Peripheral cardiovascular actions of SR58611A, 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. Tn normal dogs, i.v. SR 58611 A (100 and 200 nmol kg(-1)) induced a dose-dependent increase in heart rate with no chang e in blood pressure. After i.c. injection, SR 58611 A failed to modify bloo d 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 wit h beta-adrenoceptor antagonists [propranolol, nadolol, bupranolol or the be ta3-adrenoceptor selective antagonist, SR 59230 A (2 mg kg(-1) i.v.)] and s uppressed after sinoaortic denervation (i.e. after removal of vagal tone to the heart), These experiments do not show evidence for a primary central c ardiovascular 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 baro receptor-mediated reflex due to the beta3-adrenoceptor mediated vasodilatio n with an increase in sympathetic tone and a reduction in vagal tone to the heart. (C) Elsevier, Paris.