists first used quinazoline-based α1-adrenoceptor antagonists prazosin, doxazosin, and terazosin; currently available data support their use as safe, well tolerated, and effective add-on therapy in uncontrolled hypertension with additional favourable metabolic effects. Recent findings highlight the anticancer effects of quinazoline-based α1-adrenoceptor antagonists, indicating that they may have a significant role in uncontrolled hypertensive cancer patients without signs of ischemia. PMID:26015856

  16. Effects of castration on contraction and α1-adrenoceptor expression in rat prostate

    PubMed Central

    Homma, Yukio; Hamada, Kozo; Nakayama, Yasuhisa; Tsujimoto, Gozoh; Kawabe, Kazuki

    2000-01-01

    The prostate function is regulated by androgens and α-adrenergic activity. Clinically, antiandrogens and/or α1-adrenergic antagonists are commonly used to treat symptomatic prostatic hypertrophy. To elucidate the effects of androgen deprivation on prostate contractility via α1-adrenoceptor, the characteristics and expression of α1-adrenoceptors were examined in castrated rats. Isolated prostate strips from intact and castrated rats were subjected to a phenylephrine stimulated contraction. Prazosin (10 nM), [3H]-prazosin and phenoxybenzamine (3–300 nM) were used for inhibition assay, receptor characterization and partial alkylation of α-adrenoceptor, respectively. The mRNA content of three subtypes of α-adrenoceptors was determined by reverse transcription combined with polymerase chain reaction (RT–PCR). Contractile response to phenylephrine increased in castrated rats, which could be explained by a relative increase of the stromal component. A lowered contraction potency was also noted in castrated rats. Receptor binding assay indicated minimal changes in the affinity or density of α1-adrenoceptor. Escalating alkylation of the α1-adrenoceptor population resulted in a rightward shift in the contraction-response curves before depressing maximal contractile force, and the suppression was detected at lower doses in castrated rats. RT–PCR study confirmed the expression of three types of α1-adrenoceptor, α1a, α1b and α1d-adrenoceptors, in intact rat prostate, and revealed that α1a-adrenoceptor, but not α1b or α1d-adrenoceptors, was down-regulated in castrates. The results show that androgen deprivation suppressed α1-adrenergic contractility of rat prostate strips, and the suppression was associated with down-regulation of receptor reserve for the α1a-adreneroceptor population expressed in intact rat prostate. PMID:11090120

  17. Chemically Homogenous Compounds with Antagonistic Properties at All α1-Adrenoceptor Subtypes but not β1-Adrenoceptor Attenuate Adrenaline-Induced Arrhythmia in Rats.

    PubMed

    Pytka, Karolina; Lustyk, Klaudia; Żmudzka, Elżbieta; Kotańska, Magdalena; Siwek, Agata; Zygmunt, Małgorzata; Dziedziczak, Agnieszka; Śniecikowska, Joanna; Olczyk, Adrian; Gałuszka, Adam; Śmieja, Jarosław; Waszkielewicz, Anna M; Marona, Henryk; Filipek, Barbara; Sapa, Jacek; Mogilski, Szczepan

    2016-01-01

    Studies proved that among all α1-adrenoceptors, cardiac myocytes functionally express only α1A- and α1B-subtype. Scientists indicated that α1A-subtype blockade might be beneficial in restoring normal heart rhythm. Therefore, we aimed to determine the role of α1-adrenoceptors subtypes (i.e., α1A and α1B) in antiarrhythmic effect of six structurally similar derivatives of 2-methoxyphenylpiperazine. We compared the activity of studied compounds with carvedilol, which is β1- and α1-adrenoceptors blocker with antioxidant properties. To evaluate the affinity for adrenergic receptors, we used radioligand methods. We investigated selectivity at α1-adrenoceptors subtypes using functional bioassays. We tested antiarrhythmic activity in adrenaline-induced (20 μg/kg i.v.), calcium chloride-induced (140 and 25 mg/kg i.v.) and barium chloride-induced (32 and 10 mg/kg i.v.) arrhythmia models in rats. We also evaluated the influence of studied compounds on blood pressure in rats, as well as lipid peroxidation. All studied compounds showed high affinity toward α1-adrenoceptors but no affinity for β1 receptors. Biofunctional studies revealed that the tested compounds blocked α1A-stronger than α1B-adrenoceptors, but except for HBK-19 they antagonized α1A-adrenoceptor weaker than α1D-subtype. HBK-19 showed the greatest difference in pA2 values-it blocked α1A-adrenoceptors around seven-fold stronger than α1B subtype. All compounds showed prophylactic antiarrhythmic properties in adrenaline-induced arrhythmia, but only the activity of HBK-16, HBK-17, HBK-18, and HBK-19 (ED50 = 0.18-0.21) was comparable to that of carvedilol (ED50 = 0.36). All compounds reduced mortality in adrenaline-induced arrhythmia. HBK-16, HBK-17, HBK-18, and HBK-19 showed therapeutic antiarrhythmic properties in adrenaline-induced arrhythmia. None of the compounds showed activity in calcium chloride- or barium chloride-induced arrhythmias. HBK-16, HBK-17, HBK-18, and HBK-19 decreased heart

  18. Chemically Homogenous Compounds with Antagonistic Properties at All α1-Adrenoceptor Subtypes but not β1-Adrenoceptor Attenuate Adrenaline-Induced Arrhythmia in Rats

    PubMed Central

    Pytka, Karolina; Lustyk, Klaudia; Żmudzka, Elżbieta; Kotańska, Magdalena; Siwek, Agata; Zygmunt, Małgorzata; Dziedziczak, Agnieszka; Śniecikowska, Joanna; Olczyk, Adrian; Gałuszka, Adam; Śmieja, Jarosław; Waszkielewicz, Anna M.; Marona, Henryk; Filipek, Barbara; Sapa, Jacek; Mogilski, Szczepan

    2016-01-01

    Studies proved that among all α1-adrenoceptors, cardiac myocytes functionally express only α1A- and α1B-subtype. Scientists indicated that α1A-subtype blockade might be beneficial in restoring normal heart rhythm. Therefore, we aimed to determine the role of α1-adrenoceptors subtypes (i.e., α1A and α1B) in antiarrhythmic effect of six structurally similar derivatives of 2-methoxyphenylpiperazine. We compared the activity of studied compounds with carvedilol, which is β1- and α1-adrenoceptors blocker with antioxidant properties. To evaluate the affinity for adrenergic receptors, we used radioligand methods. We investigated selectivity at α1-adrenoceptors subtypes using functional bioassays. We tested antiarrhythmic activity in adrenaline-induced (20 μg/kg i.v.), calcium chloride-induced (140 and 25 mg/kg i.v.) and barium chloride-induced (32 and 10 mg/kg i.v.) arrhythmia models in rats. We also evaluated the influence of studied compounds on blood pressure in rats, as well as lipid peroxidation. All studied compounds showed high affinity toward α1-adrenoceptors but no affinity for β1 receptors. Biofunctional studies revealed that the tested compounds blocked α1A-stronger than α1B-adrenoceptors, but except for HBK-19 they antagonized α1A-adrenoceptor weaker than α1D-subtype. HBK-19 showed the greatest difference in pA2 values—it blocked α1A-adrenoceptors around seven-fold stronger than α1B subtype. All compounds showed prophylactic antiarrhythmic properties in adrenaline-induced arrhythmia, but only the activity of HBK-16, HBK-17, HBK-18, and HBK-19 (ED50 = 0.18–0.21) was comparable to that of carvedilol (ED50 = 0.36). All compounds reduced mortality in adrenaline-induced arrhythmia. HBK-16, HBK-17, HBK-18, and HBK-19 showed therapeutic antiarrhythmic properties in adrenaline-induced arrhythmia. None of the compounds showed activity in calcium chloride- or barium chloride-induced arrhythmias. HBK-16, HBK-17, HBK-18, and HBK-19 decreased heart

  19. The α1 adrenoceptors in ventrolateral orbital cortex contribute to the expression of morphine-induced behavioral sensitization in rats.

    PubMed

    Wei, Lai; Zhu, Yuan-Mei; Zhang, Yu-Xiang; Liang, Feng; Li, Teng; Gao, Hong-Yu; Huo, Fu-Quan; Yan, Chun-Xia

    2016-01-01

    The aim of the present study was to investigate the effect of microinjection of benoxathian, selective α1 adrenoceptor antagonist, into the ventrolateral orbital cortex (VLO) on morphine-induced behavioral sensitization and its underlying molecular mechanism in rats. A single morphine treatment protocol was used in establishing the behavioral sensitization model. The effect of bilateral intra-VLO benoxathian injection on locomotor activity was examined and the protein expression levels of α1 adrenoceptors and activation of extracellular signal-regulated kinase (ERK) in the VLO were detected after locomotor test. The results showed that a single injection of morphine could induce behavioral sensitization by a low challenge dosage of morphine after a 7-days drug free period. Benoxathian significantly suppressed the expression but not the development of morphine-induced behavioral sensitization. Morphine treatment significantly elicited ERK phosphorylation and downregulated the expression level of α1 adrenoceptors in the VLO. In addition, intra-VLO benoxathian injection enhanced the expression levels of α1 adrenoceptors and phosphorylated ERK. These results suggest that α1 adrenoceptors in the VLO are involved in regulating the expression of morphine-induced behavioral sensitization. The effect of decreased locomotor activity by blocking α1 adrenoceptors might be associated with activation of ERK in the VLO. PMID:26520466

  20. Proliferation of the human urothelium is induced by atypical β1 -adrenoceptors.

    PubMed

    Winder, M; Wasén, C; Aronsson, P; Giglio, D

    2015-09-01

    We wanted to assess whether β-adrenoceptors mediate proliferation in the normal and malignant urothelial cell lines UROtsa and T24, respectively. Urothelial cells were cultured for 24 h in the presence of the β-adrenoceptor agonists isoprenaline (β1/2/3 ), dobutamine (β1 ), salbutamol (β2 ), BRL 37344 (β3 ), CGP 12177 (a partial β-agonist) or β-adrenoceptor antagonists (metoprolol; β1 , propranolol; β1/2 ). Phosphorylation of kinases was screened with a Human Phospho-Kinase Array Kit (R&D systems). Intracellular pathways activated by proliferation of urothelial cells were characterized by incubating cells with the MEK1/2 inhibitor PD 98,059, the p38 kinase inhibitor losmapimod or with the Akt 1/2 kinase inhibitor. Proliferation was assessed with the MTT proliferation assay (ATCC). Western blot and immunocytochemistry were used for detection of the β1 -adrenoceptor. Isoprenaline and dobutamine induced proliferation, while salbutamol and BRL 37344 did not. Dobutamine-induced proliferation was not affected by metoprolol or propranolol but was instead antagonized by CGP 12177 in T24 but not in UROtsa. In response to stimulation with dobutamine, Akt1/2/3 was phosphorylated in UROtsa, while ERK1/2 and p38 were phosphorylated in T24. MEK1/2 inhibition blocked basal and dobutamine-induced proliferation in T24 but only basal proliferation in UROtsa. Losmapimod slightly inhibited basal proliferation in T24 but not dobutamine-induced proliferation. Akt 1/2 inhibitor blocked basal and dobutamine-induced proliferation in UROtsa. Immunocytochemistry and Western blot revealed expression of β1 -adrenoceptors in both urothelial cell lines. The present data show that the urothelium expresses atypical β1-adrenoceptors that activate intracellular kinases inducing urothelial proliferation. PMID:26913580

  1. Expression of distinct α1-adrenoceptor phenotypes in the iris of pigmented and albino rabbits

    PubMed Central

    Muramatsu, I; Suzuki, F; Nishimune, A; Anisuzzaman, ASM; Yoshiki, H; Su, T-H; Chang, C-K; Morishima, S

    2009-01-01

    Background and purpose: The expression of multiple pharmacological phenotypes including α1L-adrenoceptor has recently been reported for α1-adrenoceptors. The purpose of the present study was to identify α1-adrenoceptor phenotypes in the irises of pigmented and albino rabbits. Experimental approach: Radioligand binding and functional bioassay experiments were performed in segments or strips of iris of pigmented and albino rabbits, and their pharmacological profiles were compared. Key results: [3H]-silodosin at subnanomolar concentrations bound to intact segments of iris of pigmented and albino rabbits at similar densities (approximately 240 fmol·mg−1 protein). The binding sites in the iris of a pigmented rabbit were composed of a single component showing extremely low affinities for prazosin, hydrochloride [N-[2-(2-cyclopropylmethoxyphenoxy)ethyl]-5-chloro-α,α-dimethyl-1H-indole-3-ethamine hydrochloride (RS-17053)] and 5-methylurapidil, while two components with high and low affinities for prazosin, RS-17053 and 5-methylurapidil were identified in irises from albino rabbits. In contrast, specific binding sites for [3H]-prazosin were not clearly detected because a high proportion of non-specific binding and/or low affinity for prazosin occurred. Contractile responses of iris dilator muscle to noradrenaline were antagonized by the above ligands, and their antagonist affinities were consistent with the binding estimates at low-affinity sites identified in both strains of rabbits. Conclusions and implications: A typical α1L phenotype with extremely low affinity for prazosin is exclusively expressed in the iris of pigmented rabbits, while two distinct phenotypes (α1A and α1L) with high and moderate affinities for prazosin are co-expressed in the iris of albino rabbits. This suggests that a significant difference in the expression of phenotypes of the α1-adrenoceptor occurs in the irises between the two strains of rabbits. PMID:19466984

  2. EFFECT OF α1-ADRENOCEPTOR ANTAGONIST EXPOSURE ON PROSTATE CANCER INCIDENCE: AN OBSERVATIONAL COHORT STUDY

    PubMed Central

    Harris, Andrew M.; Warner, Bradley W.; Wilson, John M.; Becker, Aaron; Rowland, Randall G.; Conner, William; Lane, Matthew; Kimbler, Kimberly; Durbin, Eric B.; Baronand, Andre T.; Kyprianou, Natasha

    2007-01-01

    PURPOPSE Quinazoline-based α1-adrenoceptor antagonists (α1-blockers), doxazosin and terazosin, suppress prostate tumor growth via induction of apoptosis and reduction of tissue vascularity. We hypothesize that by inducing apoptosis and targeting angiogenesis these drugs serve as chemopreventive agents of human prostate cancer. We therefore performed an exploratory observational cohort study to assess whether α1-blocker exposure affects the incidence prostate cancer and overall survival experience. MATERIALS AND METHODS The medical records of all male patients enrolled at the Lexington Veterans Administration (VA) Medical Center were searched to identify men treated with quinazoline-based α1-adrenoreceptor antagonists between Jan 1, 1998 and Dec 31, 2002 for either hypertension and/or benign prostate enlargement. Medical records were subsequently linked to the Markey Cancer Center’s Kentucky Cancer Registry (KCR), a statewide population-based central cancer registry that is part of the NCI’s Surveillance, Epidemiology, and End Results (SEER) Program to identify all incident prostate cancer cases diagnosed. All newly diagnosed, prostate cancer cases unexposed to α1-adrenoreceptor antagonists in the total male VA population during this time period also were identified from the KCR’s database. Measures of disease incidence, relative risk, and attributable risk were calculated to compare the risk of developing prostate cancer for α1-blocker-exposed versus unexposed men. Kaplan Meier curves and Cox regression models were used to compare the overall survival between α1-blocker-exposed and unexposed prostate cancer cases. RESULTS Our analysis revealed a cumulative incidence of 1.65% among the α1-blocker-exposed men compared to 2.41% in the unexposed group. These data yield an unadjusted risk ratio of 0.683 (95% CI: 0.532, 0.876) and risk difference of −0.0076, which indicates that 7.6 fewer prostate cancer cases developed per 1000 exposed men. Exposure to

  3. Effects of α1-adrenoceptor antagonists on phenylephrine-induced salivary secretion and intraurethral pressure elevation in anesthetized rats.

    PubMed

    Yanai-Inamura, Hiroko; Ohtake, Akiyoshi; Noguchi, Yukiko; Hatanaka, Toshiki; Suzuki, Masanori; Ueshima, Koji; Sato, Shuichi; Sasamata, Masao

    2012-03-15

    α(1)-Adrenoceptor antagonists are widely used for the treatment of voiding dysfunction associated with benign prostatic hyperplasia. Activation of α(1)-adrenoceptors is reported to induce salivary secretion in rats and humans. However, the effects of α(1)-adrenoceptor antagonists on salivary secretion remain unknown. Here, we investigated the effects of the α(1)-adrenoceptor antagonists prazosin, silodosin, tamsulosin and urapidil on phenylephrine-induced salivary secretion and compared the results with the effects on phenylephrine-induced intraurethral pressure (IUP) elevation in anesthetized rats. All antagonists inhibited phenylephrine-induced salivary secretion and IUP elevation in a dose-dependent fashion. Comparison of DR(10) values (the dose required to shift the dose-response curve 10-fold to the right) in both tissues showed that the inhibitory effect of silodosin was significantly more potent in the salivary gland than in the urethra (18-fold), but tamsulosin (2.3-fold), prazosin (1.7-fold) and urapidil (1.1-fold) did not show comparable tissue selectivity. These results suggest that α(1)-adrenoceptor antagonists inhibit not only urethral contraction but also salivary secretion, and that high tissue selectivity for the salivary gland over the urethra as shown by silodosin may contribute to the incidence of dry mouth. PMID:22314219

  4. ATP is not involved in α1-adrenoceptor-mediated vasoconstriction in resistance arteries.

    PubMed

    Angus, James A; Wright, Christine E

    2015-12-15

    Recent publications suggest that α1-adrenoceptor stimulation by exogenous agonists such as phenylephrine in resistance arteries cause contraction through the release of ATP from within the vascular smooth muscle cells. This ATP exits the cell through pannexin-1 channels to act back "autocrine-like" on P2 receptors on the smooth muscle that cause the contraction. In this work we directly test this hypothesis by using a selective P2X1 purinoceptor antagonist NF449 (1-10µM) against phenylephrine and ATP concentration-response curves in small mesenteric arteries of the rat and thoracodorsal arteries of the mouse. We show that NF449 is a simple competitive antagonist of ATP with a pKB of 6.43 and 6.41 in rat and mouse arteries, respectively, but did not antagonise phenylephrine concentration-response curves. This work cautions against the growing overstated role of the reputed pannexin-1/ATP release axis following α1-adrenoceptor activation in small resistance arteries. PMID:26593428

  5. Functional characterization of α1-adrenoceptor subtypes in human skeletal muscle resistance arteries

    PubMed Central

    Jarajapu, Yagna P R; Coats, Paul; McGrath, John C; Hillier, Chris; MacDonald, Allan

    2001-01-01

    α1-adrenoceptor subtypes in human skeletal muscle resistance arteries were characterized using agonists noradrenaline (non-selective) and A61603 (α1A-selective), the antagonists prazosin (non-selective), 5-methyl-urapidil (α1A-selective) and BMY7378 (α1D-selective) and the alkylating agent chloroethylclonidine (preferential for α1B). Small arteries were obtained from the non-ischaemic skeletal muscle of limbs amputated for critical limb ischaemia and isometric tension recorded using wire myography. Prazosin antagonized responses to noradrenaline with a pA2 value of 9.18, consistent with the presence of α1-adrenoceptors, although the Schild slope (1.32) was significantly different from unity. 5-Methyl-urapidil competitively antagonized responses to noradrenaline with a pKB value of 8.48 and a Schild slope of 0.99, consistent with the presence of α1A-adrenoceptors. In the presence of 300 nM 5-methyl-urapidil, noradrenaline exhibited biphasic concentration response curves, indicating the presence of a minor population of a 5-methyl-urapidil-resistant subtype. Contractile responses to noradrenaline were not affected by 1 μM chloroethylclonidine suggesting the absence of α1B-adrenoceptors. Maximum responses to noradrenaline and A61603 were reduced to a similar extent by 10 μM chloroethylclonidine, suggesting an effect of chloroethylclonidine at α1A-adrenoceptors at the higher concentration. BMY7378 (10 and 100 nM) had no effect on responses to noradrenaline. BMY7378 (1 μM) poorly shifted the potency of noradrenaline giving a pA2 of 6.52. These results rule out the presence of the α1D-subtype. These results show that contractile responses to noradrenaline in human skeletal muscle resistance arteries are predominantly mediated by the α1A-adrenoceptor subtype with a minor population of an unknown α1-adrenoceptor subtype. PMID:11429392

  6. Characterization of the α1-adrenoceptor subtype mediating contractions of the pig internal anal sphincter

    PubMed Central

    Mills, K A; Hausman, N; Chess-Williams, R

    2008-01-01

    Background and purpose: The internal anal sphincter has been shown to contract in response to α1-adrenoceptor stimulation and therefore α1-adrenoceptor agonists may be useful in treating faecal incontinence. This study characterizes the α1-adrenoceptor subtype responsible for mediating contraction of the internal anal sphincter of the pig. Experimental approach: The potency of agonists and the affinities of several receptor subtype selective antagonists were determined on smooth muscle strips for the pig internal anal sphincter. Cumulative concentration–response curves were performed using phenylephrine and noradrenaline. Key results: The potency of the α1A-adrenoceptor selective agonist A61603 (pEC50=7.79±0.04) was 158-fold greater than that for noradrenaline (pEC50=5.59±0.02). Phenylephrine (pEC50=5.99±0.05) was 2.5-fold more potent than noradrenaline. The α1D-adrenoceptor selective antagonist BMY7378 caused rightward shifts of the concentration–response curves to phenylephrine and noradrenaline, yielding low affinity estimates of 6.59±0.15 and 6.33±0.13, respectively. Relatively high affinity estimates were obtained for the α1A-adrenoceptor selective antagonists, RS100329 (9.01±0.14 and 9.06±0.22 with phenylephrine and noradrenaline, respectively) and 5-methylurapidil (8.51±0.10 and 8.31±0.10, respectively). Prazosin antagonized responses of the sphincter to phenylephrine and noradrenaline, yielding mean affinity estimates of 8.58±0.10 and 8.15±0.08, respectively. The Schild slope for prazosin with phenylephrine was equal to unity (1.01±0.24), however the Schild slope using noradrenaline was significantly less than unity (0.50±0.11, P<0.05). Conclusion and implications: The results suggest that contraction of circular smooth muscle from the pig internal anal sphincter is mediated via a population of adrenoceptors with the pharmacological characteristics of the α1A/L-adrenoceptor, most probably the α1L-adrenoceptor form of this receptor

  7. Autoantibodies against β1-adrenoceptor induce blood glucose enhancement and insulin insufficient via T lymphocytes.

    PubMed

    Gong, Yulin; Xiong, Haiyan; Du, Yunhui; Wu, Ye; Zhang, Suli; Li, Xiao; Liu, Huirong

    2016-04-01

    Diabetes mellitus is a chronic metabolic disorder with a high morbidity and mortality, but its pathogenesis is not fully understood. An increasing amount of evidence indicates that an immune mechanism plays an important role in the pathogenesis of diabetes. We demonstrated previously that the long-term presence of autoantibodies against the second extracellular loop of the β1-adrenoceptor (β1-AA) could change the ratio of peripheral CD4+T/CD8+T in rats, which was accompanied by lymphocytes infiltration in the rat heart, liver, and kidneys. To investigate whether β1-AA is involved in the pathogenesis of diabetes, BALB/c or nude mice were passively immunized with monoclonal antibodies against β1-AR (β1-AR mAb). Compared with vehicle control mice, β1-AA-positive BALB/c mice exhibited significantly increased blood glucose (P < 0.01) and increased fasting insulin (P < 0.05). However, the same changes did not occur in the nude mice. And altered islet morphology was found at week 28 in β1-AA immunization group compared with vehicle control. The basal insulin level of NIT-1 β-cells was decreased markedly (P < 0.01), and the lactate dehydrogenase level was increased (P < 0.01) after the administration of conditioned media from T lymphocytes that had been treated with β1-AA alone. However, these effects were reversed by treatment with metoprolol or peptides of the second extracellular loop of β1-adrenoceptor (β1-AR-ECII). These results suggest that β1-AA could induce hyperglycemia in both rats and mice, and also impair insulin secretion and change islet structure. T lymphocytes may play a key role in the pathogenesis of these changes in the islets. PMID:26639354

  8. Reconstitution of beta 1-adrenoceptor-dependent adenylate cyclase from purified components.

    PubMed Central

    Feder, D; Im, M J; Klein, H W; Hekman, M; Holzhöfer, A; Dees, C; Levitzki, A; Helmreich, E J; Pfeuffer, T

    1986-01-01

    In continuation of our efforts to reconstitute from purified components into lipid vesicles the signal transmission chain from beta 1-adrenoceptors to adenylate cyclase, we now report on the total reconstitution of the hormone-dependent adenylate cyclase. In these reconstitution experiments we have employed the purified adenylate cyclase (C) from bovine brain and rabbit heart, the stimulatory GTP-binding protein (GS) purified from turkey erythrocytes and rabbit liver and the beta 1-adrenoceptor (R) from turkey erythrocytes. Several detergents were compared with respect to their suitability to allow reconstitution of subunits into phospholipid vesicles. While octyl-polyoxyethylene (octyl-POE) was almost as potent as lauroyl-sucrose for preparation of vesicles containing GS.C, the latter detergent was clearly superior for vesicles enabling productive R.GS and R.GS.C coupling. The catalytic subunit from either bovine brain or rabbit heart was equally efficient in reconstitution. However, GS from turkey erythrocytes and rabbit liver revealed significant differences in RGS and RGS.C containing vesicles. While isoproterenol-induced activation of GS by GTP gamma S was first order in both instances, kon with turkey GS was 0.12 min-1, whereas kon with rabbit liver GS was 0.6 min-1. Moreover, GTP gamma S activation of erythrocyte GS was significantly more dependent on the presence of hormone than that of liver GS, confirming observations made on the native membrane-bound system. Compared with stimulation by isoproterenol (GTP gamma S) (4-fold), stimulation by isoproterenol/GTP was modest (1.3- to 1.6-fold).(ABSTRACT TRUNCATED AT 250 WORDS) Images Fig. 1. PMID:3017696

  9. Detection of the secondary, low-affinity β1-adrenoceptor site in living cells using the fluorescent CGP 12177 derivative BODIPY-TMR-CGP

    PubMed Central

    Gherbi, K; Briddon, S J; Hill, S J

    2014-01-01

    Background and Purpose CGP 12177 not only inhibits agonist effects mediated through the catecholamine site of the β1-adrenoceptor with high affinity, but also exhibits agonist effects of its own at higher concentrations through a secondary, low-affinity β1-adrenoceptor site or conformation. β-blocker affinities for this ‘CGP 12177’ site of the human β1-adrenoceptor have thus far only been characterized in functional studies. Here, we used the fluorescent CGP 12177 analogue BODIPY-TMR-CGP to directly investigate receptor–ligand interactions at the secondary binding site of the β1-adrenoceptor. Experimental Approach The human β1-adrenoceptor was stably expressed in CHO cells containing a cAMP response element (CRE)-secreted placental alkaline phosphatase (SPAP) reporter gene construct. Functional responses of BODIPY-TMR-CGP were determined in the CRE-SPAP reporter gene assay, and manual and automated confocal microscopy platforms used to investigate the binding properties of BODIPY-TMR-CGP. Key Results BODIPY-TMR-CGP displayed a pharmacological profile similar to that of CGP 12177, retaining agonist activity at the secondary β1-adrenoceptor site. In confocal microscopy studies, specific BODIPY-TMR-CGP binding allowed clear visualization of β1-adrenoceptors in live cells. Using a wider concentration range of labelled ligand in a high-content fluorescence-based binding assay than is possible in radioligand binding assays, two-site inhibition binding curves of β-adrenoceptor antagonists were revealed in CHO cells expressing the human β1-adrenoceptor, but not the β2-adrenoceptor. Conclusions and Implications The fluorescent CGP 12177 analogue allowed the detection of the β1-adrenoceptor secondary site in both functional and binding studies. This suggests that BODIPY-TMR-CGP presents an important and novel fluorescent tool to investigate the nature of the secondary β1-adrenoceptor site. PMID:25052258

  10. α1-Adrenoceptors and muscarinic receptors in voiding function – binding characteristics of therapeutic agents in relation to the pharmacokinetics

    PubMed Central

    Yamada, Shizuo; Ito, Yoshihiko; Tsukada, Hideo

    2011-01-01

    In vivo and ex vivo binding of α1-adrenoceptor and muscarinic receptors involved in voiding function is reviewed with therapeutic agents (α1-adrenoceptor antagonists: prazosin, tamsulosin and silodosin; and muscarinic receptor antagonists: oxybutynin, tolterodine, solifenacin, propiverine, imiafenacin and darifenacin) in lower urinary tract symptoms. This approach allows estimation of the inhibition of a well-characterized selective (standard) radioligand by unlabelled potential drugs or direct measurement of the distribution and receptor binding of a standard radioligand or radiolabelled form of a novel drug. In fact, these studies could be conducted in various tissues from animals pretreated with radioligands and/or unlabelled novel drugs, by conventional radioligand binding assay, radioactivity measurement, autoradiography and positron emission tomography. In vivo and ex vivo receptor binding with α1-adrenoceptor antagonists and muscarinic receptor antagonists have been proved to be useful in predicting the potency, organ selectivity and duration of action of drugs in relation to their pharmacokinetics. Such evaluations of drug–receptor binding reveal that adverse effects could be avoided by the use of new α1-adrenoceptor antagonists and muscarinic receptor antagonists for the treatment of lower urinary tract symptoms. Thus, the comparative analysis of α1-adrenoceptor and muscarinic receptor binding characteristics in the lower urinary tract and other tissues after systemic administration of therapeutic agents allows the rationale for their pharmacological characteristics from the integrated viewpoint of pharmacokinetics and pharmacodynamics. The current review emphasizes the usefulness of in vivo and ex vivo receptor binding in the discovery and development of novel drugs for the treatment of not only urinary dysfunction but also other disorders. PMID:21265873

  11. Stimulation of α1-adrenoceptors facilitates GABAergic transmission onto pyramidal neurons in the medial prefrontal cortex.

