Peripheral cardiovascular actions of SR 58611 A, a beta 3‐adrenoceptor agonist, in the dog: lack of central effect

In order to investigate the putative role of beta3-adrenoceptors in central and peripheral cardiovascular regulations, the effects of intracisternal (i.c.) and intravenous (i.v.) injections of SR 58611 A (10, 50, 100 and 200 nmol kg-1), a selective beta3-adrenoceptor agonist, were investigated in chloralose anaesthetized dogs. In normal dogs, i.v. SR 58611 A (100 and 200 nmol kg-1) induced a dose-dependent increase in heart rate with no change in blood pressure. After i.c. injection, SR 58611 A failed to modify blood pressure and heart rate (except at the highest dose 200 nmol kg-1 which induced a positive chronotropic effect). The positive chronotropic effect of SR 58611 A (200 nmol kg-1) appeared earlier and was significantly more pronounced after i.v. than i.c. administration. The positive chronotropic effect of i.v. SR 58611 A (200 nmol kg-1) was reduced by pretreatment with beta-adrenoceptor antagonists propranolol, nadolol, bupranolol or the beta3-adrenoceptor selective antagonist, SR 59230 A (2 mg kg-1 i.v.) and suppressed after sinoaortic denervation (i.e. after removal of vagal tone to the heart). These experiments do not show evidence for a primary central cardiovascular effect of SR 58611 A. The positive chronotropic effect of i.v. SR 58611 A is mainly of peripheral origin and can be attributed to a baroreceptor-mediated reflex due to the beta3-adrenoceptor mediated vasodilation with an increase in sympathetic tone and a reduction in vagal tone to the heart.