Key result
Isomazole increases contractile force ~178% in nonfailing human hearts but barely affects failing hearts.
Why the study?
The mechanisms underlying the differential positive inotropic effects of isomazole on nonfailing versus failing human hearts were unclear, particularly regarding PDE isoenzyme inhibition and cAMP signaling.
Isomazole significantly increases the force of contraction in nonfailing human hearts but has marginal effects in failing hearts, likely due to defective receptor-adenylate cyclase coupling rather than impaired PDE inhibition.
Positive inotropy via PDE III/IV inhibition in nonfailing myocardium; hypothesis-generating for failing hearts, no practice change.
The phosphodiesterase (PDE) inhibitor isomazole increased the force of contraction to 278.3 +/- 89.1% (n = 7) of the predrug value in ventricular trabeculae carneae isolated from nonfailing human hearts. This effect can be attributed mainly to a PDE III or a combined PDE III/IV inhibition since at the concentration of the maximal positive inotropic effect of isomazole, PDE III and PDE IV were completely inhibited. In explanted failing human hearts (end-stage myocardial failure, NYHA IV), isomazole increased the force of contraction only marginally to 110.1 +/- 10.7% of the predrug value. The lack of a distinct positive inotropic efficacy of isomazole in failing human hearts could not be explained by an impairment of PDE inhibition since the properties of the PDE I-IV isoenzymes separated by DEAE-Sepharose chromatography and the inhibitory effects of isomazole did not differ in both preparations. The positive inotropic effect of the beta-adrenoceptor agonist isoprenaline was also reduced in failing hearts. However, in the presence of isomazole, the diminished positive inotropic effect of isoprenaline was restored to values obtained with isoprenaline alone in nonfailing hearts. Thus, the decreased effect of inotropic drugs like isoprenaline or isomazole in preparations from failing human heart might be explained mainly by a diminished cAMP formation due to a defect in receptor-adenylate cyclase coupling.
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Bethke et al. (1991) studied Heart failure (end-stage myocardial failure, NYHA IV). Isomazole vs. Predrug baseline was evaluated on Force of contraction (% of predrug value). Isomazole increased the force of contraction to 278.3% of predrug values in nonfailing human hearts, but only marginally to 110.1% in failing human hearts.
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