Reduction of beta-adrenoceptor density and evaluation of positive inotropic responses in isolated, diseased human myocardium

Abstract

Cardiac beta-adrenoceptors and the positive inotropic effects of adenylate cyclase-dependent (dobutamine, histamine, forskolin) and adenylate cyclase-independent agents (isobutylmethylxanthine (IBMX), dibutyryl-cAMP (db-cAMP), digoxin, digitoxin and calcium were measured in papillary muscle strips from severely failing (NYHA IV), moderately failing (NYHA II-III) and non-failing (NYHA I) human hearts. The density of beta-adrenoceptors in three NYHA I patients were 40.0, 42.0 and 42.9 fmol mg-1 protein. The density of cardiac beta-adrenoceptors was significantly reduced in NYHA II-III to 18.0 +/- 1.1 fmol mg-1 protein (n = 16) and further reduced in NYHA IV to 9.5 +/- 1.6 fmol mg-1 protein (n = 7). The KD values did not differ between the groups. Correspondingly, the positive inotropic effect of dobutamine was significantly reduced in NYHA II-III and almost lost in NYHA IV. The positive inotropic effect of histamine was similar in non-failing and moderately failing myocardium but reduced in preparations from severely failing hearts (NYHA IV). The positive inotropic effect of IBMX was diminished in moderately and severely failing myocardium depending on the functional class of heart failure. In contrast, the effects of forskolin, db-cAMP, digoxin and digitoxin were not impaired in NYHA IV when compared with the maximal positive inotropic effect of calcium. It is concluded that in the failing human heart (a) the number of cardiac beta-adrenoceptors is reduced proportional to the severity of heart failure; (b) the receptor coupling of H2-receptors to adenylate cyclase may be impaired, but only in severe heart failure; (c) the basal cAMP formation may be diminished; and that (d) the catalytic subunit of the adenylate cyclase and the cAMP-dependent protein kinases may be promising targets for drugs to restore force of contraction in human heart failure.