The goal of our study was to compare the effects of two beta 3-adrenergic receptor agonists, i.e., BRL37344 (BRL) and CL316243 (CL), in conscious dogs, rats and nonhuman primates, instrumented with aortic and atrial catheters, ascending aortic flow probes and left ventricular (LV) pressure gauges. In conscious dogs, CL, 10 micrograms/kg, i.v., reduced, P < .05, mean arterial pressure by 8 +/- 4% and total peripheral resistance by 51 +/- 4% and increased, P < .05, LV dP/dt by 79 +/- 10% and heart rate by 88 +/- 8%. These responses were similar to those induced by BRL, 8.3 micrograms/kg, i.v. After autonomic blockade (beta 1/beta 2-adrenergic, cholinergic and ganglionic), CL still reduced total peripheral resistance by 49 +/- 4%, and increased LV dP/dt by 21 +/- 4%, without an effect on heart rate. In conscious rats, 10 times the dose of CL 100 micrograms/kg, i.v., reduced, P < .05, total peripheral resistance by 18 +/- 4%, without major effects on LV dP/dt and heart rate. BRL, 83 micrograms/kg i.v., reduced total peripheral resistance similarly by 31 +/- 3%, and increased heart rate (25 +/- 3%) and LV dP/dt (27 +/- 5%) more, P < .05. In conscious monkeys and baboons, CL, 100 micrograms/kg, i.v., did not induce significant effects, whereas BRL, 83 micrograms/kg, i.v., increased heart rate (36 +/- 6%), LV dP/dt (85 +/- 9%) and decreased total peripheral resistance (30 +/- 2%). After beta 1/beta 2-adrenergic receptor blockade in rats and primates, there were almost no differences between BRL and CL, i.e., in primates there were almost no significant cardiovascular effects with either compound. Both CL and BRL increased circulating free fatty acids in the dog, but not in the baboon. Thus, CL appears to be a more specific beta 3-adrenergic receptor agonist than BRL. More importantly, beta 3-adrenergic receptor stimulation was most profound in dogs, where even a direct effect on LV contractility was identified, was diminished but still significant in rats, and essentially absent in primates.