Deficient production of cyclic AMP: pharmacologic evidence of an important cause of contractile dysfunction in patients with end-stage heart failure.

Abstract

We studied the effects of different classes of inotropic drugs on human working myocardium in vitro that was isolated from the hearts of patients with end-stage heart failure, and compared the responses to these drugs with those noted in muscles from nonfailing control hearts. Although peak isometric force generated in response to increased extracellular calcium reached control levels in the muscles from patients with heart failure, the time course of contraction and rate of relaxation were greatly prolonged. The inotropic effectiveness of the ,B-adrenergic agonist isoproterenol and the phosphodiesterase inhibitors milrinone, caffeine, and isobutylmethylxanthine was markedly reduced in muscles from the patients with heart failure. In contrast, the effectiveness of inotropic stimulation with acetylstrophanthidin and the adenylate cyclase activator forskolin was preserved. After a minimally effective dose of forskolin was given to elevate intracellular cyclic AMP levels, the inotropic responses of muscles from the failing hearts to phosphodiesterase inhibitors were markedly potentiated. These data indicate that an abnormality in cyclic AMP production may be a fundamental defect present in patients with end-stage heart failure that can markedly diminish the effectiveness of agents that depend on generation of this nucleotide for production of a positive inotropic effect.

Effects of cantharidin on force of contraction and phosphatase activity in nonfailing and failing human hearts

“…In end-stage human heart failure the fJ-adrenoceptor/ adenylyl cyclase signalling pathway is desensitized, characterized by a reduction of f3-adrenoceptor density and an increase in inhibitory GTP-binding proteins (Bristow et al, 1982;Feldman et al, 1988;Neumann et al, 1988). The positive inotropic effect of P-adrenoceptor agonists and of phosphodiesterase inhibitors, which act via cyclic AMP are diminished in human heart failure (Bristow et al, 1982;Feldman et al, 1987). Cyclic AMP via cyclic AMP-dependent protein kinase leads to phosphorylation of cardiac regulatory proteins (e.g.…”

Incomplete reversal of β‐adrenoceptor desensitization in human and guinea‐pig cardiomyocytes by cyclic nucleotide phosphodiesterase inhibitors

“…Inhibition of PDE results in an increase in cyclic AMP, similar to P-adrenoceptor agonist stimulation of adenylate cyclase. The resulting increased activation of cyclic AMP-dependent protein kinase elicits increased phosphorylation of several regulatory proteins in the heart, with subsequent increased contractility (Feldman et al, 1987;Karczewski et al, 1990;Bristow et al, 1990). The initial aim of this study was to characterize the inotropic effects of PDE inhibition in ventricular myocytes isolated from both human and guineapig hearts.…”

“…Previous work on PDE inhibition in cardiac I Author for correspondence. muscle has been carried out on whole muscle preparations (Feldman et al, 1987;Gristwood et al, 1987;Weishaar et al, 1987;Bohm et al, 1988a,d;Schmitz et al, 1989;Bethke et al, 1991;von der Leyen et al, 1991). The advantages of myocyte over multicellular preparations are numerous.…”

“…Attenuated contractile response to P-adrenoceptor stimulation, as a consequence of a decrease in both the receptor number (Bristow et al, 1982) and cyclic AMP production (Feldman et al, 1987;Danielsen et al, 1989), is well documented in heart failure (Bohm et al, 1988a,c;Bristow et al, 1990). This is believed to be a result of chronic exposure to the observed high plasma noradrenaline levels of patients with heart failure (Thomas & Marks, 1978).…”

Neurohormonal interactions and adaptations in congestive heart failure.

“…On the other hand, to the extent that the sympathetic nervous system acts to support myocardial contractility, any decrease in catecholamine responsiveness may exacerbate the hemodynamic abnormalities seen in heart failure. 5 We can attempt to distinguish between these two possibilities by observing the hemodynamic and clinical reaction to specific therapeutic interventions.…”