    PubMed

    Luo, F; Tang, H; Cheng, Z-Y

    2015-08-01

    Whereas activation of α1-adrenoceptors (α1-ARs) modulates glutamatergic transmission, the roles of α1-ARs in GABAergic transmission in the medial prefrontal cortex (mPFC) are elusive. Here, we examined the effects of the α1-AR agonist phenylephrine (Phe) on GABAergic transmission onto pyramidal neurons in the deep layers of the mPFC. We found that bath application of Phe dose-dependently increased the amplitude of evoked IPSCs (eIPSCs). Phe increased the frequency but not the amplitude of miniature IPSCs (mIPSCs). Ca(2+) influx through T-type voltage-gated calcium channels is required for Phe-induced increases in GABA release. Phe increases GABA release probability and the number of releasable vesicles. Phe depolarizes the fast-spiking (FS) interneurons without effects on the firing rate of action potentials (APs) of interneurons. Phe-induced depolarization is independent of extracellular Na(+), Ca(2+) and T-type calcium channels, but requires inward rectifier K(+) channels (Kirs). The present study demonstrates that Phe enhances GABAergic transmission onto mPFC pyramidal neurons through inhibiting interneurons Kirs, which further depolarizes interneurons leading to increase in Ca(2+) influx via T-type calcium channels. Our results may provide a cellular and molecular mechanism that helps explain α1-AR-induced PFC dysfunction. PMID:25943480

  12. Marked behavioral activation from inhibitory stimulation of locus coeruleus α1-adrenoceptors by a full agonist

    PubMed Central

    Stone, Eric A.; Lin, Yan; Sarfraz, Yasmeen; Quartermain, David

    2009-01-01

    α1-Adrenoceptors are concentrated in the locus coeruleus (LC) where they appear to regulate various active behaviors but have been difficult to stimulate effectively. The present study examined the behavioral, pharmacological and neural effects of possible stimulation of these receptors with 6-fluoronorepinephrine (6FNE), the only known selective α-agonist that has full efficacy at all brain α-receptors. Infusion of this compound in the mouse LC was found to produce extreme activation of diverse motivated behaviors of exploration, wheel running and operant approach responding in different environments consistent with a global behavioral function of the dorsal noradrenergic system. Infusion of selective antagonists of α1- (terazosin) or α2-(atipamezole) receptors or of either the partial α1-agonist, phenylephrine, or full α2-agonist, dexmedetomidine, indicated that the behavioral effects of 6FNE were due largely due to activation of LC α1-receptors consistent with the known greater density of α1-than α2-adrenoreceptors in the mouse nucleus. Immunohistochemistry of fos in tyrosine hydroxylase-positive LC neurons following IV ventricular infusions indicated that 6FNE markedly depressed whereas terazosin strongly enhanced the apparent functional activity of the nucleus. The changes in fos expression following 6FNE and terazosin were significantly greater than those following dexmedetomidine and atipamezole. It is hypothesized that the α1-receptors of the mouse LC are strongly activated by 6FNE and serve to potently inhibit its tonic or stress-induced activity which in turn disinhibits prepotent motivated behaviors. PMID:19632210

  13. Rayleigh light scattering detection of three α1-adrenoceptor antagonists coupled with high performance liquid chromatograph

    NASA Astrophysics Data System (ADS)

    Li, Ai Ping; Peng, Huanjun; Peng, Jing Dong; Zhou, Ming Qiong; Zhang, Jing

    2015-08-01

    Herein, a Rayleigh light-scattering (RLS) detection method combined with high performance liquid chromatograph (HPLC) without any post-column probe was developed for the separation and determination of three α1-adrenoceptor antagonists. The quantitative analysis is benefiting from RLS signal enhancement upon addition of methanol which induced molecular aggregation to form an hydrophobic interface between aggregates and water that produce a sort of superficial enhanced scattering effect. A good chromatographic separation among the compounds was achieved using a Gemini 5u C18 reversed phase column (250 mm × 4.6 mm; 4 μm) with a mobile phase consisting of methanol and ammonium acetate-formic acid buffer solution (25 mM; pH = 3.0) at the flow rate of 0.7 mL min-1. The RLS signal was monitored at λex = λem = 354 nm. A limit of detection (LOD) of 0.065-0.70 μg L-1 was reached and a linear range was found between peak height and concentration in the range of 0.75-15 μg L-1 for doxazosin mesylate (DOX), 0.075-3.0 μg L-1 for prazosin hydrochloride (PRH), and 0.25-5 μg L-1 for terazosin hydrochloride (TEH), with linear regression coefficients all above 0.999. Recoveries from spiked urine samples were 88.4-99.0% which is within acceptable limits. The proposed method is convenient, reliable and sensitive which has been used successfully in human urine samples.

  14. Pannexin-1 channels do not regulate α1-adrenoceptor-mediated vasoconstriction in resistance arteries.

    PubMed

    Angus, James A; Betrie, Ashenafi H; Wright, Christine E

    2015-03-01

    Recent reports have provided evidence for a new concept that in small resistance arteries α1D-adrenoceptor-mediated contraction is intimately linked to pannexin-1 (Px1) hemichannels that open to allow the release of ATP, from the smooth muscle effector cell, that acts back on P2Y purinoceptors to cause contraction. This concept mainly relied on using mefloquine 10-20μM as a putative selective Px1 channel-blocking agent to completely inhibit the contraction to phenylephrine, but not K(+) 40mM. Lower concentrations of mefloquine had no effect. The purpose of the present study was to explore the specificity of mefloquine for Px1 channels and the role of these channels in small artery contraction. In mouse and rat isolated small resistance arteries, either pressurised or set up for wire myography, the effects of mefloquine on contractions to K(+), phenylephrine and a range of vasoconstrictor agents were assessed and compared with the Px1 channel inhibitor carbenoxolone. Mefloquine had a wide range of inhibitory actions at 10-20μM, some 200-fold above the concentrations previously shown to inhibit expressed Px1 channel activity. Mefloquine 3-10μM inhibited phenylephrine, U46619, vasopressin, endothelin-1, sympathetic nerve stimulation and K(+) 40mM-mediated contractions in rat and mouse small mesenteric, and mouse thoracodorsal, arteries. Carbenoxolone 1-100μM did not inhibit the contractile responses to these agents in small resistance arteries. The present study demonstrates that in small resistance arteries there is no evidence that Px1 channels releasing ATP have any role in the constrictor actions of α1-adrenoceptor activation. PMID:25637780

  15. Proliferation in cardiac fibroblasts induced by β1-adrenoceptor autoantibody and the underlying mechanisms

    PubMed Central

    Lv, Tingting; Du, Yunhui; Cao, Ning; Zhang, Suli; Gong, Yulin; Bai, Yan; Wang, Wen; Liu, Huirong

    2016-01-01

    Chronic sustained stimulation of β-adrenoceptor is closely related to cardiac fibrosis which is bad for cardiac function. Growing evidence showed that the high prevalence of β1-adrenoceptor autoantibody (β1-AA) in the sera of patients with various types of cardiovascular diseases decreased cardiac function. In the current study, we demonstrated that β1-AA impaired the cardiac function evaluated by echocardiography and that β1-AA triggered cardiac fibrosis in terms of increased expression of α-smooth muscle actin as the marker of myofibroblast and collagen deposition in a passive β1-AA immunized mice model during 16 weeks. Further, we showed that β1-AA activated β1-AR/cAMP/PKA pathway and promoted proliferation in primary cardiac fibroblasts through specific binding to β1-AR but not to β2-AR. Moreover, β1-AA was also likely to promote proliferation in cardiac fibroblasts through activating p38MAPK and ERK1/2 as p38MAPK inhibitor SB203580 and ERK1/2 inhibitor PD98059 partially reversed the proliferative effect. The persistent activating signalling of PKA and P38MAPK in 1 h induced by β1-AA was associated with lacking agonist-induced desensitization phenomena. The conditioned medium from β1-AA-stimulated cardiac fibroblasts induced cardiomyocyte apoptosis, which indicated that β1-AA changed the secretion of cardiac fibroblasts contributing to cardiac injury. These findings will contribute to our understanding of the pathological mechanisms of β1-AA. PMID:27577254

  16. Proliferation in cardiac fibroblasts induced by β1-adrenoceptor autoantibody and the underlying mechanisms.

    PubMed

    Lv, Tingting; Du, Yunhui; Cao, Ning; Zhang, Suli; Gong, Yulin; Bai, Yan; Wang, Wen; Liu, Huirong

    2016-01-01

    Chronic sustained stimulation of β-adrenoceptor is closely related to cardiac fibrosis which is bad for cardiac function. Growing evidence showed that the high prevalence of β1-adrenoceptor autoantibody (β1-AA) in the sera of patients with various types of cardiovascular diseases decreased cardiac function. In the current study, we demonstrated that β1-AA impaired the cardiac function evaluated by echocardiography and that β1-AA triggered cardiac fibrosis in terms of increased expression of α-smooth muscle actin as the marker of myofibroblast and collagen deposition in a passive β1-AA immunized mice model during 16 weeks. Further, we showed that β1-AA activated β1-AR/cAMP/PKA pathway and promoted proliferation in primary cardiac fibroblasts through specific binding to β1-AR but not to β2-AR. Moreover, β1-AA was also likely to promote proliferation in cardiac fibroblasts through activating p38MAPK and ERK1/2 as p38MAPK inhibitor SB203580 and ERK1/2 inhibitor PD98059 partially reversed the proliferative effect. The persistent activating signalling of PKA and P38MAPK in 1 h induced by β1-AA was associated with lacking agonist-induced desensitization phenomena. The conditioned medium from β1-AA-stimulated cardiac fibroblasts induced cardiomyocyte apoptosis, which indicated that β1-AA changed the secretion of cardiac fibroblasts contributing to cardiac injury. These findings will contribute to our understanding of the pathological mechanisms of β1-AA. PMID:27577254

  17. Alpha 1D- and alpha 1A-adrenoceptors mediate contraction in rat renal artery.

    PubMed

    Villalobos-Molina, R; López-Guerrero, J J; Ibarra, M

    1997-03-19

    To investigate the alpha 1-adrenoceptor subtype(s) mediating contraction in rat renal artery, we have compared the effect of the alpha 1-adrenoceptor antagonists, 5-methylurapidil, BMY 7378 (8-(2-(4-(2-methoxyphenyl)-1-piperazinyl) ethyl) 8-azaspiro (4.5) decane-7,9-dione 2HCl) and chloroethylclonidine on functional responses to noradrenaline. A clear blockade by chloroethylclonidine (10(-4) M) of noradrenaline-induced contraction was observed and, along with this effect. pKB values of 9.12 and 8.40 for BMY 7378 and 9.75 and 10.06 for 5-methylurapidil were obtained, indicating that the renal artery expresses the alpha 1D-adrenoceptor subtype as the one involved in contraction and not only the alpha 1A subtype as has been reported. PMID:9098691

  18. Existence of different α1-adrenoceptor subtypes in junctional and extrajunctional neurovascular regions in canine splenic arteries

    PubMed Central

    Yang, Xiao-Ping; Chiba, Shigetoshi

    2001-01-01

    The present study attempted to characterize the α1-adrenoceptor subtypes mediating vasoconstrictor responses to administered and nerve stimulation-evoked noradrenaline (NA) release in the isolated and perfused canine splenic artery.A previous study demonstrated that periarterial electrical nerve stimulation (30 s trains of pulses at a frequency of 1, 4 or 10 Hz) induced a double peaked vasoconstriction consisting of an initial transient, predominantly P2X-purinoceptor-mediated constriction followed by a prolonged, mainly α1-adrenoceptor-mediated response in the canine splenic artery.The effects of α1-adrenoceptor subtype antagonists on neuronally-mediated second peaked vasoconstrictions were analysed. BMY 7378 (10 – 100 nM), a selective α1D-adrenoceptor antagonist produced a dose-dependent inhibition of the second peak responses at all frequencies used. BMY 7378 (100 nM) reduced these responses by approximately 30%. Exposure of tissues to chloroethylclonidine (CEC, 60 μM), a selective α1B-adrenoceptor antagonist attenuated the second peak response by approximately 60%, even in the presence of BMY 7378 (100 nM). On the other hand, WB 4101 (100 nM), a selective α1A-adrenoceptor antagonist potentiated nerve-stimulation-evoked double peaked vasoconstrictions, especially at low frequencies (1 and 4 Hz).Vasoconstrictor responses to administered NA were dose-dependently antagonized by WB 4101 (10 – 100 nM), but were not significantly affected by either BMY 7378 (10 – 100 nM) or by CEC (60 μM).The present results indicate that NA released from sympathetic nerves may junctionally exert its vasoconstrictor effect via activation of postjunctional α1B- and in part α1D-adrenoceptors, whereas exogenous NA extrajunctionally activates α1A-adrenoceptors to produce its vascular action in canine splenic arteries. PMID:11309258

  19. Relevance of anaesthesia for dofetilide-induced torsades de pointes in α1-adrenoceptor-stimulated rabbits

    PubMed Central

    Vincze, D; Farkas, A S; Rudas, L; Makra, P; Csík, N; Leprán, I; Forster, T; Csanády, M; Papp, J G; Varró, A; Farkas, A

    2007-01-01

    Background and purpose: No information is available concerning the effects of anaesthetics in the most frequently used in vivo pro-arrhythmia model. Accordingly, in this study we examined the effect of pentobarbital, propofol or α-chloralose anaesthesia on the pro-arrhythmic activity of the class III anti-arrhythmic dofetilide in α1-adrenoceptor-stimulated rabbits. Experimental approach: Rabbits anaesthetized intravenously with pentobarbital, propofol or α-chloralose were infused simultaneously with the α1-adrenoceptor agonist phenylephrine (15 μg kg−1 min−1, i.v.) and dofetilide (0.04 mg kg−1 min−1, i.v.). The electrocardiographic QT interval, the T peak–T end interval and certain QT variability parameters were measured. The heart rate variability and the baroreflex sensitivity were utilized to assess the vagal nerve activity. The spectral power of the systolic arterial pressure was calculated in the frequency range 0.15–0.5 Hz to assess the sympathetic activity. Key results: Pentobarbital considerably reduced, whereas propofol did not significantly affect the incidence of dofetilide-induced torsades de pointes (TdP) as compared with the results with α-chloralose (40% (P=0.011) and 70% (P=0.211) vs 100%, respectively). In additional experiments, neither doubling of the rate of the dofetilide infusion nor tripling of the rate of phenylephrine infusion elevated the incidence of TdP to the level seen with α-chloralose. None of the repolarization-related parameters predicted TdP. The indices of the parasympathetic and sympathetic activity were significantly depressed in the α-chloralose and propofol anaesthesia groups. Conclusions and implications: In rabbits, anaesthetics may affect drug-induced TdP genesis differently, which must be considered when results of different studies are compared. PMID:17965737

  20. Characterization of central alpha-adrenoceptors using /sup 3/H-clonidine and its derivatives

    SciTech Connect

    Jarrott, B.; Louis, W.J.; Summers, R.J.

    1983-02-01

    alpha-Adrenoceptors in brain can be studied readily by radioligand binding techniques. This provides valuable information not only on the distribution of receptors in brain regions, but also on the regulation of receptors. The usefulness of this technique is dependent in part on a radioligand with high specificity for the receptor under study. Researchers' studies have shown that /sup 3/H-clonidine does not bind exclusively to alpha 2-adrenoceptor subtypes, but also interacts with alpha 1-adrenoceptors. In contrast, /sup 3/H-guanfacine labels a high affinity alpha 2 subtype with good selectivity, but /sup 3/H-lofexidine probably labels with both alpha 2 and alpha 1-adrenoceptor binding sites.

  1. Demonstration of. beta. /sub 1/-adrenoceptor mediating relaxation of porcine coronary artery by radioligand binding and pharmacological methods

    SciTech Connect

    Yamada, S.; Kashiwabara, T.; Yamazawa, T.; Harada, Y.; Nakayama, K.

    1988-01-01

    ..beta..-adrenoceptors in the porcine coronary artery were characterized by a radioligand binding assay using (-)-(/sup 3/H)dihydroalprenolol (DHA) and also by measuring the relaxant response of isolated coronary artery to norepinephrine. Specific (-)-(/sup 3/H)DHA binding in the porcine coronary artery was saturable, reversible and of high affinity with a maximal number of binding sites of 63 fmol/mg protein, and it showed a pharmacological specificity as well as stereoselectivity which characterized ..beta..-adrenoceptors. The Hofstee analysis of inhibition of (-)-(/sup 3/H)DHA binding by atenolol, practolol and ICI 118551 has shown that the averaged concentration of ..beta../sub 1/ and ..beta../sub 2/-adrenoceptors in this tissue was 68% and 32% respectively. The relaxant response of isolated coronary artery to norepinephrine was competitively antagonized by (-)propranolol, (+)propranolol, atenolol, practolol and ICI 118551. The pA/sub 2/ values of these adrenoceptor antagonists were significantly correlated with the Ki values for ..beta../sub 1/ but not ..beta../sub 2/-adrenoceptors determined by the (-)-(/sup 3/H)DHA binding assay. Thus, the present study demonstrates that the relaxant response of porcine coronary artery to norepinephrine is predominantly mediated through the stimulation of ..beta../sub 1/-adrenoceptors on vascular smooth muscles.

  2. Neuroprotective effects of selective β-1 adrenoceptor antagonists, landiolol and esmolol, on transient forebrain ischemia in rats; a dose-response study.

    PubMed

    Goyagi, Toru; Horiguchi, Takashi; Nishikawa, Toshiaki; Tobe, Yoshitsugu; Masaki, Yoko

    2012-06-21

    Although selective beta-1 adrenoceptor antagonists are known to provide neuroprotective effects after brain ischemia, dose-response relationships of their neuroprotective effects have not been examined. The present study was conducted to evaluate whether the degree of brain protection against transient forebrain ischemia would be influenced by different doses of selective beta-1 adrenoceptor antagonists, esmolol and landiolol, in rats. Adult male S.D. rats received intravenous infusion of saline 0.5 ml/h, esmolol 20, 200, 2,000 μg/kg/min, or landiolol 5, 50, 500 μg/kg/min. Infusion was initiated 30 min prior to ischemia and continued for 24h. Ten-minute forebrain ischemia was induced by hemorrhagic hypotension and occlusion of the bilateral carotid arteries. Neurological and histological examinations were performed. Neurological deficit scores at 1, 4 and 7 days were lower, and the number of intact neurons in CA1 hippocampal region was larger in the rats treated with esmolol and landiolol after ischemia, compared with saline-treated rats (P<0.05), whereas no difference was found among different doses of esmolol and landiolol. These results suggested that selective beta-1 adrenoceptor antagonists improved neurological and histological outcomes following forebrain ischemia in rats, irrespective of their doses. PMID:22583856

  3. Alpha adrenoceptor subtypes involved in the emetic action in dogs.

    PubMed

    Hikasa, Y; Ogasawara, S; Takase, K

    1992-05-01

    In order to assess the involvement of alpha-1 and alpha-2 adrenoceptors in emesis, the emetic effect of eight alpha agonists was studied in dogs. The i.m. administration of each agonist elicited dose-dependent emesis. The order of potency in inducing emesis was: clonidine greater than oxymetazoline greater than tramazoline greater than naphazoline greater than xylazine greater than epinephrine greater than methoxamine = phenylephrine. The clonidine-induced emesis was antagonized by adrenoceptor antagonists showing alpha-2 blocking activity, yohimbine, tolazoline and phentolamine. Among these antagonists, yohimbine was the most effective. The alpha-1 and beta adrenergic, cholinergic, dopaminergic, histaminergic, serotonergic and opioid receptor antagonists did not prevent the clonidine-induced emesis. The emesis induced by oxymetazoline, tramazoline, xylazine, naphazoline and epinephrine was also antagonized by a selective alpha-2 adrenoceptor antagonist, yohimbine, but not by a selective alpha-1 adrenoceptor antagonist, prazosin. In contrast, methoxamine and phenylephrine-induced emesis was antagonized by prazosin, but not by yohimbine. Neither yohimbine nor prazosin prevented the morphine- and histamine-induced emesis. These results indicate that alpha-2 adrenoceptors are involved in the mediation of emetic action, and that the alpha adrenoceptor-mediated emesis does not involve beta adrenergic, cholinergic, dopaminergic, histaminergic, serotonergic and opioid receptors in the emetic pathway. This study further suggests that alpha adrenoceptors involved in the emesis are mainly of the alpha-2 type, although the involvement of alpha-1 adrenoceptors cannot be ruled out. PMID:1349647

  4. Ectopic activity in the rat pulmonary vein can arise from simultaneous activation of α1- and β1-adrenoceptors

    PubMed Central

    Maupoil, V; Bronquard, C; Freslon, J-L; Cosnay, P; Findlay, I

    2007-01-01

    Background and purpose: Atrial fibrillation (AF) is the most common electrical cardiac disorder in clinical practice. The major trigger for AF is focal ectopic activity of unknown origin in sleeves of cardiac muscle that extend into the pulmonary veins. We examined the role of noradrenaline in the genesis of ectopic activity in the pulmonary vein. Experimental approach: Mechanical activity of strips of pulmonary vein isolated from male Wistar rats was recorded via an isometric tension meter. Twitch contractions of cardiac myocytes were evoked by electrical field stimulation in a tissue bath through which flowed Krebs-Heinseleit solution warmed to 36-37°C and gassed with 95% O2 5% CO2. Key results: The superfusion of noradrenaline induced ectopic contractions in 71 of 76 different isolated pulmonary veins. Ectopic contractions in the pulmonary vein were not associated with electrically evoked twitch contractions. The effect of noradrenaline on the pulmonary vein could be replicated by the simultaneous, but not separate, application of the α adrenoceptor agonist phenylephrine and the β adrenoceptor agonist isoprenaline. The use of selective agonists and antagonists for adrenoceptor subtypes showed that ectopic activity in the pulmonary vein arose from the simultaneous stimulation of α1 and β1 adrenoceptors. The application of noradrenaline to isolated strips of left atrium did not induce ectopic contractions (n=10). Conclusions: These findings suggest an origin for ectopic activity in the pulmonary vein that requires activation of both α and β adrenoceptors. They also open new perspectives towards our understanding of the triggering of AF. PMID:17325650

  5. Functional characterization of α1-adrenoceptor subtypes in vascular tissues using different experimental approaches:a comparative study

    PubMed Central

    Gisbert, Regina; Madrero, Yolanda; Sabino, Valentina; Noguera, M Antonia; Ivorra, M Dolores; D'Ocon, Pilar

    2003-01-01

    The α1-adrenergic responses of rat aorta and tail artery have been analysed measuring the contractility and the inositol phosphate (IP) formation induced by noradrenaline. Three antagonists, prazosin, 5-methylurapidil (α1A selective) and BMY 7378 (α1D selective) have been used in different experimental procedures. Noradrenaline possesses a greater potency inducing contraction and IP accumulation in aorta (pEC50-contraction=7.32±0.04; pEC50-IPs=6.03±0.08) than in the tail artery (pEC50-contraction=5.71±0.07; pEC50-IPs=5.51±0.10). Although the maximum contraction was similar in both tissues (Emax-tail=619.1±55.6 mg; Emax-aorta-698.2±40.8 mg), there were marked differences in the ability of these tissues to generate intracellular second messengers the tail artery being more efficient (Emax-tail=1060±147%; Emax-aorta=108.1±16.9%). Concentration response curves of noradrenaline in presence of antagonist together with concentration inhibition curves for antagonists added before (CICb) or after (CICa) noradrenaline-induced maximal response in Ca2+-containing or Ca2+-free medium have been performed. A comparative analysis of the different procedures as well as the mathematical approaches used in each case to calculate the antagonist potencies, were completed. The CICa was the simplest method to characterize the predominant α1-adrenoceptor subtype involved in the functional response of a tissue. In aorta, where constitutively active α1D-adrenoeptors are present, the use of different experimental procedures evidenced a complex equilibrium between α1D- and α1A-adrenoceptor subtypes. The appropriate management of LiCl in IP accumulation studies allowed us to reproduce the different experimental procedures performed in contractile experiments giving more technical possibilities to this methodology. PMID:12540527

  6. The α1 adrenoceptor antagonist prazosin enhances sleep continuity in fear-conditioned Wistar-Kyoto rats

    PubMed Central

    Laitman, Benjamin M.; Gajewski, Nicholas D.; Mann, Graziella L.; Kubin, Leszek; Morrison, Adrian R.; Ross, Richard J.

