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 V1 proportions in control (31.7 +/- 1.8% V1) and treated (58.3 +/- 2.5% V1) 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 V1 proportion.
Vetter
R
R
Max Delbrück Center for Molecular Medicine, Berlin-Buch, Germany.
Rupp
H
H
D000818:Animals; D002118:Calcium / Q000378:metabolism; D002135:Calcium-Binding Proteins / Q000378:metabolism; D000252:Calcium-Transporting ATPases / Q000378:metabolism; D002334:Carnitine O-Palmitoyltransferase / Q000037:antagonists & inhibitors*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D004852:Epoxy Compounds / Q000494:pharmacology*; D006321:Heart / Q000187:drug effects*; D006352:Heart Ventricles / Q000187:drug effects / Q000378:metabolism; D017136:Ion Transport / Q000187:drug effects; D008055:Lipids / Q000097:blood; D008297:Male; D009218:Myosins / Q000378:metabolism*; D010766:Phosphorylation; D051381:Rats; D017208:Rats, Wistar; D012433:Ryanodine / Q000494:pharmacology; D012519:Sarcoplasmic Reticulum / Q000187:drug effects*; D013237:Stereoisomerism; D014336:Troponin / Q000378:metabolism; D019210:Troponin I; D000099211:Phospholamban
D002118:Calcium; D002135:Calcium-Binding Proteins; D000252:Calcium-Transporting ATPases; D002334:Carnitine O-Palmitoyltransferase; D017868:Cyclic AMP-Dependent Protein Kinases; D004852:Epoxy Compounds; D008055:Lipids; D009218:Myosins; D012433:Ryanodine; D014336:Troponin; D019210:Troponin I; D000099211:Phospholamban; C054207:etomoxir