Molecular Pharmacology of Selective beta3-Adrenergic Receptors

在分离的犬右室肌上，我们研究了非选择性激动剂异丙肾上腺素和β-1选择性激动剂T-0509对正性变力作用的拮抗作用的差异。选择性β1受体阻滞剂阿替洛尔或比索洛尔和非选择性β受体阻滞剂纳多洛尔单相拮抗T-0509的PIE，PA2值分别为7.05、7.63和7.58。另一方面，两种阻滞剂都对异丙肾上腺素(ISO)的PIE产生双相拮抗作用，因此得到两个pKb值(分别为7.75和4.25；7.82和5.76；7.42和4.39)。由于三种β受体阻滞剂在T-0509和ISO之间的不同拮抗模式不能用β受体激动剂和阻滞剂在心脏中的选择性来解释，犬的心室肌中可能同时存在两种β1受体亚型，阿替洛尔、比索洛尔和纳多洛尔可能是这两种亚型(β1受体和非典型β或β3受体)的拮抗剂。65周龄地诺帕胺组的存活率高于对照组。地诺帕明治疗降低了血浆去甲肾上腺素和多巴胺水平(P&lt；0.05)，但不影响心肌收缩能力和β-肾上腺素能受体密度。总而言之，地诺帕明显著降低了心肌病仓鼠的死亡率。其降低血浆儿茶酚胺水平的作用可能与地诺帕明的有益作用有关。

In isolated canine right ventricular muscles, we investigated the differences in antagonisms by beta-blockers against the positive inotropic effects (PIEs) of isoproterenol, a nonselective agonist, and T-0509, a beta1-selective agonist. The selective beta1-blockers atenolol or bisoprolol, and nadolol, a nonselective beta-blocker antagonized the PIE of T-0509 monophasically in Schild analysis, showing pA2 values of 7.05,7.63, and 7.58, respectively. On the other hand, both blockers produced biphasic antagonism against the PIE of isoproterenol (ISO) ; therefore, two pKB values were obtained (7.75 and 4.25 ; 7.82 and 5.76 ; 7.42 and 4.39, respectively). Because the different mode of antagonism by three beta-blockers between T-0509 and ISO could not be explained by the selectivities of beta-agonists and blockers for beta1- and beta2-adrenoceptors in the heart, two subtypes of beta1-adrenoceptors may exist together in canine ventricular muscles, and atenolol, bisoprolol, and nadolol may act as antagonists for the two subtypes (beta1- and atypical beta- or beta3-adrenoceptors) with two different affinities.The influences were investigated of denopamine, beta1-adrenoceptor partial agonist, on the life span of cardiomyopathic hamsters (BIO 14.6 strain) in the heart failure period. The survival rate of denopamine group at 65 weeks of age was higher than control group. Denopamine treatment lowered plasma levels of noradrenaline and dopamine (P < 0.05), but affected neither the cardiac contractility nor the beta-adrenoceptor density. In summary, denopamine significantly decreases the mortality of cardiomyopathic hamsters. Its effect to lower the plasma catecholamine levels may be responsible for the beneficial effect of denopamine.