Article date: December 2000
By: Heinz Rupp, Roland Vetter in Volume 131, Issue 8, pages 1748-1756
Failing cardiac hypertrophy is associated with an inadequate sarcoplasmic reticulum (SR) function. The hypothesis was examined that pressure overloaded hearts fail to increase SR Ca2+ 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 Ca2+ 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 Ca2+ release channel by ruthenium red. SERCA2 protein level was reduced (P<0.05) by 30.4±0.8%.
SR Ca2+ uptake rate was inversely correlated (P<0.05) with left ventricular weight but was not affected by the occurrence of pulmonary congestion. Because SR Ca2+ uptake rate of whole ventricles was not reduced, a hypertrophy proportional dilution of SR Ca2+ 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 Ca2+ uptake rate of left ventricle and myosin isozyme V1 were increased (P<0.05).
Etomoxir represents a candidate approach for prevention of heart failure by inducing a hypertrophy proportional increase in SR Ca2+ uptake rate.
Failing cardiac hypertrophy is associated with an inadequate sarcoplasmic reticulum (SR) function. The hypothesis was examined that pressure overloaded hearts fail to increase SR Ca2+ 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 Ca2+ 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 Ca2+ release channel by ruthenium red. SERCA2 protein level was reduced (P<0.05) by 30.4±0.8%.
SR Ca2+ uptake rate was inversely correlated (P<0.05) with left ventricular weight but was not affected by the occurrence of pulmonary congestion. Because SR Ca2+ uptake rate of whole ventricles was not reduced, a hypertrophy proportional dilution of SR Ca2+ 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 Ca2+ uptake rate of left ventricle and myosin isozyme V1 were increased (P<0.05).
Etomoxir represents a candidate approach for prevention of heart failure by inducing a hypertrophy proportional increase in SR Ca2+ uptake rate.
British Journal of Pharmacology (2000) 131, 1748–1756; doi:10.1038/sj.bjp.0703741
DOI: 10.1038/sj.bjp.0703741
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