?2-Adrenoceptor-mediated positive inotropic effect of adrenaline in human ventricular myocardium

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Abstract
Experiments were designed to unravel the relative contribution of β1- and β2-adrenoceptors to the positive inotropic effects of adrenaline and noradrenaline in isolated tissues of left ventricular myocardium of man. We also analyzed relationships between the fractions of human left ventricular β1- and β2-adrenoceptors, estimated from binding assays, and stimulation of adenylate cyclase and contractile force by adrenaline and noradrenaline. 1) Selective blockade of β2-adrenoceptors by erythro(±)-(α-methyl-indan-4-yloxy)-3-isopropylaminobutan-2-ol (ICI 118,551) attenuated the increase of contractile force caused by adrenaline but not by noradrenaline, suggesting some involvement of β2-adrenoceptors. Selective blockade of β2-adrenoceptors without affecting α1-adrenoceptors still enabled both adrenaline and noradrenaline to cause maximum possible increases of contractile force through β1-adrenoceptors. 2) A direct involvement of β2-adrenoceptors became manifest by selectively antagonizing β1-adrenoceptors by 1-[2((3-carbamoyl-4-hydroxy)phenoxy)ethylamino]3-[4(1-methyl-4-trifluoromethyl-2-imidazolyl)phenoxy]-2-propanol (CGP 20712 A) without affecting β2-adrenoceptor. β2-adrenoceptors can mediate half of the maximum increase of contractile force elicited by low concentrations of adrenaline and also contribute to the increase of contractile force caused by high concentrations of noradrenaline. 3) β-adrenoceptors were labelled in membrane particles with 3H-(−)-bupranolol in the absence (β1 & β2) and presence of 500 nmol/l CGP 20712 A (β2). 71 % of the β-adrenoceptors Were β1 and 29% β2. Binding inhibition experiments with CGP 20712 A and ICI 118,551 yielded 74% β1 and 26% β2-4) With the help of ICI 118,551 and CGP 20712 A it was found that, in membrane particles, 33–36% and 64–67% of maximum stimulation of the adenylate cyclase by noradrenaline was mediated through β1- and β2-adrenoceptors, respectively. Adrenaline caused 11–25% and 75–89% of maximum cyclase stimulation through β1- and β2-adrenoceptors, respectively. 5) The contribution of β1- and β2-adrenoceptors to the positive inotropic effects of adrenaline and noradrenaline cannot be inferred straightforwardly from biochemical estimates of receptor fractions and fractional adenylate cyclase stimulation.