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

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Abstract
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. British Journal of Pharmacology (2002) 136, 217–229; doi:10.1038/sj.bjp.0704700

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