Hom G J, Forrest M J, Bach T J, Brady E, Candelore M R, Cascieri M A, Fletcher D J, Fisher M H, Iliff S A, Mathvink R, Metzger J, Pecore V, Saperstein R, Shih T, Weber A E, Wyvratt M, Zafian P, MacIntyre D E
Merck Research Laboratories, Department of Animal Pharmacology, P.O. Box 2000, Rahway, NJ 07065, USA.
J Pharmacol Exp Ther. 2001 Apr;297(1):299-307.
The effects of two beta(3)-adrenergic receptor agonists, (R)-4-[4-(3-cyclopentylpropyl)-4,5-dihydro-5-oxo-1H-tetrazol-1-yl]-N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]benzenesulfonamide and (R)-N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)- ethyl]amino]ethyl]phenyl]-1-(4-octylthiazol-2-yl)-5-indolinesulfonamide, on indices of metabolic and cardiovascular function were studied in anesthetized rhesus monkeys. Both compounds are potent and specific agonists at human and rhesus beta(3)-adrenergic receptors. Intravenous administration of either compound produced dose-dependent lipolysis, increase in metabolic rate, peripheral vasodilatation, and tachycardia with no effects on mean arterial pressure. The increase in heart rate in response to either compound was biphasic with an initial rapid component coincident with the evoked peripheral vasodilatation and a second more slowly developing phase contemporaneous with the evoked increase in metabolic rate. Because both compounds exhibited weak binding to and activation of rhesus beta(1)-adrenergic receptors in vitro, it was hypothesized that the increase in heart rate may be reflexogenic in origin and proximally mediated via release of endogenous norepinephrine acting at cardiac beta(1)-adrenergic receptors. This hypothesis was confirmed by determining that beta(3)-adrenergic receptor agonist-evoked tachycardia was attenuated in the presence of propranolol and in ganglion-blocked animals, under which conditions there was no reduction in the evoked vasodilatation, lipolysis, or increase in metabolic rate. It is not certain whether the beta(3)-adrenergic receptor-evoked vasodilatation is a direct effect of compounds at beta(3)-adrenergic receptors in the peripheral vasculature or is secondary to the release or generation of an endogenous vasodilator. Peripheral vasodilatation in response to beta(3)-adrenergic receptor agonist administration was not attenuated in animals administered mepyramine, indomethacin, or calcitonin gene-related peptide(8-37). These findings are consistent with a direct vasodilator effect of beta(3)-adrenergic receptor agonists.
在麻醉的恒河猴中研究了两种β(3)-肾上腺素能受体激动剂，(R)-4-[4-(3-环戊基丙基)-4,5-二氢-5-氧代-1H-四唑-1-基]-N-[4-[2-[[2-羟基-2-(3-吡啶基)乙基]氨基]乙基]苯基]苯磺酰胺和(R)-N-[4-[2-[[2-羟基-2-(3-吡啶基)乙基]氨基]乙基]苯基]-1-(4-辛基噻唑-2-基)-5-吲哚啉磺酰胺对代谢和心血管功能指标的影响。这两种化合物都是人和恒河猴β(3)-肾上腺素能受体的强效特异性激动剂。静脉注射任何一种化合物都会产生剂量依赖性的脂解作用、代谢率增加、外周血管舒张和心动过速，而对平均动脉压无影响。对任何一种化合物的心率增加都是双相的，最初的快速成分与诱发的外周血管舒张同时出现，第二个较慢发展的阶段与诱发的代谢率增加同时出现。由于这两种化合物在体外对恒河猴β(1)-肾上腺素能受体表现出弱结合和激活作用，因此推测心率增加可能起源于反射性，并且近端是通过作用于心脏β(1)-肾上腺素能受体的内源性去甲肾上腺素释放介导的。通过确定在普萘洛尔存在下和神经节阻断的动物中β(3)-肾上腺素能受体激动剂诱发的心动过速减弱，证实了这一假设，在这些条件下，诱发的血管舒张、脂解或代谢率增加没有降低。尚不确定β(3)-肾上腺素能受体诱发的血管舒张是化合物在外周血管系统中对β(3)-肾上腺素能受体的直接作用，还是内源性血管舒张剂释放或产生的继发作用。在给予美吡拉敏、吲哚美辛或降钙素基因相关肽(8-37)的动物中，对β(3)-肾上腺素能受体激动剂给药的外周血管舒张没有减弱。这些发现与β(3)-肾上腺素能受体激动剂的直接血管舒张作用一致。
