Hemodynamic Response to Molsidomine in Patients with Ischemic Cardiomyopathy Tolerant to Isosorbide Dinitrate

Unlike nitrates, molsidomine is able to relax vascular smooth muscle without depending on the availability of sulfhydryl groups. To assess the clinical relevance of this property, the hemodynamic effects of a 24-h i.v. infusion of molsidomine were studied in 14 patients with ischemic cardiomyopathy rendered tolerant to i.v. isosorbide dinitrate. In order to determine the role of neurohormonal activation, six of these patients were studied in the presence of an angiotensin-converting enzyme (ACE) inhibitor (enalapril, 5 mg, b.i.d.) (group 2). Six patients out of eight in group 1 (without ACE inhibition) and all patients in group 2 responded to molsidomine with a marked reduction of pulmonary artery wedge pressure (PAWP) (49% +/- 5 and 50% +/- 4 versus baseline value, respectively). However, the reduction of PAWP in group 1 was no longer significant at 12 h, and at 24 h the loss of the peak effect reached 67% +/- 7. On the contrary, PAWP remained persistently reduced in group 2 (loss of peak effect, 20% +/- 3 at 24 h, p less than 0.005). In addition, a significant decrease in hematocrit and increase in epinephrine occurred in group 1 but not in group 2. These results suggest that both the absence of dependence on sulfhydryl groups and the blockade of neurohormonal reactions are needed to avoid nitrate tolerance.