Contraction of Rat Cauda Epididymis Smooth Muscle to α1-Adrenoceptor Activation Is Mediated by α1A-Adrenoceptors

J Pharmacol Exp Ther. 2018 Jul;366(1):21-28. doi: 10.1124/jpet.117.246710. Epub 2018 Apr 23.

Abstract

The cauda epididymis (CE), the site of sperm storage until the ejaculation, is densely innervated by the sympathetic nervous system. Contraction of CE smooth muscle via α1-adrenoceptors (α1-ARs) plays a key role during the seminal emission phase of ejaculation and α1-AR antagonism has been suggested as a nonhormonal and reversible male contraceptive target. Since the α1-AR subtype mediating contraction of rat CE is not known, this study investigates the expression and role of α1-AR subtypes on the proximal and distal rat CE duct contraction to norepinephrine in vitro. Alpha1a, α1b, and α1d transcripts were detected by real-time quantitative polymerase chain reaction in proximal and distal CE segments and α1a and α1d were shown to predominate over α1b The inhibition of [3H]prazosin specific binding to intact CE segments from proximal and distal CE by RS 100329 and 5-methylurapidil (α1A-selective) and BMY 7378 (α1D-selective) showed that α1A- and α1D-ARs are expressed at similar densities. Norepinephrine-induced contractions of CE were competitively antagonized with high affinity by RS 100329 (pKB ≈ 9.50) and 5-methylurapidil (pKB ≈ 9.0) and with low affinity by BMY 7378 (pKB ≈ 7.0) and the α1B-selective L-765,314 (pA2 < 7.0), suggesting contractions are mediated by α1A-ARs. The clinically used α1A/D-ARs antagonist tamsulosin potently (pA2 ≈ 10.0) inhibited the norepinephrine-induced CE contractions. Altogether, our results show that α1A- and α1D-ARs are expressed in the CE duct and α1A-AR is the main subtype mediating contraction to norepinephrine. Our results highlight the importance of α1A-AR in the peripheral control of ejaculation and strengthen the α1A-AR as a target for a nonhormonal approach to male contraception.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adrenergic alpha-1 Receptor Antagonists / pharmacology
  • Animals
  • Epididymis / drug effects
  • Epididymis / physiology*
  • Gene Expression Regulation / drug effects
  • Male
  • Muscle Contraction* / drug effects
  • Muscle, Smooth / drug effects
  • Muscle, Smooth / physiology*
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Rats
  • Receptors, Adrenergic, alpha-1 / genetics
  • Receptors, Adrenergic, alpha-1 / metabolism*

Substances

  • Adrenergic alpha-1 Receptor Antagonists
  • RNA, Messenger
  • Receptors, Adrenergic, alpha-1