Atorvastatin, sildenafil and their combination down‐regulate matrix metalloproteinases (MMPs) in 2K1C hypertension

Abstract

Atorvastatin (ATORVA) and sildenafil (SILD) may downregulate MMPs, especially when both drugs are combined (ATORVA+SILD), and therefore attenuated the vascular changes found in hypertension. We evaluated whether these drugs attenuate vascular MMP‐2 levels/activity in 2kidney‐1clip (2K1C) hypertension. Sham or 2K1C hypertensive rats were treated with vehicle, ATORVA (50 mg/Kg), SILD (45 mg/Kg) or both for 8 weeks. Systolic blood pressure (SBP) was monitored weekly. Aortic MMP‐2 levels/activity was evaluated by gelatin and in situ zymography and by immunofluorescence. We studied whether these drugs directly inhibit human recombinant MMP‐2 (hrMMP‐2) in vitro activity. All treatments attenuated 2K1C hypertension. Aortas from 2K1C rats showed higher MMP‐2 levels (75, 72 and 64 kDa) compared with sham. All treatments attenuated 2K1C hypertension‐induced increases in MMP‐2 levels. All treatments attenuated the increases in total MMP activity and in MMP‐2 levels without additive effects. However these drugs had no effects on hr‐MMP‐2 activity. ATORVA and SILD reduced the SBP and vascular proteolytic activity in 2K1C hypertension, without additive effects. Our results suggest that both drugs can prevent, at least in part, the vascular dysfunction of hypertension by downregulating vascular MMP levels. Supported by: Fundação de Amparo a Pesquisa do Estado de São Paulo (FAPESP), Conselho Nacional de Desenvolvimento Cientifico e Tecnológico (CNPq).