    2014-01-01

    Fragmentation of rapid eye movement sleep (REMS) is well described in individuals with posttraumatic stress disorder (PTSD) and likely has significant functional consequences. Fear-conditioned rodents may offer an attractive model of the changes in sleep that characterize PTSD. Following fear conditioning (FC), Wistar-Kyoto (WKY) rats, a strain known to be particularly stress-sensitive, have increased REMS fragmentation that can be quantified as a shift in the distribution of REMS episodes towards the more frequent occurrence of sequential REMS (inter-REMS episode interval ≤ 3 min) vs. single REMS (interval > 3 min). The α1 adrenoceptor antagonist prazosin has demonstrated efficacy in normalizing sleep in PTSD. To determine the utility of fear-conditioned WKY rats as a model of sleep disturbances typical of PTSD and as a platform for the development of new treatments, we tested the hypothesis that prazosin would reduce REMS fragmentation in fear-conditioned WKY rats. Sleep parameters and freezing (a standard measure of anxiety in rodents) were quantified at baseline and on days 1, 7, and 14 following FC, with either prazosin (0.01 mg/kg, i.p.) or vehicle injections administered prior to testing in a between-group design. Fear conditioning was achieved by pairing tones with a mild electric foot shock (1.0 mA, 0.5 s). One, 7, and 14 days following FC, prazosin or vehicle was injected, the tone was presented, freezing was measured, and then sleep was recorded from 11 AM to 3 PM. WKY rats given prazosin, compared to those given vehicle, had a lower amount of seq-REMS relative to total REMS time 14 days after FC. They also had a shorter non-REMS latency and fewer non-REMS arousals at baseline and on days 1 and 7 after FC. Thus, in FC rats, prazosin reduced both REMS fragmentation and non-REMS discontinuity. PMID:24246572

  7. Chronic activation of the low affinity site of β1-adrenoceptors stimulates haemodynamics but exacerbates pressure-overload cardiac remodelling

    PubMed Central

    Kiriazis, Helen; Tugiono, Niquita; Xu, Qi; Gao, Xiao-Ming; Jennings, Nicole L; Ming, Ziqui; Su, Yidan; Klenowski, Paul; Summers, Roger J; Kaumann, Alberto; Molenaar, Peter; Du, Xiao-Jun

    2013-01-01

    BACKGROUND AND PURPOSE The β1-adrenoceptor has at least two binding sites, high and low affinity sites (β1H and β1L, respectively), which mediate cardiostimulation. While β1H-adrenoceptor can be blocked by all clinically used β-blockers, β1L-adrenoceptor is relatively resistant to blockade. Thus, chronic β1L-adrenoceptor activation may mediate persistent cardiostimulation, despite the concurrent blockade of β1H-adrenoceptors. Hence, it is important to determine the potential significance of β1L-adrenoceptors in vivo, particularly in pathological situations. EXPERIMENTAL APPROACH C57Bl/6 male mice were used. Chronic (4 or 8 weeks) β1L-adrenoceptor activation was achieved by treatment, via osmotic mini pumps, with (-)-CGP12177 (10 mg·kg−1·day−1). Cardiac function was assessed by echocardiography and micromanometry. KEY RESULTS (-)-CGP12177 treatment of healthy mice increased heart rate and left ventricular (LV) contractility. (-)-CGP12177 treatment of mice subjected to transverse aorta constriction (TAC), during weeks 4–8 or 4–12 after TAC, led to a positive inotropic effect and exacerbated fibrogenic signalling while cardiac hypertrophy tended to be more severe. (-)-CGP12177 treatment of mice with TAC also exacerbated the myocardial expression of hypertrophic, fibrogenic and inflammatory genes compared to untreated TAC mice. Washout of (-)-CGP12177 revealed a more pronounced cardiac dysfunction after 12 weeks of TAC. CONCLUSIONS AND IMPLICATIONS β1L-adrenoceptor activation provides functional support to the heart, in both normal and pathological (pressure overload) situations. Sustained β1L-adrenoceptor activation in the diseased heart exacerbates LV remodelling and therefore may promote disease progression from compensatory hypertrophy to heart failure. PMID:23750586

  8. Evidence for an age-dependent functional expression of alpha 1D-adrenoceptors in the rat vasculature.

    PubMed

    Ibarra, M; Terrón, J A; López-Guerrero, J J; Villalobos-Molina, R

    1997-03-19

    The role of the alpha 1-adrenoceptor subtypes, and their possible change with maturation, in alpha 1-adrenoceptor-induced pressor responses in the rat has not been established. Thus, the effects of the alpha 1D-, alpha 1A/1D- and alpha 1B/1D-adrenoceptor antagonists, BMY 7378 (8-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl) 8-azaspiro (4.5) decane-7,9-dione 2HCl), 5-methyl-urapidil and chloroethylclonidine, respectively, on the pressor responses induced by phenylephrine in 1- and 5-month-old pithed rats were investigated. The pressor responses induced by phenylephrine were competitively antagonized by both BMY 7378 and chloroethylclonidine in 5-month-old, but not in young immature animals; in marked contrast, 5-methylurapidil antagonized with similar potency the phenylephrine-induced pressor responses in animals of both ages. The present pharmacological data suggest that functional expression of alpha 1D-adrenoceptors in the rat resistance vessels increases with age; alpha 1A-, but not alpha 1B- or alpha 1D-adrenoceptors, seem to predominate in immature animals. These findings represent the first evidence that age-related changes in functional alpha 1-adrenoceptor subtypes occur in the systemic vasculature in vivo. PMID:9098690

  9. Basal activity of voltage-gated Ca(2+) channels controls the IP3-mediated contraction by α(1)-adrenoceptor stimulation of mouse aorta segments.

    PubMed

    Leloup, Arthur J; Van Hove, Cor E; De Meyer, Guido R Y; Schrijvers, Dorien M; Fransen, Paul

    2015-08-01

    α1-Adrenoceptor stimulation of mouse aorta causes intracellular Ca(2+) release from sarcoplasmic reticulum Ca(2+) stores via stimulation of inositoltriphosphate (IP3) receptors. It is hypothesized that this Ca(2+) release from the contractile and IP3-sensitive Ca(2+) store is under the continuous dynamic control of time-independent basal Ca(2+) influx via L-type voltage-gated Ca(2+) channels (LCC) residing in their window voltage range. Mouse aortic segments were α1-adrenoceptor stimulated with phenylephrine in the absence of external Ca(2+) (0Ca) to measure phasic isometric contractions. They gradually decreased with time in 0Ca, were inhibited with 2-aminoethoxydiphenyl borate, and declined with previous membrane potential hyperpolarization (levcromakalim) or with previous inhibition of LCC (diltiazem). Former basal stimulation of LCC with depolarization (15 mM K(+)) or with BAY K8644 increased the subsequent phasic contractions by phenylephrine in 0Ca. Although exogenous NO (diethylamine NONOate) reduced the phasic contractions by phenylephrine, stimulation of endothelial cells with acetylcholine in 0Ca failed to attenuate these phasic contractions. Finally, inhibition of the basal release of NO with N(Ω)-nitro-L-arginine methyl ester also attenuated the phasic contractions by phenylephrine. Results indicated that α1-adrenoceptor stimulation with phenylephrine causes phasic contractions, which are controlled by basal LCC and endothelial NO synthase activity. Endothelial NO release by acetylcholine was absent in 0Ca. Given the growing interest in the active regulation of arterial compliance, the dependence of contractile SR Ca(2+) store-refilling in basal conditions on the activity of LCC and basal eNOS may contribute to a more thorough understanding of physiological mechanisms leading to arterial stiffness. PMID:25913240

  10. Alpha1L-adrenoceptors mediate contractions of the isolated mouse prostate.

    PubMed

    Gray, Katherine T; Ventura, Sabatino

    2006-07-01

    The subtype of alpha1-adrenoceptor mediating noradrenaline-induced contractile responses in isolated mouse prostate glands was investigated. Adrenoceptor agonists were able to produce concentration-dependent contractions with the following rank order of potency: adrenaline > or = noradrenaline > or = clonidine = phenylephrine > dopamine > or = isoprenaline. Concentration-response curves to noradrenaline of the prostatic smooth muscle were antagonised by prazosin, N-[2-(2-cyclopropylmethoxyphenoxy)ethyl]-5-chloro-alpha, alpha-dimethyl-1H-indole-3-ethanamine (RS-17053), 2-(2,6-dimethoxyphenoxyethyl)aminomethyl-1,4-benzodioxane (WB 4101), tamsulosin and yohimbine with mean antagonist affinity estimates (pA2 or apparent pKB) of 8.12+/-0.10, 6.56+/-0.11, 8.38+/-0.06, 10.14+/-0.19 and 7.38+/-1.36 respectively. Propranolol (1 microM) had no antagonist activity (P = 0.994, n = 6). Yohimbine (0.01, 0.1, 1 microM) had no antagonist activity in the presence of prazosin (0.1 microM) (P > or = 0.059). The results obtained indicate that alpha1-adrenoceptors mediate the contractile response in isolated preparations of the mouse prostate. Furthermore, the particular subtype of alpha1-adrenoceptor mediating the response to exogenously administered noradrenaline corresponds to the alpha1L-subtype, the same subtype as that which has been shown to mediate noradrenaline-induced contractile activity in the human prostate. PMID:16716294

  11. Pharmacological analysis of the novel, selective α1-adrenoceptor antagonist, KMD-3213, and its suitability as a tritiated radioligand

    PubMed Central

    Murata, Satoshi; Taniguchi, Takanobu; Muramatsu, Ikunobu

    1999-01-01

    Pharmacological profiles of tritiated KMD-3213, a new antagonist of α1-adrenoceptor (AR), were examined in recombinant and native α1-AR, and compared with those of prazosin (PZ) and tamsulosin (YM-617). In saturation experiments, [3H]-KMD (10–2000 pM) showed high affinity for α1a-AR (pKD=10.5). However, no significant binding to α1b-AR and insufficient/unsaturated binding to α1d-AR were observed at concentrations up to 2000 pM. In contrast, [3H]-PZ and [3H]-YM bound to all subtypes with high affinity (pKD>9). In competition experiments, KMD-3213 also had higher affinity for α1a-AR than for other two subtypes; pKi=10.4, 8.1 and 8.6 for α1a-, α1b- and α1d-AR, respectively. [3H]-KMD also bound to the native α1A-AR (rat submaxillary gland) with high affinity, but not to α1B-AR (rat liver). In rat kidney which expresses α1A- and α1B-AR, [3H]-KMD and [3H]-PZ bound to a single high-affinity site (pKD=10.8 and 10.1, respectively) with distinct amount of binding sites (Bmax=159 and 267 fmol mg−1 protein, respectively). [3H]-PZ binding sites consisted of low- and high-affinity sites for KMD-3213 (pKi=7.6 and 10.7, respectively), for WB4101 (pKi=8.1 and 10.0) and for YM-617 (pKi=8.7 and 10.8). The proportion of the high affinity site was approximately 60% in these drugs which was compatible to the ratio between Bmax of [3H]-KMD and [3H]-PZ. [3H]-KMD binding sites consisted of a single site for these drugs with affinities which were similar to those of the high affinity sites in [3H]-PZ binding. In functional experiments, KMD-3213 antagonized the contractile responses to NS-49 or noradrenaline (NA) with higher affinity in functional α1A- (rat caudal artery, pA2=10.0 against NS-49) and α1L-AR (dog mesenteric artery, pA2=9.9 against NA) than in α1B- (dog carotid artery, pA2=7.7 against NA) and α1D-AR (rat thoracic aorta, pA2=8.3 against NA). These results confirm the α1A-AR selectivity and high affinity of KMD-3213, and indicate that [3H]-KMD can

  12. Blockade of voltage-gated calcium channel Cav1.2 and α1-adrenoceptors increases vertebral artery blood flow induced by the antivertigo agent difenidol.

    PubMed

    Murakami, Kohji; Inoue, Naoki; Fuchikami, Chiaki; Tajima, Koyuki; Hashino, Asami; Fukui, Hisashi; Noda, Kumiko; Oka, Michiko

    2012-08-15

    Difenidol (1,1-diphenyl-4-piperidino-1-butanol hydrochloride) is an effective drug for the treatment of vertigo and dizziness. This drug is known to improve the blood flow in vertebral arteries, though the precise mechanism underlying this action remains unclear. In the present study, we investigated the effect of difenidol on voltage-gated calcium channel Ca(v)1.2 and α(1)-adrenoceptor subtypes that regulate the intracellular calcium concentration ([Ca(2+)](i)), as well as their possible involvement in the action of difenidol on vertebral artery relaxation and blood flow in dogs. In vitro binding assays demonstrated that difenidol at micromolar concentrations bound to the α(1A)-, α(1B)- and α(1D)-adrenoceptor subtypes. Difenidol inhibited the phenylephrine-induced increase in [Ca(2+)](i) in Chinese hamster ovary cells expressing human α(1A)-, α(1B)- or α(1D)-adrenoceptor subtypes with similar IC(50) values in the low micromolar range. In an electrophysiological assay, difenidol inhibited L-type calcium channel (Ca(v)1.2 subunit). In dogs, i.v. difenidol preferentially enhanced vertebral over femoral arterial blood flow. Phenylephrine and potassium induced contraction of dog vertebral arterial rings, and difenidol inhibited this action. Inhibition of phenylephrine-induced contraction by difenidol was mimicked by the α(1)-adrenoceptor antagonist phentolamine, the α(1A)-adrenoceptor antagonist RS 17,053 (N-[2-(2-cyclopropylmethoxyphenoxy)ethyl]-5-chloro-α,α-dimethyl-1H-indole-3-ethanamine hydrochloride) and the α(1D)-adrenoceptor antagonist BMY 7378 (8-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-8-azaspiro[4,5]decane-7,9-dione dihydrochloride). In addition, the L-type calcium channel blocker nifedipine, like difenidol, attenuated the potassium-induced contraction. These findings suggest that the difenidol-induced increase in vertebral arterial blood flow may be due to vascular relaxation mediated by mixed blocking actions at α(1)-adrenoceptors and

  13. Preferential reduction of binding of sup 125 I-iodopindolol to beta-1 adrenoceptors in the amygdala of rat after antidepressant treatments

    SciTech Connect

    Ordway, G.A.; Gambarana, C.; Tejani-Butt, S.M.; Areso, P.; Hauptmann, M.; Frazer, A. )

    1991-05-01

    This study utilized quantitative receptor autoradiography to examine the effects of repeated administration of antidepressants to rats on the binding of the beta adrenoceptor antagonist, {sup 125}I-iodopindolol ({sup 125}I-IPIN) to either beta-1 or beta-2 adrenoceptors in various regions of brain. Antidepressants were selected to represent various chemical and pharmacological classes including tricyclic compounds (desipramine and protriptyline), monoamine oxidase inhibitors (clorgyline, phenelzine and tranylcypromine), atypical antidepressants (mianserin and trazodone) and selective inhibitors of the uptake of serotonin (citalopram and sertraline). Additionally, rats were treated with various psychotropic drugs that lack antidepressant efficacy (cocaine, deprenyl, diazepam and haloperidol). Repeated treatment of rats with desipramine, protriptyline, clorgyline, phenelzine, tranylcypromine or mianserin reduced the binding of {sup 125}I-IPIN to beta-1 adrenoceptors in many brain areas. Only in the basolateral and lateral nuclei of the amygdala did all six of these antidepressants significantly reduce {sup 125}I-IPIN binding to beta-1 adrenoceptors. In these amygdaloid nuclei, the magnitude of the reduction in the binding of {sup 125}I-IPIN caused by each of these drugs was comparable to or greater than the reduction in binding produced in any other region of brain. Reductions of binding of {sup 125}I-IPIN after antidepressant treatments were not consistently observed in the cortex, the area of brain examined most often in homogenate binding studies. Only the monoamine oxidase inhibitors caused reductions in the binding of {sup 125}I-IPIN to beta-2 adrenoceptors, and this effect was generally localized to the amygdala and hypothalamus.

  14. Mediation of noradrenaline-induced contractions of rat aorta by the alpha 1B-adrenoceptor subtype.

    PubMed Central

    Testa, R; Guarneri, L; Poggesi, E; Simonazzi, I; Taddei, C; Leonardi, A

    1995-01-01

    1. The subtypes of alpha 1-adrenoceptor mediating contractions to exogenous noradrenaline (NA) in rat aorta have been examined in both biochemical and functional studies. 2. Incubation of rat aortic membranes with the irreversible alpha 1B-adrenoceptor antagonist, chloroethylclonidine (CEC: 10 microM) did not change the KD of [3H]-prazosin binding in comparison to untreated membranes, but reduced by 88% the total number of binding sites (Bmax). 3. Contractions of rat aortic strips to NA after CEC (50 microM for 30 min) incubation followed by repetitive washing, showed a marked shift in the potency of NA and a partial reduction in the maximum response. The residual contractions to NA after CEC incubation were not affected by prazosin (10 nM). 4. The competitive antagonists prazosin, terazosin, (R)-YM-12617, phentolamine, 5-methylurapidil and spiperone inhibited contractions to NA with estimated pA2 values of 9.85, 8.54, 9.34, 7.71, 7.64 and 8.41, respectively. 5. The affinity of the same antagonists for the alpha 1A- and alpha 1B- adrenoceptors was evaluated by utilizing membranes from rat hippocampus pretreated with CEC, and rat liver, respectively. 5-Methylurapidil and phentolamine were confirmed as selective for the alpha 1A-adrenoceptors, whereas spiperone was alpha 1B-selective. 6. A significant correlation was found between the pA2 values of the alpha 1-adrenoceptor antagonists tested and their affinity for the alpha 1B-adrenoceptor subtype, but not for the alpha 1A-subtype. 7. In conclusion, these findings indicate that in rat aorta most of the contraction is mediated by alpha 1B-adrenoceptors, and that the potency (pA2) of an antagonist in this tissue should be related to its antagonistic effect on this subtype of the alpha 1-adrenoceptor population. PMID:7773533

  15. Distribution and function of peripheral alpha-adrenoceptors in the cardiovascular system.

    PubMed

    Ruffolo, R R

    1985-05-01

    alpha-Adrenoceptors may be subdivided based on their anatomical distribution within the synapse. Presynaptic alpha-adrenoceptors are generally of the alpha 2-subtype and modulate neurotransmitter liberation via a negative feedback mechanism. Postsynaptic alpha-adrenoceptors are usually of the alpha 1-subtype and mediate the response of the effector organ. Although this "anatomical" subclassification is generally applicable, many exceptions exist. A more useful classification of alpha-adrenoceptor subtypes is based on a pharmacological characterization in which selective agonists and antagonists are used. Peripheral alpha-adrenoceptors are critical in the regulation of the cardiovascular system. Postsynaptic alpha-adrenoceptors in arteries and veins represent a mixed population of alpha 1/alpha 2-adrenoceptors, with both subtypes mediating vasoconstriction. In the peripheral arterial circulation, postsynaptic vascular alpha 1-adrenoceptors are found in the adrenergic neuroeffector junction, whereas postsynaptic vascular alpha 2-adrenoceptors are located extrajunctionally. In the venous circulation, it appears that alpha 2-adrenoceptors may be predominantly junctional, whereas alpha 1-adrenoceptors may be predominantly extrajunctional. It has been proposed that junctional alpha-adrenoceptors will respond predominantly to norepinephrine liberated from sympathetic neurons, whereas extrajunctional alpha-adrenoceptors likely respond to circulating catecholamines. The functional role of extrajunctional alpha-adrenoceptors may be more important in disease states such as hypertension and congestive heart failure where circulating levels of catecholamines may be high and contribute to the maintenance of elevated vascular resistance. alpha 2-Adrenoceptors are also associated with the intima and may play a role in the release of an endogenous relaxing factor from the endothelium.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:2989947

  16. The affinity of betaxolol, a beta 1-adrenoceptor-selective blocking agent, for beta-adrenoceptors in the bovine trachea and heart.

    PubMed Central

    Satoh, E.; Narimatsu, A.; Hosohata, Y.; Tsuchihashi, H.; Nagatomo, T.

    1993-01-01

    1. The specificity of betaxolol, a beta-adrenoceptor antagonist, for beta 1- and beta 2-adrenoceptors was compared with that of other beta-antagonists, atenolol, ICI-118551, butoxamine and (+/-)-propranolol, in the bovine trachea and heart by competitive interaction with [3H]-CGP12177 as a radioligand. 2. The radioligand Kd values were 0.75 +/- 0.12 and 1.60 +/- 0.11 nM in the trachea and heart, respectively, and the Bmax values were 34.00 +/- 4.41 and 21.54 +/- 2.94 fmol mg-1 protein, respectively. 3. Using ICI-118551, we determined the ratio of beta 1:beta 2-adrenoceptors in the trachea and heart to be approximately 29:71 and 56:44, respectively. 4. In the trachea, a beta 2-predominant tissue, betaxolol and atenolol were more selective for beta 1-adrenoceptor binding sites than beta 2-adrenoceptor binding sites, whereas ICI-118551 and butoxamine were more selective for beta 2-adrenoceptor binding sites. 5. The beta 1-selectivity of betaxolol was 2.2 and 2.7 fold higher than that of atenolol in the bovine trachea and heart. These findings suggest that betaxolol may be useful in the treatment of hypertension, cardiac arrhythmia and angina pectoris. PMID:8383566

  17. Comparison of 7 α(1)-adrenoceptor antagonists in patients with lower urinary tract symptoms associated with benign prostatic hyperplasia:a short-term crossover study.

    PubMed

    Araki, Tohru; Monden, Koichi; Araki, Motoo

    2013-01-01

    A crossover study was conducted to identify the best α1-adrenoceptor (α1AR) antagonist for individual patients with lower urinary tract symptoms (LUTS) associated with benign prostatic hyperplasia (BPH). One hundred thirteen patients (mean age 70.8 years) were enrolled. All patients met BPH clinical study guidelines. Seven agents were utilized:tamsulosin 0.2mg, silodosin 8mg, urapidil 60mg, naftopidil 50mg, prazosin 1mg, terazosin 2mg, and doxazosin 1mg. Patients were initially prescribed tamsulosin or silodosin for a week and then urapidil for a week. Two weeks later, they were prescribed the better of the 2 agents for a week and a new agent for the next week. This cycle was repeated until all 7 agents were tested. Efficacy was evaluated with the International Prostate Symptom Score. The agent rankings were doxazosin (25 [22%]), silodosin (22 [19%]), urapidil (19 [17%]), naftopidil (17 [15%]), terazosin (12 [11%]), tamsulosin (11 [10%]), prazosin (7 [6%]). Only 12 patients (11%) changed agents after the crossover study was completed. The major reason was adverse events (83%). We found that each of the 7 α1AR antagonists has its own supporters. Further, the one-week crossover study was useful in identifying the best agent for the treatment of each individual with LUTS. PMID:23970323

  18. Activation of β1-adrenoceptor triggers oxidative stress mediated myocardial membrane destabilization in isoproterenol induced myocardial infarcted rats: 7-hydroxycoumarin and its counter action.

    PubMed

    Jagadeesh, Govindan Sangaran; Nagoor Meeran, Mohamed Fizur; Selvaraj, Palanisamy

    2016-04-15

    Activation of β1-adrenoceptor stimulates myocardial membrane destabilization in isoproterenol induced rats. Male albino Wistar rats were pre and co-treated with 7-hydroxycoumarin (16mg/kg body weight) daily for 8 days. Myocardial infarction was induced into rats by the subcutaneous administration of isoproterenol (100mg/kg body weight) at an interval of 24h daily for a period of two days (7th and 8th day). The levels/activities of serum cardiac troponin-T, lactate dehydrogenase and the concentrations of heart lipid peroxidation products were significantly increased and the antioxidant status was significantly decreased in isoproterenol induced rats. Furthermore, the activity of sodium/potassium-dependent adenosine triphosphatase was significantly decreased and the activities of calcium and magnesium-dependent adenosine triphosphatases were significantly increased in the heart of isoproterenol induced myocardial infarcted rats. Isoproterenol induced rats also revealed increased concentrations of sodium and calcium and decreased concentrations of potassium in the heart. 7-hydroxycoumarin pre- and co-treatment showed considerable impact on all biochemical parameters assessed. Also, 7-HC greatly reduced the infarct size of the myocardium. The in vitro study confirmed its potent free radical scavenging activity. Thus, the present study revealed that 7-HC attenuates myocardial membrane destabilization by reinstating the activities/levels of adenosine triphosphatases and minerals in isoproterenol induced rats by inhibiting oxidative stress. These effects are attributed to the membrane stabilizing and free radical scavenging properties of 7-hydroxycoumarin. PMID:26930228

  19. Chronic Stress Impairs α1-Adrenoceptor-Induced Endocannabinoid-Dependent Synaptic Plasticity in the Dorsal Raphe Nucleus

    PubMed Central

    Shen, Roh-Yu

    2014-01-01

    Alpha 1-adrenergic receptors (α1-ARs) control the activity of dorsal raphe nucleus (DRn) serotonin (5-HT) neurons and play crucial role in the regulation of arousal and stress homoeostasis. However, the precise role of these receptors in regulating glutamate synapses of rat DRn 5-HT neurons and whether chronic stress exposure alters such regulation remain unknown. In the present study, we examined the impact of chronic restraint stress on α1-AR-mediated regulation of glutamate synapses onto DRn 5-HT neurons. We found that, in the control condition, activation of α1-ARs induced an inward current and long-term depression (LTD) of glutamate synapses of DRn 5-HT neurons. The α1-AR LTD was initiated by postsynaptic α1-ARs but mediated by a decrease in glutamate release. The presynaptic expression of the α1-AR LTD was signaled by retrograde endocannabinoids (eCBs). Importantly, we found that chronic exposure to restraint stress profoundly reduced the magnitude of α1-AR LTD but had no effect on the amplitude of α1-AR-induced inward current. Chronic restraint stress also reduced the CB1 receptor-mediated inhibition of EPSC and the eCB-mediated depolarization-induced suppression of excitation. Collectively, these results indicate that chronic restraint stress impairs the α1-AR LTD by reducing the function of presynaptic CB1 receptors and reveal a novel mechanism by which noradrenaline controls synaptic strength and plasticity in the DRn. They also provide evidence that chronic stress impairs eCB signaling in the DRn, which may contribute, at least in part, to the dysregulation of the stress homeostasis. PMID:25355210

  20. Alpha 1A-adrenoceptor-mediated contractile responses of the human vas deferens.

    PubMed Central

    Furukawa, K.; Rosario, D. J.; Smith, D. J.; Chapple, C. R.; Uchiyama, T.; Chess-Williams, R.

    1995-01-01

    1. The predominant alpha 1-adrenoceptor mediating contractions of the human vas deferens has been characterised in vitro by use of subtype selective antagonists. 2. Responses of human epididymal vas deferens were obtained to phenylephrine in the presence of amine uptake inhibitors and propranolol. The effects of the alpha 1-adrenoceptor antagonists, 5-methylurapidil, oxymetazoline, WB4101, prazosin and chloroethylclonidine were examined and also the L-type calcium channel blocker, nifedipine. 3. 5-Methylurapidil, WB4101, oxymetazoline and prazosin acted as competitive antagonists of the responses to phenylephrine, yielding pA2 values of 8.8, 9.2, 7.7 and 8.8 respectively. All four antagonists produced Schild plots with slopes similar to unity and maximum responses to phenylephrine were not altered in the presence of any of the antagonists. 4. Tamsulosin (1 nM) caused rightward shifts of phenylephrine concentration-response curves yielding an apparent pKB value of 10.0. However, maximum responses were also reduced by 51% with this concentration of antagonist. 5. Incubation of tissues with chloroethylclonidine (100 microM for 40 min) failed to alter responses significantly but the presence of nifedipine (1 microM) reduced maximum responses to phenylephrine by 32%. 6. The high affinity of 5-methylurapidil, oxymetazoline and WB4101, together with the failure of chloroethylclonidine to antagonize responses, indicate that the predominant alpha 1-adrenoceptor mediating contraction of the human vas deferens has the characteristics previously described for the pharmacologically-defined alpha 1A-adrenoceptor. The data are also consistent with those described for the cloned alpha 1c-adrenoceptor subtype thereby supporting the hypothesis that the two receptors are identical. The human vas deferens therefore represents a readily accessible preparation for functional studies of the human alpha 1A-adrenoceptor. PMID:8564226

  1. α1-Adrenoceptor activation of PKC-ε causes heterologous desensitization of thromboxane receptors in the aorta of spontaneously hypertensive rats

    PubMed Central

    Zhao, Yingzi; Vanhoutte, Paul M; Leung, Susan W S

    2015-01-01

    Background and Purpose In the aorta of adult spontaneously hypertensive (SHR), but not in that of normotensive Wistar-Kyoto (WKY), rats, previous exposure to phenylephrine inhibits subsequent contractions to PGE2. The present experiments were designed to examine the mechanism(s) underlying this inhibition. Experimental Approach Isometric tension was measured in isolated rings of SHR and WKY aortae. Gene expression and protein presence were measured by quantitative real-time PCR and Western blotting respectively. Key Results In aorta of 18 weeks SHR, but not age-matched WKY, pre-exposure to phenylephrine inhibited subsequent contractions to PGE2 that were mediated by thromboxane prostanoid (TP) receptors. This inhibition was not observed in preparations of pre-hypertensive 5-week-old SHR, and was significantly larger in those of 36- than 18-week-old SHR. Pre-exposure to the PKC activator, phorbol 12,13-dibutyrate, also inhibited subsequent contractions to PGE2 in SHR aortae. The selective inhibitor of PKC-ε, ε-V1-2, abolished the desensitization caused by pre-exposure to phenylephrine. Two molecular PKC bands were detected and their relative intensities differed in 36-week-old WKY and SHR vascular smooth muscle. The mRNA expressions of PKC-α, PKC-ε, PK-N2 and PKC-ζ and of G protein-coupled kinase (GRK)-2, GRK4 and β-arrestin2 were higher in SHR than WKY aortae. Conclusions and Implications These experiments suggest that in the SHR but not the WKY aorta, α1-adrenoceptor activation desensitizes TP receptors through activation of PKC-ε. This heterologous desensitization is a consequence of the chronic exposure to high arterial pressure. PMID:25857252

  2. The 2.1 Å resolution structure of cyanopindolol-bound β1-adrenoceptor identifies an intramembrane Na+ ion that stabilises the ligand-free receptor.

