The alpha 1-adrenergic receptor that mediates smooth muscle contraction in human prostate has the pharmacological properties of the cloned human alpha 1c subtype

C Forray, JA Bard, JM Wetzel, G Chiu, E Shapiro, R Tang, H Lepor, PR Hartig, RL Weinshank and TA Branchek

Synaptic Pharmaceutical Corporation, Paramus, New Jersey 07652.

Molecular cloning studies have revealed the existence of three subtypes of alpha 1-adrenergic receptors. However, the link between any individual subtype and its functional role in the body has remained elusive. In an effort to bridge the gap between molecular biology and pathophysiology, we have chosen a model smooth muscle system, the human prostate, and investigated the role of alpha 1 subtypes in this tissue. To determine which alpha 1-adrenergic receptor subtype mediates the contractile response of the human prostate, we first studied the pharmacological properties of three cloned human alpha 1 subtypes (alpha 1a/d, alpha 1b, and alpha 1c). Prazosin, terazosin, doxazosin, alfuzosin, and abanoquil showed no selectivity for the human alpha 1 subtypes. WB-4101 and 5-methylurapidil showed a rank order of potency of alpha 1c > alpha 1a/d >> alpha 1b. Indoramin and (+)-niguldipine were selective for the alpha 1c-adrenergic receptor, with at least 10- fold lower affinity at either alpha 1a/d or alpha 1b subtypes. SK&F104856 was found to be 6-fold more potent at the alpha 1a/d receptor subtype than at alpha 1b- or alpha 1c-adrenergic receptors. We next determined the potency of these antagonists to inhibit the phenylephrine-induced contraction of human prostatic tissue in vitro. The potencies of indoramin, 5-methylurapidil, and SK&F104856 to inhibit the contractile response and to displace [3H]prazosin from the cloned human alpha 1c subtype were similar. Our data suggest that the alpha 1 receptor that mediates the contraction of human prostate smooth muscle has the pharmacological properties of the cloned human alpha 1c- adrenergic receptor. The findings of the present study suggest that selective alpha 1c-adrenergic receptor antagonists may be clinically more efficacious and better tolerated agents for the treatment of symptomatic benign prostatic hyperplasia.

Volume 45, Issue 4, pp. 703-708, 04/01/1994
Copyright © 1994 by American Society for Pharmacology and Experimental Therapeutics

This article has been cited by other articles:

				M. T.C.C. Patrao, D. B.C. Queiroz, G. Grossman, P. Petrusz, M. d. F. M. Lazari, and M. C. W. Avellar Cloning, expression and immunolocalization of {alpha}1-adrenoceptor in different tissues from rhesus monkey and human male reproductive tract Mol. Hum. Reprod., February 1, 2008; 14(2): 85 - 96. [Abstract] [Full Text] [PDF]

				K. Rasmussen, M. J. Benvenga, F. P. Bymaster, D. O. Calligaro, I. R. Cohen, J. F. Falcone, S. K. Hemrick-Luecke, F. M. Martin, N. A. Moore, L. K. Nisenbaum, et al. Preclinical Pharmacology of FMPD [6-Fluoro-10-[3-(2-methoxyethyl)-4-methyl-piperazin-1-yl]-2-methyl-4H-3-thia-4,9-diaza-benzo[f]azulene]: A Potential Novel Antipsychotic with Lower Histamine H1 Receptor Affinity Than Olanzapine J. Pharmacol. Exp. Ther., December 1, 2005; 315(3): 1265 - 1277. [Abstract] [Full Text] [PDF]

				S. Tambaro, S. Ruiu, C. Dessi, R. Mongeau, G. Marchese, and L. Pani Evaluation of Tamsulosin and Alfuzosin Activity in the Rat Vas Deferens: Relevance to Ejaculation Delays J. Pharmacol. Exp. Ther., February 1, 2005; 312(2): 710 - 717. [Abstract] [Full Text] [PDF]

				D. A. Schwinn, D. T. Price, and P. Narayan {alpha}1-Adrenoceptor Subtype Selectivity and Lower Urinary Tract Symptoms Mayo Clin. Proc., November 1, 2004; 79(11): 1423 - 1434. [Abstract] [PDF]

