[Frontiers in Bioscience E4, 1787-1794, January 1, 2012]

Mechanism of the relaxant effect of rosuvastatin lactone on rat aortic rings

Polanco-Ponce Ana Cecilia1,2, Perez-Alvarez Victor Manuel4, Wens-Flores Isabel4, Castillo-Henkel Enrique1, Lopez-Sanchez Pedro1, Lopez-Canales Jorge Skiold1,3, Castillo-Hernandez Maria del Carmen1, Castillo-Henkel Carlos1

1Seccion de Estudios de Posgrado e Investigacion de la Escuela Superior de Medicina, I.P.N. Plan de San Luis y Diaz Miron, Col. Casco de Sto. Tomas, Mexico 11340, Mexico, D.F., 2AstraZeneca, Mexico, 3Instituto Nacional de Perinatología, Isidro Espinoza De Los Reyes, Mexico D.F., 4Centro de investigacion y estudios avanzados (CINVESTAV), unidad zacatenco. Mexico, D.F.

TABLE OF CONTENTS

1. Abstract
2. Introduction
3. Materials and methods
3.1. Materials
3.2. Preparation of aortic rings
3.3. Experimental protocol
3.4. NOS immunoblot Experimental protocol
3.5. Statistical analysis
4. Results
4.1. Effect of rosuvastatin lactone on aortic rings precontracted with Phenylephrine
4.2. The effect of rosuvastatin and its lactone on precontracted aortic rings
4.3. Effects of L-NAME, 1400 W and indomethacin on the relaxant effect of the lactone on denuded rings
4.4. Participation of K+ channels in the relaxant effect of the lactone
4.5. Participation of protein synthesis in the relaxant effect of the lactone
4.6. Participation of HMG CoA reductase in the relaxant effect of the lactone
4.7. Immunoblot
5. Discussion
6. Acknowledgment
7. References

1. ABSTRACT

The relaxant effect of the lactone of rosuvastatin was evaluated on aortic rings from male Wistar rats (250-300 g) with and without endothelium, precontracted with 1.0 µM phenylephrine. The lactone presented a greater potency than rosuvastatin in relaxing aortic rings. Unlike rosuvastatin, the effect of its lactone was endothelium-independent. Pretreatment with either indomethacin (10 microM) or mevalonate (1 mM) did not inhibit the relaxant effect of the lactone. L-NAME (10 microM), 1400 W (10 µM), or tetraethylammonium (TEA, 10 mM) partially inhibited the relaxant effect of the lactone on endothelium-denuded aortic rings. However, cycloheximide (10 µM) or the combination of TEA plus L-NAME completely inhibited the relaxant effect. The NOS-2 was only present in endothelium-denuded aortic rings, as demonstrated by immunoblot with lactone treated rings. In conclusion, rosuvastatin was associated with a relaxant effect dependent on both endothelium and HMG-CoA reductase in rat aorta, whereas the lactone exhibited an endothelium and HMG-CoA reductase-independent relaxant effect. Both nitric oxide produced by NOS-2 and K+ channels are involved in the relaxant effect of the lactone.