The negative inotropic effect of β3-adrenoceptor stimulation in the beating guinea pig heart

Although beta(3)-adrenoceptors (ARs) have been extensively characterized in brown and white adipocytes, their actions in the beating heart are unclear. We examined the effects of a beta(3)-AR agonist, BRL37344, on cardiac function and calcium transients in Langendorff-perfused guinea pig hearts by simultaneously measuring left ventricular (LV) pressure and Ca(2+)-dependent indo-1 fluorescence. BRL37344 induced a dose-dependent negative inotropic effect at concentrations from 10(-11) to 10(-8) M. Maximally, LV developed pressure decreased to 80 +/- 2%, +dP/dt to 81 +/- 2%, and -dP/dt to 81 +/- 3% of their respective control values (p < 0.01). The amplitude of the Ca(2+) transient also decreased (to 92 +/- 3% of the control level; p < 0.01). The BRL37344 dose-response curve was not altered by nadolol (10(-5) M), a potent beta(1)- and beta(2)-AR antagonist, but completely suppressed by bupranolol (10(-6) M), a potent beta(1)- beta(2)- and beta(3)-AR antagonist. To assess the potential rule of a nitric oxide synthase (NOS) pathway, we determined whether the NOS inhibitor, N(G)-nitro-L-arginine methyl ester (NAME), modified the contractile response to BRL37344. L-NAME (10(-7) and 10(-4) M) attenuated the negative inotropic effects on LV developed pressure by 35 and 50%, suggesting that beta(3)-AR stimulation induces a negative inotropic effect on guinea pig hearts partly through a decrease in the Ca(2+) transient and partly by the NOS pathway.