Preservation of NO production by statins in the treatment of heart failure.
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 (MVO(2)) 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 MVO(2) 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.
Trochu
Jean-Noel
JN
Department of Physiology, New York Medical College, Basic Sciences Building, Valhalla, NY 10595, USA.
Mital
Seema
S
Zhang
Xiao ping
Xp
Xu
Xiaobin
X
Ochoa
Manuel
M
Liao
James K
JK
Recchia
Fabio A
FA
Hintze
Thomas H
TH
D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D002304:Cardiac Pacing, Artificial; D003331:Coronary Vessels; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism; D006333:Heart Failure / Q000188:drug therapy* / Q000378:metabolism; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000378:metabolism / Q000627:therapeutic use*; D066298:In Vitro Techniques; D009206:Myocardium / Q000378:metabolism*; D009569:Nitric Oxide / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III; D010101:Oxygen Consumption; D019821:Simvastatin / Q000378:metabolism / Q000627:therapeutic use*; D014665:Vasodilator Agents / Q000494:pharmacology; D014702:Veratrine / Q000494:pharmacology
D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D014665:Vasodilator Agents; D009569:Nitric Oxide; D019821:Simvastatin; D019001:Nitric Oxide Synthase; D052250:Nitric Oxide Synthase Type III; D014702:Veratrine; D000109:Acetylcholine