Mechanism of the relaxant effect of rosuvastatin lactone on rat aortic rings.
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 microM 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 microM), or tetraethylammonium (TEA, 10 mM) partially inhibited the relaxant effect of the lactone on endothelium-denuded aortic rings. However, cycloheximide (10 microM) 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.
Seccion de Estudios de Posgrado e Investigacion de Escuela Superior de Medicina, IPN Plan de San Luis y Diaz Miron, Col. Casco de Sto. Tomas, Mexico 11340, DF, Mexico.
Polanco-Ponce
PP
Ana Cecilia
Perez-Alvarez
PA
Victor Manuel
Wens-Flores
WF
Isabel
Castillo-Henkel
CH
Enrique
Lopez-Sanchez
LS
Pedro
Lopez-Canales
LC
Jorge Skiold
Castillo-Hernandez
CH
Maria del Carmen
Castillo-Henkel
CH
Carlos
D000818:Animals; D001011:Aorta / Q000187:drug effects* / Q000201:enzymology / Q000502:physiology; D006903:Hydroxymethylglutaryl CoA Reductases / Q000378:metabolism; D007097:Imines / Q000494:pharmacology; D066298:In Vitro Techniques; D007213:Indomethacin / Q000494:pharmacology; D007783:Lactones / Q000494:pharmacology*; D008297:Male; D009126:Muscle Relaxation / Q000187:drug effects; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D010656:Phenylephrine / Q000494:pharmacology; D015221:Potassium Channels / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D013449:Sulfonamides / Q000494:pharmacology*
D007097:Imines; D007783:Lactones; C496401:N-((3-(aminomethyl)phenyl)methyl)ethanimidamide; D015221:Potassium Channels; D013449:Sulfonamides; D010656:Phenylephrine; D006903:Hydroxymethylglutaryl CoA Reductases; D052247:Nitric Oxide Synthase Type II; C551068:rosuvastatin lactone; D019331:NG-Nitroarginine Methyl Ester; D007213:Indomethacin