Contrasting preload-dependent hemodynamic and neurohumoral effects of isomazole, a partial phosphodiesterase inhibitor and calcium sensitizer.

BACKGROUND

Currently evaluated positive inotropic agents that act predominantly through phosphodiesterase III-inhibiting properties, have been disappointing in the treatment of heart failure. Lack of efficacy as a result of diminished cellular cyclic adenosine monophosphate and vasodilating tolerance and side effects are prevalent. In contrast, calcium sensitization is preserved in heart failure and agents that combine phosphodiesterase-inhibiting and calcium-sensitizing properties may be more efficacious. Isomazole is such a novel agent with combined properties. This study investigated the acute hemodynamic and neurohormonal effects of intravenous isomazole (3 micrograms/kg/min for 30 minutes).

METHODS AND RESULTS

The effects of preexisting preload were evaluated in 18 patients with heart failure, New York Heart Association class II/III, and elevated (> 15 mmHg, n = 11, group I) and normal; (n = 7, group II) pulmonary wedge pressure at baseline. In the overall group, isomazole increased myocardial contractility and relaxation and decreased systemic resistance by 20%. Left and right filling pressures fell by 35-45%, accompanied by a 69% reduction in cardiac atrial natriuretic peptide release. In contrast, levels of arterial norepinephrine and renin both increased by 27%. Cardiac output increased in group I (23%), but fell in group II (18%), accompanied by a 51% increase in arterial norepinephrine. Cardiac atrial natriuretic peptide decreased in group I, but not in group II.

CONCLUSIONS

Isomazole induced positive inotropic and lusitropic effects and arterial vasodilation in all patients. Cardiac pump function improved only in group I, accompanied by a reduction in sympathetic activity and renin-angiotensin and aldosterone levels and a more pronounced decrease in cardiac atrial natriuretic peptide release. In contrast, in patients with normal to low preload, the further reduction in preload led to a deterioration of pump function and increased sympathetic tone.