Interspecies differences in the cardiac negative inotropic effects of beta(3)-adrenoceptor agonists

The aim of the present study was to compare the effects of three preferenti al (BRL 37344, SR 58611, CL 316 243) and a partial (CGP 12177) beta-adrenoc eptor (beta(3)-AR) agonists on the contractility of ventricular strips samp led from various mammalian species including humans. In the human heart, al l beta(3)-AR agonists tested decreased contractility by 40 to 60% below con trol with an order of potency: BRL 37344 > CL 316 243 = SR 58611 >> CGP 121 77. In the dog, the negative inotropic effects produced by beta(3)-AR stimu lation were less pronounced than in humans, approximate to 30% below contro l. The order of potency of beta(3)-AR agonists was CGP 12177 > BRL 37344 = SR 58611 >> CL 316 243; i.e., very different from that observed in humans. In rat, only BRL 37344 was efficient to decrease contractility. In guinea p ig, only CL 316 243 significantly reduced peak tension. In both species, th e reduction in peak tension did not exceed 20 to 30%. Finally, in the ferre t, none of the agonists tested induced a negative inotropic effect. In dog, the negative inotropic effects of CGP 12177 were not modified by nadolol, but were abolished by bupranolol, a beta(1-3)-AR. beta(3)-AR transcripts we re detected in the dog but not in the rat ventricle by using a reverse tran scription-polymerase chain reaction assay. We conclude that cardiac negativ e inotropic effects related to beta(3)-AR agonist stimulation vary markedly depending on the species. A comparable interspecies variation previously h as been reported concerning the lipolytic effects of beta(3)-AR agonist sti mulation. Our study demonstrates that the pharmacological profile of a beta (3)-AR agonist on the human myocardium cannot be extrapolated from usual an imal models.