Effects of chronic treatment with simvastatin on endothelial dysfunction in spontaneously hypertensive rats

Abstract

Objective: To investigate the effects of chronic treatment with simvastatin (SV) on endothelium-dependent relaxation and ouabain-induced contractions in aortic rings from spontaneously hypertensive rats (SHR), comparing with normotensive Wistar-Kyoto rats (WKY).

Methods: After a 12-week period of administration of 1 or 2 mg/kg SV to SHR and WKY, systolic blood pressure (SBP) and vascular reactivity in endothelium-intact aortic rings were assessed.

Results: Relaxation in response to acetylcholine (ACh) in WKY remained unaltered, but in SHR treated with 1 mg/kg SV, enhanced ACh-induced relaxation (P<0.05 versus untreated SHR) reached values observed in untreated WKY. The 2 mg/kg treatment also improved ACh relaxation (P<0.01 and P<0.05 versus untreated SHR and WKY respectively). Inhibiting cyclo-oxygenase (COX) with indomethacin (INDO) improved ACh relaxation in SHR (P<0.05) but not in WKY, independent of treatment with SV. Inhibition of nitric oxide synthase (NOS) with N(G)-nitro-L-arginine (L-NOARG) abolished ACh relaxations in all cases (P<0.001). The result was unaltered when combining INDO plus L-NOARG. SV treatment also decreased ouabain-induced contractions in endothelium-intact aortic rings from SHR, diminishing the percentage effect of contraction from 64.56+/-2.95 (untreated SHR) to 26.98+/-7.06 and 38.10+/-8.21 (1 and 2 mg/kg treated SHR respectively). Response to ouabain in WKY was not significantly affected by SV treatment

Conclusions: Chronic treatment of SHR with SV improves endothelium-dependent ACh relaxation of the aortic rings, probably by an NO-involving mechanism more than by inhibiting contractile COX-derived factors. An improvement in endothelial modulation of ouabain-induced contractions was also observed after treatment with SV in SHR, which might be due to an inhibition of a calcium-sodium exchanger.