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

Statin drugs, which are cholesterol-lowering agents, can upregulate endothelial nitric oxide synthase (eNOS) in isolated endothelial cells independent of lipid lowering. We investigated the effect of short-term simvastatin administration on NO-mediated regulation of myocardial oxygen consumption (MVo₂) in tissue from rat hearts. Male Wistar rats were divided into (a) control group (n = 14), and (b) simvastatin group (n = 10, 20 mg/kg/day by oral gavage). After 2 weeks, left ventricular myocardium was isolated to measure MVo₂ using a Clark-type oxygen electrode, and aortic plasma nitrates and nitrites (NO(x)) were measured. Baseline plasma NO(x) levels (19 ± 2.6 in control vs. 20 ± 2.5 μ M/L in simvastatin) and baseline MVo₂ (288 ± 23 in control vs. 252 ± 11 nmol/g/min; p = 0.09) were not significantly different between the two groups. NO-dependent regulation of MVo₂ in response to bradykinin, ramipril, or amlodipine was augmented in simvastatin rats compared with controls (p < 0.05). Decrease of MVo₂ from baseline in response 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 ± 3%. Response to highest dose of NO donor S-nitroso N-acetyl penicillamine (SNAP) was not significantly different in the two groups (-55 ± 5% vs. -52 ± 7%). Treatment with N(w)nitro-L-arginine methyl ester, inhibitor of NO synthesis, attenuated the effect of bradykinin, ramipril, and amlodipine on MVo₂ (p < 0.05). In conclusion, short-term administration of simvastatin in rats potentiates the ability of angiotensin-converting enzyme (ACE) inhibitors and amlodipine to cause NO-mediated regulation of MVo₂.