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

摘要

Murine left atrium lacks inotropic β2-adrenoceptor function. We investigated whether β2-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.Sinoatrial tachycardia, evoked by (−)-adrenaline was resistant to blockade by β2-selective ICI 118,551 (50 nM) but antagonized by β1-selective CGP 20712A (300 nM). This pattern was unaffected by pretreatment with pertussis toxin (PTX, 600 μg kg−1 i.p. 24 h) which reversed carbachol-evoked bradycardia to tachycardia.Increases of ventricular force by (−)-adrenaline and (−)-noradrenaline were not blocked by ICI 118,551 but antagonized by CGP 20712A.Under blockade of β-adrenoceptors, (−)-adrenaline and (−)-noradrenaline depressed ventricular force (−logIC50M=7.7 and 6.9). The cardiodepressant effects of (−)-adrenaline were antagonized by phentolamine (1 μM) and prazosin (1 μM) but not by (−)-bupranolol (1 μM). Prazosin potentiated the positive inotropic effects of (−)-adrenaline (in the absence of β-blockers) from −logEC50M=6.2–6.8.PTX-treatment reduced carbachol-evoked depression of ventricular force in the presence of high catecholamine concentrations. Inhibition of ventricular function of Gi 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.(−)-Adrenaline causes murine cardiostimulation through β1-adrenoceptors but not through β2-adrenoceptors. The negative inotropic effects of (−)-adrenaline are mediated through ventricular α1-adrenoceptors but not through β3-adrenoceptors. Both Gi protein and α1-adrenoceptors restrain (−)-adrenaline-evoked increases in right ventricular force mediated through β1-adrenoceptors.