title: Simvastatin acts synergistically with ACE inhibitors or amlodipine to decrease oxygen consumption in rat hearts.
abstract: 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 (MV(O2)) 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 MV(O2) using a Clark-type oxygen electrode, and aortic plasma nitrates and nitrites (NOx) were measured. Baseline plasma NOx levels (19+/-2.6 in control vs. 20+/-2.5 microM/L in simvastatin) and baseline MV(O2) (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 MV(O2) in response to bradykinin, ramipril, or amlodipine was augmented in simvastatin rats compared with controls (p < 0.05). Decrease of MV(O2) 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 Nw-nitro-L-arginine methyl ester, inhibitor of NO synthesis, attenuated the effect of bradykinin, ramipril, and amlodipine on MV(O2) (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 MV(O2).
authors.affiliation: Division of Pediatric Cardiology, College of Physicians and Surgeons, Columbia University, New York, USA.
authors.forename: S
authors.initials: S
authors.lastname: Mital
authors.forename: A
authors.initials: A
authors.lastname: Magneson
authors.forename: K E
authors.initials: KE
authors.lastname: Loke
authors.forename: J
authors.initials: J
authors.lastname: Liao
authors.forename: P R
authors.initials: PR
authors.lastname: Forfia
authors.forename: T H
authors.initials: TH
authors.lastname: Hintze
mesh_terms: D017311:Amlodipine / Q000494:pharmacology*; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D001920:Bradykinin / Q000494:pharmacology; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D004357:Drug Synergism; D006321:Heart / Q000187:drug effects; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D066298:In Vitro Techniques; D008297:Male; D009206:Myocardium / Q000378:metabolism*; D009569:Nitric Oxide / Q000097:blood; D020030:Nitric Oxide Donors / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000096:biosynthesis; D052250:Nitric Oxide Synthase Type III; D010101:Oxygen Consumption / Q000187:drug effects*; D010396:Penicillamine / Q000031:analogs & derivatives / Q000494:pharmacology; D017257:Ramipril / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D026423:S-Nitroso-N-Acetylpenicillamine; D019821:Simvastatin / Q000494:pharmacology*; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors; D002121:Calcium Channel Blockers; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D020030:Nitric Oxide Donors; D017311:Amlodipine; D009569:Nitric Oxide; D026423:S-Nitroso-N-Acetylpenicillamine; D019821:Simvastatin; D019001:Nitric Oxide Synthase; D052250:Nitric Oxide Synthase Type III; C496316:Nos3 protein, rat; D010396:Penicillamine; D017257:Ramipril; D001920:Bradykinin