rs-100329 and 5-methylurapidil

1 The aim of the current study was to characterize the alpha(1)-adrenergic receptors (alpha(1)-ARs) present in the isolated tunica media of aorta, in normotensive Wistar Kyoto (WKY) and spontaneously hypertensive (SHR) rats during the course of ageing and hypertension (rats of 1, 3, 6 and 12 months of age). In all vessels, endothelium was removed. 2 In isolated aortic rings, phenylephrine increased contraction in a concentration- and age-dependent manner and was impaired in old SHR compared with WKY rats. 3 The alpha(1)-AR selective antagonist prazosin showed high affinity (pA(2)) in vessels from both rat strains. 4 The potency of the alpha(1A)-AR selective antagonists, RS 100329 (5-methyl-3-[3-[4-[2-(2,2,2,-trifluoroethoxy) phenyl]-1-piperazinyl] propyl]-2,4-(1H)-pyrimidinedione) and 5-methylurapidil in antagonizing aortic phenylephrine-responses was low. 5 The alpha(1D)-AR selective antagonist, BMY 7378 (8-[2-[4-(2-methoxyphenyl)-1 piperazynil] ethyl]-8-azaspiro [4.5] decane-7,9-dione) potently blocked phenylephrine-induced responses in aorta from both strains and at all ages. 6 Adventitia removal decreased E(max) in older rats and modified the relative affinity (pD(2)), but did not affect the affinity of the selective antagonists. 7 The results suggest that aorta tunica alpha(1D)-AR is the main subtype involved in phenylephrine-induced contraction of rat aorta, while alpha(1A)-AR plays only a minor role. 8 Ageing and hypertension did not modify alpha(1)-ARs in the blood vessel and the tunica adventitia does not seem to participate in contraction, even though alpha(1)-ARs are expressed.

Topics: Adrenergic alpha-1 Receptor Antagonists; Adrenergic alpha-Antagonists; Aging; Animals; Endothelium, Vascular; Fibroblasts; Hypertension; Male; Muscle Contraction; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Piperazines; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Receptors, Adrenergic, alpha-1; RNA, Messenger; Thymine; Tunica Media; Weight Gain

Sympathetically mediated urethral tone is essential for the maintenance of continence and involves the activation of postjunctional alpha(1)-adrenoceptors. This study characterizes the alpha(1)-adrenoceptor subtypes responsible for mediating contraction of the urethral circular smooth muscle of the pig. 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 microm) and corticosterone (10 microm) to inhibit amine uptake and propranolol (1 microm) to antagonize beta-adrenoceptors. 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 pEC(50) values of 7.3, 5.8, 5.7, 5.6 and 5.0 respectively. 4 The alpha(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 alpha(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-alpha,alpha-dimethyl-1H-indole-3-ethanamide (RS17053), which discriminates between responses mediated via alpha(1A) (high affinity) and alpha(1L)-adrenoceptors (low affinity) at concentrations up to 3 microm, 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 alpha(1A/L)-adrenoceptor, most probably the alpha(1L)-adrenoceptor.

Topics: Adrenergic alpha-1 Receptor Agonists; Adrenergic alpha-1 Receptor Antagonists; Adrenergic alpha-Agonists; Adrenergic alpha-Antagonists; Animals; Dose-Response Relationship, Drug; Female; In Vitro Techniques; Indoles; Muscle Contraction; Muscle, Smooth; Norepinephrine; Piperazines; Receptors, Adrenergic, alpha-1; Regression Analysis; Swine; Thymine; Urethra