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Cardiovascular Research 2003 60(2):250-258; doi:10.1016/j.cardiores.2003.08.003
© 2003 by European Society of Cardiology
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Copyright © 2003, European Society of Cardiology

Preservation of NO production by statins in the treatment of heart failure

Jean-Noel Trochua, Seema Mitala, Xiao-ping Zhanga, Xiaobin Xua, Manuel Ochoaa, James K Liaob, Fabio A Recchiaa and Thomas H Hintze*,a

aDepartment of Physiology, New York Medical College, Basic Sciences Building, Valhalla, NY 10595, USA
bBrigham and Women's Hospital, Harvard Medical School, Boston, MA 01772, USA

*Corresponding author. Tel.: +1-914-594-3633; fax: +1-914-594-4108. Email address: thomas_hintze{at}nymc.edu

Objective: Because statins promote endogenous nitric oxide (NO) production in vessels by increasing endothelial nitric oxide synthase (eNOS), we evaluated the clinical benefit and efficiency of simvastatin in preventing the decrease in NO control of coronary blood flow (CBF), NO regulation of myocardial oxygen consumption (MVO2) and decreased nitrite production in coronary microvessels, associated with pacing-induced heart failure (HF). Methods: Dogs (n = 17) were instrumented for measurement of coronary blood flow and left ventricular end diastolic pressure (LVEDP). HF was induced by pacing. Ten dogs were given simvastatin 20 mg/kg/day orally (HF+SIMVA) from the 10th day of pacing. Results: HF+SIMVA had a lower LVEDP at 4 weeks of pacing (18±1 vs. 25±1 mm Hg, p<0.05), and the NO-dependent coronary vasodilation to veratrine was preserved compared to HF (p<0.05). In coronary microvessels, SIMVA potentiated nitrite production compared to HF (p<0.05) and enhanced the NO-dependent decrease in MVO2 in cardiac tissue in response to 10–4 mol/l bradykinin, which was markedly blunted in HF (p<0.05). Using Western blotting, there was a reduction in eNOS protein during HF that was preserved at 4–5 weeks of pacing during treatment with SIMVA. Conclusions: Simvastatin maintained NO production by coronary vessels and NO bioactivity during pacing-induced dilated cardiomyopathy. Targeting the endothelium, which participates in the control of myocardial metabolism by NO, may be an important mechanism of action of statins in the treatment of heart failure.

KEYWORDS Nitric oxide; Heart failure; Statins; Hypertrophy; Oxygen consumption

Time for primary review 27 days


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