Vol. 297, Issue 1, 299-307, April 2001

₃-Adrenoceptor Agonist-Induced Increases in Lipolysis, Metabolic Rate, Facial Flushing, and Reflex Tachycardia in Anesthetized Rhesus Monkeys

Gary J. Hom, Michael J. Forrest, Thomas J. Bach, Edward Brady, Mari Rios Candelore, Margaret A. Cascieri, Donna J. Fletcher, Michael H. Fisher, Susan A. Iliff, Robert Mathvink, Joseph Metzger, Victor Pecore, Richard Saperstein, Thomas Shih, Ann E. Weber, Matthew Wyvratt, Peter Zafian and D. Euan MacIntyre

Merck Research Laboratories, Departments of Animal Pharmacology (G.J.H., M.J.F., T.J.B., E.B., D.J.F., J.M., R.S., P.Z., D.E.M.), Immunology and Rheumatology (M.R.C., M.A.C.), Medicinal Chemistry (M.H.F., R.M., T.S., A.E.W., M.W.), Comparative Medicine (S.A.I.), and Statistics (V.P.), Rahway, New Jersey

The effects of two 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 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 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 ₁-adrenergic receptors. This hypothesis was confirmed by determining that 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 ₃-adrenergic receptor-evoked vasodilatation is a direct effect of compounds at ₃-adrenergic receptors in the peripheral vasculature or is secondary to the release or generation of an endogenous vasodilator. Peripheral vasodilatation in response to 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 ₃-adrenergic receptor agonists.