				S. Suzuki, E. A Platz, I. Kawachi, W. C Willett, and E. Giovannucci Intakes of energy and macronutrients and the risk of benign prostatic hyperplasia Am. J. Clinical Nutrition, April 1, 2002; 75(4): 689 - 697. [Abstract] [Full Text] [PDF]

				R. R. Price, D. P. Morris, G. Biswas, M. P. Smith, and D. A. Schwinn Acute Agonist-mediated Desensitization of the Human alpha 1a-Adrenergic Receptor Is Primarily Independent of Carboxyl Terminus Regulation. IMPLICATIONS FOR REGULATION OF alpha 1aAR SPLICE VARIANTS J. Biol. Chem., March 8, 2002; 277(11): 9570 - 9579. [Abstract] [Full Text] [PDF]

				M. E. Brune, S. P. Katwala, I. Milicic, D. G. Witte, J. F. Kerwin Jr., M. D. Meyer, A. A. Hancock, and M. Williams Effect of Fiduxosin, an Antagonist Selective for alpha 1A- and alpha 1D-Adrenoceptors, on Intraurethral and Arterial Pressure Responses in Conscious Dogs J. Pharmacol. Exp. Ther., February 1, 2002; 300(2): 487 - 494. [Abstract] [Full Text] [PDF]

				S. Yamada, T. Okura, R. Kimura, Y. Deguchi, Y. Suzuki, T. Kobayashi, and K. Aisaka Disposition and alpha 1-Adrenoceptor Binding Characteristics of JTH-601 and Its Metabolites in Rat Tissues Drug Metab. Dispos., April 13, 2001; 28(12): 1487 - 1492. [Abstract] [Full Text]

				S. Sato, A. Ohtake, H. Matsushima, C. Saitoh, S. Usuda, and K. Miyata Pharmacological Effect of Tamsulosin in Relation to Dog Plasma and Tissue Concentrations: Prostatic and Urethral Retention Possibly Contributes to Uroselectivity of Tamsulosin J. Pharmacol. Exp. Ther., March 1, 2001; 296(3): 697 - 703. [Abstract] [Full Text]

				N. Kyprianou and C. M. Benning Suppression of Human Prostate Cancer Cell Growth By {{alpha}}1-Adrenoceptor Antagonists Doxazosin and Terazosin via Induction of Apoptosis Cancer Res., August 1, 2000; 60(16): 4550 - 4555. [Abstract] [Full Text]

				V. L. Pulito, X. Li, S. S. Varga, L. S. Mulcahy, K. S. Clark, S. A. Halbert, A. B. Reitz, W. V. Murray, and L. K. Jolliffe An Investigation of the Uroselective Properties of Four Novel alpha 1a-Adrenergic Receptor Subtype-Selective Antagonists J. Pharmacol. Exp. Ther., July 1, 2000; 294(1): 224 - 229. [Abstract] [Full Text]

				K. Akiyama, M. Hora, S. Tatemichi, N. Masuda, S. Nakamura, R. Yamagishi, and M. Kitazawa KMD-3213, a Uroselective and Long-Acting alpha 1a-Adrenoceptor Antagonist, Tested in a Novel Rat Model J. Pharmacol. Exp. Ther., October 1, 1999; 291(1): 81 - 91. [Abstract] [Full Text]

				Y. Fukuta, Y. Fukuda, R. Higashino, K. Yoshida, M. Ogishima, H. Tamaki, and M. Takei Z-350, A Novel Compound with alpha 1-Adrenoceptor Antagonistic and Steroid 5alpha -Reductase Inhibitory Actions: Pharmacological Properties In Vivo J. Pharmacol. Exp. Ther., September 1, 1999; 290(3): 1013 - 1018. [Abstract] [Full Text]

				E. A. Platz, I. Kawachi, E. B. Rimm, G. A. Colditz, M. J. Stampfer, W. C. Willett, and E. Giovannucci Physical Activity and Benign Prostatic Hyperplasia Arch Intern Med, November 23, 1998; 158(21): 2349 - 2356. [Abstract] [Full Text] [PDF]

