title: Simvastatin enhances the antihypertensive effect of ramipril in hypertensive hypercholesterolemic animals and patients. Possible role of nitric oxide, oxidative stress, and high sensitivity C-reactive protein.
abstract: In this study, the effects of simvastatin on the blood pressure and on the antihypertensive activity of ramipril in hypertensive hypercholesterolemic animals and patients were evaluated. In hypertensive hypercholesterolemic animals, repeated administration of simvastatin slightly but significantly decreased the systolic blood pressure, enhanced its progressive reductions induced by repeated administration of ramipril and corrected the compromised lipid profile. Concomitantly, repeated administration of simvastatin, ramipril or simvastatin in combination with ramipril to these animals, increased nitric oxide (NO) production and decreased the elevated serum malondialdehyde (MDA) and high sensitivity C-reactive protein (hs-CRP) levels. The effects of combined treatment were greater than those of simvastatin or ramipril alone. In hypertensive hypercholesterolemic patients, repeated administration of ramipril decreased systolic and diastolic blood pressure, increased NO production, and decreased the elevated serum MDA and hs-CRP levels. Addition of simvastatin to ramipril therapy enhanced these effects and corrected the compromised lipid profile. Simvastatin but not ramipril inhibited the contractile responses of isolated aortic rings induced by angiotensin 11. l-arginine and acetylcholine enhanced, while l-NAME inhibited effects of simvastatin, and simvastatin in combination with ramipril on these contractile responses. These findings suggest that simvastatin exerts antihypertensive effect and enhances the antihypertensive effect of ramipril in hypertensive hypercholesterolemic animals and patients. In addition to its cholesterol-lowering effect, the ability of simvastatin to ameliorate endothelial dysfunction through increasing NO bioavailability and through suppression of oxidative stress and vascular inflammation and its ability to enhance the effect of ramipril on these parameters may play a pivotal role in these effects.
authors.affiliation: Faculty of Medicine, Department of Pharmacology, Assiut University, Assiut, Egypt 71526. ahmedosmanaz@hotmail.com
authors.forename: Ahmed O
authors.initials: AO
authors.lastname: Abdel-Zaher
authors.forename: Alaa Eldin A
authors.initials: AE
authors.lastname: Elkoussi
authors.forename: Lotfy H
authors.initials: LH
authors.lastname: Abudahab
authors.forename: Mohammed H
authors.initials: MH
authors.lastname: Elbakry
authors.forename: Elsayed Abu-Elwafa
authors.initials: EA
authors.lastname: Elsayed
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D000959:Antihypertensive Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D001013:Aorta, Thoracic / Q000187:drug effects / Q000503:physiopathology; D001794:Blood Pressure / Q000187:drug effects; D002097:C-Reactive Protein / Q000378:metabolism*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D006937:Hypercholesterolemia / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism; D006973:Hypertension / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism; D066298:In Vitro Techniques; D008297:Male; D008875:Middle Aged; D009569:Nitric Oxide / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects*; D011817:Rabbits; D017257:Ramipril / Q000008:administration & dosage / Q000627:therapeutic use*; D051381:Rats; D017208:Rats, Wistar; D019821:Simvastatin / Q000008:administration & dosage / Q000627:therapeutic use*; D016896:Treatment Outcome; D014664:Vasodilation / Q000187:drug effects
chemical_list: D000959:Antihypertensive Agents; D009569:Nitric Oxide; D002097:C-Reactive Protein; D019821:Simvastatin; D017257:Ramipril