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

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.