Vesnarinone Restores Contractility and Calcium Handling in Early Endotoxemia

Abstract

Background —Endotoxin (lipopolysaccharide, LPS) is a trigger of the systemic inflammatory response. We have previously found that vesnarinone and amrinone, when given before LPS, prevented cytokine production and LPS-related cardiac dysfunction. We tested the hypothesis that vesnarinone would improve intracellular Ca 2+ handling and calcium-activated contractile force after the onset of endotoxemia. Methods and Results —Adult rabbits received a bolus injection of LPS or vehicle. Vesnarinone (3 mg/kg) was given intravenously 90 minutes later. Two hours after LPS administration, hearts were perfused in the isolated Langendorff mode. Peak left ventricular developed pressure, ±dp/dt, oxygen consumption (MV̇ o 2 ), and rate×pressure product were evaluated in conjunction with fluorescent spectroscopic determinations of intracellular calcium concentrations (Ca i ) and the rate of Ca i transient decline during diastole (τCa). Peak left ventricular developed pressure and ±dp/dt were significantly lower in the LPS group. These were completely restored by vesnarinone. There was significantly slower diastolic calcium removal (increased τCa) in LPS hearts that was also corrected by vesnarinone; however, the cytosolic calcium overload characteristic of LPS hearts was only partially improved. Reduced mechanical inefficiency (the ratio of rate-pressure product to MV̇ o 2 ) and myofilament sensitivity to Ca i were also significantly improved by vesnarinone. Conclusions —Acute endotoxemia caused contractile protein calcium insensitivity, oxygen wastage, and abnormal calcium cycling. Vesnarinone, given in the rescue mode, normalized LPS-induced myocardial dysfunction and partially restored abnormal calcium cycling. Although the mechanisms responsible for these effects require further clarification, it appears that agents such as vesnarinone may be useful to treat inflammatory-induced myocardial dysfunction.