    PubMed

    Miller-Gallacher, Jennifer L; Nehmé, Rony; Warne, Tony; Edwards, Patricia C; Schertler, Gebhard F X; Leslie, Andrew G W; Tate, Christopher G

    2014-01-01

    The β1-adrenoceptor (β1AR) is a G protein-coupled receptor (GPCR) that is activated by the endogenous agonists adrenaline and noradrenaline. We have determined the structure of an ultra-thermostable β1AR mutant bound to the weak partial agonist cyanopindolol to 2.1 Å resolution. High-quality crystals (100 μm plates) were grown in lipidic cubic phase without the assistance of a T4 lysozyme or BRIL fusion in cytoplasmic loop 3, which is commonly employed for GPCR crystallisation. An intramembrane Na+ ion was identified co-ordinated to Asp872.50, Ser1283.39 and 3 water molecules, which is part of a more extensive network of water molecules in a cavity formed between transmembrane helices 1, 2, 3, 6 and 7. Remarkably, this water network and Na+ ion is highly conserved between β1AR and the adenosine A2A receptor (rmsd of 0.3 Å), despite an overall rmsd of 2.4 Å for all Cα atoms and only 23% amino acid identity in the transmembrane regions. The affinity of agonist binding and nanobody Nb80 binding to β1AR is unaffected by Na+ ions, but the stability of the receptor is decreased by 7.5°C in the absence of Na+. Mutation of amino acid side chains that are involved in the co-ordination of either Na+ or water molecules in the network decreases the stability of β1AR by 5-10°C. The data suggest that the intramembrane Na+ and associated water network stabilise the ligand-free state of β1AR, but still permits the receptor to form the activated state which involves the collapse of the Na+ binding pocket on agonist binding. PMID:24663151

  3. In vitro α1-adrenoceptor pharmacology of Ro 70-0004 and RS-100329, novel α1A-adrenoceptor selective antagonists

    PubMed Central

    Williams, T J; Blue, D R; Daniels, D V; Davis, B; Elworthy, T; Gever, J R; Kava, M S; Morgans, D; Padilla, F; Tassa, S; Vimont, R L; Chapple, C R; Chess-Williams, R; Eglen, R M; Clarke, D E; Ford, A P D W

    1999-01-01

    It has been hypothesized that in patients with benign prostatic hyperplasia, selective antagonism of the α1A-adrenoceptor-mediated contraction of lower urinary tract tissues may, via a selective relief of outlet obstruction, lead to an improvement in symptoms.The present study describes the α1-adrenoceptor (α1-AR) subtype selectivities of two novel α1-AR antagonists, Ro 70-0004 (aka RS-100975) and a structurally-related compound RS-100329, and compares them with those of prazosin and tamsulosin. Radioligand binding and second-messenger studies in intact CHO-K1 cells expressing human cloned α1A-, α1B- and α1D-AR showed nanomolar affinity and significant α1A-AR subtype selectivity for both Ro 70-0004 (pKi 8.9: 60 and 50 fold selectivity) and RS-100329 (pKi 9.6: 126 and 50 fold selectivity) over the α1B- and α1D-AR subtypes respectively. In contrast, prazosin and tamsulosin showed little subtype selectivity.Noradrenaline-induced contractions of human lower urinary tract (LUT) tissues or rabbit bladder neck were competitively antagonized by Ro 70-0004 (pA2 8.8 and 8.9), RS-100329 (pA2 9.2 and 9.2), tamsulosin (pA2 10.4 and 9.8) and prazosin (pA2 8.7 and 8.3 respectively). Affinity estimates for tamsulosin and prazosin in antagonizing α1-AR-mediated contractions of human renal artery (HRA) and rat aorta (RA) were similar to those observed in LUT tissues, whereas Ro 70-0004 and RS-100329 were approximately 100 fold less potent (pA2 values of 6.8/6.8 and 7.3/7.9 in HRA/RA respectively).The α1A-AR subtype selectivity of Ro 70-0004 and RS-100329, demonstrated in both cloned and native systems, should allow for an evaluation of the clinical utility of a ‘uroselective' agent for the treatment of symptoms associated with benign prostatic hyperplasia. PMID:10369480

  4. [Additional administration of dutasteride in patients with benign prostatic hyperplasia who did not respond sufficiently to α1-adrenoceptor antagonist : investigation of clinical factors affecting the therapeutic effect of dutasteride].

    PubMed

    Masuda, Mitsunobu; Murai, Tetsuo; Osada, Yutaka; Kawai, Masaki; Kasuga, Jun; Yokomizo, Yumiko; Kuroda, Shinnosuke; Nakamura, Mami; Noguchi, Go

    2014-02-01

    We performed additional administration of dutasteride in patients who did not respond sufficiently to α1-adrenoceptor antagonist treatment for lower urinary tract symptoms (LUTS) associated with benign prostatic hyperplasia (BPH) (LUTS/BPH). Among 76 registered patients, efficacy was analyzed in 58 patients. International Prostate Symptom Score (IPSS), subscores for voiding and storage symptoms and quality of life (QOL) on the IPSS, and Overactive Bladder Symptom Score (OABSS) were all significantly improved from the third month of administration compared to the time of initiating additional administration of dutasteride. Additional administration of dutasteride also significantly reduced prostate volume, and residual urine with the exception of the sixth month after administration. Age at initiation of administration and voiding symptom subscore on the IPSS were clinical factors affecting the therapeutic effects of dutasteride. The rate of improvement with treatment decreased with increasing age at initiation of dutasteride administration, and increased as voiding symptom subscore on the IPSS increased. Therefore, additional administration of dutasteride appears useful for cases of LUTS/BPH in which a sufficient response is not achieved with α1-adrenoceptor antagonist treatment. Because patients who have severe voiding symptoms or begin dutasteride at an early age may be expected to respond particularly well to dutasteride in terms of clinical efficacy, they were considered to be suitable targets for additional administration. PMID:24755815

  5. alpha. -Adrenergic vasoconstriction and receptor subtypes in large coronary arteries of calves

    SciTech Connect

    Young, M.A.; Vatner, D.E.; Knight, D.R.; Graham, R.M.; Homcy, C.J.; Vatner, S.F. New England Regional Primate Research Center, Southborough, MA )

    1988-12-01

    The authors investigated {alpha}-adrenoceptor subtype distribution in large coronary arteries from both functional and biochemical perspectives. The effects of intracoronary administration of the selective {alpha}{sub 1}-adrenoceptor agonist phenylephrine, of the selective {alpha}{sub 2}-adrenoceptor agonist B-HT 920 and of the mixed {alpha}{sub 1+2}-adrenoceptor agonist norepinephrine were examined on measurements of left circumflex coronary artery diameter in conscious calves. After {beta}-adrenergic blockade, equivalent reductions in large coronary artery diameter were observed with phenylephrine, B-HT, and norepinephrine. Phenylephrine-induced constrictions were abolished by prazosin, an {alpha}{sub 1}-selective antagonist, but unaffected by rauwolscine, an {alpha}{sub 2}-selective antagonist. Conversely, the B-HT-induced constriction was abolished by rauwolscine but unaffected by prazosin. Coronary constriction with norepinephrine was attenuated with either prazosin or rauwolscine and abolished by the two antagonists combined. Ligand-binding studies in which ({sup 3}H)prazosin and ({sup 3}H)rauwolscine and sarcolemmal membranes were used revealed an {alpha}{sub 1}-adrenoceptor density of 15 {plus minus} 3.1 fmol/mg protein with a dissociation constant (K{sub D}) of 0.7 {plus minus} 0.2 nM and an {alpha}{sub 2}-adrenoceptor density of 68 {plus minus} 5.1 fmol/mg protein, with a K{sub D} of 7.4 {plus minus} 1.2 nM. Thus large coronary arteries of the calf contain both {alpha}{sub 1}- and {alpha}{sub 2}-adrenoceptor subtypes, each of which elicits constriction of the large coronary artery in the conscious animal.

  6. The pharmacology of fluparoxan: a selective alpha 2-adrenoceptor antagonist.

    PubMed Central

    Halliday, C. A.; Jones, B. J.; Skingle, M.; Walsh, D. M.; Wise, H.; Tyers, M. B.

    1991-01-01

    1. This paper describes the pharmacology of the novel alpha 2-adrenoceptor antagonist fluparoxan (GR 50360) which is currently being studied clinically as a potential anti-depressant. Idazoxan and yohimbine were included in many studies for comparison. 2. In the rat isolated, field-stimulated vas deferens and the guinea-pig isolated, field-stimulated ileum preparations, fluparoxan was a reversible competitive antagonist of the inhibitory responses to the alpha 2-adrenoceptor agonist UK-14304 with pKB values of 7.87 and 7.89 respectively. In the rat isolated anococcygeus muscle, fluparoxan was a much weaker competitive antagonist of the contractile response to the alpha 1-adrenoceptor agonist phenylephrine with a pKB of 4.45 giving an alpha 2: alpha 1-adrenoceptor selectivity ratio of greater than 2500. 3. In the conscious mouse, fluparoxan (0.2-3.0 mg kg-1) was effective by the oral route and of similar potency to idazoxan in preventing clonidine-induced hypothermia and antinociception. In the rat, UK-14304-induced hypothermia (ED50 = 1.4 mg kg-1, p.o. or 0.5 mg kg-1, i.v.) and rotarod impairment (ED50 = 1.1 mg kg-1 p.o. or 1.3 mg kg-1, i.v.) were antagonized by fluparoxan. Fluparoxan, 0.67-6 mg kg-1, p.o., also prevented UK-14304-induced sedation and bradycardia in the dog. 4. In specificity studies fluparoxan had low or no affinity for a wide range of neurotransmitter receptor sites at concentrations up to at least 1 x 10(-5) M. It displayed weak affinity for 5-HT1A (pIC50 = 5.9) and 5-HT1B (pKi = 5.5) binding sites in rat brain.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:1677298

  7. Influences of the endothelium and hypoxia on alpha 1- and alpha 2-adrenoceptor-mediated responses in the rabbit isolated pulmonary artery.

    PubMed Central

    MacLean, M. R.; McCulloch, K. M.; McGrath, J. C.

    1993-01-01

    1. The effects of the inhibitor of nitric oxide synthase, N omega-nitro-L-arginine methylester (L-NAME, 10(-4) M), mechanical disruption of the endothelium and hypoxia on contraction to noradrenaline (alpha 1- and alpha 2-adrenoceptor agonist), phenylephrine (alpha 1-adrenoceptor agonist) and UK 14304 (alpha 2-adrenoceptor agonist) were compared in the rabbit isolated pulmonary artery. The effects of the selective antagonists rauwolscine (10(-6) M, alpha 2-adrenoceptors) and prazosin (10(-7) M, alpha 1-adrenoceptors) on the contractions to noradrenaline before and after exposure to L-NAME were also assessed. 2. Noradrenaline, phenylephrine and UK 14304 all produced concentration-dependent increases in vascular tone. The responses to noradrenaline were sensitive to both rauwolscine and prazosin (effect of prazosin >> rauwolscine). L-NAME increased the potency of both noradrenaline and UK 14304, and also the maximum tension achieved. It had no effect on the responses to phenylephrine. After L-NAME, contractions to noradrenaline, although still sensitive to both rauwolscine and prazosin, were now more sensitive to inhibition by rauwolscine. 3. Endothelium removal augmented the potency and maximum contractions to noradrenaline, phenylephrine and UK 14304. 4. Hypoxia decreased both the potency of phenylephrine and its maximum contractile response, but increased the maximum response to noradrenaline without effecting responses to UK 14304. 5. In conclusion, in the rabbit pulmonary artery, augmentation of contractile responses to noradrenaline by L-NAME involves a potentiation of alpha 2-adrenoceptor-mediated contraction probably through an effect on the synthesis of endothelium-derived nitric oxide.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:8094023

  8. Differential effects of short- and long-term bupivacaine treatment on α1-adrenoceptor-mediated contraction of isolated rat aorta rings and the reversal effect of lipid emulsion

    PubMed Central

    Guo, Hao; Zhang, He-fei; Xu, Wen-qi; Du, Qian; Zhao, Jing; Ren, Lei-ming

    2015-01-01

    Aim: Arterial function is significantly influenced by bupivacaine at both clinically relevant concentrations and toxic concentrations, but the underlying mechanisms are not fully understood. In the present study we investigated the role of α1-adrenoceptors in bupivacaine effects on isolated rat aortas. Methods: Isolated aortic rings were prepared from rats and suspended in an organ bath. Phenylephrine (Phe)-induced vasoconstriction and acetylcholine (ACh)-induced vasodilation were recorded through an isometric force transducer connected to a data acquisition system. Results: Administration of bupivacaine (30–300 μmol/L) produced mild vasoconstriction, and this response declined with repeated administrations. Treatment of the aortic rings with bupivacaine (3–30 μmol/L) for 20 min enhanced Phe-induced vasoconstriction, while treatment for 40 min suppressed Phe-induced vasoconstriction. Both the short- and long-term bupivacaine treatment suppressed ACh-induced vasodilation. Incubation of the aortic rings with 0.2%–0.6% lipid emulsion (LE) for 100 min significantly increased the pD2 and Emax values of Phe-induced vasoconstriction, and incubation with 0.4% LE for 100 min reversed the inhibition of bupivacaine on vasoconstriction induced by Phe (30 μmol/L). In contrast, incubation with LE suppressed ACh-induced vasodilation, even at a lower concentration and with a 5-min incubation. Conclusion: Bupivacaine exerts dual effects on α1-adrenoceptor-mediated vasoconstriction of isolated rat aortic rings: short-term treatment enhances the response, while long-term treatment inhibits it; the inhibition may be reversed via long-term incubation with LE. PMID:26073324

  9. A quantitative analysis of antagonism and inverse agonism at wild-type and constitutively active hamster alpha1B-adrenoceptors.

    PubMed

    Hein, P; Goepel, M; Cotecchia, S; Michel, M C

    2001-01-01

    In order to characterize inverse agonism at alpha1B-adrenoceptors, we have compared the concentration-response relationships of several quinazoline and non-quinazoline alpha1-adrenoceptor antagonists at cloned hamster wild-type (WT) alpha1B-adrenoceptors and a constitutively active mutant (CAM) thereof upon stable expression in Rat-1 fibroblasts. Receptor activation or inhibition thereof was assessed as [3H]inositol phosphate (IP) accumulation. Quinazoline (alfuzosin, doxazosin, prazosin, terazosin) and non-quinazoline alpha1-adrenoceptor antagonists (BE 2254, SB 216,469, tamsulosin) concentration-dependently inhibited phenylephrine-stimulated IP formation at both WT and CAM with Ki values similar to those previously found in radioligand binding studies. At CAM in the absence of phenylephrine, the quinazolines produced concentration-dependent inhibition of basal IP formation; the maximum inhibition was approximately 55%, and the corresponding EC50 values were slightly smaller than the Ki values. In contrast, BE 2254 produced much less inhibition of basal IP formation, SB 216,469 was close to being a neutral antagonist, and tamsulosin even weakly stimulated IP formation. The inhibitory effects of the quinazolines and BE 2254 as well as the stimulatory effect of tamsulosin were equally blocked by SB 216,469 at CAM. At WT in the absence of phenylephrine, tamsulosin did not cause significant stimulation and none of the other compounds caused significant inhibition of basal IP formation. We conclude that alpha1-adrenoceptor antagonsits with a quinazoline structure exhibit greater efficacy as inverse agonists than those without. PMID:11191834

  10. alpha-Adrenoceptor antagonists in the treatment of benign prostate hyperplasia.

    PubMed

    Thiyagarajan, M

    2002-07-01

    Benign prostate hyperplasia (BPH) is a common malady affecting elderly men throughout the world, and it is the most common cause of voiding dysfunctions in man. The disease becomes prevalent, as the mean age of the population increases. In BPH the glandular cells and myofibroblasts of periurethral and transition zones proliferate excessively. This excessive growth of tissue mass physically compresses the urethra, leading to urinary obstruction and lower urinary tract symptoms (LUTS). Another major factor that contributes to LUTS in BPH is the increase in smooth muscle tone, a dynamic component. Contraction of the prostate gland is mainly under the control of the autonomic system and is mediated through alpha-adrenoceptors. In addition to alpha1-adrenoceptors, there are many other components that influence growth and contraction of the prostate gland, resulting in the development of BPH and LUTS. The prostate gland is contracted on stimulating 5-HT, endothelin, tachykinin, and muscarinic cholinergic receptors. Growth of the prostate gland is under the control of androgens, endothelin growth factor, vasoactive intestinal peptide, nerve growth factor, and growth hormone. The combination of excessive growth and the tone produced by different components results in LUTS and BPH. alpha1-Adrenoceptor antagonists were successfully used in the treatment of BPH to relieve the LUTS. The high selectivity of alpha1A-adrenoceptor antagonists reflects the uroselectivity. The uroselective compounds like terazosin, doxazosin, tamsulosin, and alfuzosin are in clinical use. Other new potent uroselective compounds, which are analogs of nigulidipine, 5-methyl-urapidil, or naftopidil, are in clinical trials. In addition to alpha-antagonists, antiandrogens (5alpha-reductase inhibitors) and polyherbal formulations are used to treat BPH. The success of BPH treatment lies in the development of new chemical entities which are efficacious as well as more uroselective and hence have least side

  11. Characterization of human recombinant α2A-adrenoceptors expressed in Chinese hamster lung cells using intracellular Ca2+ changes: evidence for cross-talk between recombinant α2A- and native α1-adrenoceptors

    PubMed Central

    Reynen, P H; Martin, G R; Eglen, R M; MacLennan, S J

    2000-01-01

    Human α2A-adrenoceptors expressed in Chinese hamster lung (CHL) fibroblasts have been pharmacologically characterized by measuring intracellular calcium (Ca2+i) changes using the Ca2+-sensitive dye Fluo3-AM, in conjunction with a fluorometric imaging plate reader (FLIPR).Several α-adrenoceptor agonists were examined including the α2-adrenoceptor agonists UK-14304, B-HT 920, dexmedetomidine and A-54741, the selective α1-adrenoceptor agonist phenylephrine and the non-selective adrenergic agonist noradrenaline. Of these only noradrenaline (mean pEC50=6.49) and A-54741 (6.90) evoked changes in Ca2+i; A-54741 was a partial agonist relative to noradrenaline, achieving only 33% of the noradrenaline maximum.Ca2+i changes induced by noradrenaline and A-54741 were antagonized by the α2-selective antagonist rauwolscine (10 nM) and by the α1-selective antagonists prazosin (0.1 nM) and doxazosin (1.0 nM).Phenylephrine (100 μM) and UK-14304 (10 μM) alone were ineffective in causing Ca2+i increase. In the presence of a fixed concentration of UK-14304 (3.0 μM), phenylephrine induced concentration-dependent increases in Ca2+i (mean pEC50=5.33). In the presence of phenylephrine (30.0 μM) UK-14304 induced Ca2+i release (pEC50=6.92). The effects of phenylephrine were abolished by prazosin (1.0 nM) or rauwolscine (100 nM).In saturation radioligand binding experiments using membranes of parental (non-transfected) CHL cells there was a small, specific binding of [3H]-prazosin (Bmax=24 fmol mg protein−1; pKD=10.24).Collectively, these data suggest that α-adrenoceptor agonist-induced Ca2+i release in CHL fibroblasts transfected with the human α2A-adrenoceptor is dependent upon co-activation of the recombinant receptor and a native α1-adrenoceptor. PMID:10742289

  12. Inhibitory effects of amiloride on alpha adrenoceptors in canine vascular smooth muscle

    SciTech Connect

    Shi, A.G.; Wang, Z.L.; Kwan, C.Y.; Daniel, E.E. )

    1990-05-01

    Amiloride inhibits vascular smooth muscle contractions from canine aorta and saphenous vein. The mechanisms were studied using radioligand binding and functional techniques. Amiloride inhibited ({sup 3}H)prazosin and ({sup 3}H)rauwolscine binding to alpha-1 and alpha-2 adrenoceptors in a concentration-dependent manner. Amiloride increased Kd values for ({sup 3}H)rauwolscine without affecting the maximum binding of ({sup 3}H)prazosin. These results suggest that the drug interacts with the alpha-1 adrenoceptor binding sites in a competitive manner and with the alpha-2 adrenoceptor binding sites in a noncompetitive manner. Amiloride reduced maximal contractile responses to agonists selective for both alpha adrenoceptors and to elevated K+, the EC50 values were increased by about 10-fold in the presence of amiloride. In Ca+(+)-free Krebs' solution, contractions induced in saphenous vein after addition of Ca++ in saphenous vein in the presence of adrenoceptor agonists were inhibited by amiloride. Our results suggest that amiloride reduced alpha-1 and alpha-2 adrenoceptor-mediated responses and inhibited Ca++ influx.

  13. Different contractile effects of alpha1- and alpha2-adrenergic agonists on horse isolated common digital artery smooth muscle ring preparations in vitro.

    PubMed

    Cavalli, M; Carcano, R; Beretta, C

    2002-10-01

    Despite assays on ring preparations in vitro confirmed that the vasoconstrictor sympathetic control in the horse common digital artery mainly depends on alpha(1)-adrenoceptors stimulation, selective alpha(2)-adrenoceptor agonists were investigated under the same experimental conditions. Both detomidine (DET) and UK 14304 differed from noradrenaline (NA) and phenylephrine (PHE) in provoking contractile effects which were slowly onsetting, concentrations-unrelated and unremovable by repeated washings. While prazosin (PRA) clearly antagonized the effects of NA and PHE, neither pre- nor post-treatments of the preparations with alpha(2)-antagonists succeeded in antagonizing or removing the effects of the two alpha(2)-agonists tested, which moreover were unaffectable either by lowering the organ bath temperature or by depriving the nutritive medium of Ca(2+). To explain this unusual behavior of alpha(2)-adrenoceptors stimulation it has been hypothesized that a Ca(2+) mobilization from the endoplasmic reticulum of the smooth muscle cell occurs which is followed by a hindered reuptake of them. PMID:12361691

  14. Stimulation of prostaglandin E2-synthesis by noradrenaline in primary cell cultures from rabbit splenic pulpa is mediated by atypical alpha-adrenoceptors.

    PubMed

    Brückner-Schmidt, R; Jackisch, R; Hertting, G

    1981-02-01

    In primary cell cultures originating from rabbit splenic pulpa the effects of various adrenoceptor agonists on prostaglandin (PG)-synthesis were studied. The cells - microscopically identified as fibroblasts - released PGs into the medium: especially PGE2 besides small amounts of PGF2alpha and PGD2. Noradrenaline increased dose-dependently the amount of PGs released into the medium. Besides noradrenaline, only the catecholamines adrenaline and alpha-methylnoradrenaline strongly activated PG-synthesis. Other alpha-adrenoceptor agonists like the phenylethylamine and imidazoline derivatives were only weak agonists or completely ineffective. All adrenoceptor agonists without intrinsic activity in these cells antagonized the noradrenaline effect on PG-synthesis, the imidazolines being more potent antagonists than the phenylethylamines. The beta-adrenoceptor agonist isoprenaline stimulated PG-synthesis at high concentration only. The effects of both noradrenaline and isoprenaline were inhibited by low concentrations of phentolamine phenoxybenzamine, but not by propranolol. The preferential alpha2-adrenoceptor antagonists yohimbine and rauwolscine were about 50 times more potent in blocking the noradrenaline effect on PG-synthesis than the more alpha1-specific antagonist corynanthine. However, prazosin, another alpha1-adrenoceptor antagonist, was about equipotent with yohimbine. It is concluded that noradrenaline elicits PG-synthesis in rabbit splenic fibroblasts via alpha-adrenoceptor stimulation. The alpha-adrenoceptor involved has properties which are different from those reported so far for alpha1- or alpha2-adrenoceptors. PMID:6268994

  15. The relationship between density of alpha-adrenoceptor binding sites and contractile responses in several porcine isolated blood vessels.

    PubMed Central

    Wright, I K; Blaylock, N A; Kendall, D A; Wilson, V G

    1995-01-01

    1. The aim of this study was to investigate constrictor alpha-adrenoceptors in three isolated blood vessels of the pig, the thoracic aorta (TA), the splenic artery (SA) and marginal ear vein (MEV) and then compare the functional response with the densities of alpha 1- and alpha 2-adrenoceptor binding sites in these and several other porcine vascular tissues, palmar common digital artery (PCDA), palmar lateral vein (PLV) and ear artery (EA). 2. Noradrenaline (NA), phenylephrine (PE) and UK14304 (all at 0.03-10 microM) elicited concentration-dependent contractions in the TA and MEV, with a rank order of potency of UK14304 > NA > PE. UK14304 produced maximal responses which were 58% (TA) and 65% (MEV) of that of NA. In the SA, UK14304 and PE produced maximal responses which were less than 10% and 50% of the NA-induced maximal response respectively, with an order of potency of NA > PE. In the SA, NA-induced contractions were competitively antagonized by prazosin (pA2 = 8.60 +/- 0.15). Further, rauwolscine (1-10 microM) antagonized NA-induced contractions with an apparent pKB of 6.09 +/- 0.11 (n = 6), indicating an action at alpha 1-adrenoceptors. The combination of the two antagonists at concentrations selective for alpha 1- (0.1 microM) and alpha 2-adrenoceptors (1 microM) had no greater effect than either antagonist alone. This suggests that the SA expresses only post-junctional alpha 1-adrenoceptors. 3. In the TA, prazosin produced non-parallel shifts in the NA-induced CRC and this was also observed with rauwolscine, where reductions in the maximal responses were also observed. In the MEV, prazosin was largely inactive in antagonizing NA-induced contractions. In both these vessels a combination of these two antagonists had a greater effect than either alone, indicating the presence of functional alpha 1- and alpha 2-adrenoceptors. The post-junctional alpha 2-adrenoceptors in all of these vessels were resistant to prazosin, suggesting the alpha 2-adrenoceptor to be

  16. Alpha Particle

    NASA Astrophysics Data System (ADS)

    Murdin, P.

    2000-11-01

    Term that is sometimes used to describe a helium nucleus, a positively charged particle that consists of two protons and two neutrons, bound together. Alpha particles, which were discovered by Ernest Rutherford (1871-1937) in 1898, are emitted by atomic nuclei that are undergoing alpha radioactivity. During this process, an unstable heavy nucleus spontaneously emits an alpha particle and transmut...

