B. J. Davis, M. Wiener, C. R. Chapple, D. J. Sellers, R. Chess-Williams
{"title":"Functional and radioligand binding characterization of the α1L-adrenoceptor subtype of the human vas deferens","authors":"B. J. Davis, M. Wiener, C. R. Chapple, D. J. Sellers, R. Chess-Williams","doi":"10.1111/aap.12023","DOIUrl":null,"url":null,"abstract":"<div>\n \n <p>\n \n </p><ol>\n \n \n <li>Alpha<sub>1</sub>-adrenoceptor antagonists can cause ejaculatory dysfunction as an adverse effect. Contractions of the human vas deferens are mediated via α<sub>1A</sub>-adrenoceptors, and this study investigated whether the low affinity state of this receptor (α<sub>1L</sub>-adrenoceptor) is involved in mediating contractions of this tissue.</li>\n \n \n <li>The potency of agonists and the affinity of receptor subtype selective antagonists were determined in functional experiments and in [<sup>3</sup>H]tamsulosin binding experiments to identify the α<sub>1</sub>-adrenoceptor subtype population present in the human vas deferens.</li>\n \n \n <li>The α<sub>1A</sub>-adrenoceptor selective agonist A61603 was a full agonist and was 250-fold more potent than noradrenaline. Prazosin antagonized contractile responses to phenylephrine with a low affinity (pK<sub>d</sub> = 8.6). Only high concentrations of RS17053 antagonized responses to phenylephrine and yielded a relatively low affinity estimate of 7.0. BMY7378 (α<sub>1D</sub>-adrenoceptor selective) gave a low affinity estimate (pK<sub>d</sub> = 6.7), whilst tamsulosin (α<sub>1A</sub>- and α<sub>1D</sub>-adrenoceptor selective) had a high affinity (pK<sub>d</sub> = 9.9).</li>\n \n \n <li>[<sup>3</sup>H]Tamsulosin bound to human vas deferens membranes with a high affinity (pK<sub>d</sub> = 10.0). Prazosin, RS17053 and BMY7378 competed with [<sup>3</sup>H]tamsulosin with low affinities for a single population of binding sites (pK<sub>d</sub> values of 8.5, 7.2 and 6.3, respectively).</li>\n \n \n <li>These functional and radioligand binding data indicate that the human vas deferens possesses a homogeneous population of α<sub>1</sub>-adrenoceptors which have the pharmacological properties of the putative α<sub>1L</sub>-adrenoceptor, the same functional receptor previously identified in the human prostate.</li>\n </ol>\n \n </div>","PeriodicalId":100151,"journal":{"name":"Autonomic and Autacoid Pharmacology","volume":"34 3-4","pages":"41-49"},"PeriodicalIF":0.0000,"publicationDate":"2015-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1111/aap.12023","citationCount":"5","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Autonomic and Autacoid Pharmacology","FirstCategoryId":"1085","ListUrlMain":"https://onlinelibrary.wiley.com/doi/10.1111/aap.12023","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"","JCRName":"","Score":null,"Total":0}
引用次数: 5
Abstract
Alpha1-adrenoceptor antagonists can cause ejaculatory dysfunction as an adverse effect. Contractions of the human vas deferens are mediated via α1A-adrenoceptors, and this study investigated whether the low affinity state of this receptor (α1L-adrenoceptor) is involved in mediating contractions of this tissue.
The potency of agonists and the affinity of receptor subtype selective antagonists were determined in functional experiments and in [3H]tamsulosin binding experiments to identify the α1-adrenoceptor subtype population present in the human vas deferens.
The α1A-adrenoceptor selective agonist A61603 was a full agonist and was 250-fold more potent than noradrenaline. Prazosin antagonized contractile responses to phenylephrine with a low affinity (pKd = 8.6). Only high concentrations of RS17053 antagonized responses to phenylephrine and yielded a relatively low affinity estimate of 7.0. BMY7378 (α1D-adrenoceptor selective) gave a low affinity estimate (pKd = 6.7), whilst tamsulosin (α1A- and α1D-adrenoceptor selective) had a high affinity (pKd = 9.9).
[3H]Tamsulosin bound to human vas deferens membranes with a high affinity (pKd = 10.0). Prazosin, RS17053 and BMY7378 competed with [3H]tamsulosin with low affinities for a single population of binding sites (pKd values of 8.5, 7.2 and 6.3, respectively).
These functional and radioligand binding data indicate that the human vas deferens possesses a homogeneous population of α1-adrenoceptors which have the pharmacological properties of the putative α1L-adrenoceptor, the same functional receptor previously identified in the human prostate.