CPT-1 INHIBITION BY ETOMOXIR HAS A CHAMBER-RELATED ACTION ON CARDIAC SARCOPLASMIC-RETICULUM AND ISOMYOSINS

To characterize the effect of an altered substrate utilization for cardiac sarcoplasmic reticulum (SR) Ca2+ transport, normotensive rats were treated for 5 wk with 15 mg.kg(-1) day(-1) enantiomeric etomoxir, which inhibits mitochondrial carnitine palmitoyltransferase-1 (CPT-1) and fatty acid synthesis. Ca2+ uptake rates of left and right ventricular homogenates were differentially (P < 0.05, two-way analysis of variance) increased by 38 and 13%, respectively. Increased (P < 0.05) transport rates were also observed in the presence of ryanodine. The differences were considerably reduced in the protein kinase A-stimulated state. The levels of phosphorylated phospholamban (PLB) and troponin I as well as immunoreactive PLB were not affected. By contrast, phosphoenzyme levels (E-P) of the SR Ca2+ pump were increased in left ventricular (LV) homogenates. Values of LV E-P and Ca2+ uptake were linearly correlated (P < 0.05) with the myosin V-1 proportions in control (31.7 +/- 1.8% V-1) and treated (58.3 +/- 2.5% V-1) rats. Thus in the left ventricle the metabolic influences have a coordinated action on two distinct proteins involved in relaxation or contraction. The chamber-specific differences in SR function suggest a more pronounced effect of etomoxir in functional states characterized by a reduced Ca2+ transport rate and myosin V-1 proportion.