Decreased inotropic but relatively preserved relaxation response to cyclic adenosine monophosphate-dependent agents in myopathic human myocardium

• Published in: Journal of cardiac failure 1996-12, Vol.2 (4), p.285-292
• Main Authors: Gutstein, David E., Flemmal, Kristen, Bruce, Erika, Travers, Kerry E., Gwathmey, Judith K., Ransil, Bernard J., Markis, John E., Grossman, William, Morgan, James P.
• Format: Article
• Language: English
• Subjects: 1-Methyl-3-isobutylxanthine - administration & dosage; 1-Methyl-3-isobutylxanthine - pharmacology; acetylstrophanthidin; Adrenergic beta-Antagonists - administration & dosage; Adrenergic beta-Antagonists - pharmacology; Adult; Analysis of Variance; beta-adrenergic system; Cardiotonic Agents - administration & dosage; Cardiotonic Agents - pharmacology; Culture Techniques; Dose-Response Relationship, Drug; heart failure; Heart Failure - pathology; Heart Failure - physiopathology; Heart Transplantation; Humans; Isoproterenol - administration & dosage; Isoproterenol - pharmacology; Middle Aged; Milrinone; Myocardial Contraction - drug effects; phosphodiesterase inhibitor; Phosphodiesterase Inhibitors - administration & dosage; Phosphodiesterase Inhibitors - pharmacology; Pyridones - administration & dosage; Pyridones - pharmacology; Reference Values; Strophanthidin - administration & dosage; Strophanthidin - analogs & derivatives; Strophanthidin - pharmacology
• ISSN: 1071-9164; 1532-8414
• DOI: 10.1016/S1071-9164(96)80015-7

Increased intracellular concentrations of cyclic adenosine monophosphate (AMP) stimulate a positive inotropic and lusitropic response in healthy myocardial tissue. Heart failure results in an attenuated inotropic response to cyclic AMP-dependent agents. This study compares the inotropic versus relaxation response to cyclic AMP-dependent and cyclic AMP-independent agents in myocardium from patients with end-stage heart failure and control patients without heart failure. Fifty-four control and 59 myopathic human ventricular trabeculae, 1 mm or less in diameter were placed in physiologic saline, 2.5 mM Ca 2+, and stretched to the length at which maximal isometric force developed at 30°C, 0.33 Hz. Dose-response curves plotted as percentage change from baseline versus concentration of drug were determined for acetylstrophanthidin, isoproterenol, isobutylmethylxanthine, and milrinone. Acetylstrophanthidin, a cyclic AMP-independent agent, showed similar increases in peak tension relative to baseline over the entire dose range tested for both control and myopathic heart muscle; its effect on relaxation of control and failing cardiac muscle was equivalent over the dose range tested. In contrast, the inotropic actions of the cyclic AMP-dependent agents, isoproterenol and the phosphodiesterase inhibitors, were significantly decreased in myopathic muscle compared with control muscle, but effects on relaxation in the control and myopathic groups remained relatively preserved. A relatively preserved relaxant effect is associated with the cyclic AMP-dependentagents, despite significant diminution of their inotropic effects. Thus, in advanced heart failure, patients may continue to benefit from the lusitropic effects of the cyclic AMP-dependent agents, even when the inotropic effects of these agents are severely attenuated.