Leptin modulates the negative inotropic effect of interleukin-1β in cardiac myocytes

Interleukin-1 beta (IL-1 beta) is a potent negative inotrope implicated in the functional abnormalities of heart failure. Because the adipokine, leptin, protects against some of the cardiovascular effects of endotoxin, we hypothesized that leptin may modulate the cardiosuppressive effects of IL-1 beta in isolated cardiomyocytes. Ventricular cardiac myocytes isolated from adult male Sprague Dawley rats were analyzed simultaneously for electrically stimulated contractility and calcium transients following 30 min exposure to IL-1 beta (10 ng/ml) with or without 60 min pretreatment with leptin (25 ng/ml). IL-1 beta decreased cell shortening, depressed maximal velocities of shortening and relengthening, and prolonged the time to 90% relaxation. The change in fura2-AM fluorescence ratio amplitude (Delta[Ca(2+)]) was significantly depressed and the time to return to baseline [Ca(2+)] was prolonged. The negative inotropic effects of IL-1 beta were blocked by the neutral sphingomyelinase inhibitor Manumycin A (5 mu M) or the ceramidase inhibitor N-oleoyl ethanolamine (1 mu M). Prior exposure of myocytes to leptin blocked IL-1 beta-induced cardiosuppression in conjunction with a blunting of IL-1 beta stimulated ceramide accumulation. These data suggest that leptin may modulate IL-1 beta signaling through the sphingolipid signaling pathway in cardiomyocytes.