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Sarcoplasmic reticulum function and carnitine palmitoyltransferase‐1 inhibition during progression of heart failure

2000; Wiley; Volume: 131; Issue: 8 Linguagem: Inglês

10.1038/sj.bjp.0703741

1476-5381

Heinz Rupp, Roland Vetter,

Mitochondrial Function and Pathology

Failing cardiac hypertrophy is associated with an inadequate sarcoplasmic reticulum (SR) function. The hypothesis was examined that pressure overloaded hearts fail to increase SR Ca 2+ uptake rate proportionally to the hypertrophy and that carnitine palmitoyltransferase‐1 inhibition by etomoxir ((±)‐ethyl 2[6(4‐chlorophenoxy)hexyl] oxirane‐2‐carboxylate) can counteract this process. Severe left ventricular pressure overload was induced in rats by constricting the ascending aorta for 8, 10, 14 and 28 weeks leading to cardiac hypertrophy (+62–+103% of sham‐operated rats) and pulmonary congestion. Homogenate oxalate‐facilitated SR Ca 2+ uptake rate g wet wt −1 was reduced ( P <0.05) by 29.9±1.8% irrespective of phospholamban phosphorylation (in the presence of catalytic subunit of protein kinase A) and inhibition of SR Ca 2+ release channel by ruthenium red. SERCA2 protein level was reduced ( P <0.05) by 30.4±0.8%. SR Ca 2+ uptake rate was inversely correlated ( P <0.05) with left ventricular weight but was not affected by the occurrence of pulmonary congestion. Because SR Ca 2+ uptake rate of whole ventricles was not reduced, a hypertrophy proportional dilution of SR Ca 2+ uptake has to be inferred which precedes pulmonary congestion. Treatment with etomoxir (15 mg kg body wt −1 day −1 for 10 weeks) did not affect left ventricular weight but decreased ( P <0.05) the right ventricular hypertrophy related to pulmonary congestion. In parallel, SR Ca 2+ uptake rate of left ventricle and myosin isozyme V 1 were increased ( P <0.05). Etomoxir represents a candidate approach for prevention of heart failure by inducing a hypertrophy proportional increase in SR Ca 2+ uptake rate. British Journal of Pharmacology (2000) 131 , 1748–1756; doi: 10.1038/sj.bjp.0703741