Cardiovascular effects of beta 3-adrenoceptor stimulation in perinephritichypertension

Background A new beta 3-adrenoceptor (beta (3)-AR) has been shown to mediat e peripheral vasodilation. This study was conducted to evaluate effects of the beta (3)-AR agonist, SR58611 in normal and hypertensive dogs. Materials and Methods In protocol 1, SR58611 was infused in normal dogs aft er placebo, after beta1/beta2 blockade with nadolol, after beta1/beta2/beta 3 blockade with bupranolol and after combined autonomic blockade (CAB). In protocol 2, perinephritic hypertension was produced in dogs, which received SR58611 at 3 and 6 weeks of hypertension. Effects of SR58611 were evaluate d at 7 weeks of hypertension after CAB. Results In normal dogs, SR58611 produced a dose-dependent decrease in mean aortic pressure (AOP) (from 116 +/- 19 to 100 +/- 19 mmHg, - 14%; P < 0.05) that was accompanied by baroreflex activation (heart rate increased by 70% ; P < 0.01). This hypotensive effect resulting from peripheral vasodilation persisted after nadolol or CAB while baroreflex activation was blunted or abolished. A biphasic response of cardiac output, characterized by a rise a nd a decline (P < 0.05) reflected a reduction in after- and pre-load. After CAB, SR58611 did not modify cardiac contractility. SR58611 stimulated lipo lysis as reflected by a 4-fold increase in blood free fatty acids (FFA) (P < 0.0005). Under CAB, the rise of FFA was reduced (P < 0.01). In hypertensi ve dogs, SR58611 produced a dose-dependent decrease in mean AOP (from 168 /- 32 to 125 +/- 35 mmHg; -26%, P < 0.0001), that was greater than in norma l dogs (P < 0.05). Reflex-mediated tachycardia also occurred but at higher blood pressure values. Blood FFA rose similarly (P < 0.0001). Under CAB, he art rate remained unchanged but SR58611 still induced a decrease (P < 0.000 1) in mean AOP concomitantly with a rise of (dP/dt)/DP40 (P < 0.005), an ef fect not observed in normal dogs. Conclusions beta (3)-AR stimulation exerts hypotensive effects, increases c ardiac contractility and stimulates lipolysis in hypertensive dogs.