Alpha1A/L-adrenoceptors mediate contraction of the circular smooth muscle of the pig urethra

1 Sympathetically mediated urethral tone is essential for the maintenance of continence and involves the activation of postjunctional α₁- adrenoceptors. This study characterizes the α₁-adrenoceptor subtypes responsible for mediating contraction of the urethral circular smooth muscle of the pig. 2 The potency order of a number of agonists and the affinities of several receptor selective antagonists were determined on pig-isolated circular smooth muscle strips in the presence of cocaine (1 μm) and corticosterone (10 μm) to inhibit amine uptake and propranolol (1 μm) to antagonize β-adrenoceptors. 3 The potency order for agonists was N-[5-(4,5-dihydro-1H-imidazol-2yl)-2-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl] methanesulphonamide (A61603) > noradrenaline = phenylephrine = M6434 > methoxamine with pEC₅₀ values of 7.3, 5.8, 5.7, 5.6 and 5.0 respectively. 4 The α_1D-adrenoceptor-selective antagonist 8-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-8-azaspiro[4,5]decane-7,9-dione (BMY7378) caused rightward shifts of the concentration-response curves to noradrenaline, yielding a low affinity estimate (6.6) for the urethral receptor. The α_1A-adrenoceptor-selective antagonists, RS100329 and 5-methylurapidil, gave relatively high affinity estimates (9.6 and 8.8 respectively) for this receptor. All three antagonists produced Schild plots with slopes close to unity but did reduce maximum responses at higher concentrations. Prazosin antagonized responses of the urethra to noradrenaline, yielding a mean affinity estimate of 9.0. Although the Schild plot for prazosin again had a slope of unity, this drug also reduced maximum responses to noradrenaline at all concentrations examined (10-100 nm). N-[2-(2- cyclopropylmethoxyphenoxy)ethyl]-5-chloro-α,α-dimethyl-1H-indole-3- ethanamide (RS17053), which discriminates between responses mediated via α_1A (high affinity) and α_1L-adrenoceptors (low affinity) at concentrations up to 3 μm, failed to antagonize responses of the urethra. 5 These results suggest that contraction of urethral circular smooth muscle in the pig is mediated via a single population of adrenoceptors with the pharmacological characteristics of the α_1A/L- adrenoceptor, most probably the α_1L-adrenoceptor.