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

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.

[Study of the effect of light and heat on rosuvastatin calcium stability]

The effect of light on the stability of rosuvastatin was investigated by exposing rosuvastatin powder to white light [neon light] between 100 to 3000 Luxes for 3 days, according to health and safety requirements. In addition, five series of rosuvastatin powder was exposed, for 3 days, to different colors of light: White, blue, green, orange and red, with intensity 1000 Luxes. Also, the effect of heat on stability of rosuvastatin was studied. Three series were stored in the dark for 24 hours. The first series was stored without any additive under heat temperatures 30, 40, 50, 60 and 90°C with HR 100%. The second series was conducted under the same previous conditions of humidity and temperatures with 20% Calcium ascorbate as an anti oxidant. The third one was incubated in dry heat under the same temperatures, without any additive. All samples were analyzed using HPLC with a column C18 octadecyl, [250 mm X 4.6 mm]. The Studies have shown that rosuvastatin starts to deteriorate when exposed to white light, intensity of 200 Luxes for three days. The percentage of deteriorated rosuvastatin increases to reach more than 50% as light intensity increase to 3000 luxes. The study shows that the increase of temperature with the existence of humidity [relative humidity 100%] destroys rosuvastatin, and the addition of calcium ascorbat improves its stability in these conditions, while dry temperature up to 90° has no negative effect on its stability, and the lights [white, green, blue] destroy mainly Rosuvastatin, on the other side the lights red and orange have no any destroying effect on it, therefore we can use these lights [red and orange] successfully for lighting the laboratories and production sections during its preparation and its control in drugs factories for conservation its stability