Inamasu M, Totsuka T, Ikeo T, Nagao T, Takeyama S
Biochem Pharmacol. 1987 Jun 15;36(12):1947-54. doi: 10.1016/0006-2952(87)90493-x.
Effects of the new selectively beta 1-adrenergic cardiotonic drug denopamine (TA-064), (-)-(R)-1-(p-hydroxyphenyl)-2-[(3,4-dimethoxyphenethyl)amino]ethanol, on the adenylate cyclase-adenosine-3',5'-monophosphate (c-AMP) system of various tissues and cells in rats and guinea pigs were investigated in comparison with those of isoproterenol. Denopamine at concentrations above 10(-6) M stimulated lipolysis in vitro, and, above 10(-5) M, elevated the c-AMP level in isolated rat fat cells. The c-AMP level of guinea-pig heart ventricular muscle was also elevated when the heart was perfused with 3 X 10(-6) M denopamine or when slices of ventricular muscle were incubated with 10(-6) M denopamine. These changes were abolished in the presence of beta-adrenergic antagonists. Incubation with denopamine did not cause substantial elevation of c-AMP levels in rat reticulocytes and diaphragm. Denopamine activated adenylate cyclase of the rat cell membranes in a concentration-dependent manner. Although dose dependence was less apparent, denopamine also activated adenylate cyclase of the membrane fraction from guinea pig cardiac muscle, but it hardly activated the same enzyme from rat reticulocytes. Isoproterenol, on the other hand, showed marked concentration-dependent activation of adenylate cyclase in all these preparations. Denopamine did not inhibit c-AMP phosphodiesterase of both particulate and supernatant fractions of guinea-pig cardiac muscle. The stimulation of lipolysis by denopamine was observed even when elevation of the c-AMP level was not detected, while the stimulation of lipolysis by isoproterenol was always accompanied with an elevation of c-AMP. When guinea-pig hearts were perfused with 3 X 10(-6) M denopamine or 10(-7) M isoproterenol, their cardiotonic effects were of the same magnitude whereas the degree of c-AMP elevation in the ventricular tissue by denopamine was significantly less than that by isoproterenol. It was concluded that stimulation of the adenylate cyclase-c-AMP system by denopamine was restricted to the tissues whose receptors were predominantly of the beta 1-type, and that the elevation of c-AMP levels in these tissues by denopamine was less marked than by isoproterenol, suggesting that the stimulation of lipolysis and heart by denopamine may be mediated by a special pool of c-AMP or some other unknown factor(s).
研究了新型选择性β1 - 肾上腺素能强心药多巴胺（TA - 064），即(-)-(R)-1-(对羟基苯基)-2-[(3,4-二甲氧基苯乙基)氨基]乙醇，对大鼠和豚鼠各种组织及细胞的腺苷酸环化酶 - 腺苷 - 3',5'- 单磷酸（c - AMP）系统的影响，并与异丙肾上腺素进行了比较。浓度高于10(-6) M的多巴胺在体外刺激脂肪分解，高于10(-5) M时可提高分离的大鼠脂肪细胞中的c - AMP水平。当用3×10(-6) M多巴胺灌注豚鼠心脏或用10(-6) M多巴胺孵育心室肌切片时，心室肌的c - AMP水平也会升高。在β - 肾上腺素能拮抗剂存在的情况下，这些变化会消失。用多巴胺孵育不会使大鼠网织红细胞和膈肌中的c - AMP水平大幅升高。多巴胺以浓度依赖性方式激活大鼠细胞膜的腺苷酸环化酶。虽然剂量依赖性不太明显，但多巴胺也能激活豚鼠心肌膜部分的腺苷酸环化酶，但几乎不能激活大鼠网织红细胞的同一种酶。另一方面，异丙肾上腺素在所有这些制剂中均显示出明显的浓度依赖性腺苷酸环化酶激活作用。多巴胺不抑制豚鼠心肌颗粒和上清部分的c - AMP磷酸二酯酶。即使未检测到c - AMP水平升高，多巴胺仍能刺激脂肪分解，而异丙肾上腺素刺激脂肪分解时总是伴随着c - AMP升高。当用3×10(-6) M多巴胺或10(-7) M异丙肾上腺素灌注豚鼠心脏时，它们的强心作用强度相同，但多巴胺引起的心室组织中c - AMP升高程度明显低于异丙肾上腺素。得出的结论是，多巴胺对腺苷酸环化酶 - c - AMP系统的刺激仅限于其受体主要为β1型的组织，且多巴胺使这些组织中c - AMP水平升高的程度不如异丙肾上腺素明显，这表明多巴胺对脂肪分解和心脏的刺激可能由c - AMP的特殊池或其他一些未知因素介导。