  17. alpha-Adrenergic inhibition of the beta-adrenoceptor-dependent chloride current in guinea-pig ventricular myocytes.

    PubMed Central

    Iyadomi, I; Hirahara, K; Ehara, T

    1995-01-01

    1. alpha 1-Adrenoceptor-mediated inhibition of the beta-adrenoceptor-dependent Cl- current was investigated in guinea-pig ventricular myocytes using the patch clamp technique. The Cl- conductance activated by noradrenaline (0.1-10 microM) with an alpha 1-blocker (prazosin, 5 microM) was significantly greater than that activated by noradrenaline alone. Phenylephrine and methoxamine, alpha 1-agonists, exerted an inhibitory effect on the Cl- conductance activated by isoprenaline. The dose-response relationship for isoprenaline and the Cl- current activation was shifted to higher doses in the presence of phenylephrine (30 microM). 2. The interaction of alpha 1- and beta-agonists on Cl- current was also observed on the single channel level; in some of the outside-out membrane patches, phenylephrine (50 microM) depressed the activity of the single Cl- channel which was induced by 5 microM adrenaline. 3. Phenylephrine had no effect on the Cl- conductance induced by forskolin (0.5-5 microM), an activator of adenylate cyclase. The Cl- conductance activated persistently by isoprenaline in GTP gamma S-loaded cells was also insensitive to phenylephrine. The results suggest that the observed alpha 1-adrenergic attenuation of the beta-adrenergic response is not primarily due to inhibition of adenylate cyclase activity. The alpha 1-adrenergic action may interfere with the processes leading to enzyme activation in the beta-adrenergic pathway. PMID:8583419

  18. Cardiovascular effects of alpha-blockers used for the treatment of symptomatic BPH: impact on safety and well-being.

    PubMed

    de Mey, C

    1998-01-01

    Alpha-adrenoceptor antagonists (alpha-blockers) are efficacious in treating lower urinary tract symptoms (LUTS) suggestive of benign prostatic obstruction (BPO), also termed symptomatic benign prostatic hyperplasia (BPH), causing bladder outlet obstruction (BOO). There is little difference among the various alpha-blockers in terms of efficacy in treating LUTS. However, conventional quinazoline derivatives such as terazosin, doxazosin and alfuzosin, originally developed for hypertension, have inherent cardiovascular extension effects, which influence the well being and safety of patients with LUTS by impairing physiological blood pressure (BP) control, even when their effect on unchallenged BP may be quite low. Preclinically, tamsulosin, a sulphonamide-substituted phenethylamine, has a relative selectivity for the alpha 1-adrenoceptors of the lower urinary tract. Clinically, this is associated with fewer cardiovascular extension effects with tamsulosin (modified release capsule) 0.4 mg once daily. This allows the use of convenient regimens of 0.4 mg tamsulosin administered once daily after breakfast from initiation of treatment without the need for 'step-up' increases of dose to avoid 'first-dose' hypotension. Extensive investigation, including multiple orthostatic stress testing (which otherwise is unusual in the characterization of alpha-blockers because of their inherent safety), confirms that tamsulosin 0.4 mg definitely carries a lower risk of impaired BP control. PMID:9732825

  19. Alpha Thalassemia

    MedlinePlus

    ... an apparently normal individual has a child with hemoglobin H disease or alpha thalassemia minor. It can ... gene on one chromosome 25% 25% 25% 25% hemoglobin H disease there is a 25% chance with ...

  20. Modification of certain pharmacological effects of ethanol by lipophilic alpha-1 adrenergic agonists

    SciTech Connect

    Menon, M.K.; Dinovo, E.C.; Haddox, V.G.

    1987-09-28

    The influence of four centrally-acting alpha-1 adrenoceptor agonists, namely, 2(2-chloro-5-trifluoromethylphenylimino) imidazolidine (St 587), cirazoline, (-) 1,2,3,4-tetrahydro-8-methoxy-5-methylthio-2-naphthalenamine ((-)SKF 89748A) and 2-(2-methylindazol-4-imino)imidazolidine (Sgd 101/75) on the pharmacological effects of ethanol was investigated. All four drugs reduced the duration of ethanol-induced hypnosis in C57B1/6 mice, this effect being proportional to their relative potencies to exert central alpha-1 agonism. In prazosin-pretreated mice, St 587 failed to reduce the hypnotic effect of ethanol, which provided strong evidence for the role of alpha-1 agonism for the hypnosis reducing effect of St 587. Hyperactivity induced in C57B1/6 mice by a subhypnotic dose of ethanol and St 587 was reported earlier. In the present study, St 587, cirazoline and (-)SKF 89748A produced similar response, but no correlation between this effect and ethanol hypnosis blockade could be established. 19 references, 8 figures, 2 tables.

  1. Correlation between phosphatidylinositol labeling and contraction in rabbit aorta: effect of alpha-1 adrenergic activation

    SciTech Connect

    Villalobos-Molina, R.; Uc, M.; Hong, E.; Garcia-Sainz, J.A.

    1982-07-01

    Activation of rabbit aortic strips with alpha adrenergic agonists increased the labeling (with (/sup 32/P)Pi) of phosphatidylinositol (PI) and phosphatidic acid and contracted the vascular preparations in dose-related fashion. Epinephrine, norepinephrine and methoxamine produced maximal effects, whereas clonidine behaved as partial agonist and B-HT 933 (2-amino-6-ethyl-4,5,7,8-tetrahydro-6H-oxazole-(5,4-d) azepin dihydrochloride) was almost without activity in the two experimental models used. Phenylephrine was a full agonist in producing contraction, but failed to elicit the maximal increase in PI labeling. The EC50 values to produce contraction of aortic strips were lower for all agonists than those required to increase the incorporation of radioactive phosphate into PI, but there was a good correlation between the two sets of data. The increased PI labeling and contraction of aortic strips induced by epinephrine were antagonized by prazosin and yohimbine in dose-related fashion, but the first alpha blocker was about three orders of magnitude more potent than the second in antagonizing the two effects. The present results indicate that both stimulation of PI labeling and contraction are mediated through activation of alpha-1 adrenoceptors in rabbit aorta.

  2. Alpha-1 Antitrypsin Deficiency

    MedlinePlus

    ... Liver Disease Information > Alpha-1 Antitrypsin Deficiency Alpha-1 Antitrypsin Deficiency Explore this section to learn more about alpha-1 antitrypsin deficiency, including a description of the disorder ...

  3. Evidence that two stereochemically different alpha-2 adrenoceptors modulate norepinephrine release in rat cerebral cortex

    SciTech Connect

    Harsing, L.G. Jr.; Vizi, E.S. )

    1991-01-01

    Cerebral cortex slices from the rat were loaded with (3H)norepinephrine ((3H)NE) and superfused in order to measure the release of radioactivity at rest and in response to electrical stimulation. The (-)-isomer and the (+)-isomer of CH-38083 (7,8-(methylenedioxy)-14- alpha-hydroxyalloberbane HCl), a selective alpha-2-adrenoceptor antagonist with an alloberbane skeleton, increased the electrically induced release of (3H)NE in a concentration-dependent manner, and a similar effect was observed with racemic CH-38083 and idazoxan. The stereoisomers of CH-38083 applied in a concentration range of 10(-8) to 10(-6) mol/l were equipotent in facilitating stimulation-evoked (3H)NE release: concentrations needed to enhance tritium outflow by 50% were 1.3 X 10(-7) mol/l for (-)-CH-38083 and 1.4 X 10(-7) mol/l for (+)-CH-38083. Exogenous NE decreased the electrically stimulated release of (3H)NE, and the stereoisomers of CH-38083 antagonized this inhibition with different potencies: the dissociation constant (KB) values for (-)-isomer and for (+)-isomer of CH-38083 were 14.29 and 97.18 nmol/l. These data indicate that presynaptic alpha-2 adrenoceptors that are available for NE released from axon terminals do not show stereospecificity toward enantiomers of CH-38083, whereas those that are occupied by exogenous NE are much more sensitive toward (-)-CH-38083. The alpha-1 adrenoceptor antagonist prazosin also differentiated between the alpha-2 adrenoceptor subtypes: prazosin (10(-6) mol/l) did not alter the increase of electrically induced (3H)NE release evoked by (-)- and (+)-CH-38083; however, in its presence, the stereoisomers of CH-38083 failed to antagonize the inhibitory effect of exogenous NE on its own release.

  4. Lower urinary tract symptoms suggestive of benign prostatic hyperplasia: latest update on alpha-adrenoceptor antagonists.

    PubMed

    Milani, Shirin; Djavan, Bob

    2005-06-01

    An update of a systematic review of alpha1-adrenoceptor (AR) antagonists in the treatment of lower urinary tract symptoms suggestive of benign prostatic hyperplasia (LUTS/BPH) showed that these agents have comparable efficacy. The total symptom score is improved by 30-45% and maximum urinary flow rate by 15-30% vs baseline. alpha1-AR antagonists that can be started at their therapeutic dose have a more rapid onset of action than alpha1-AR antagonists that have to be titrated. alpha1-AR antagonists can be differentiated according to their tolerability. Alfuzosin (especially the 10 mg once daily dose) and tamsulosin (especially the 0.4 mg once daily dose) are better tolerated than doxazosin and terazosin. However, alfuzosin might induce more cardiovascular adverse events (AEs) in the elderly and/or patients with cardiovascular comorbidity and/or comedication. Tamsulosin tends to interfere less with blood pressure regulation and induce less vasodilatory AEs than alfuzosin, especially in the elderly, and is well tolerated in patients with cardiovascular comorbidity and/or comedication. Cardiovascular AEs might lead to potentially serious complications such as falls, fractures and institutionalization. Abnormal ejaculation has mainly been reported in placebo-controlled trials with tamsulosin but in direct comparative trials its rate with tamsulosin 0.4 mg was similar to, or only slightly higher than, the rate with alfuzosin. In addition, abnormal ejaculation is not reported as bothersome by the patient or associated with serious complications. It can be concluded that an alpha1-AR antagonist with a low potential to interfere with blood pressure regulation and to induce cardiovascular AEs, also in patients with cardiovascular comorbidity and/or comedication, can be considered a first-choice treatment option in LUTS/BPH. PMID:15871733

  5. Effects of yohimbine, rauwolscine and corynanthine on contractions and calcium fluxes induced by depolarization and prostaglandin F2 alpha in rat aorta.

    PubMed Central

    Godfraind, T.; Miller, R. C.; Socrates Lima, J.

    1983-01-01

    The effects of the selective alpha 2-adrenoceptor antagonists yohimbine and its stereo-isomer rauwolscine and the selective alpha 1-adrenoceptor antagonist corynanthine (a third yohimbine stereoisomer) on contractions induced in rat aorta by depolarization and prostaglandin F2 alpha (PGF2 alpha) have been compared. In calcium-free solution, depolarization with 100 mM K+ failed to produce a contraction of rat aorta but PGF2 alpha (3 microM) stimulated a contraction equal to about 23% of maximal elicited in normal physiological solution. Yohimbine had no significant effect on depolarization-induced contractions except at concentrations greater than 30 microM. Rauwolscine and corynanthine (1 to 100 microM) depressed depolarization-induced contractions in a concentration-dependent manner, but the characteristics of inhibition were not identical. Contractions induced by PGF2 alpha (3 microM) were depressed in a concentration-dependent manner by rauwolscine (3 to 100 microM) but were unaffected by yohimbine or corynanthine. Depolarization-stimulated 45Ca influx was depressed by rauwolscine and corynanthine to about the same extent as were the contractions; while rauwolscine (100 microM) completely inhibited PGF2 alpha-stimulated 45Ca influx, it also depressed part of the PGF2 alpha-stimulated contraction dependent on intracellular calcium. Rauwolscine (100 microM) partly inhibited PGF2 alpha-stimulated release of 45Ca from aortic smooth muscle in calcium-free solution. It is concluded that the yohimbine structure possesses a calcium entry blocking action as well as a depressant action on contractions not dependent on calcium entry. The predominant effect depends on the structural configuration and the nature of the stimulating agent. PMID:6580937

  6. Alpha-1 Antitrypsin Deficiency

    MedlinePlus

    ... from the NHLBI on Twitter. What Is Alpha-1 Antitrypsin Deficiency? Alpha-1 antitrypsin (an-tee-TRIP-sin) deficiency, or AAT ... as it relates to lung disease. Overview Alpha-1 antitrypsin, also called AAT, is a protein made ...

  7. Age-related change of the role of alpha1L-adrenoceptor in canine urethral smooth muscle.

    PubMed

    Suzuki, Y; Moriyama, N; Okaya, Y; Nishimatsu, H; Kawabe, K; Aisaka, K

    1999-10-01

    To examine age-related alteration of the role of alpha1L-adrenoceptor in the urethra, young non-parous and aged parous female dogs were used. In a functional study, we evaluated phenylephrine-induced contraction and antagonistic effects of JTH-601, a newly synthesized alpha1-adrenoceptor antagonist, and prazosin; in a localization survey using autoradiographic technique, we investigated specific [3H]JTH-601 and [3H]tamsulosin binding. Concentration-response curves were obtained for phenylephrine (pD2 = 5.0-5.3). JTH-601 and prazosin antagonized this contraction with pA2 values of 8.2-8.3 and 8.0-8.1, respectively. Specific binding of both [3H]JTH-601 and [3H]tamsulosin were observed in the bladder neck and proximal section of urethra. There were no significant differences of the pD2, pA2, and radio ligand binding between young non-parous and aged parous dogs. PMID:10523074

  8. Stimulatory effect of isoferulic acid on alpha1A-adrenoceptor to increase glucose uptake into cultured myoblast C2C12 cell of mice.

    PubMed

    Liu, I M; Tsai, C C; Lai, T Y; Cheng, J T

    2001-05-14

    In an attempt to elucidate the effect of isoferulic acid on alpha1-adrenoceptor (AR), the myoblast C2C12 cells of mice were employed to investigate the change of glucose uptake in the present study. Isoferulic acid enhanced the uptake of radioactive glucose into C2C12 cells in a concentration-dependent manner, which were abolished by pretreatment with prazosin. Effect of isoferulic acid on alpha1-AR was further characterized using the displacement of [3H]YM617 binding in C2C12 cells. The radioactive glucose uptake increasing action of isoferulic acid was abolished by tamsulosin or WB 4101 at concentration sufficient to block alpha1A-adrenoceptor (alpha1A-AR) but it was not modified by chlorethylclonidine (CEC) at the concentration sufficient to abolish alpha1B-AR. An activation of alpha1A-AR by isoferulic acid in C2C12 cells can thus be considered. Pharmacological inhibition of phospholipase C (PLC) by U73312 resulted in a concentration-dependent reduction of isoferulic acid-stimulated glucose uptake in C2C12 cells. This inhibition by U73112 was specific because the inactive congener, U73343, failed to modify the action of isoferulic acid. Also, chelerythrine and GF 109203X diminished the action of isoferulic acid at concentration sufficient to inhibit the activity of protein kinase C (PKC). The obtained data suggest that an activation of alpha1A-AR by isoferulic acid may increase the glucose uptake via PLC-PKC pathway in C2C12 cells. PMID:11474559

  9. Measurement of 3-methoxy-4-hydroxyphenylglycol (MHPG) in mouse brain by h.p.l.c. with electrochemical detection, as an index of noradrenaline utilisation and presynaptic alpha 2-adrenoceptor function.

    PubMed Central

    Heal, D. J.; Prow, M. R.; Buckett, W. R.

    1989-01-01

    1. A novel method for measurement of 3-methoxy-4-hydroxyphenylglycol (MHPG) in mouse brain by use of high performance liquid chromatography (h.p.l.c.) with electrochemical detection is described. This technique incorporates an ethyl acetate purification procedure and uses 3-hydroxy-4-methoxyphenylglycol (iso-MHPG) as the internal standard. 2. Inhibition of monoamine oxidase by injection of tranylcypromine (5 and 10 mg kg-1) or pargyline (50 and 100 mg kg-1) markedly decreased brain MHPG concentrations. After injection of the tyrosine hydroxylase inhibitor, alpha-methyl-p-tyrosine (200 mg kg-1), there were time-dependent linear decreases in the concentrations of noradrenaline and MHPG in mouse brain. In addition, a very good correlation (r = 0.95, n = 30; P less than 0.001) was found between the concentrations of noradrenaline and MHPG present in the brains of the same mice after alpha-methyl-p-tyrosine treatment. 3. Mouse brain MHPG concentrations were dose-dependently reduced after administration of the alpha 2-adrenoceptor agonist, clonidine (1-3000 micrograms kg-1), and elevated by the antagonists, idazoxan (1 and 5 mg kg-1), and yohimbine (1 and 5 mg kg-1). Intracerebroventricular injection of the alpha 1-adrenoceptor agonist, phenylephrine (5-50 micrograms) dose-dependently increased MHPG levels. The alpha 1-adrenoceptor antagonist, prazosin, had no effect at the moderate dose of 1 mg kg-1, but increased MHPG concentrations at 5 mg kg-1. The beta-adrenoceptor agonist, clenbuterol (10-1000 micrograms kg-1) and the antagonist, pindolol (1 and 5 mg kg-1), were both without effect. 4. The decrease in brain MHPG concentrations induced by clonidine (100 micrograms kg-1) was prevented by prior injection of 1 mg kg-1 of idazoxan or yohimbine, but not by prazosin or pindolol. 5. MHPG levels were decreased after administration of the noradrenaline reuptake inhibitor desipramine (5 and 10 mg kg-1) and the non-selective monoamine reuptake inhibitors, sibutramine HCl (BTS

  10. Changes in [3H]-UK 14304 binding to alpha 2-adrenoceptors in morphine-dependent guinea-pigs.

    PubMed Central

    Varani, K.; Beani, L.; Bianchi, C.; Borea, P. A.; Simonato, M.

    1995-01-01

    1. The aim of this study was to investigate the effect of a noradrenergic input in the cortex of morphine-dependent animals. Binding of the alpha 1-adrenoceptor ligand [3H]-prazosin did not change in cortical membranes taken from morphine-dependent as compared to control guinea-pigs. However, binding of the alpha 2-adrenoceptor ligand [3H]-UK 14304 showed decreased KD (-30%) in the absence of significant changes in Bmax, either in cortical membranes or in synaptosomes. 2. Several characteristics of this phenomenon were identified. First, it occurs in a time-dependent fashion, in that it takes 5 days of chronic morphine treatment to start developing. Second, it can be observed after acute administration of high doses of morphine (100 mg kg-1). Third, it does not require a connection with the locus coeruleus or with other subcortical structures, in that it can be reproduced in vitro in isolated cortical slices. Fourth, it requires the integrity of cortical structures, since it cannot be reproduced in vitro in cortical synaptosomes. 3. Release studies were run to attempt identification of a functional correlate of the above observations. No changes were observed in the ability of the alpha 2-adrenoceptor agonist UK 14304 to inhibit 35 mM K(+)-evoked [3H]-noradrenaline outflow from cortical synaptosomes taken from morphine-dependent as compared to control guinea-pigs. However, a large decrease in the IC50 of UK 14304 for the inhibition of 35 mM K(+)-evoked [3H]-gamma-aminobutyric acid ([3H]-GABA) outflow (41 vs. 501 nM) was observed in morphine-dependent as compared to control animals. 4. These data suggest that, in the guinea-pig, chronic morphine treatment is associated with a shift from a low to high affinity agonist state in alpha 2-adrenoceptors on cortical GABA terminals. PMID:8719786

  11. Regulation of coronary vascular tone via redox modulation in the alpha1-adrenergic-angiotensin-endothelin axis of the myocardium.

    PubMed

    Yamaguchi, Osamu; Kaneshiro, Takashi; Saitoh, Shu-ichi; Ishibashi, Toshiyuki; Maruyama, Yukio; Takeishi, Yasuchika

    2009-01-01

    We hypothesized that alpha(1)-adrenoceptor stimulation of cardiac myocytes results in the production of an endothelin (ET)-releasing factor that stimulates the coronary vasculature to release ET and, by manipulating the redox state of cardiac and vascular cells, may influence the extent of alpha(1)-adrenergic-ET-1 vasoconstriction. Dihydroethidium (DHE) and dichlorodihydrofluorescein (DCF) intensities were increased by phenylephrine stimulation in isolated rat cardiac myocytes, which were enhanced by the mitochondrial electron transport chain complex I inhibitor rotenone (DHE: 20.4 +/- 1.2-fold and DCF: 25.2 +/- 0.9-fold, n = 8, P < 0.01, respectively) but not by the NADPH oxidase inhibitor apocynin. Olmesartan, an angiotensin II type 1 receptor antagonist, and enalaprilate did not change DHE and DCF intensities by phenylephrine. Next, we measured the vasoconstriction of isolated, pressurized rat coronary arterioles (diameter: 74 +/- 8 microm) in response to supernatant collected from isolated cardiac myocytes. The addition of supernatant from phenylephrine-stimulated myocytes to a 2-ml vessel bath (n = 8 each) caused volume-dependent vasoconstriction (500 microl: -14.8 +/- 2.2%). Olmesartan and TA0201, an ET type A receptor antagonist, converted vasoconstriction into vasodilation (8.5 +/- 1.2% and 10.5 +/- 0.5%, P < 0.01, respectively) in response to supernatant from phenylephrine-stimulated myocytes, which was eliminated with catalase. Vasoconstriction was weakened using supernatant from phenylephrine with rotenone-treated myocytes. Treatment of arterioles with apocynin to myocyte supernatant converted vasoconstriction into vasodilation (7.8 +/- 0.8%, P < 0.01). These results suggest that alpha(1)-adrenergic stimulation in cardiac myocytes produces angiotensin I and H(2)O(2) and that angiotensin releases ET-1 through NADPH oxidase in coronary arterioles. Thus, coronary vasoconstriction via the alpha-adrenergic-angiotensin-ET axis appears to require redox

  12. Ab initio alpha-alpha scattering

    NASA Astrophysics Data System (ADS)

    Elhatisari, Serdar; Lee, Dean; Rupak, Gautam; Epelbaum, Evgeny; Krebs, Hermann; Lähde, Timo A.; Luu, Thomas; Meißner, Ulf-G.

    2015-12-01

    Processes such as the scattering of alpha particles (4He), the triple-alpha reaction, and alpha capture play a major role in stellar nucleosynthesis. In particular, alpha capture on carbon determines the ratio of carbon to oxygen during helium burning, and affects subsequent carbon, neon, oxygen, and silicon burning stages. It also substantially affects models of thermonuclear type Ia supernovae, owing to carbon detonation in accreting carbon-oxygen white-dwarf stars. In these reactions, the accurate calculation of the elastic scattering of alpha particles and alpha-like nuclei—nuclei with even and equal numbers of protons and neutrons—is important for understanding background and resonant scattering contributions. First-principles calculations of processes involving alpha particles and alpha-like nuclei have so far been impractical, owing to the exponential growth of the number of computational operations with the number of particles. Here we describe an ab initio calculation of alpha-alpha scattering that uses lattice Monte Carlo simulations. We use lattice effective field theory to describe the low-energy interactions of protons and neutrons, and apply a technique called the ‘adiabatic projection method’ to reduce the eight-body system to a two-cluster system. We take advantage of the computational efficiency and the more favourable scaling with system size of auxiliary-field Monte Carlo simulations to compute an ab initio effective Hamiltonian for the two clusters. We find promising agreement between lattice results and experimental phase shifts for s-wave and d-wave scattering. The approximately quadratic scaling of computational operations with particle number suggests that it should be possible to compute alpha scattering and capture on carbon and oxygen in the near future. The methods described here can be applied to ultracold atomic few-body systems as well as to hadronic systems using lattice quantum chromodynamics to describe the interactions of

  13. Ab initio alpha-alpha scattering.

    PubMed

    Elhatisari, Serdar; Lee, Dean; Rupak, Gautam; Epelbaum, Evgeny; Krebs, Hermann; Lähde, Timo A; Luu, Thomas; Meißner, Ulf-G

    2015-12-01

    Processes such as the scattering of alpha particles ((4)He), the triple-alpha reaction, and alpha capture play a major role in stellar nucleosynthesis. In particular, alpha capture on carbon determines the ratio of carbon to oxygen during helium burning, and affects subsequent carbon, neon, oxygen, and silicon burning stages. It also substantially affects models of thermonuclear type Ia supernovae, owing to carbon detonation in accreting carbon-oxygen white-dwarf stars. In these reactions, the accurate calculation of the elastic scattering of alpha particles and alpha-like nuclei--nuclei with even and equal numbers of protons and neutrons--is important for understanding background and resonant scattering contributions. First-principles calculations of processes involving alpha particles and alpha-like nuclei have so far been impractical, owing to the exponential growth of the number of computational operations with the number of particles. Here we describe an ab initio calculation of alpha-alpha scattering that uses lattice Monte Carlo simulations. We use lattice effective field theory to describe the low-energy interactions of protons and neutrons, and apply a technique called the 'adiabatic projection method' to reduce the eight-body system to a two-cluster system. We take advantage of the computational efficiency and the more favourable scaling with system size of auxiliary-field Monte Carlo simulations to compute an ab initio effective Hamiltonian for the two clusters. We find promising agreement between lattice results and experimental phase shifts for s-wave and d-wave scattering. The approximately quadratic scaling of computational operations with particle number suggests that it should be possible to compute alpha scattering and capture on carbon and oxygen in the near future. The methods described here can be applied to ultracold atomic few-body systems as well as to hadronic systems using lattice quantum chromodynamics to describe the interactions of

  14. alpha-Hexachlorocyclohexane (alpha-HCH)

    Integrated Risk Information System (IRIS)

    alpha - Hexachlorocyclohexane ( alpha - HCH ) ; CASRN 319 - 84 - 6 Human health assessment information on a chemical substance is included in the IRIS database only after a comprehensive review of toxicity data , as outlined in the IRIS assessment development process . Sections I ( Health Hazard Ass

  15. Alpha-1 antitrypsin test

    MedlinePlus

    ... page: //medlineplus.gov/ency/article/003715.htm Alpha-1 antitrypsin test To use the sharing features on this page, please enable JavaScript. Alpha-1 antitrypsin is a laboratory test to measure the ...

  16. Alpha-1 Antitrypsin Test

    MedlinePlus

    ... measures the level of the protein AAT in blood. Alpha-1 antitrypsin phenotype testing evaluates the amount and type of AAT being produced and compares it to normal patterns. Alpha-1 antitrypsin genotype testing ( DNA testing) can ...

  17. A possible structural determinant of selectivity of boldine and derivatives for the alpha 1A-adrenoceptor subtype.

    PubMed Central

    Madrero, Y.; Elorriaga, M.; Martinez, S.; Noguera, M. A.; Cassels, B. K.; D'Ocon, P.; Ivorra, M. D.

