Simvastatin acts synergistically with ACE inhibitors or amlodipine to decrease oxygen consumption in rat hearts

Statin drugs. which are cholesterol-lowering agents, can upregulate endothe lial nitric oxide synthase (eNOS) in isolated endothelial cells independent of lipid lowering. We investigated the effect of short-term simvastatin ad ministration an NO-mediated regulation of myocardial oxygen consumption (MV o(2)) in tissue from rat hearts. Male Wistar rats were divided into (a) con trol group (n = 14). and (b) simvastatin group (n = 10, 20 mg/kg/day by ora l gavage). After 2 weeks, left ventricular myocardium was isolated to measu re MVo(2) using a Clark-type oxygen electrode, and aortic plasma nitrates a nd nitrites (NOx) were measured. Baseline plasma NOx levels (19 +/- 2.6 in control vs. 20 +/- 2.5 mu M/L in simvastatin) and baseline MVo(2) (288 +/- 23 in control vs. 252 +/- 11 nmol/g/min; p = 0.09) were not significantly d ifferent between the two groups. NO-dependent regulation of MVo(2) in respo nse to bradykinin, ramipril, or amlodipine was augmented in simvastatin rat s compared with controls (p < 0.05). Decrease of MVo(2) from baseline in re sponse to highest doses in control versus simvastatin groups was as follows -bradykinin, -28 +/- 5% vs. -44 +/- 6%; ramipril, -35 +/- 5% vs. -50 +/- 8% ; and amlodipine, -32 +/- 9% vs. -42 +/- %. Response to highest dose of NO donor S-nitroso N-acetyl penicillamine (SNAP) was not significantly differe nt in the two groups (-55 +/- 52 vs. -52 +/- 7%). Treatment with N-W-nitro- L-arginine methyl ester, inhibitor of NO synthesis, attenuated the effect o f bradykinin, ramipril, and amlodipine on MVo(2) (p < 0.05). In conclusion, short-term administration of simvastatin in rats potentiates the ability o f angiolensin-converting enzyme (ACE) inhibitors and amlodipine to cause NO -mediated regulation of MVo(2).