The methyl ester of rosuvastatin elicited an endothelium-independent and 3-hydroxy-3-methylglutaryl coenzyme A reductase-independent relaxant effect in rat aorta

J.S López-Canales,C Castillo-Henkel,E Castillo-Henkel,P López-Sanchez,I Wens-Flores,V.M Perez-Alvarez,A.C Polanco

doi:10.1590/s0100-879x2011007500032

Abstract

The relaxant effect of the methyl ester of rosuvastatin was evaluated on aortic rings from male Wistar rats (250-300 g, 6 rats for each experimental group) with and without endothelium precontracted with 1.0 µM phenylephrine. The methyl ester presented a slightly greater potency than rosuvastatin in relaxing aortic rings, with log IC50 values of -6.88 and -6.07 M, respectively. Unlike rosuvastatin, the effect of its methyl ester was endothelium-independent. Pretreatment with 10 µM indomethacin did not inhibit, and pretreatment with 1 mM mevalonate only modestly inhibited the relaxant effect of the methyl ester. Nω-nitro-L-arginine methyl ester (L-NAME, 10 µM), the selective nitric oxide-2 (NO-2) inhibitor 1400 W (10 µM), tetraethylammonium (TEA, 10 mM), and cycloheximide (10 µM) partially inhibited the relaxant effect of the methyl ester on endothelium-denuded aortic rings. However, the combination of TEA plus either L-NAME or cycloheximide completely inhibited the relaxant effect. Inducible NO synthase (NOS-2) was only present in endothelium-denuded aortic rings, as demonstrated by immunoblot with methyl ester-treated rings. In conclusion, whereas rosuvastatin was associated with a relaxant effect dependent on endothelium and hydroxymethylglutaryl coenzyme A reductase in rat aorta, the methyl ester of rosuvastatin exhibited an endothelium-independent and only slightly hydroxymethylglutaryl coenzyme A reductase-dependent relaxant effect. Both NO produced by NOS-2 and K+ channels are involved in the relaxant effect of the methyl ester of rosuvastatin.

Highlights

In addition to their beneficial lipid modulation effects, statins exert a variety of “pleiotropic” actions that may be clinically beneficial [1,2,3]
The results of the present study clearly show that the methyl ester of rosuvastatin has an acute concentrationdependent relaxant effect on vascular smooth muscle, Figure 5
The relaxant effect of the methyl ester is independent of the endothelial layer, even though the relaxant effect of rosuvastatin is partially endothelium-dependent [7,18]

Summary

Introduction

In addition to their beneficial lipid modulation effects, statins exert a variety of “pleiotropic” actions that may be clinically beneficial [1,2,3]. Examples of the pleiotropic actions of statins such as pravastatin, cerivastatin, atorvastatin, simvastatin, and rosuvastatin [5,6,7] include direct acute vascular effects associated with increased production of either endothelial nitric oxide synthase (eNOS or NOS-3) in endothelial cells [8] or inducible NOS (iNOS or NOS-2) in smooth muscle cells [9], antithrombotic effects, anti-inflammatory effects [10,11], and decreased nitrotyrosine production [12]. A substantial number of experimental and clinical studies have demonstrated the favorable cardiovascular effects of rosuvastatin, one of the most commonly employed statins. These effects are generally associated with endothelial function. Several protective effects of this statin related to its vascular effects have been demonstrated, including the prevention of inflammation

Methods

Results

Conclusion