    1996-01-01

    1. The selectivity of action of boldine and the related aporphine alkaloids, predicentrine (9-O-methylboldine) and glaucine (2,9-O-dimethylboldine) and alpha 1-adrenoceptor subtypes was studied by examining [3H]-prazosin competition binding in rat cerebral cortex. WB 4101 and benoxathian were used as selective alpha 1A-adrenoceptor antagonists. 2. In the competition experiments [3H]-prazosin (0.2 nM) binding was inhibited by WB 4101 and benoxathian. The inhibition curves displayed shallow slopes which could be subdivided into high and low affinity components (pKi = 9.92 and 8.29 for WB 4101, 9.35 and 7.94 for benoxathian). The two antagonists recognized approximately 37% of the sites with high affinity from among the total [3H]-prazosin specific binding sites. 3. Boldine, predicentrine and glaucine also competed for [3H]-prazosin (0.2 nM) binding with shallow and biphasic curves recognizing 30-40% of the sites with high affinity. Drug affinities (pKi) at the high and low affinity sites were, 8.31 and 6.50, respectively, for boldine, 8.13 and 6.39 for predicentrine, and 7.12 and 5.92 for glaucine. The relative order of selectivity for alpha 1A-adrenoceptors was boldine (70 fold alpha 1A-selective) = predicentrine (60 fold, alpha 1A-selective) > glaucine (15 fold, alpha 1A-selective). 4. Pretreatment of rat cerebral cortex membranes with chloroethylclonidine (CEC, 10 microM) for 30 min at 37 degrees C followed by thorough washing out reduced specific [3H]-prazosin binding by approximately 70%. The CEC-insensitive [3H]-prazosin binding was inhibited by boldine monophasically (Hill slope = 0.93) with a single pKi value (7.76). 5. These results suggest that whereas the aporphine structure shared by these alkaloids is responsible for their selectively of action for the alpha 1A-adrenoceptor subtype in rat cerebral cortex, defined functional groups, namely the 2-hydroxy function, induces a significant increase in alpha 1A-subtype selectivity and affinity. PMID:8982502

  18. A possible structural determinant of selectivity of boldine and derivatives for the alpha 1A-adrenoceptor subtype.

    PubMed

    Madrero, Y; Elorriaga, M; Martinez, S; Noguera, M A; Cassels, B K; D'Ocon, P; Ivorra, M D

    1996-12-01

    1. The selectivity of action of boldine and the related aporphine alkaloids, predicentrine (9-O-methylboldine) and glaucine (2,9-O-dimethylboldine) and alpha 1-adrenoceptor subtypes was studied by examining [3H]-prazosin competition binding in rat cerebral cortex. WB 4101 and benoxathian were used as selective alpha 1A-adrenoceptor antagonists. 2. In the competition experiments [3H]-prazosin (0.2 nM) binding was inhibited by WB 4101 and benoxathian. The inhibition curves displayed shallow slopes which could be subdivided into high and low affinity components (pKi = 9.92 and 8.29 for WB 4101, 9.35 and 7.94 for benoxathian). The two antagonists recognized approximately 37% of the sites with high affinity from among the total [3H]-prazosin specific binding sites. 3. Boldine, predicentrine and glaucine also competed for [3H]-prazosin (0.2 nM) binding with shallow and biphasic curves recognizing 30-40% of the sites with high affinity. Drug affinities (pKi) at the high and low affinity sites were, 8.31 and 6.50, respectively, for boldine, 8.13 and 6.39 for predicentrine, and 7.12 and 5.92 for glaucine. The relative order of selectivity for alpha 1A-adrenoceptors was boldine (70 fold alpha 1A-selective) = predicentrine (60 fold, alpha 1A-selective) > glaucine (15 fold, alpha 1A-selective). 4. Pretreatment of rat cerebral cortex membranes with chloroethylclonidine (CEC, 10 microM) for 30 min at 37 degrees C followed by thorough washing out reduced specific [3H]-prazosin binding by approximately 70%. The CEC-insensitive [3H]-prazosin binding was inhibited by boldine monophasically (Hill slope = 0.93) with a single pKi value (7.76). 5. These results suggest that whereas the aporphine structure shared by these alkaloids is responsible for their selectively of action for the alpha 1A-adrenoceptor subtype in rat cerebral cortex, defined functional groups, namely the 2-hydroxy function, induces a significant increase in alpha 1A-subtype selectivity and affinity. PMID:8982502

  19. The Alpha Centauri System.

    ERIC Educational Resources Information Center

    Soderblom, David R.

    1987-01-01

    Describes the Alpha Centauri star system, which is the closest star system to the sun. Discusses the difficulties associated with measurements involving Alpha Centauri, along with some of the recent advances in stellar seismology. Raises questions about the possibilities of planets around Alpha Centauri. (TW)

  20. Alpha-adrenoceptor mediated responses of the cauda epididymis of the guinea-pig.

    PubMed Central

    Haynes, J. M.; Hill, S. J.

    1996-01-01

    1. The subtypes of alpha-adrenoceptor mediating the contractile responses of the cauda epididymis of the guinea-pig were investigated. The alpha 1-adrenoceptor agonist phenylephrine, but not the alpha 2-adrenoceptor agonist, xylazine (up to 10 microM), elicited concentration-dependent contractions from preparations of cauda epididymis (EC50 3.4 microM). The L-type Ca2+ channel antagonist, nifedipine (10 microM), reduced the maximal response to phenylephrine (by 77%). Preincubation of tissues with the alpha 1B-adrenoceptor-alkylating agent, chloroethylclonidine (50 microM, 30 min), shifted phenylephrine concentration-response curves to the right (4 fold) only when the alpha 2-adrenoceptor antagonist idazoxan (100 nM) was included during the pre-incubation with chloroethylclonidine. 2. Xylazine (1 microM) significantly shifted phenylephrine concentration-response curves to the left (3 fold); this effect was attenuated by idazoxan (100 nM). Both the incubation of preparations with nifedipine (10 microM) and the pre-incubation of preparations with chloroethylclonidine (50 microM, 30 min) attenuated the potentiating effects of xylazine (1 microM). Protection of alpha 2-adrenoceptors with idazoxan (100 nM) during the chloroethylclonidine (50 microM, 30 min) incubation restored the xylazine-mediated enhancement of phenylephrine concentration-response curves. Pertussis toxin (200 ng ml-1, 24 h) attenuated the xylazine (1 microM)-mediated potentiation of phenylephrine concentration-response curves. 3. Following the pre-incubation of preparations with chloroethylclonidine (50 microM, 30 min) 5-methylurapidil (10 nM to 3 microM) shifted phenylephrine concentration-response curves, in parallel, to the right with mean pKB values in the range of 8.27 (at 10 nM 5-methylurapidil) to 7.76 (at 3 microM 5-methylurapidil), the addition of idazoxan (100 nM) to the incubation medium did not significantly affect the 5-methylurapidil (10 to 300 nM) pKB values (8.41 to 7.64, respectively

  1. Structure-affinity/activity relationships of 1,4-dioxa-spiro[4.5]decane based ligands at α<alpha>1 and 5-HT1A receptors.

    PubMed

    Franchini, Silvia; Battisti, Umberto M; Baraldi, Annamaria; Prandi, Adolfo; Fossa, Paola; Cichero, Elena; Tait, Annalisa; Sorbi, Claudia; Marucci, Gabriella; Cilia, Antonio; Pirona, Lorenza; Brasili, Livio

    2014-11-24

    Recently, 1-(1,4-dioxaspiro[4,5]dec-2-ylmethyl)-4-(2-methoxyphenyl)piperazine (1) was reported as a highly selective and potent 5-HT1AR ligand. In the present work we adopted an in-parallel synthetic strategy to rapidly explore a new set of arylpiperazine (7-32) that is structurally related to 1. The compounds were tested for binding affinity and functional activity at 5-HT1AR and α<alpha>1-adrenoceptor subtypes and SAR studies were drawn. In particular, compounds 9, 27 and 30 emerged as promising α<alpha>1 receptor antagonists, while compound 10 behaves as the most potent and efficacious 5-HT1AR agonist. All the compounds were docked into the 5HT1AR theoretical model and the results were in agreement with the biological experimental data. These findings may represent a new starting point for developing more selective α<alpha>1 or 5-HT1AR ligands. PMID:25261823

  2. Calibration issues in delta alpha /alpha .

    NASA Astrophysics Data System (ADS)

    Molaro, Paolo; Centurión, Miriam; Levshakov, Sergei

    Laser Comb Wavelength calibration shows that the ThAr one is locally unreliable with possible deviations of up to 100 {m s}-1 within one order range, while delivering an overall 1 {m s}-1 accuracy (Wilken et al 2009). Such deviation corresponds to delta alpha /alpha ≈ 7* 10-6 for a Fe II-Mg II pair. Comparison of line shifts among the 5 Fe II lines, with almost identical sensitivity to fine structure constant changes, offers a clean way to directly test the presence of possible local wavelength calibration errors of whatever origin. We analyzed 5 absorption systems, with zabs ranging from 1.15 to 2.19 towards 3 bright QSOs. The results show that while some lines are aligned within 20 {m s}-1, others reveal large deviations reaching 200 {m s}-1 or higher and corresponding to a delta alpha /alpha > 10-5 level. The origin of these deviations is not clearly identified but could be related to the adaptation of wavelength calibration to CCD manufacturing irregularities. These results suggest that to draw conclusions from delta alpha /alpha analysis based on one or only few lines must be done with extreme care.

  3. Evidence that locus coeruleus is the site where clonidine and drugs acting at alpha 1- and alpha 2-adrenoceptors affect sleep and arousal mechanisms.

    PubMed Central

    De Sarro, G. B.; Ascioti, C.; Froio, F.; Libri, V.; Nisticò, G.

    1987-01-01

    The behavioural and electrocortical (ECoG) effects of clonidine were studied after microinjection into the third cerebral ventricle, or microinfusion into some specific areas of the rat brain rich in noradrenaline-containing cell bodies (locus coeruleus) or into areas receiving noradrenergic terminals (dorsal hippocampus, amygdaloid complex, thalamus, frontal and sensimotor cortex). The ECoG effects were continuously analysed and quantified by means of a Berg-Fourier analyser as total power and as power in preselected bands of frequency. Clonidine (9.4 to 75 nmol) given into the third cerebral ventricle produced behavioural sedation and sleep and a dose-dependent increase in ECoG total voltage power as well as in the lower frequency bands. Much lower doses were required to produce similar behavioural and ECoG spectrum power effects after either unilateral or bilateral microinfusion of clonidine into the locus coeruleus. Doses of clonidine equimolar to those given into the third cerebral ventricle, were almost ineffective in inducing behavioural and ECoG sleep after their microinfusion into the dorsal hippocampus. In addition, a dose (0.56 nmol) of clonidine which, given into the locus coeruleus, produced marked behavioural sleep and ECoG synchronization, lacked effects when given into the ventral or anterior thalamus, into the amygdaloid complex or onto the frontal and sensimotor cortex. The behavioural and ECoG spectrum power effects of clonidine given into the third cerebral ventricle or into the locus coeruleus were prevented by antagonists of alpha 2-adrenoceptors but not by alpha 1-adrenoceptor antagonists. Intraventricular microinjection, or microinfusion into the locus coeruleus, of yohimbine, a selective alpha 2-adrenoceptor antagonist, produced behavioural arousal, increase in locomotor and exploratory activity, tachypnoea and ECoG desynchronization with a significant reduction in total voltage power. Similar stimulatory effects were also observed after

  4. Alpha-adrenoceptors in dog mesenteric vessels--subcellular distribution and number of ( sup 3 H)prazosin and ( sup 3 H)rauwolscine binding sites

    SciTech Connect

    Shi, A.G.; Ahmad, S.; Kwan, C.Y.; Daniel, E.E. )

    1990-04-01

    Binding of the alpha-adrenergic antagonists ({sup 3}H)prazosin and ({sup 3}H)rauwolscine to well-characterized subcellular membrane fractions isolated from dog mesenteric arteries and veins was studied. Binding of both ligands was saturable with Kd values of 0.5 +/- 0.1 nM for ({sup 3}H)prazosin and 5.85 +/- 0.85 nM for ({sup 3}H)rauwolscine in arteries, and 0.87 +/- 0.4 nM for ({sup 3}H)prazosin and 6.6 +/- 1.5 nM for ({sup 3}H)rauwolscine in veins. In veins, the maximum number of binding sites for ({sup 3}H)rauwolscine was higher than that for ({sup 3}H)prazosin, whereas in arteries the maximum number of binding sites for each ligand was similar. In microsomes from dog aorta, the maximum number of bindings sites for ({sup 3}H)prazosin was higher than that for ({sup 3}H)rauwolscine. Neuronal membrane contamination in these studies was minimized by dissection procedures and evaluated by the comparison of ({sup 3}H)saxitoxin binding in various preparations. Only mesenteric veins responded functionally to agonists acting on alpha 2 adrenoceptors. This study thus identified two distinct populations of ({sup 3}H)prazosin and ({sup 3}H)rauwolscine binding sites in the plasma membranes of dog mesenteric vessels and suggests that a much higher density of alpha 2-compared to alpha 1-adrenoceptor binding sites is required for a contractile response.

  5. The 5-HT and alpha-adrenoceptor antagonist effect of four benzylisoquinoline alkaloids on rat aorta.

    PubMed

    Catret, M; Ivorra, M D; D'Ocón, M P; Anselmi, E

    1998-03-01

    The action of four benzylisoquinoline alkaloids (two aporphines-glaucine and apomorphine, a benzylisoquinoline-papaverine and a bisbenzyltetrahydroisoquinoline-antioquine) on 5-HT-induced contraction in rat thoracic aorta has been examined and compared with that of the control drugs: ketanserin, nifedipine, prazosin and phentolamine. The relaxant action on 5-HT-induced contraction was contrasted with that on the contraction induced by noradrenaline and KCl. The results obtained with control drugs show that ketanserin has clear selectivity for 5-HT receptors, whereas prazosin and phentolamine have high selectivity for the alpha1-adrenoceptor and nifedipine seems to have a more potent effect on KCl-induced contraction than on that induced by 5-HT or noradrenaline. The contraction evoked by 5-HT (10 microM) was inhibited in a concentration-dependent manner by all the alkaloids. The order of potency was: papaverine = glaucine > apomorphine > antioquine. Papaverine had a non-specific relaxant action on 5-HT-, noradrenaline- and KCl-induced contraction, antioquine had a weak relaxant action on the agonist assays, and glaucine and apomorphine inhibited noradrenaline- and 5-HT-induced contraction more potently than they inhibited the K+-depolarized response. These results indicate that the aporphines assayed, S-glaucine and R-aporphine, had selective action against agonist (noradrenaline or 5-HT)-induced contraction rather than against KCl-depolarization of rat aorta. In contrast papaverine, a benzylisoquinoline alkaloid, relaxes all agents used non-selectively as could be expected from the lack of specificity that characterizes this alkaloid. PMID:9600725

  6. Alpha-particle diagnostics

    SciTech Connect

    Young, K.M.

    1991-01-01

    This paper will focus on the state of development of diagnostics which are expected to provide the information needed for {alpha}- physics studies in the future. Conventional measurement of detailed temporal and spatial profiles of background plasma properties in DT will be essential for such aspects as determining heating effectiveness, shaping of the plasma profiles and effects of MHD, but will not be addressed here. This paper will address (1) the measurement of the neutron source, and hence {alpha}-particle birth profile, (2) measurement of the escaping {alpha}-particles and (3) measurement of the confined {alpha}-particles over their full energy range. There will also be a brief discussion of (4) the concerns about instabilities being generated by {alpha}-particles and the methods necessary for measuring these effects. 51 refs., 10 figs.

  7. Event counting alpha detector

    DOEpatents

    Bolton, Richard D.; MacArthur, Duncan W.

    1996-01-01

    An electrostatic detector for atmospheric radon or other weak sources of alpha radiation. In one embodiment, nested enclosures are insulated from one another, open at the top, and have a high voltage pin inside and insulated from the inside enclosure. An electric field is produced between the pin and the inside enclosure. Air ions produced by collision with alpha particles inside the decay volume defined by the inside enclosure are attracted to the pin and the inner enclosure. With low alpha concentrations, individual alpha events can be measured to indicate the presence of radon or other alpha radiation. In another embodiment, an electrical field is produced between parallel plates which are insulated from a single decay cavity enclosure.

  8. Imaging alpha particle detector

    DOEpatents

    Anderson, D.F.

    1980-10-29

    A method and apparatus for detecting and imaging alpha particles sources is described. A dielectric coated high voltage electrode and a tungsten wire grid constitute a diode configuration discharge generator for electrons dislodged from atoms or molecules located in between these electrodes when struck by alpha particles from a source to be quantitatively or qualitatively analyzed. A thin polyester film window allows the alpha particles to pass into the gas enclosure and the combination of the glass electrode, grid and window is light transparent such that the details of the source which is imaged with high resolution and sensitivity by the sparks produced can be observed visually as well. The source can be viewed directly, electronically counted or integrated over time using photographic methods. A significant increase in sensitivity over other alpha particle detectors is observed, and the device has very low sensitivity to gamma or beta emissions which might otherwise appear as noise on the alpha particle signal.

  9. Imaging alpha particle detector

    DOEpatents

    Anderson, David F.

    1985-01-01

    A method and apparatus for detecting and imaging alpha particles sources is described. A conducting coated high voltage electrode (1) and a tungsten wire grid (2) constitute a diode configuration discharge generator for electrons dislodged from atoms or molecules located in between these electrodes when struck by alpha particles from a source (3) to be quantitatively or qualitatively analyzed. A thin polyester film window (4) allows the alpha particles to pass into the gas enclosure and the combination of the glass electrode, grid and window is light transparent such that the details of the source which is imaged with high resolution and sensitivity by the sparks produced can be observed visually as well. The source can be viewed directly, electronically counted or integrated over time using photographic methods. A significant increase in sensitivity over other alpha particle detectors is observed, and the device has very low sensitivity to gamma or beta emissions which might otherwise appear as noise on the alpha particle signal.

  10. Event counting alpha detector

    DOEpatents

    Bolton, R.D.; MacArthur, D.W.

    1996-08-27

    An electrostatic detector is disclosed for atmospheric radon or other weak sources of alpha radiation. In one embodiment, nested enclosures are insulated from one another, open at the top, and have a high voltage pin inside and insulated from the inside enclosure. An electric field is produced between the pin and the inside enclosure. Air ions produced by collision with alpha particles inside the decay volume defined by the inside enclosure are attracted to the pin and the inner enclosure. With low alpha concentrations, individual alpha events can be measured to indicate the presence of radon or other alpha radiation. In another embodiment, an electrical field is produced between parallel plates which are insulated from a single decay cavity enclosure. 6 figs.

  11. The alpha channeling effect

    SciTech Connect

    Fisch, N. J.

    2015-12-10

    Alpha particles born through fusion reactions in a tokamak reactor tend to slow down on electrons, but that could take up to hundreds of milliseconds. Before that happens, the energy in these alpha particles can destabilize on collisionless timescales toroidal Alfven modes and other waves, in a way deleterious to energy confinement. However, it has been speculated that this energy might be instead be channeled into useful energy, so as to heat fuel ions or to drive current. Such a channeling needs to be catalyzed by waves Waves can produce diffusion in energy of the alpha particles in a way that is strictly coupled to diffusion in space. If these diffusion paths in energy-position space point from high energy in the center to low energy on the periphery, then alpha particles will be cooled while forced to the periphery. The energy from the alpha particles is absorbed by the wave. The amplified wave can then heat ions or drive current. This process or paradigm for extracting alpha particle energy collisionlessly has been called alpha channeling. While the effect is speculative, the upside potential for economical fusion is immense. The paradigm also operates more generally in other contexts of magnetically confined plasma.

  12. Alpha-thalassaemia.

    PubMed

    Harteveld, Cornelis L; Higgs, Douglas R

    2010-01-01

    Alpha-thalassaemia is inherited as an autosomal recessive disorder characterised by a microcytic hypochromic anaemia, and a clinical phenotype varying from almost asymptomatic to a lethal haemolytic anaemia.It is probably the most common monogenic gene disorder in the world and is especially frequent in Mediterranean countries, South-East Asia, Africa, the Middle East and in the Indian subcontinent. During the last few decades the incidence of alpha thalassaemia in North-European countries and Northern America has increased because of demographic changes. Compound heterozygotes and some homozygotes have a moderate to severe form of alpha thalassaemia called HbH disease. Hb Bart's hydrops foetalis is a lethal form in which no alpha-globin is synthesized. Alpha thalassaemia most frequently results from deletion of one or both alpha genes from the chromosome and can be classified according to its genotype/phenotype correlation. The normal complement of four functional alpha-globin genes may be decreased by 1, 2, 3 or all 4 copies of the genes, explaining the clinical variation and increasing severity of the disease. All affected individuals have a variable degree of anaemia (low Hb), reduced mean corpuscular haemoglobin (MCH/pg), reduced mean corpuscular volume (MCV/fl) and a normal/slightly reduced level of HbA2. Molecular analysis is usually required to confirm the haematological observations (especially in silent alpha-thalassaemia and alpha-thalassaemia trait). The predominant features in HbH disease are anaemia with variable amounts of HbH (0.8-40%). The type of mutation influences the clinical severity of HbH disease. The distinguishing features of the haemoglobin Bart's hydrops foetalis syndrome are the presence of Hb Bart's and the total absence of HbF. The mode of transmission of alpha thalassaemia is autosomal recessive. Genetic counselling is offered to couples at risk for HbH disease or haemoglobin Bart's Hydrops Foetalis Syndrome. Carriers of alpha+- or

  13. Alpha Particle Diagnostic

    SciTech Connect

    Fisher, Ray, K.

    2009-05-13

    The study of burning plasmas is the next frontier in fusion energy research, and will be a major objective of the U.S. fusion program through U.S. collaboration with our international partners on the ITER Project. For DT magnetic fusion to be useful for energy production, it is essential that the energetic alpha particles produced by the fusion reactions be confined long enough to deposit a significant fraction of their initial ~3.5 MeV energy in the plasma before they are lost. Development of diagnostics to study the behavior of energetic confined alpha particles is a very important if not essential part of burning plasma research. Despite the clear need for these measurements, development of diagnostics to study confined the fast confined alphas to date has proven extremely difficult, and the available techniques remain for the most part unproven and with significant uncertainties. Research under this grant had the goal of developing diagnostics of fast confined alphas, primarily based on measurements of the neutron and ion tails resulting from alpha particle knock-on collisions with the plasma deuterium and tritium fuel ions. One of the strengths of this approach is the ability to measure the alphas in the hot plasma core where the interesting ignition physics will occur.

  14. ALPHA MIS: Reference manual

    SciTech Connect

    Lovin, J.K.; Haese, R.L.; Heatherly, R.D.; Hughes, S.E.; Ishee, J.S.; Pratt, S.M.; Smith, D.W.

    1992-02-01

    ALPHA is a powerful and versatile management information system (MIS) initiated and sponsored and by the Finance and Business Management Division of Oak Ridge National Laboratory, who maintain and develop it in concert with the Business Systems Division for its Information Center. A general-purpose MIS, ALPHA allows users to access System 1022 and System 1032 databases to obtain and manage information. From a personal computer or a data terminal, Energy Systems employees can use ALPHA to control their own report reprocessing. Using four general commands (Database, Select, Sort, and Report) they can (1) choose a mainframe database, (2) define subsets within it, (3) sequentially order a subset by one or more variables, and (4) generate a report with their own or a canned format.

  15. The Apollo Alpha Spectrometer.

    NASA Technical Reports Server (NTRS)

    Jagoda, N.; Kubierschky, K.; Frank, R.; Carroll, J.

    1973-01-01

    Located in the Science Instrument Module of Apollo 15 and 16, the Alpha Particle Spectrometer was designed to detect and measure the energy of alpha particles emitted by the radon isotopes and their daughter products. The spectrometer sensor consisted of an array of totally depleted silicon surface barrier detectors. Biased amplifier and linear gate techniques were utilized to reduce resolution degradation, thereby permitting the use of a single 512 channel PHA. Sensor identification and in-flight radioactive calibration were incorporated to enhance data reduction.

  16. The Lyman alpha coronagraph

    NASA Technical Reports Server (NTRS)

    Kohl, J. L.; Reeves, E. M.; Kirkham, B.

    1977-01-01

    The rocket-borne Lyman alpha coronagraph (RLAC) is to be used in the absence of a natural solar eclipse to determine coronal temperatures from measurements of the line width of Lyman-alpha and to determine neutral hydrogen densities of coronal material from the absolute intensity. The coronagraph consists of a 75-cm Fastie-Ebert scanning spectrometer with an AMR 641 photoelectric detection system, an off-axis parabolic primary mirror, and an occulting system. A special optical arrangement achieves rejection of radiation from the solar disk.

  17. [alpha]-Oxocarboxylic Acids

    ERIC Educational Resources Information Center

    Kerber, Robert C.; Fernando, Marian S.

    2010-01-01

    Several [alpha]-oxocarboxylic acids play key roles in metabolism in plants and animals. However, there are inconsistencies between the structures as commonly portrayed and the reported acid ionization constants, which result because the acids are predominantly hydrated in aqueous solution; that is, the predominant form is RC(OH)[subscript 2]COOH…

  18. From Alpha to Omega

    ERIC Educational Resources Information Center

    Czaja, Paul Clement

    2006-01-01

    The Alpha point of the authors' life as a Montessori educator began in 1959, when he was a graduate student studying philosophy at Fordham University in the Bronx, New York. While studying the works of the great American philosopher William James, the author came across the writings of Maria Montessori and immediately became captivated by her…

  19. Summary of Alpha Particle Transport

    SciTech Connect

    Medley, S.S.; White, R.B.; Zweben, S.J.

    1998-08-19

    This paper summarizes the talks on alpha particle transport which were presented at the 5th International Atomic Energy Agency's Technical Committee Meeting on "Alpha Particles in Fusion Research" held at the Joint European Torus, England in September 1997.

  20. Alpha Condensates in Atomic Nuclei

    SciTech Connect

    Suzuki, Y.; Matsumura, H.

    2005-11-21

    Recent issues on Bose-Einstein condensation (BEC) of {alpha}-particles in nuclei are reviewed. A candidate of condensates is discussed for some states in 12C and 16O by defining the amount of {alpha} condensation.

  1. Development and identification of monoclonal antibodies against meso-Tetra (alpha,alpha,alpha,alpha,-O-phenylacetamide benzene) porphyrin.

    PubMed

    Wang, Fengyang; Huang, Xueying; Du, Li; Li, Weiguo; Qi, Chao

    2007-04-01

    The small molecule meso-Tetra (alpha,alpha,alpha,alpha-o-phenylacetamide benzene) porphyrin was synthesized through the condensation of o-nitrobenzaldehyde and pyrrole followed by reduction of the meso-tetra (o-nitrophenyl) porphyrin. The small molecule, without carrier, was used as complete antigen to immunize BALB/ C mice. Spleen cells producing high titer antibody were removed and fused with myeloma cells of SP2/0 origin. Using a conventional immunization protocol, stable murine monoclonal antibodies (MAbs) producing cell lines to meso-Tetra (alpha,alpha,alpha,alpha-o-phenylacetamide benzene) porphyrin 1F2 were obtained. Subclass determination showed that the clones produce IgG2a types of MAbs. The analytical results of HPLC and MALDI/TOFMS suggest that the purity of MAb 1F2 is 100%, and MAb 1F2 has a relative molecular weight of 156678.8 Da. Our results demonstrated that small molecule meso-Tetra (alpha,alpha,alpha,alpha-o-phenylacetamide benzene) porphyrin, as semiantigen without carrier, can elicit the formation of MAbs. PMID:17451352

  2. Alpha-globin loci in homozygous beta-thalassemia intermedia.

    PubMed

    Triadou, P; Lapoumeroulie, C; Girot, R; Labie, D

    1983-01-01

    Homozygous beta-thalassemia intermediate (TI) differs from thalassemia major (TM) in being less severe clinically. Associated alpha-thalassemia could account for the TI phenotype by reducing the alpha/non-alpha chain imbalance. We have analyzed the alpha loci of 9 TI and 11 TM patients by restriction endonuclease mapping. All the TM and 7 of the TI patients have the normal complement of four alpha-globin genes (alpha alpha/alpha alpha). One TI patient has three alpha-globin genes (alpha alpha/-alpha), and another TI patient has five alpha genes (alpha alpha/alpha alpha alpha). PMID:6305827

  3. Alpha-mannosidosis

    PubMed Central

    Malm, Dag; Nilssen, Øivind

    2008-01-01

    Alpha-mannosidosis is an inherited lysosomal storage disorder characterized by immune deficiency, facial and skeletal abnormalities, hearing impairment, and intellectual disability. It occurs in approximately 1 of 500,000 live births. The children are often born apparently normal, and their condition worsens progressively. Some children are born with ankle equinus or develop hydrocephalus in the first year of life. Main features are immune deficiency (manifested by recurrent infections, especially in the first decade of life), skeletal abnormalities (mild-to-moderate dysostosis multiplex, scoliosis and deformation of the sternum), hearing impairment (moderate-to-severe sensorineural hearing loss), gradual impairment of mental functions and speech, and often, periods of psychosis. Associated motor function disturbances include muscular weakness, joint abnormalities and ataxia. The facial trait include large head with prominent forehead, rounded eyebrows, flattened nasal bridge, macroglossia, widely spaced teeth, and prognathism. Slight strabismus is common. The clinical variability is significant, representing a continuum in severity. The disorder is caused by lysosomal alpha-mannosidase deficiency. Alpha-mannosidosis is inherited in an autosomal recessive fashion and is caused by mutations in the MAN2B1 gene located on chromosome 19 (19 p13.2-q12). Diagnosis is made by measuring acid alpha-mannosidase activity in leukocytes or other nucleated cells and can be confirmed by genetic testing. Elevated urinary secretion of mannose-rich oligosaccharides is suggestive, but not diagnostic. Differential diagnoses are mainly the other lysosomal storage diseases like the mucopolysaccharidoses. Genetic counseling should be given to explain the nature of the disease and to detect carriers. Antenatal diagnosis is possible, based on both biochemical and genetic methods. The management should be pro-active, preventing complications and treating manifestations. Infections must be

  4. Background canceling surface alpha detector

    DOEpatents

    MacArthur, Duncan W.; Allander, Krag S.; Bounds, John A.