				P. J. Gonzalez-Cabrera, P. L. Iversen, M. F. Liu, M. A. Scofield, and W. B. Jeffries Selective Inhibition of alpha 1B-Adrenergic Receptor Expression and Function Using a Phosphorothioate Antisense Oligodeoxynucleotide Mol. Pharmacol., June 1, 1998; 53(6): 1034 - 1039. [Abstract] [Full Text]

				H. Yokoyama, M. Yasutake, and M. Avkiran {alpha}1-Adrenergic Stimulation of Sarcolemmal Na+-H+ Exchanger Activity in Rat Ventricular Myocytes : Evidence for Selective Mediation by the {alpha}1A-Adrenoceptor Subtype Circ. Res., June 1, 1998; 82(10): 1078 - 1085. [Abstract] [Full Text] [PDF]

				A. A. Hancock, M. E. Brune, D. G. Witte, K. C. Marsh, S. Katwala, I. Milicic, L. M. Ireland, D. Crowell, M. D. Meyer, and J. F. Kerwin Jr. Actions of A-131701, a Novel, Selective Antagonist for Alpha-1A Compared with Alpha-1B Adrenoceptors on Intraurethral and Blood Pressure Responses in Conscious Dogs and a Pharmacodynamic Assessment of in Vivo Prostatic Selectivity J. Pharmacol. Exp. Ther., May 1, 1998; 285(2): 628 - 642. [Abstract] [Full Text]

				M. A. Razik, K. Lee, R. R. Price, M. R. Williams, R. R. Ongjoco, M. K. Dole, X. L. Rudner, M. M. Kwatra, and D. A. Schwinn Transcriptional Regulation of the Human alpha 1a-Adrenergic Receptor Gene. CHARACTERIZATION OF THE 5'-REGULATORY AND PROMOTER REGION J. Biol. Chem., November 7, 1997; 272(45): 28237 - 28246. [Abstract] [Full Text] [PDF]

				D. J. Martin, P. Lluel, E. Guillot, A. Coste, D. Jammes, and I. Angel Comparative Alpha-1 Adrenoceptor Subtype Selectivity and Functional Uroselectivity of Alpha-1 Adrenoceptor Antagonists J. Pharmacol. Exp. Ther., July 1, 1997; 282(1): 228 - 235. [Abstract] [Full Text]

				A. Leonardi, J. P. Hieble, L. Guarneri, D. P. Naselsky, E. Poggesi, G. Sironi, A. C. Sulpizio, and R. Testa J. Pharmacol. Exp. Ther., June 1, 1997; 281(3): 1272 - 1283. [Abstract] [Full Text]

				R. Testa, L. Guarneri, P. Angelico, E. Poggesi, C. Taddei, G. Sironi, D. Colombo, A. C. Sulpizio, D. P. Naselsky, J. P. Hieble, et al. J. Pharmacol. Exp. Ther., June 1, 1997; 281(3): 1284 - 1293. [Abstract] [Full Text]

				K. Taguchi, M. Saitoh, S. Sato, M. Asano, and M. C. Michel Effects of Tamsulosin Metabolites at Alpha-1 Adrenoceptor Subtypes J. Pharmacol. Exp. Ther., January 1, 1997; 280(1): 1 - 5. [Abstract] [Full Text]

				R. M. Graham, D. M. Perez, J. Hwa, and M. T. Piascik {alpha}1-Adrenergic Receptor Subtypes : Molecular Structure, Function, and Signaling Circ. Res., May 1, 1996; 78(5): 737 - 749. [Full Text]

				J. Hwa, R. M. Graham, and D. M. Perez Identification of Critical Determinants of alpha(1)-Adrenergic Receptor Subtype Selective Agonist Binding J. Biol. Chem., September 29, 1995; 270(39): 23189 - 23195. [Abstract] [Full Text] [PDF]

				H.-T. Li, C. S. Long, D. G. Rokosh, N. Y. Honbo, and J. S. Karliner Chronic Hypoxia Differentially Regulates {alpha}1-Adrenergic Receptor Subtype mRNAs and Inhibits {alpha}1-Adrenergic Receptor–Stimulated Cardiac Hypertrophy and Signaling Circulation, August 15, 1995; 92(4): 918 - 925. [Abstract] [Full Text]