ACUTE HEMODYNAMIC-EFFECTS AND PRELOAD-DEPENDENT CARDIOVASCULAR PROFILE OF THE PARTIAL PHOSPHODIESTERASE INHIBITOR NANTERINONE IN PATIENTS WITH MILD-TO-MODERATE HEART-FAILURE

Nanterinone (UK-61,260) is a novel positive inotropic and balanced-typ e vasodilating drug, only partially based on phosphodiesterase III inh ibition. Preliminary data from controlled studies suggest satisfactory long-term efficacy and safety. As its acute hemodynamic effects in hu mans are unknown, an oral dose of 2 mg nanterinone was studied in 14 p atients with heart failure (NYHA class II-III) on chronic diuretic and angiotensin-converting enzyme (ACE) inhibitor treatment. Before the s tudy, patients were on a 2 g salt-balanced diet, and they received the ir last medication 16 hours before each study day. Hemodynamic measure ments were carried out before and 0.5, 1, 1.5, 2, 2.5, 3, 4, 8, 12, an d 24 hours after administration of the study drug. All patients receiv ed placebo and nanterinone on 2 consecutive days. Following nanterinon e, systemic vascular resistance decreased immediately from 1699 +/- 82 (mean +/- SEM) at baseline to 1368 +/- 80 at 1 hour. Changes persiste d for 12 hours. Concomitantly, there was an immediate and significant fall in pulmonary wedge pressure to 38% of baseline at 1.5 hours, toge ther with a 20% reduction in pulmonary artery pressure. Heart rate rem ained unchanged and arterial pressures showed only a short, significan t decrease. Cardiac index rose significantly from 2.28 +/- 0.15 at bas eline to a highest value of 2.65 +/- 0.14 1/min/m(2) at 1 hour. Change s persisted for 3 hours. Placebo had no effect on these variables. As, in view of its potential venodilating properties, hemodynamic improve ment by nanterinone may depend on pre-existing left ventricular fillin g pressure, patients were subsequently grouped according to baseline p ulmonary wedge pressure of >12 mmHg (H-PCWP) and less than or equal to 12 mmHg (L-PCWP). Cardiac index improved by 26% in H-PCWP and by 17% in L-PCWP (NS). In contrast, PCWP fell more markedly in H-PWCP than in L-PCWP (40% and 23%, respectively, p < 0.05). Thus, oral nanterinone results in a significant acute hemodynamic improvement and is well tol erated. Although changes in left ventricular filling pressure are more pronounced in patients with elevated pre-existing PCWP, cardiac pump function improves equally in patients with normal or low left ventricu lar filling pressure at baseline.