    1996-01-01

    A background canceling long range alpha detector which is capable of providing output proportional to both the alpha radiation emitted from a surface and to radioactive gas emanating from the surface. The detector operates by using an electrical field between first and second signal planes, an enclosure and the surface or substance to be monitored for alpha radiation. The first and second signal planes are maintained at the same voltage with respect to the electrically conductive enclosure, reducing leakage currents. In the presence of alpha radiation and radioactive gas decay, the signal from the first signal plane is proportional to both the surface alpha radiation and to the airborne radioactive gas, while the signal from the second signal plane is proportional only to the airborne radioactive gas. The difference between these two signals is proportional to the surface alpha radiation alone.

  5. Background canceling surface alpha detector

    DOEpatents

    MacArthur, D.W.; Allander, K.S.; Bounds, J.A.

    1996-06-11

    A background canceling long range alpha detector which is capable of providing output proportional to both the alpha radiation emitted from a surface and to radioactive gas emanating from the surface. The detector operates by using an electrical field between first and second signal planes, an enclosure and the surface or substance to be monitored for alpha radiation. The first and second signal planes are maintained at the same voltage with respect to the electrically conductive enclosure, reducing leakage currents. In the presence of alpha radiation and radioactive gas decay, the signal from the first signal plane is proportional to both the surface alpha radiation and to the airborne radioactive gas, while the signal from the second signal plane is proportional only to the airborne radioactive gas. The difference between these two signals is proportional to the surface alpha radiation alone. 5 figs.

  6. Proteinaceous alpha-amylase inhibitors.

    PubMed

    Svensson, Birte; Fukuda, Kenji; Nielsen, Peter K; Bønsager, Birgit C

    2004-02-12

    Proteins that inhibit alpha-amylases have been isolated from plants and microorganisms. These inhibitors can have natural roles in the control of endogenous alpha-amylase activity or in defence against pathogens and pests; certain inhibitors are reported to be antinutritional factors. The alpha-amylase inhibitors belong to seven different protein structural families, most of which also contain evolutionary related proteins without inhibitory activity. Two families include bifunctional inhibitors acting both on alpha-amylases and proteases. High-resolution structures are available of target alpha-amylases in complex with inhibitors from five families. These structures indicate major diversity but also some similarity in the structural basis of alpha-amylase inhibition. Mutational analysis of the mechanism of inhibition was performed in a few cases and various protein engineering and biotechnological approaches have been outlined for exploitation of the inhibitory function. PMID:14871655

  7. Long range alpha particle detector

    DOEpatents

    MacArthur, Duncan W.; Wolf, Michael A.; McAtee, James L.; Unruh, Wesley P.; Cucchiara, Alfred L.; Huchton, Roger L.

    1993-01-01

    An alpha particle detector capable of detecting alpha radiation from distant sources. In one embodiment, a high voltage is generated in a first electrically conductive mesh while a fan draws air containing air molecules ionized by alpha particles through an air passage and across a second electrically conductive mesh. The current in the second electrically conductive mesh can be detected and used for measurement or alarm. The detector can be used for area, personnel and equipment monitoring.

  8. Long range alpha particle detector

    DOEpatents

    MacArthur, D.W.; Wolf, M.A.; McAtee, J.L.; Unruh, W.P.; Cucchiara, A.L.; Huchton, R.L.

    1993-02-02

    An alpha particle detector capable of detecting alpha radiation from distant sources. In one embodiment, a high voltage is generated in a first electrically conductive mesh while a fan draws air containing air molecules ionized by alpha particles through an air passage and across a second electrically conductive mesh. The current in the second electrically conductive mesh can be detected and used for measurement or alarm. The detector can be used for area, personnel and equipment monitoring.

  9. Modeling Solar Lyman Alpha Irradiance

    NASA Technical Reports Server (NTRS)

    Pap, J.; Hudson, H. S.; Rottman, G. J.; Willson, R. C.; Donnelly, R. F.; London, J.

    1990-01-01

    Solar Lyman alpha irradiance is estimated from various solar indices using linear regression analyses. Models developed with multiple linear regression analysis, including daily values and 81-day running means of solar indices, predict reasonably well both the short- and long-term variations observed in Lyman alpha. It is shown that the full disk equivalent width of the He line at 1083 nm offers the best proxy for Lyman alpha, and that the total irradiance corrected for sunspot effect also has a high correlation with Lyman alpha.

  10. ISS Update: Alpha Magnetic Spectrometer

    NASA Video Gallery

    NASA Public Affairs Officer Kelly Humphries interviews Trent Martin, Johnson Space Center project manager for the Alpha Magnetic Spectrometer (AMS) aboard the International Space Station. Questions...

  11. Alpha Kappa Alpha Sorority's Reading Improvement Program for Minorities.

    ERIC Educational Resources Information Center

    Marable, June Morehead

    This document discusses the founding and establishment of Alpha Kappa Alpha Sorority's reading experience pilot project. The efforts of this project were aligned with those of Right to Read and Reading Is Fundamental (RIF). Because of the response from parents and children, plans are being made to increase present operations within the next…

  12. Microscopic cluster model of {alpha}+n, {alpha}+p, {alpha}+ {sup 3}He, and {alpha}+{alpha} elastic scattering from a realistic effective nuclear interaction

    SciTech Connect

    Dohet-Eraly, J.; Baye, D.

    2011-07-15

    An effective nucleon-nucleon interaction adapted to cluster-model calculations of collisions is derived from the realistic Argonne potential AV18 with the unitary correlation operator method. The unitary correlation is determined from the {alpha}+{alpha} elastic phase shifts calculated in a cluster approach by the generator coordinate method coupled with the microscopic R-matrix method. With this interaction, the elastic phase shifts for the {alpha}+n, {alpha}+p, and {alpha}+{sup 3}He collisions are calculated within the same model. Without further adjustment, a good agreement with experimental data is obtained with a small model space.

  13. Alpha glucosidase inhibitors.

    PubMed

    Kalra, Sanjay

    2014-04-01

    Alpha glucosidase inhibitors (AGIs) are a unique class of anti-diabetic drugs. Derived from bacteria, these oral drugs are enzyme inhibitors which do not have a pancreato -centred mechanism of action. Working to delay carbohydrate absorption in the gastrointestinal tract, they control postprandial hyperglycaemia and provide unquestioned cardiovascular benefit. Specially suited for a traditional Pakistani carbohydrate-rich diet, AGIs have been termed the 'untapped diamonds' of diabetology. The use of these oral antidiabetic drugs (OADs) that target pathophysiology in the early stages of type 2 diabetes, notably to reduce postprandial hyperglycaemia and hyperinsulinaemia will inevitably increase with time. This review describes the history of their development, mechanism of action, basic and clinical pharmacology, and suggests practical, evidence-based guidance for their optimal use. PMID:24864650

  14. DFT CONFORMATIONAL STUDIES OF ALPHA-MALTOTRIOSE

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Recent DFT optimization studies on alpha-maltose improved our understanding of the preferred conformations of alpha-maltose and the present study extends these studies to alpha-maltotriose with three alpha-D-glucopyranose residues linked by two alpha-[1-4] bridges, denoted herein as DP-3's. Combina...

  15. Prothymosin alpha in human blood.

    PubMed Central

    Panneerselvam, C; Haritos, A A; Caldarella, J; Horecker, B L

    1987-01-01

    The major cross-reacting peptide in human plasma detected with a radioimmunoassay (RIA) for thymosin alpha 1 was identified as prothymosin alpha, based on its elution properties in gel-filtration chromatography and its amino acid composition after purification by HPLC. A small quantity (less than 10%) of the total cross-reacting material was recovered in fractions corresponding to lower molecular weight thymosin alpha 1-like peptides. The total quantity of cross-reacting material detected in human blood, expressed as thymosin alpha 1 equivalents, was 11-14 pmol/ml (approximately 90% was recovered in the leukocyte fraction, approximately 10% was in the plasma fraction, and 1-2% was in the erythrocyte fraction). The peptide present in leukocytes was also identified as prothymosin alpha. After correction for the 5-times lower molar reactivity of prothymosin alpha in the thymosin alpha 1 RIA employed in these experiments, we estimate that the content of prothymosin alpha in human blood is 55-70 pmol/ml (0.6-0.8 microgram/ml). The relatively small quantities recovered in the erythrocyte and plasma fractions may be attributed to contamination of the former by leukocytes or to leakage from leukocytes into the plasma. PMID:3474615

  16. Alpha particle emitters in medicine

    SciTech Connect

    Fisher, D.R.

    1989-09-01

    Radiation-induced cancer of bone, liver and lung has been a prominent harmful side-effect of medical applications of alpha emitters. In recent years, however, the potential use of antibodies labeled with alpha emitting radionuclides against cancer has seemed promising because alpha particles are highly effective in cell killing. High dose rates at high LET, effectiveness under hypoxic conditions, and minimal expectancy of repair are additional advantages of alpha emitters over antibodies labeled with beta emitting radionuclides for cancer therapy. Cyclotron-produced astatine-211 ({sup 211}At) and natural bismuth-212 ({sup 212}Bi) have been proposed and are under extensive study in the United States and Europe. Radium-223 ({sup 223}Ra) also has favorable properties as a potential alpha emitting label, including a short-lived daughter chain with four alpha emissions. The radiation dosimetry of internal alpha emitters is complex due to nonuniformly distributed sources, short particle tracks, and high relative specific ionization. The variations in dose at the cellular level may be extreme. Alpha-particle radiation dosimetry, therefore, must involve analysis of statistical energy deposition probabilities for cellular level targets. It must also account fully for nonuniform distributions of sources in tissues, source-target geometries, and particle-track physics. 18 refs., 4 figs.

  17. EEG Alpha Power and Intelligence.

    ERIC Educational Resources Information Center

    Doppelmayr, M.; Klimesch, W.; Stadler, W.; Pollhuber, D.; Heine, C.

    2002-01-01

    Tested whether alpha power in different sub-bands is selectively related to intelligence. For 74 Austrian subjects, the EEG was recorded during a resting session and 2 different intelligence tests were performed. Findings show a strong positive correlation between intelligence and alpha power. (SLD)

  18. Alpha Schottky junction energy source

    NASA Astrophysics Data System (ADS)

    Litz, Marc S.; Fan, Zhaoyang; Carroll, James J.; Bayne, Stephen

    2012-06-01

    Isotope batteries offer solutions for long-lived low-power sensor requirements. Alpha emitting isotopes have energy per decay 103 times that of beta emitters. Alpha particles are absorbed within 20 μm of most materials reducing shielding mitigation. However, damage to materials from the alphas limits their practical use. A Schottky Barrier Diode (SBD) geometry is considered with an alpha emitting contact-layer on a diamond-like crystal semiconductor region. The radiation tolerance of diamond, the safety of alpha particles, combined with the internal field of the SBD is expected to generate current useful for low-power electronic devices over decades. Device design parameters and calculations of the expected current are described.

  19. Genetics Home Reference: alpha-mannosidosis

    MedlinePlus

    ... Me Understand Genetics Home Health Conditions alpha-mannosidosis alpha-mannosidosis Enable Javascript to view the expand/collapse boxes. Download PDF Open All Close All Description Alpha-mannosidosis is a rare inherited disorder that causes ...

  20. Alpha-particle spectrometer experiment

    NASA Technical Reports Server (NTRS)

    Gorenstein, P.; Bjorkholm, P.

    1972-01-01

    Mapping the radon emanation of the moon was studied to find potential areas of high activity by detection of radon isotopes and their daughter products. It was felt that based on observation of regions overflown by Apollo spacecraft and within the field of view of the alpha-particle spectrometer, a radon map could be constructed, identifying and locating lunar areas of outgassing. The basic theory of radon migration from natural concentrations of uranium and thorium is discussed in terms of radon decay and the production of alpha particles. The preliminary analysis of the results indicates no significant alpha emission.

  1. Binding of tumor necrosis factor alpha to activated forms of human plasma alpha 2 macroglobulin.

    PubMed Central

    Wollenberg, G. K.; LaMarre, J.; Rosendal, S.; Gonias, S. L.; Hayes, M. A.

    1991-01-01

    We tested the hypothesis that human plasma alpha 2 macroglobulin (alpha 2M) is a latent binding glycoprotein for human tumor necrosis factor alpha (TNF-alpha). Human recombinant 125I-TNF-alpha was incubated for 2 hours (37 degrees C) with purified native alpha 2M and with alpha 2M that was modified by reaction with methylamine or various proteinases. 125I-TNF-alpha/alpha 2M complexes were detected by nondenaturing polyacrylamide gel electrophoresis after autoradiography or by liquid chromatography on Superose-6. 125I-TNF-alpha bound strongly but noncovalently to alpha 2M-plasmin and alpha 2M-methylamine. There was minimal binding of 125I-TNF-alpha to native alpha 2M, alpha 2M-trypsin, or alpha 2M-thrombin. A 10(6) molar excess of porcine heparin did not reduce the binding of 125I-TNF-alpha to alpha 2M-methylamine or alpha 2M-plasmin. alpha 2M-plasmin or alpha 2M-methylamine added to human plasma or serum preferentially bound 125I-TNF-alpha in the presence of native alpha 2M. 125I-TNF-alpha also bound to 'fast' alpha-macroglobulins in methylamine-reacted human, rat, mouse, swine, equine, and bovine plasma. However, TNF-alpha, preincubated with either alpha 2M-plasmin or alpha 2M-methylamine, remained a potent necrogen for cultured L929 cells. Purified 125I-TNF-alpha/alpha 2M-plasmin complex injected intravenously in CD-1 mice rapidly cleared from the circulation, unless the alpha 2M-receptor pathway was blocked by coinjection of excess alpha 2M-trypsin. These findings demonstrate that alpha 2M is a latent plasmin-activated binding glycoprotein for TNF-alpha and that TNF-alpha/alpha 2M-plasmin complexes can be removed from the circulation by the alpha 2M-receptor pathway. This suggests that alpha 2M may be an important regulator of the activity and distribution of TNF-alpha in vivo. Images Figure 1 Figure 3 PMID:1704186

  2. Genetics Home Reference: alpha thalassemia

    MedlinePlus

    ... in each cell. Each copy is called an allele. For each gene, one allele is inherited from a person's father, and the ... person's mother. As a result, there are four alleles that produce alpha-globin. The different types of ...

  3. Alpha Magnetic Spectrometer (AMS) Overview

    NASA Video Gallery

    The Alpha Magnetic Spectrometer (AMS) is flying to the station on STS-134. The AMS experiment is a state-of-the-art particle physics detector being operated by an international team composed of 60 ...

  4. International Space Station (ISS) Alpha

    NASA Technical Reports Server (NTRS)

    1994-01-01

    An artist's concept of a fully deployed International Space Station (ISS) Alpha. The ISS-A is a multidisciplinary laboratory, technology test bed, and observatory that will provide an unprecedented undertaking in scientific, technological, and international experiments.

  5. Detecting Alpha-1 Antitrypsin Deficiency.

    PubMed

    Stoller, James K

    2016-08-01

    Alpha-1 antitrypsin deficiency is a widely underrecognized condition, with evidence of persisting long diagnostic delays and patients' frequent need to see multiple physicians before initial diagnosis. Reasons for underrecognition include inadequate understanding of alpha-1 antitrypsin deficiency by physicians and allied health care providers; failure to implement available, guideline-based practice recommendations; and the belief that effective therapy is unavailable. Multiple studies have described both the results of screening and targeted detection of individuals with alpha-1 antitrypsin deficiency, with both varying strategies employed to identify at-risk individuals and varying results of testing. Also, various strategies to enhance detection of affected individuals have been examined, including use of the electronic medical record to prompt testing and empowerment of allied health providers, especially respiratory therapists, to promote testing for alpha-1 antitrypsin deficiency. Such efforts are likely to enhance detection with the expected result that the harmful effects of delayed diagnosis can be mitigated. PMID:27564667

  6. Alpha decay in electron surrounding

    SciTech Connect

    Igashov, S. Yu.; Tchuvil’sky, Yu. M.

    2013-12-15

    The influence of atomic electron shells on the constant of alpha decay of heavy and mediummass nuclei was considered in detail. A method for simultaneously taking into account the change in the potential-barrier shape and the effect of reflection of a diverging Coulomb wave in the classically allowed region was developed. The ratios of decay probabilities per unit time for a bare nucleus and the respective neutral atom were found for some alpha-decaying isotopes.

  7. 21 CFR 882.1610 - Alpha monitor.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 21 Food and Drugs 8 2010-04-01 2010-04-01 false Alpha monitor. 882.1610 Section 882.1610 Food and... NEUROLOGICAL DEVICES Neurological Diagnostic Devices § 882.1610 Alpha monitor. (a) Identification. An alpha... electroencephalogram which is referred to as the alpha wave. (b) Classification. Class II (performance standards)....

  8. 21 CFR 882.1610 - Alpha monitor.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 21 Food and Drugs 8 2012-04-01 2012-04-01 false Alpha monitor. 882.1610 Section 882.1610 Food and... NEUROLOGICAL DEVICES Neurological Diagnostic Devices § 882.1610 Alpha monitor. (a) Identification. An alpha... electroencephalogram which is referred to as the alpha wave. (b) Classification. Class II (performance standards)....

  9. 21 CFR 882.1610 - Alpha monitor.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 21 Food and Drugs 8 2013-04-01 2013-04-01 false Alpha monitor. 882.1610 Section 882.1610 Food and... NEUROLOGICAL DEVICES Neurological Diagnostic Devices § 882.1610 Alpha monitor. (a) Identification. An alpha... electroencephalogram which is referred to as the alpha wave. (b) Classification. Class II (performance standards)....

  10. 21 CFR 882.1610 - Alpha monitor.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 21 Food and Drugs 8 2014-04-01 2014-04-01 false Alpha monitor. 882.1610 Section 882.1610 Food and... NEUROLOGICAL DEVICES Neurological Diagnostic Devices § 882.1610 Alpha monitor. (a) Identification. An alpha... electroencephalogram which is referred to as the alpha wave. (b) Classification. Class II (performance standards)....

  11. 21 CFR 882.1610 - Alpha monitor.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 21 Food and Drugs 8 2011-04-01 2011-04-01 false Alpha monitor. 882.1610 Section 882.1610 Food and... NEUROLOGICAL DEVICES Neurological Diagnostic Devices § 882.1610 Alpha monitor. (a) Identification. An alpha... electroencephalogram which is referred to as the alpha wave. (b) Classification. Class II (performance standards)....

  12. Binding of actin to lens alpha crystallins

    NASA Technical Reports Server (NTRS)

    Gopalakrishnan, S.; Takemoto, L.; Spooner, B. S. (Principal Investigator)

    1992-01-01

    Actin has been coupled to a cyanogen bromide-activated Sepharose 4B column, then tested for binding to alpha, beta, and gamma crystallin preparations from the bovine lens. Alpha, but not beta or gamma, crystallins bound to the actin affinity column in a time dependent and saturable manner. Subfractionation of the alpha crystallin preparation into the alpha-A and alpha-B species, followed by incubation with the affinity column, demonstrated that both species bound approximately the same. Together, these studies demonstrate a specific and saturable binding of lens alpha-A and alpha-B with actin.

  13. Mechanism of alpha-tocopheryl-phosphate (alpha-TP) transport across the cell membrane

    Technology Transfer Automated Retrieval System (TEKTRAN)

    We have reported that alpha-TP is synthesized and hydrolyzed in animal cells and tissues; it modulates also several cell functions (FRBM 39:970, and UBMB Life, 57:23, 2005). While it is similar to alpha-tocopherol (alpha-T), alpha-TP appears to be more potent than alpha-T in inhibiting cell prolifer...

  14. Modulation of gene expression by alpha-tocopherol and alpha-tocopheryl phosphate

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The naturally occurring vitamin E analogue, alpha-tocopheryl phosphate (alphaTP), has been reported to be more potent in reducing cell proliferation and the expression of the CD36 scavenger receptor than the un-phosphorylated alpha-tocopherol (alpha T). We have now assessed the effects of alpha T an...

  15. Workshop on Precision Measurements of $\\alpha_s$

    SciTech Connect

    Bethke, Siegfried; Hoang, Andre H.; Kluth, Stefan; Schieck, Jochen; Stewart, Iain W.; Aoki, S.; Beneke, M.; Bethke, S.; Blumlein, J.; Brambilla, N.; Brodsky, S.; /MIT, LNS

    2011-10-01

    These are the proceedings of the Workshop on Precision Measurements of {alpha}{sub s} held at the Max-Planck-Institute for Physics, Munich, February 9-11, 2011. The workshop explored in depth the determination of {alpha}{sub s}(m{sub Z}) in the {ovr MS} scheme from the key categories where high precision measurements are currently being made, including DIS and global PDF fits, {tau}-decays, electro-weak precision observables and Z-decays, event-shapes, and lattice QCD. These proceedings contain a short summary contribution from the speakers, as well as the lists of authors, conveners, participants, and talks.

  16. Immunodiagnosis of alpha chain disease.

    PubMed Central

    Doe, W F; Danon, F; Seligmann, M

    1979-01-01

    Since the early diagnosis of alpha chain disease (alphaCD)) is essential to successful treatment and to epidemiological studies, the available immunodiagnostic techniques were compared for their sensitivity, specificity and ease of performance on a panel of sixteen sera, comprising ten alphaCD sera and six control sera containing either IgA myeloma protein or high levels of polyclonal IgA. Immunoselection by immunoelectrophoresis into gel containing a specially developed anti-Fabalpha antiserum provided the most sensitive and specific detection system for alphaCD protein. The same technique using anti-light chain antiserum for immunoselection was also highly sensitive, but proved less specific, being prone to false positives with difficult IgA myeloma proteins. Somewhat less sensitive, but specific and simple to perform, was immunoelectrophoresis using an antiserum recognizing the conformational specificities of Fabalpha as well as those of the constant region of alpha chains. Immunoselection using the Ouchterlony or rocket techniques proved to be less sensitive and prone to false positives when some IgA myeloma sera were tested. Images FIG. 1 FIG. 2 FIG. 3 FIG. 4 FIG. 5 FIG. 6 FIG. 7 PMID:113152

  17. Space Station alpha joint bearing

    NASA Technical Reports Server (NTRS)

    Everman, Michael R.; Jones, P. Alan; Spencer, Porter A.

    1987-01-01

    Perhaps the most critical structural system aboard the Space Station is the Solar Alpha Rotary Joint which helps align the power generation system with the sun. The joint must provide structural support and controlled rotation to the outboard transverse booms as well as power and data transfer across the joint. The Solar Alpha Rotary Joint is composed of two transition sections and an integral, large diameter bearing. Alpha joint bearing design presents a particularly interesting problem because of its large size and need for high reliability, stiffness, and on orbit maintability. The discrete roller bearing developed is a novel refinement to cam follower technology. It offers thermal compensation and ease of on-orbit maintenance that are not found in conventional rolling element bearings. How the bearing design evolved is summarized. Driving requirements are reviewed, alternative concepts assessed, and the selected design is described.

  18. alpha-Thalassemia caused by an unstable alpha-globin mutant.

    PubMed Central

    Liebhaber, S A; Kan, Y W

    1983-01-01

    In a previous study, molecular cloning of the alpha-globin genes from a patient with nondeletion Hb-H disease (genotype--/alpha alpha) showed that a single nucleotide mutation (CTG to CCG) in one of the genes resulted in a leucine to proline substitution. This paper describes the approach we used to detect the abnormal alpha-globin chain. The chain was identified using a cell-free translation system. It turned over rapidly both in vitro and in vivo in the patient's reticulocytes. The unusual feature of this unstable alpha-globin is that the alpha-globin deficiency causes alpha-thalassemia. Simple heterozygotes for this lesion (alpha Pro alpha/alpha alpha) resemble alpha-thalassemia carriers and do not exhibit the hemolytic anemia usually associated with unstable hemoglobins. Images PMID:6826718

  19. Bremsstrahlung in {alpha} Decay Reexamined

    SciTech Connect

    Boie, H.; Scheit, H.; Jentschura, U. D.; Koeck, F.; Lauer, M.; Schwalm, D.; Milstein, A. I.; Terekhov, I. S.

    2007-07-13

    A high-statistics measurement of bremsstrahlung emitted in the {alpha} decay of {sup 210}Po has been performed, which allows us to follow the photon spectra up to energies of {approx}500 keV. The measured differential emission probability is in good agreement with our theoretical results obtained within the quasiclassical approximation as well as with the exact quantum mechanical calculation. It is shown that, due to the small effective electric dipole charge of the radiating system, a significant interference between the electric dipole and quadrupole contributions occurs, which is altering substantially the angular correlation between the {alpha} particle and the emitted photon.

  20. NACA Physicist Studying Alpha Rays

    NASA Technical Reports Server (NTRS)

    1957-01-01

    NACA Physicits studying Alpha Rays in a continuous cloud chamber. A cloud chamber is used by Lewis scientists to obtain information aimed at minimizing undesirable effects of radiation on nuclear-powered aircraft components. Here, alpha particles from a polonium source emit in a flower-like pattern at the cloud chamber's center. The particles are made visible by means of alcohol vapor diffusing from an area at room temperature to an area at minus -78 deg. Centigrade. Nuclear-powered aircraft were never developed and aircraft nuclear propulsion systems were canceled in the early 1960s.

  1. Test chamber for alpha spectrometry

    DOEpatents

    Larsen, Robert P.

    1977-01-01

    Alpha emitters for low-level radiochemical analysis by measurement of alpha spectra are positioned precisely with respect to the location of a surface-barrier detector by means of a chamber having a removable threaded planchet holder. A pedestal on the planchet holder holds a specimen in fixed engagement close to the detector. Insertion of the planchet holder establishes an O-ring seal that permits the chamber to be pumped to a desired vacuum. The detector is protected against accidental contact and resulting damage.

