Vasodilation and mechanoenergetic inefficiency dominates the effect of the "Ca2+-sensitizer" MCI-154 in intact pigs

Abstract

Objective-Ca2+-sensitizing agents hold potential as ideal cardiac inotropes, but effects in intact animals are scarcely described. We evaluated a pyridazinone derivative, MCI-154, for hemodynamic, inotropic, mechanoenergetic and oxidative metabolic effects. Design-Intracavitary left ventricular (LV) pressure and conductance (volume) was assessed in open chest anesthetized pigs (n = 6). Contractile performance, pressure-volume area (PVA) and myocardial oxygen consumption (MVO2) were assessed. Myocardial substrate uptake and production of 14CO2 (from glucose) and 3H2O (from fatty acids) were monitored. MCI-154 administration: "low range": 0.1, 0.2, 0.3, 0.5 μg/kg/min and "high range": 0.75, 1.0, 2.0, 3.0 μg/kg/min. Parameters were compared with baseline and a time reference group (n = 7). Results-MCI-154 induced a progressive dose-dependent decrease in systemic vascular resistance, with a concomitant increase in heart rate and cardiac output. Contractility increased only in the high-dose range, and mechanoenergetic efficiency was significantly reduced by drug infusion in all doses. Conclusion-The pyridazinone derivative MCI-154 has minimal inotropic action, induces a significant "oxygen waste", and decreases vascular resistance in intact pigs. A potent phosphodiesterase inhibitory effect may explain this, which suggests further drug refinement.