Vasodilation and Mechanoenergetic Inefficiency Dominates the Effect of the "Ca 2+ -sensitizer" MCI-154 in Intact Pigs

Publisher Website
Google Scholar
Abstract
Objective : Ca 2+ -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 (MVO 2 ) were assessed. Myocardial substrate uptake and production of 14 CO 2 (from glucose) and 3 H 2 O (from fatty acids) were monitored. MCI-154 administration: "low range": 0.1, 0.2, 0.3, 0.5 µ g/kg/min and "high range": 0.75, 1.0, 2.0, 3.0 µ g/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.