Effect of simvastatin on the antihypertensive activity of losartan in hypertensive hypercholesterolemic animals and patients: role of nitric oxide, oxidative stress, and high-sensitivity C-reactive protein

Fundam Clin Pharmacol. 2014 Jun;28(3):237-48. doi: 10.1111/fcp.12020. Epub 2013 Mar 13.


This study investigated whether simvastatin has antihypertensive activity and can enhance the antihypertensive effect of losartan in hypertensive hypercholesterolemic animals and patients. Hypertension and hypercholesterolemia were induced in rats by L-NAME and cholesterol-enriched diet, respectively. In these animals, repeated administration of simvastatin decreased the systolic blood pressure, enhanced its progressive reductions induced by repeated administration of losartan, and corrected the compromised lipid profile. Concomitantly, repeated administration of simvastatin, losartan, or simvastatin in combination with losartan to these animals increased nitric oxide (NO) production and decreased the elevated serum malondialdehyde (MDA) and high-sensitivity C-reactive protein (hs-CRP) levels. Effects of combined treatment were greater than those of simvastatin or losartan alone. In hypertensive hypercholesterolemic patients, repeated administration of losartan decreased systolic and diastolic blood pressure, increased NO production, and decreased the elevated serum MDA and hs-CRP levels. Addition of simvastatin to losartan therapy enhanced these effects and corrected the compromised lipid profile. Simvastatin inhibited the contractile responses of isolated aortic rings induced by angiotensin II and enhanced the inhibitory effect of losartan on this preparation. l-arginine and acetylcholine enhanced, while L-NAME inhibited the effects of simvastatin, losartan, and their combination on these contractile responses. Thus, simvastatin exerts antihypertensive effect in hypertensive hypercholesterolemic animals and enhances the antihypertensive effect of losartan in hypertensive hypercholesterolemic animals and patients. Besides, 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 may play an important role in these effects.

Keywords: endothelial dysfunction; losartan; oxidative stress; simvastatin.

Publication types

  • Clinical Trial

MeSH terms

  • Adult
  • Aged
  • Animals
  • Anticholesteremic Agents / administration & dosage
  • Anticholesteremic Agents / pharmacology
  • Anticholesteremic Agents / therapeutic use*
  • Antihypertensive Agents / administration & dosage
  • Antihypertensive Agents / pharmacology
  • Antihypertensive Agents / therapeutic use*
  • Aorta / drug effects
  • Aorta / metabolism
  • Blood Pressure / drug effects
  • C-Reactive Protein / metabolism*
  • Disease Models, Animal
  • Drug Therapy, Combination
  • Endothelium, Vascular / drug effects
  • Endothelium, Vascular / metabolism
  • Female
  • Humans
  • Hypercholesterolemia / complications
  • Hypercholesterolemia / drug therapy*
  • Hypercholesterolemia / metabolism
  • Hypertension / complications
  • Hypertension / drug therapy*
  • Hypertension / metabolism
  • In Vitro Techniques
  • Isometric Contraction / drug effects
  • Losartan / administration & dosage
  • Losartan / pharmacology
  • Losartan / therapeutic use*
  • Male
  • Middle Aged
  • Nitric Oxide / metabolism*
  • Oxidative Stress / drug effects*
  • Rabbits
  • Rats, Wistar
  • Simvastatin / administration & dosage
  • Simvastatin / pharmacology
  • Simvastatin / therapeutic use*
  • Treatment Outcome


  • Anticholesteremic Agents
  • Antihypertensive Agents
  • Nitric Oxide
  • C-Reactive Protein
  • Simvastatin
  • Losartan