beta(3)-adrenoceptor agonist-induced increases in lipolysis, metabolic rate, racial flushing, and reflex tachycardia in anesthetized rhesus monkeys

The effects of two beta (3)-adrenergic receptor agonists, (R)-4-[4-(3-cyclo pentylpropyl)-4,5-dihydro-5-oxo-1H-tetrazol-1-yl]-N-[4-[2[[2-hydroxy-2-(3-p yridinyl)ethyl]amino]ethyl]phenyl]benzenesulfonamide and (R)-N-[4-[2-[[2-hy droxy-2-(3-pyridinyl)ethyl] amino]ethyl]phenyl]-1-(4-octylthiazol-2-yl)-5-i ndolinesulfonamide, on indices of metabolic and cardiovascular function wer e studied in anesthetized rhesus monkeys. Both compounds are potent and spe cific agonists at human and rhesus beta (3)-adrenergic receptors. Intraveno us administration of either compound produced dose-dependent lipolysis, inc rease 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 developi ng phase contemporaneous with the evoked increase in metabolic rate. Becaus e both compounds exhibited weak binding to and activation of rhesus beta (1 )-adrenergic receptors in vitro, it was hypothesized that the increase in h eart rate may be reflexogenic in origin and proximally mediated via release of endogenous norepinephrine acting at cardiac beta (1)-adrenergic recepto rs. This hypothesis was confirmed by determining that beta (3)-adrenergic r eceptor agonist-evoked tachycardia was attenuated in the presence of propra nolol 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 va sodilatation is a direct effect of compounds at beta (3)-adrenergic recepto rs in the peripheral vasculature or is secondary to the release or generati on of an endogenous vasodilator. Peripheral vasodilatation in response to b eta (3)-adrenergic receptor agonist administration was not attenuated in an imals administered mepyramine, indomethacin, or calcitonin gene-related pep tide(8-37). These findings are consistent with a direct vasodilator effect of beta (3)-adrenergic receptor agonists.