Physiological antagonism between ventricular β1-adrenoceptors and α1-adrenoceptors but no evidence for β2- and β3-adrenoceptor function in murine heart

1 Murine left atrium lacks inotropic beta(2)-adrenoceptor function. We investigated whether beta(2)-adrenoceptors are involved in the cardiostimulant effects of (-)-adrenaline on spontaneously beating right atria and paced right ventricular myocardium of C57BL6 mice. We also studied a negative inotropic effect of (-)-adrenaline. 2 Sinoatrial tachycardia, evoked by (-)-adrenaline was resistant to blockade by beta(2)-selective ICI 118,551 (50 nM) but antagonized by beta(1)-selective CGP 20712A (300 nM). This pattern was unaffected by pretreatment with pertussis toxin (PTX, 600 mug kg(-1) i.p. 24 h) which reversed carbachol-evoked bradycardia to tachycardia. 3 Increases of ventricular force by (-)-adrenaline and (-)-noradrenaline were not blocked by ICI 118,551 but antagonized by CGP 20712A. 4 Under blockade of beta-adrenoceptors, (-)-adrenaline and (-)-noradrenaline depressed ventricular force (-logIC(50)M = 7.7 and 6.9). The cardiodepressant effects of (-)-adrenaline were antagonized by phentolamine (1 muM) and prazosin (1 muM) but not by (-)-bupranolol (1 muM). Prazosin potentiated the positive inotropic effects of (-)-adrenaline (in the absence of beta-blockers) from - logEC(50)M = 6.2 - 6.8. 5 PTX-treatment reduced carbachol-evoked depression of ventricular force in the presence of high catecholamine concentrations. Inhibition of ventricular function of G(i) protein was verified by 82% reduction of in vitro ADP-ribosylation. PTX-treatment tended to increase the positive inotropic potency of (-)-adrenaline under all conditions investigated, including the presence of ICI 118,551. 6 (-)-Adrenaline causes murine cardiostimulation through beta(1)-adrenoceptors but not through beta(2)-adrenoceptors. The negative inotropic effects of (-)-adrenaline are mediated through ventricular alpha(1)-adrenoceptors but not through beta(3)-adrenoceptors. Both G(i) protein and alpha(1)-adrenoceptors restrain (-)-adrenaline-evoked increases in right ventricular force mediated through beta(1)-adrenoceptors.