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.

在孤立的犬右心室肌肉中，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β1-选择性激动剂T-0509的阳性肌力作用（PIE）的拮抗作用差异。选择性的β1受体阻滞剂阿替洛尔或双洛洛尔，以及一种非选择性β受体阻滞剂Nadolol在SCHILD分析中单单相拮抗T-0509的PIE，显示PA2值分别为7.05,7.63和7.58。另一方面，两个阻滞剂都产生了针对异丙肾上腺素（ISO）的双相拮抗作用。因此，获得两个PKB值（分别为7.75和4.25； 7.82和5.76； 7.42和4.39）。因为T-0509和ISO之间三个β受体阻滞剂的对抗模式无法通过心脏中β1-和beta2-肾上腺素的β-激动剂和阻滞剂的选择性来解释，而beta1-肾上腺肾上腺的两个亚型可能存在于犬胸腔肌肉和boylolololololololololol，Asoproloy，Asoproloy，Asoproloy，and and and anderololololololotol，and Asoproloy and and and and。具有两个不同亲和力的亚型（beta1-和非典型β-或beta3-肾上腺素受体）。在心脏衰竭期间，研究了对心肌病仓鼠（BIO 14.6菌株）的寿命的Denopamine，beta1-肾上腺肾上腺素受体部分激动剂的影响。在65周龄时，非洲非洲胺基的存活率高于对照组。黑肾上腺素治疗降低了去甲肾上腺素和多巴胺的血浆水平（P <0.05），但既不影响心脏收缩性也没有影响β-肾上腺素受体密度。总而言之，非洲类药物大大降低了心肌病仓鼠的死亡率。它降低血浆儿茶酚胺水平的作用可能导致了非洲胺的有益作用。