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.

Effects of Angiotensin II Type 1 Receptor Blockade and Angiotensin-Converting Enzyme Inhibition on Cardiac β-Adrenergic Signal Transduction

“…[11][12][13][14][15][16] The diminished formation of the second-messenger cAMP after stimulation of cardiac ␤-adrenergic receptors is due to a decline in the number of ␤-adrenergic receptors, [11][12][13] an uncoupling of ␤-adrenergic receptors, and an increase in inhibitory G protein ␣ subunits. 14 -16 The underlying mechanism inducing these desensitization processes is an activation of the sympathetic nervous system and, in particular, sympathetic activation in the heart itself.…”

“…9 This model exhibits an activation of the cardiac tissue RAS as well as an activation of the sympathetic nervous system within the heart. 10 These mechanisms lead to similar ␤-adrenergic signal transduction defects, 10 as occur in cardiomyopathic human hearts with terminal heart failure (ie, downregulation of ␤-adrenergic receptors [11][12][13] and an increase in inhibitory G protein ␣ subunits [G i␣ ]). 14 -16 Although TG(mREN2)27 rats are not in heart failure and might not represent all pathobiochemical alterations observed in this condition, it can be taken as valuable model to study drug effects on ␤-adrenergic signal transduction.…”

Progressive hypertrophy and heart failure in β 1 -adrenergic receptor transgenic mice

“…The majority of cardiac ␤-adrenergic receptors are of the ␤ 1 -subtype, and the minority are of the ␤ 2 -subtype (2). In chronic heart failure, these receptors are reduced in number (3,4) and in function (1,(4)(5)(6). Reductions in receptor number seem to occur early in the development of heart failure (7) and to correlate with the severity of the disease (8,9).…”

The management of heart failure and the scope for new therapies: what role for xamoterol?

“…Receptor regulation is fast emerging as an important therapeutic area for development (Bristow et al, 1982). Sympathetic down-regulation may be seen as protecting the myocardium, but current evidence suggests that modest receptor up-regulation is clinically useful and can be supported by available energy sources (Bohm et al, 1988). Perhaps in the past therapeutic inotropic drive has been too gross.…”