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Molecular Pharmacology of Selective beta3-Adrenergic Receptors

选择性 β3-肾上腺素能受体的分子药理学

基本信息

批准号：
07557327
负责人：
YANAGISAWA Teruyuki
金额：
$ 3.97万
依托单位：
Tohoku University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (A)
财政年份：
1995
资助国家：
日本
起止时间：
1995 至 1997
项目状态：
已结题

项目摘要

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.

在离体犬右心室肌中，我们研究了β受体阻滞剂对异丙肾上腺素（一种非选择性激动剂）和T-0509（一种β 1选择性激动剂）的正性变力作用（PIEs）的拮抗作用的差异。选择性β 1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在Schild分析中单相拮抗T-0509的PIE，显示pA 2值分别为7.05、7.63和7.58。另一方面，两种阻滞剂均对异丙肾上腺素（ISO）的PIE产生双相拮抗作用;因此，获得了两个pKB值（分别为7.75和4.25 ; 7.82和5.76 ; 7.42和4.39）。由于T-0509和ISO之间三种β受体阻滞剂的不同拮抗模式不能用β受体激动剂和受体阻滞剂对心脏β 1和β 2肾上腺素受体的选择性来解释，因此两种β 1肾上腺素受体亚型可能同时存在于犬心室肌中，阿替洛尔、比索洛尔、纳多洛尔可能是这两种亚型的拮抗剂（β 1-和非典型β或β 3-肾上腺素受体）具有两种不同的亲和力。研究了地诺帕明，β 1-肾上腺素受体部分激动剂，对心力衰竭期心肌病仓鼠（BIO 14.6品系）寿命的影响。地诺帕明组65周龄存活率高于对照组。地诺帕明治疗可降低血浆去甲肾上腺素和多巴胺水平（P < 0.05），但不影响心肌收缩力和β受体密度。总之，地诺帕明显著降低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是地诺帕明的有益作用的原因。