  2. Synthesis and structure-activity relationships of novel arylpiperazines as potent antagonists of α1-adrenoceptor.

    PubMed

    Silva, Renata Oliveira; de Oliveira, Andressa Souza; Nunes Lemes, Laís Flávia; de Camargo Nascente, Luciana; Coelho do Nascimento Nogueira, Patrícia; Silveira, Edilberto R; Brand, Guilherme D; Vistoli, Giulio; Cilia, Antonio; Poggesi, Elena; Buccioni, Michela; Marucci, Gabriella; Bolognesi, Maria Laura; Romeiro, Luiz Antonio Soares

    2016-10-21

    Arylpiperazines 2-11 were synthesized, and their biological profiles at α1-adrenergic receptors (α1-ARs) assessed by binding assays in CHO cells expressing human cloned subtypes and by functional experiments in isolated rat vas deferens (α1A), spleen (α1B), and aorta (α1D). Modifications at the 1,3-benzodioxole and phenyl phamacophoric units resulted in the identification of a number of potent compounds (moderately selective with respect to the α1b-AR), in binding experiments. Notably, compound 7 (LDT451) showed a subnanomolar pKi of 9.41 towards α1a-AR. An encouragingly lower α1B-potency was a general trend for all the series of compounds, which showed α1A/D over α1B selectivity in functional assays. If adequately optimized, such peculiar selectivity could have relevance for a potential LUTS/BPH therapeutic application. PMID:27448917

  3. Interaction of β1-adrenoceptor with RAGE mediates cardiomyopathy via CaMKII signaling

    PubMed Central

    Woo, Anthony Y.H.; Huang, Ying; Xu, Chanjuan; Liu, Jian-Feng; Lv, Fengxiang; Zhang, Yan; Xiao, Rui-ping

    2016-01-01

    Stimulation of β1-adrenergic receptor (β1AR), a GPCR, and the receptor for advanced glycation end-products (RAGE), a pattern recognition receptor (PRR), have been independently implicated in the pathogenesis of cardiomyopathy caused by various etiologies, including myocardial infarction, ischemia/reperfusion injury, and metabolic stress. Here, we show that the two distinctly different receptors, β1AR and RAGE, are mutually dependent in mediating myocardial injury and the sequelae of cardiomyopathy. Deficiency or inhibition of RAGE blocks β1AR- and RAGE-mediated myocardial cell death and maladaptive remodeling. Ablation or blockade of β1AR fully abolishes RAGE-induced detrimental effects. Mechanistically, RAGE and β1AR form a complex, which in turn activates Ca2+/calmodulin-dependent kinase II (CaMKII), resulting in loss of cardiomyocytes and myocardial remodeling. These results indicate that RAGE and β1AR not only physically crosstalk at the receptor level, but also functionally converge at the common mediator, CaMKII, highlighting a combined inhibition of RAGE and β1AR as a more effective therapy to treat diverse cardiovascular diseases, such as myocardial infarction, ischemia/reperfusion injury, and diabetic cardiovascular complications. PMID:26966719

  4. "Ejaculatory disorders and α1-adrenoceptor antagonists therapy: clinical and experimental researches"

    PubMed Central

    Grasso, Marco; Fortuna, Flavio; Lania, Caterina; Blanco, Salvatore

    2006-01-01

    Background It is well known that the use of the α-adrenergic receptor antagonists in the BPH therapy may induce ejaculatory disorder. A review of clinical literature shows a greater incidence of ejaculatory disorder during the use of tamsulosin compared with alfuzosin. Anejaculation has been until now referred to retrograde ejaculation due to relaxation of prostatic and bladder neck smooth muscle tone. In a recent researches was evaluated the effect of tamsulosin and alfuzosin on rat vas deferent "in vitro", concluding that tamsulosin may "cause ejaculatory dysfunction by altering the progression and emission of sperm". An abnormal increase of contraction would be the cause of ejaculatory disorder. The aim of our paper is to compare human and rat vas deferens contractile activity and to evaluate with a clinical study if tamsulosin causes retrograde ejaculation disorder. Methods We have revaluated the human and rat vas deferens contractile activity in vitro according to our experience and literature. We have also performed a clinical study on 10 patients (48–72 y) affected by anejaculation. Post-coital urine was examined to search spermatozoa. Results Human and rat vas deferens activity is not comparable. Contractile activity induced by norepinephrin after tamsulosin incubation in rat prostatic vas deferens strips is similar to the contractile activity evoked by norepinephrin in human strips. Spermatozoa were found in post coital urine of 6 patients. Conclusion In our opinion the treatment with tamsulosin may induce retrograde ejaculation but not other ejaculatory disorder due to abnormal sperm progression. PMID:16842616

  5. The Role of α1-Adrenoceptor Antagonists in the Treatment of Prostate and Other Cancers.

    PubMed

    Batty, Mallory; Pugh, Rachel; Rathinam, Ilampirai; Simmonds, Joshua; Walker, Edwin; Forbes, Amanda; Anoopkumar-Dukie, Shailendra; McDermott, Catherine M; Spencer, Briohny; Christie, David; Chess-Williams, Russ

    2016-01-01

    This review evaluates the role of α-adrenoceptor antagonists as a potential treatment of prostate cancer (PCa). Cochrane, Google Scholar and Pubmed were accessed to retrieve sixty-two articles for analysis. In vitro studies demonstrate that doxazosin, prazosin and terazosin (quinazoline α-antagonists) induce apoptosis, decrease cell growth, and proliferation in PC-3, LNCaP and DU-145 cell lines. Similarly, the piperazine based naftopidil induced cell cycle arrest and death in LNCaP-E9 cell lines. In contrast, sulphonamide based tamsulosin did not exhibit these effects. In vivo data was consistent with in vitro findings as the quinazoline based α-antagonists prevented angiogenesis and decreased tumour mass in mice models of PCa. Mechanistically the cytotoxic and antitumor effects of the α-antagonists appear largely independent of α 1-blockade. The proposed targets include: VEGF, EGFR, HER2/Neu, caspase 8/3, topoisomerase 1 and other mitochondrial apoptotic inducing factors. These cytotoxic effects could not be evaluated in human studies as prospective trial data is lacking. However, retrospective studies show a decreased incidence of PCa in males exposed to α-antagonists. As human data evaluating the use of α-antagonists as treatments are lacking; well designed, prospective clinical trials are needed to conclusively demonstrate the anticancer properties of quinazoline based α-antagonists in PCa and other cancers. PMID:27537875

  6. Revisiting the homology modeling of G-protein coupled receptors: β1-adrenoceptor as an example.

    PubMed

    Zhu, Mengyuan; Li, Minyong

    2012-06-01

    G-protein coupled receptors (GPCRs) are recognized to constitute the largest family of membrane proteins. Due to the disproportion in the quantity of crystal structures and their amino acid sequences, homology modeling contributes a reasonable and feasible approach to GPCR theoretical coordinates. With the brand new crystal structures resolved recently, herein we deliberated how to designate them as templates to carry out homology modeling in four aspects: (1) various sequence alignment methods; (2) protein weight matrix; (3) different sets of multiple templates; (4) active and inactive state of templates. The accuracy of models was evaluated by comparing the similarity of stereo conformation and molecular docking results between models and the experimental structure of Meleagris gallopavo β(1)-adrenergic receptor (Mg_Adrb1) that we desired to develop as an example. Our results proposed that: (1) Cobalt and MAFFT, two algorithms of sequence alignment, were suitable for single- and multiple-template modeling, respectively; (2) Blosum30 is applicable to align sequences in the case of low sequence identity; (3) multiple-template modeling is not always better than single-template one; (4) the state of template is an influential factor in simulating the GPCR structures as well. PMID:22454032

  7. The Role of α1-Adrenoceptor Antagonists in the Treatment of Prostate and Other Cancers

    PubMed Central

    Batty, Mallory; Pugh, Rachel; Rathinam, Ilampirai; Simmonds, Joshua; Walker, Edwin; Forbes, Amanda; Anoopkumar-Dukie, Shailendra; McDermott, Catherine M.; Spencer, Briohny; Christie, David; Chess-Williams, Russ

    2016-01-01

    This review evaluates the role of α-adrenoceptor antagonists as a potential treatment of prostate cancer (PCa). Cochrane, Google Scholar and Pubmed were accessed to retrieve sixty-two articles for analysis. In vitro studies demonstrate that doxazosin, prazosin and terazosin (quinazoline α-antagonists) induce apoptosis, decrease cell growth, and proliferation in PC-3, LNCaP and DU-145 cell lines. Similarly, the piperazine based naftopidil induced cell cycle arrest and death in LNCaP-E9 cell lines. In contrast, sulphonamide based tamsulosin did not exhibit these effects. In vivo data was consistent with in vitro findings as the quinazoline based α-antagonists prevented angiogenesis and decreased tumour mass in mice models of PCa. Mechanistically the cytotoxic and antitumor effects of the α-antagonists appear largely independent of α 1-blockade. The proposed targets include: VEGF, EGFR, HER2/Neu, caspase 8/3, topoisomerase 1 and other mitochondrial apoptotic inducing factors. These cytotoxic effects could not be evaluated in human studies as prospective trial data is lacking. However, retrospective studies show a decreased incidence of PCa in males exposed to α-antagonists. As human data evaluating the use of α-antagonists as treatments are lacking; well designed, prospective clinical trials are needed to conclusively demonstrate the anticancer properties of quinazoline based α-antagonists in PCa and other cancers. PMID:27537875

  8. Functional Rescue of β1-Adrenoceptor Dimerization and Trafficking by Pharmacological Chaperones

    PubMed Central

    Kobayashi, Hiroyuki; Ogawa, Koji; Yao, Rong; Lichtarge, Olivier; Bouvier, Michel

    2009-01-01

    Site-directed mutagenesis guided by evolutionary trace analysis revealed that substitution of V179 and W183 within a cluster of evolutionarily important residues on the surface of the fourth transmembrane domain of the β1-adrenergic receptor (β1AR) significantly reduced the propensity of the receptor to self-assemble into homodimers as assessed by bioluminescence resonance energy transfer in living cells. These results suggest that mutation of V179 and W183 result in conformational changes that reduce homodimerization either directly by interfering with the dimerization interface or indirectly by causing local misfolding that result in reduced self-assembly. However, the mutations did not cause a general misfolding of the β1AR as they did not prevent heterodimerization with the β2AR. The homodimerization-compromised mutants were significantly retained in the endoplasmic reticulum (ER) and could not be properly matured and trafficked to the cell surface. Lipophilic β-adrenergic ligands acted as pharmacological chaperones by restoring both dimerization and plasma membrane trafficking of the ER-retained dimerization-compromised β1AR mutants. These results clearly indicate that homodimerization occurs early in the biosynthetic process in the ER and that pharmacological chaperones can promote both dimerization and cell surface targeting, most likely by stabilizing receptor conformations compatible with the two processes. PMID:19515093

  9. Alpha Testing Escape from Diab

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Alpha testing was conducted of sessions 2 and 3 from Diab to assess whether the activities worked as expected, and whether children in the target ages enjoyed it. Data include both RA observations of child performance while playing the games and cognitive interview responses from the players after t...

  10. Alcoholism, Alpha Production, and Biofeedback

    ERIC Educational Resources Information Center

    Jones, Frances W.; Holmes, David S.

    1976-01-01

    Electroencephalograms of 20 alcoholics and 20 nonalcoholics were obtained. Data indicated that alcoholics produced less alpha than nonalcoholics. In one training condition subjects were given accurate biofeedback, whereas in the other condition subjects were given random (noncontingent) feedback. Accurate biofeedback did not result in greater…

  11. Alpha proton x ray spectrometer

    NASA Technical Reports Server (NTRS)

    Rieder, Rudi; Waeke, H.; Economou, T.

    1994-01-01

    Mars Pathfinder will carry an alpha-proton x ray spectrometer (APX) for the determination of the elemental chemical composition of Martian rocks and soils. The instrument will measure the concentration of all major and some minor elements, including C, N, and O at levels above typically 1 percent.

  12. Meet the Alpha-Pets.

    ERIC Educational Resources Information Center

    Zitlaw, Jo Ann Bruce; Frank, Cheryl Standish

    1985-01-01

    "Alpha-Pets" are the focal point of an integrated, multidisciplinary curriculum. Each pet is featured for a week in a vocabulary-rich story and introduces related activities beginning with the featured letter, such as the four food groups during Freddie Fish's week or universe during Ulysses Unicorn's week. (MT)

  13. Sparse Coding for Alpha Matting

    NASA Astrophysics Data System (ADS)

    Johnson, Jubin; Varnousfaderani, Ehsan Shahrian; Cholakkal, Hisham; Rajan, Deepu

    2016-07-01

    Existing color sampling based alpha matting methods use the compositing equation to estimate alpha at a pixel from pairs of foreground (F) and background (B) samples. The quality of the matte depends on the selected (F,B) pairs. In this paper, the matting problem is reinterpreted as a sparse coding of pixel features, wherein the sum of the codes gives the estimate of the alpha matte from a set of unpaired F and B samples. A non-parametric probabilistic segmentation provides a certainty measure on the pixel belonging to foreground or background, based on which a dictionary is formed for use in sparse coding. By removing the restriction to conform to (F,B) pairs, this method allows for better alpha estimation from multiple F and B samples. The same framework is extended to videos, where the requirement of temporal coherence is handled effectively. Here, the dictionary is formed by samples from multiple frames. A multi-frame graph model, as opposed to a single image as for image matting, is proposed that can be solved efficiently in closed form. Quantitative and qualitative evaluations on a benchmark dataset are provided to show that the proposed method outperforms current state-of-the-art in image and video matting.

  14. Modulation of gene expression by alpha-tocopherol and alpha-tocopheryl phosphate in thp-1 monocytes

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The naturally occurring vitamin E analogue, alpha-tocopheryl phosphate (alphaTP), has been reported to be more potent than the un-phosphorylated alpha alpha-tocopherol (alphaT). We have now measured plasma levels of alphaTP and compared the cellular effects of alphaTP and gamma-tocopheryl phosphate ...

  15. Coexistence of {alpha}+{alpha}+n+n and {alpha}+t+t cluster structures in {sup 10}Be

    SciTech Connect

    Itagaki, N.; Ito, M.; Milin, M.; Hashimoto, T.; Ishiyama, H.; Miyatake, H.

    2008-06-15

    The coexistence of the {alpha}+{alpha}+n+n and {alpha}+t+t cluster structures in the excited states of {sup 10}Be has been discussed. In the previous analysis, all the low-lying states of {sup 10}Be were found to be well described by the motion of the two valence neutrons around two {alpha} clusters. However, the {alpha}+t+t cluster structure was found to coexist with the {alpha}+{alpha}+n+n structure around E{sub x}=15 MeV, close to the corresponding threshold. We have introduced a microscopic model to solve the coupling effect between these two configurations. The K=0 and K=1 states are generated from the {alpha}+t+t configurations due to the spin coupling of two triton clusters. The present case of {sup 10}Be is one of the few examples in which completely different configurations of triton-type ({alpha}+t+t three-center) and {alpha}-type ({alpha}+{alpha}+n+n two-center) clusters coexist in a single nucleus in the same energy region.

  16. What Causes Alpha-1 Antitrypsin Deficiency?

    MedlinePlus

    ... from the NHLBI on Twitter. What Causes Alpha-1 Antitrypsin Deficiency? Alpha-1 antitrypsin (AAT) deficiency is an inherited disease. "Inherited" ... have AAT deficiency inherit two faulty AAT genes, one from each parent. These genes tell cells in ...

  17. How Is Alpha-1 Antitrypsin Deficiency Treated?

    MedlinePlus

    ... from the NHLBI on Twitter. How Is Alpha-1 Antitrypsin Deficiency Treated? Alpha-1 antitrypsin (AAT) deficiency has no cure, but its ... of these treatments are the same as the ones used for a lung disease called COPD (chronic ...

  18. Genetics Home Reference: 5-alpha reductase deficiency

    MedlinePlus

    ... gene provides instructions for making an enzyme called steroid 5-alpha reductase 2. This enzyme is involved ... external genitalia. Mutations in the SRD5A2 gene prevent steroid 5-alpha reductase 2 from effectively converting testosterone ...

  19. Aversive Situational Effects on Alpha Feedback Training

    ERIC Educational Resources Information Center

    Orne, Martin T.; Paskeqitz, David A.

    1974-01-01

    Anticipation of electric shock did not depress alpha activity in a feedback situation. Contrary to previous reports, a reduction in alpha activity is not a necessary consequence of apprehension or heightened arousal. (Author)

  20. Q (Alpha) Function and Squeezing Effect

    NASA Technical Reports Server (NTRS)

    Yunjie, Xia; Xianghe, Kong; Kezhu, Yan; Wanping, Chen

    1996-01-01

    The relation of squeezing and Q(alpha) function is discussed in this paper. By means of Q function, the squeezing of field with gaussian Q(alpha) function or negative P(a)function is also discussed in detail.

  1. Association of actin with alpha crystallins

    NASA Technical Reports Server (NTRS)

    Gopalakrishnan, S.; Boyle, D.; Takemoto, L.; Spooner, B. S. (Principal Investigator)

    1993-01-01

    The alpha crystallins are cytosolic proteins that co-localize and co-purify with actin-containing microfilaments. Affinity column chromatography employing both covalently-coupled actin or alpha crystallin was used to demonstrate specific and saturable binding of actin with alpha crystallin. This conclusion was confirmed by direct visualization of alpha aggregates bound to actin polymerized in vitro. The significance of this interaction in relation to the functional properties of these two polypeptides will be discussed.

  2. The ultraviolet spectra of Alpha Aquilae and Alpha Canis Minoris

    NASA Technical Reports Server (NTRS)

    Morton, D. C.; Bruzual A., G.; Kurucz, R. L.; Spinrad, H.

    1977-01-01

    Scans of Alpha Aql (A7 IV, V) and Alpha CMi (F5 IV-V) obtained with the Copernicus satellite spectrometer over the wavelength range from 2100 to 3200 A are presented along with a spectrum of the integrated solar disk over the same range procured during a calibrated rocket flight. About 1500 fairly strong absorption lines in the Alpha CMi spectrum between 2400 and 2961 A are identified by comparison with a solar atlas and by using a theoretical spectrum synthesized from a blanketed LTE model with an effective temperature of 6500 K and a surface gravity of 10,000 cm/sec per sec. The Mg II resonance doublet at 2795.528 and 2802.704 A is found to be present in all three stars together with a discontinuity at 2635 A due to Fe II, Fe I, Cr I, and Mn II. It is concluded that the Mg II resonance lines and the 2635-A continuum break would be the best spectral features for estimating the redshift of a galaxy observed at low resolution provided the redshift is not less than about 0.75.

  3. Effectiveness of Alpha Biofeedback Therapy: Negative Results.

    ERIC Educational Resources Information Center

    Watson, Charles G.; Herder, Joseph

    1980-01-01

    Assessed the utility of alpha biofeedback training in the treatment of patients (N=66). Biofeedback and placebo biofeedback groups were given alpha or mock-alpha training sessions. Improvement on 54 variables was compared to that of no-treatment controls. Only a chance number of significant changes appeared among the groups. (Author)

  4. Recent Results on the CKM Angle Alpha

    SciTech Connect

    Mihalyi, A.; /Wisconsin U., Madison

    2005-10-18

    The method to measure the CKM angle {alpha} and the modes sensitive to it are discussed. It is shown that the B {yields} {rho}{rho} decays provide the most stringent constraint on {alpha}, which is found to be {alpha} = 96{sup o} {+-} 10{sup o}(stat) {+-} 4{sup o}(syst){+-} 13{sup o}(penguin).

  5. 6 alpha-Fluoro- and 6 alpha,9 alpha-difluoro-11 beta,21-dihydroxy-16 alpha,17 alpha-propylmethylenedioxypregn-4-ene-3,20-dione: synthesis and evaluation of activity and kinetics of their C-22 epimers.

    PubMed

    Thalén, B A; Axelsson, B I; Andersson, P H; Brattsand, R L; Nylander, B; Wickström, L I

    1998-01-01

    It is generally accepted that the anti-inflammatory effect of glucocorticosteroids cannot be separated from their adverse effects at the receptor level. However, modification of the pharmacokinetics through structural alterations could provide steroids with a better therapeutic index than those currently used. Thus, new 16 alpha,17 alpha-acetals between butyraldehyde and 6 alpha-fluoro- or 6 alpha,9 alpha-difluoro-16 alpha-hydroxycortisol were synthesized and studied. Acetalization of the corresponding 16 alpha,17 alpha-diols or transacetalization of their 16 alpha,17 alpha-acetonides in dioxane produced mixtures of C-22 epimers, which were resolved by preparative chromatography. Alternatively, an efficient method was used to produce the 22R-epimer stereoselectively through performing the acetalization and transacetalization in a hydrocarbon with an inert material present. The C-22 configuration of (22R)-6 alpha,9 alpha-difluoro-11 beta,21-dihydroxy-16 alpha,17 alpha-propylmethylenedioxypregn-4-ene-3,20-dione was unambiguously established by single crystal X-ray diffraction. The present compounds, especially the 22R-epimer just mentioned, bind to the rat thymus glucocorticoid receptor with high potency. The C-22 epimers of the 6 alpha,9 alpha-difluoro derivatives showed a 10-fold higher biotransformation rate than the budesonide 22R-epimer when incubated with human liver S9 subcellular fraction. The high receptor affinity in combination with the high biotransformation rate indicates that (22R)-6 alpha,9 alpha-difluoro-11 beta,21-dihydroxy-16 alpha,17 alpha-propylmethylenedioxypregn-4-ene-3,20-dione may be an improved 16 alpha,17 alpha-acetal glucocorticosteroid for therapy of inflammatory diseases, in which the mucous membranes are involved, such as those in the intestinal tract as well in the respiratory tract. PMID:9437793

  6. THE LYMAN ALPHA REFERENCE SAMPLE: EXTENDED LYMAN ALPHA HALOS PRODUCED AT LOW DUST CONTENT

    SciTech Connect

    Hayes, Matthew; Oestlin, Goeran; Duval, Florent; Guaita, Lucia; Melinder, Jens; Sandberg, Andreas; Schaerer, Daniel; Verhamme, Anne; Orlitova, Ivana; Mas-Hesse, J. Miguel; Oti-Floranes, Hector; Adamo, Angela; Atek, Hakim; Cannon, John M.; Herenz, E. Christian; Kunth, Daniel; Laursen, Peter

    2013-03-10

    We report on new imaging observations of the Lyman alpha emission line (Ly{alpha}), performed with the Hubble Space Telescope, that comprise the backbone of the Lyman alpha Reference Sample. We present images of 14 starburst galaxies at redshifts 0.028 < z < 0.18 in continuum-subtracted Ly{alpha}, H{alpha}, and the far ultraviolet continuum. We show that Ly{alpha} is emitted on scales that systematically exceed those of the massive stellar population and recombination nebulae: as measured by the Petrosian 20% radius, R{sub P20}, Ly{alpha} radii are larger than those of H{alpha} by factors ranging from 1 to 3.6, with an average of 2.4. The average ratio of Ly{alpha}-to-FUV radii is 2.9. This suggests that much of the Ly{alpha} light is pushed to large radii by resonance scattering. Defining the Relative Petrosian Extension of Ly{alpha} compared to H{alpha}, {xi}{sub Ly{alpha}} = R {sup Ly{alpha}}{sub P20}/R {sup H{alpha}}{sub P20}, we find {xi}{sub Ly{alpha}} to be uncorrelated with total Ly{alpha} luminosity. However, {xi}{sub Ly{alpha}} is strongly correlated with quantities that scale with dust content, in the sense that a low dust abundance is a necessary requirement (although not the only one) in order to spread Ly{alpha} photons throughout the interstellar medium and drive a large extended Ly{alpha} halo.

  7. Alpha channeling in a rotating plasma.

    PubMed

    Fetterman, Abraham J; Fisch, Nathaniel J

    2008-11-14

    The wave-particle alpha-channeling effect is generalized to include rotating plasma. Specifically, radio frequency waves can resonate with alpha particles in a mirror machine with ExB rotation to diffuse the alpha particles along constrained paths in phase space. Of major interest is that the alpha-particle energy, in addition to amplifying the rf waves, can directly enhance the rotation energy which in turn provides additional plasma confinement in centrifugal fusion reactors. An ancillary benefit is the rapid removal of alpha particles, which increases the fusion reactivity. PMID:19113347

  8. Alpha voltaic batteries and methods thereof

    NASA Technical Reports Server (NTRS)

    Raffaelle, Ryne P. (Inventor); Jenkins, Phillip (Inventor); Wilt, David (Inventor); Scheiman, David (Inventor); Chubb, Donald (Inventor); Castro, Stephanie (Inventor)

    2011-01-01

    An alpha voltaic battery includes at least one layer of a semiconductor material comprising at least one p/n junction, at least one absorption and conversion layer on the at least one layer of semiconductor layer, and at least one alpha particle emitter. The absorption and conversion layer prevents at least a portion of alpha particles from the alpha particle emitter from damaging the p/n junction in the layer of semiconductor material. The absorption and conversion layer also converts at least a portion of energy from the alpha particles into electron-hole pairs for collection by the one p/n junction in the layer of semiconductor material.

  9. Subjective pain perception mediated by alpha rhythms.

    PubMed

    Peng, Weiwei; Babiloni, Claudio; Mao, Yanhui; Hu, Yong

    2015-07-01

    Suppression of spontaneous alpha oscillatory activities, interpreted as cortical excitability, was observed in response to both transient and tonic painful stimuli. The changes of alpha rhythms induced by pain could be modulated by painful sensory inputs, experimental tasks, and top-down cognitive regulations such as attention. The temporal and spatial characteristics, as well as neural functions of pain induced alpha responses, depend much on how these factors contribute to the observed alpha event-related desynchronization/synchronization (ERD/ERS). How sensory-, task-, and cognitive-related changes of alpha oscillatory activities interact in pain perception process is reviewed in the current study, and the following conclusions are made: (1) the functional inhibition hypothesis that has been proposed in auditory and visual modalities could be applied also in pain modality; (2) the neural functions of pain induced alpha ERD/ERS were highly dependent on the cortical regions where it is observed, e.g., somatosensory cortex alpha ERD/ERS in pain perception for painful stimulus processing; (3) the attention modulation of pain perception, i.e., influences on the sensory and affective dimensions of pain experience, could be mediated by changes of alpha rhythms. Finally, we propose a model regarding the determinants of pain related alpha oscillatory activity, i.e., sensory-discriminative, affective-motivational, and cognitive-modulative aspects of pain experience, would affect and determine pain related alpha oscillatory activities in an integrated way within the distributed alpha system. PMID:26026894

  10. Identification of noncollagenous sites encoding specific interactions and quaternary assembly of alpha 3 alpha 4 alpha 5(IV) collagen: implications for Alport gene therapy.

    PubMed

    Kang, Jeong Suk; Colon, Selene; Hellmark, Thomas; Sado, Yoshikazu; Hudson, Billy G; Borza, Dorin-Bogdan

    2008-12-12

    Defective assembly of alpha 3 alpha 4 alpha 5(IV) collagen in the glomerular basement membrane causes Alport syndrome, a hereditary glomerulonephritis progressing to end-stage kidney failure. Assembly of collagen IV chains into heterotrimeric molecules and networks is driven by their noncollagenous (NC1) domains, but the sites encoding the specificity of these interactions are not known. To identify the sites directing quaternary assembly of alpha 3 alpha 4 alpha 5(IV) collagen, correctly folded NC1 chimeras were produced, and their interactions with other NC1 monomers were evaluated. All alpha1/alpha 5 chimeras containing alpha 5 NC1 residues 188-227 replicated the ability of alpha 5 NC1 to bind to alpha3NC1 and co-assemble into NC1 hexamers. Conversely, substitution of alpha 5 NC1 residues 188-227 by alpha1NC1 abolished these quaternary interactions. The amino-terminal 58 residues of alpha3NC1 encoded binding to alpha 5 NC1, but this interaction was not sufficient for hexamer co-assembly. Because alpha 5 NC1 residues 188-227 are necessary and sufficient for assembly into alpha 3 alpha 4 alpha 5 NC1 hexamers, whereas the immunodominant alloantigenic sites of alpha 5 NC1 do not encode specific quaternary interactions, the findings provide a basis for the rational design of less immunogenic alpha 5(IV) collagen constructs for the gene therapy of X-linked Alport patients. PMID:18930919