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


RESULTS
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.


CONCLUSIONS
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.
Gutstein
D E
DE
Charles A. Dana Research Institute, Boston, Massachusetts, USA.
Flemmal
K
K
Bruce
E
E
Travers
K E
KE
Gwathmey
J K
JK
Ransil
B J
BJ
Markis
J E
JE
Grossman
W
W
Morgan
J P
JP
D015056:1-Methyl-3-isobutylxanthine / Q000008:administration & dosage / Q000494:pharmacology*; D000319:Adrenergic beta-Antagonists / Q000008:administration & dosage / Q000494:pharmacology*; D000328:Adult; D000704:Analysis of Variance; D002316:Cardiotonic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D046508:Culture Techniques; D004305:Dose-Response Relationship, Drug; D006333:Heart Failure / Q000473:pathology / Q000503:physiopathology*; D016027:Heart Transplantation; D006801:Humans; D007545:Isoproterenol / Q000008:administration & dosage / Q000494:pharmacology*; D008875:Middle Aged; D020105:Milrinone; D009200:Myocardial Contraction / Q000187:drug effects*; D010726:Phosphodiesterase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D011728:Pyridones / Q000008:administration & dosage / Q000494:pharmacology*; D012016:Reference Values; D013327:Strophanthidin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology
D000319:Adrenergic beta-Antagonists; D002316:Cardiotonic Agents; D010726:Phosphodiesterase Inhibitors; D011728:Pyridones; D013327:Strophanthidin; C004681:acetylstrophanthidin; D020105:Milrinone; D007545:Isoproterenol; D015056:1-Methyl-3-isobutylxanthine