acetylstrophanthidin and Heart-Failure

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 Ca2+, and stretched to the length at which maximal isometric force developed at 30 degrees 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-dependent agents, 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.

Topics: 1-Methyl-3-isobutylxanthine; Adrenergic beta-Antagonists; Adult; Analysis of Variance; Cardiotonic Agents; Culture Techniques; Dose-Response Relationship, Drug; Heart Failure; Heart Transplantation; Humans; Isoproterenol; Middle Aged; Milrinone; Myocardial Contraction; Phosphodiesterase Inhibitors; Pyridones; Reference Values; Strophanthidin

To study the changes in myocardial digitalis binding sites in heart failure, we measured myocardial ouabain binding sites, Na-K-adenosinetriphosphatase (ATPase) activity, and ventricular muscle mechanical responses to acetylstrophanthidin in dogs with right-heart failure (RHF) produced by tricuspid avulsion and pulmonary artery constriction. Sham-operated dogs were studied as the control. RHF produced a significant decrease in ouabain binding sites in the right and left ventricular myocardium, which was accompanied by a proportional decrease in Na-K-ATPase activity. However, RHF and sham-operated dogs did not differ in systemic hemodynamic or right ventricular trabeculate muscle isometric contractile responses to acetylstrophanthidin. To determine whether chronic beta-adrenergic stimulation contributed to the development of Na-K-ATPase downregulation, we administered nadolol (40 mg/day) to a separate group of dogs during an early stage of RHF development. Nadolol effectively prevented the reduction of myocardial ouabain binding sites that occurred in RHF. Thus we conclude that myocardial ouabain binding sites and Na-K-ATPase activity are reduced in dogs with experimental heart failure and that these changes probably occur as a result of the attendant heightened sympathetic activity.

Topics: Animals; Binding Sites; Dogs; Heart Failure; Hemodynamics; Isometric Contraction; Male; Myocardial Contraction; Myocardium; Nadolol; Ouabain; Sodium-Potassium-Exchanging ATPase; Strophanthidin; Ventricular Function, Right

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 beta-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.

Topics: 1-Methyl-3-isobutylxanthine; Caffeine; Calcium; Cardiotonic Agents; Colforsin; Cyclic AMP; Heart Failure; Humans; Isoproterenol; Milrinone; Myocardial Contraction; Myocardium; Pyridones; Stimulation, Chemical; Strophanthidin

Topics: Blood Circulation; Blood Pressure; Dogs; Heart; Heart Failure; Heart Function Tests; Hypoxia; Metabolism; Myocardium; Oxygen Consumption; Pharmacology; Research; Strophanthidin; Strophanthins

Topics: Animals; Cardiac Glycosides; Chlorides; Digitalis Glycosides; Dogs; Electrolytes; Factor Analysis, Statistical; Heart Failure; Histocytochemistry; Myocardium; Potassium; Pulmonary Valve Stenosis; Research; Sodium; Strophanthidin; Water; Water-Electrolyte Balance

Topics: Carbohydrate Metabolism; Electrolytes; Heart Failure; Myocardium; Strophanthidin; Strophanthins

Topics: Animals; Dogs; Heart; Heart Failure; Humans; Strophanthidin; Strophanthins

Topics: Digitalis; Heart Failure; Humans; Strophanthidin; Strophanthins

Topics: Arteries; Heart Failure; Humans; Hypertension, Pulmonary; Mitral Valve Stenosis; Pulmonary Artery; Pulmonary Circulation; Strophanthidin; Strophanthins

Topics: Biomedical Research; Heart Failure; Strophanthidin; Strophanthins