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Positive inotropic effect of ceramide in adult ventricular myocytes: mechanisms dissociated from its reduction in Ca²⁺ influx

Department of Pharmaceutical Sciences and Department of Pharmacology and Toxicology, University of Arkansas for Medical Sciences, Little Rock, Arkansas 7220

Submitted 17 December 2002 ; accepted in final form 25 April 2003

Ceramide, a sphingolipid metabolite produced by activation of sphingomyelinase, has been previously shown to reduce L-type Ca²⁺ channel current (I_Ca,L) in adult rat ventricular myocytes; however, its effect on contractile function is unknown. In this study, we investigated the effects of ceramide on excitation-contraction coupling in adult ventricular myocytes and on left ventricular (LV) function in isolated hearts. Surprisingly, in patch-clamped myocytes, ceramide increased contraction concomitant with reductions in I_Ca,L. In intact myocytes, ceramide increased cell shortening (CS) concurrently with enhancing maximum rates of shortening and relaxation and the duration of contraction. Ceramide also increased the amplitudes of postrest potentiated (PRP) contraction. In fura-PE3-loaded myocytes, ceramide increased systolic Ca²⁺ and the magnitude and maximum rates of the rising and declining phases of Ca²⁺ transients. Ceramide-elicited decreases in magnitudes of PRP relative to steady-state contraction and the Ca²⁺ transient suggest an increased fractional Ca²⁺ release from the sarcoplasmic reticulum (SR). However, ceramide slightly reduced the caffeine-induced Ca²⁺ transient and had no significant effect on the amplitude of the PRP-elicited Ca²⁺ transient. Additionally, the ceramide-induced upward shift in the relationship of contraction and the Ca²⁺ transient and increase in the Ca²⁺ responsiveness of CS suggest an increase in myofilament Ca²⁺ sensitivity. In isolated hearts, ceramide increased LV developed pressure and maximum rates of contraction and relaxation at balloon volumes of 30–50 µl. In summary, regardless of decreasing I_Ca,L, ceramide elicits distinct positive inotropic and lusitropic effects, resulting probably from enhanced SR Ca²⁺ release and uptake, and increased Ca²⁺ sensitivity of ventricular myocytes.

calcium; lipid metabolites; excitation-contraction coupling; contractile function; sphingolipid; heart

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