title: Atorvastatin and sildenafil lower blood pressure and improve endothelial dysfunction, but only atorvastatin increases vascular stores of nitric oxide in hypertension.
abstract: Nitric oxide (NO)-derived metabolites including the anion nitrite can recycle back to NO and thus complement NO formation independent of NO synthases. While nitrite is as a major vascular storage pool and source of NO, little is known about drugs that increase tissue nitrite concentrations. This study examined the effects of atorvastatin or sildenafil, or the combination, on vascular nitrite concentrations and on endothelial dysfunction in the 2 kidney-1 clip (2K1C) hypertension model. Sham-operated or 2K1C hypertensive rats were treated with vehicle, atorvastatin (50 mg/Kg), sildenafil (45 mg/Kg), or both for 8 weeks. Systolic blood pressure (SBP) was monitored weekly. Nitrite concentrations were assessed in the aortas and in plasma samples by ozone-based reductive chemiluminescence assay. Aortic rings were isolated to assess endothelium-dependent and independent relaxation. Aortic NADPH activity and ROS production were evaluated by luminescence and dihydroethidium, respectively, and plasma TBARS levels were measured. Aortic nitrotyrosine staining was evaluated to assess peroxynitrite formation. Atorvastatin and sildenafil, alone or combined, significantly lowered SBP by approximately 40 mmHg. Atorvastatin significantly increased vascular nitrite levels by 70% in hypertensive rats, whereas sildenafil had no effects. Both drugs significantly improved the vascular function, and decreased vascular NADPH activity, ROS, and nitrotyrosine levels. Lower plasma TBARS concentrations were found with both treatments. The combination of drugs showed no improved responses compared to each drug alone. These findings show evidence that atorvastatin, but not sildenafil, increases vascular NO stores, although both drugs exert antioxidant effects, improve endothelial function, and lower blood pressure in 2K1C hypertension.
authors.affiliation: Department of Pharmacology, Ribeirao Preto Medical School, University of Sao Paulo, Av. Bandeirantes 3900, Ribeirao Preto 14049-900, SP, Brazil.
authors.forename: Danielle A
authors.initials: DA
authors.lastname: Guimarães
authors.affiliation: Department of Pharmacology, Ribeirao Preto Medical School, University of Sao Paulo, Av. Bandeirantes 3900, Ribeirao Preto 14049-900, SP, Brazil.
authors.forename: Elen
authors.initials: E
authors.lastname: Rizzi
authors.affiliation: Department of Pharmacology, Ribeirao Preto Medical School, University of Sao Paulo, Av. Bandeirantes 3900, Ribeirao Preto 14049-900, SP, Brazil.
authors.forename: Carla S
authors.initials: CS
authors.lastname: Ceron
authors.affiliation: Department of Pharmacology, Ribeirao Preto Medical School, University of Sao Paulo, Av. Bandeirantes 3900, Ribeirao Preto 14049-900, SP, Brazil.
authors.forename: Lucas C
authors.initials: LC
authors.lastname: Pinheiro
authors.affiliation: Department of Morphology, Physiology, and Basic Pathology, University of Sao Paulo, s/n Av. Café, Ribeirao Preto 14040-904, SP, Brazil.
authors.forename: Raquel F
authors.initials: RF
authors.lastname: Gerlach
authors.affiliation: Department of Pharmacology, Ribeirao Preto Medical School, University of Sao Paulo, Av. Bandeirantes 3900, Ribeirao Preto 14049-900, SP, Brazil.
authors.forename: Jose E
authors.initials: JE
authors.lastname: Tanus-Santos
mesh_terms: D000818:Animals; D001011:Aorta / Q000378:metabolism / Q000473:pathology; D000069059:Atorvastatin; D001794:Blood Pressure / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D004195:Disease Models, Animal; D004359:Drug Therapy, Combination; D006538:Heptanoic Acids / Q000008:administration & dosage* / Q000494:pharmacology; D006978:Hypertension, Renovascular / Q000188:drug therapy* / Q000473:pathology*; D008297:Male; D009569:Nitric Oxide / Q000097:blood* / Q000378:metabolism; D010879:Piperazines / Q000008:administration & dosage* / Q000494:pharmacology; D011687:Purines / Q000008:administration & dosage / Q000494:pharmacology; D011758:Pyrroles / Q000008:administration & dosage* / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D000068677:Sildenafil Citrate; D013449:Sulfonamides / Q000008:administration & dosage* / Q000494:pharmacology
chemical_list: D006538:Heptanoic Acids; D010879:Piperazines; D011687:Purines; D011758:Pyrroles; D013449:Sulfonamides; D009569:Nitric Oxide; D000069059:Atorvastatin; D000068677:Sildenafil Citrate
keywords: 2K1C hypertension; Atorvastatin; Endothelial dysfunction; Nitric oxide; Nitrite; Oxidative stress; Sildenafil