Copyright © 1988 by the European Society of Cardiology.
© 1988 The European Society of Cardiology
Reduction of beta-adrenoceptor density and evaluation of positive inotropic responses in isolated, diseased human myocardium
*Medizinische Klinik 1
Herzchirurgische klinik, Universität München D-8000 München 70, Marchioninistrasse 15, F.R.G.
Received 2 September 1987; revised 22 January 1988; .
Send correspondence and offprint request to:Michael Böhm at the above address.
Abstract
Cardiac beta-adrenoceptors and the positive inotropic effects of adenylate cyclase-depentdent (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–1protein. The density of cardiac beta-adrenoceptors was significantly reduced in NYHA II–III to 18.0 ±1.1 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–II 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.
Key Words: Heart failure • beta-adrenoceptors • phosphodiesterase inhibitors • positive inotropic effect.
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