title: The methyl ester of rosuvastatin elicited an endothelium-independent and 3-hydroxy-3-methylglutaryl coenzyme A reductase-independent relaxant effect in rat aorta.
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.
authors: Sección de Estudios de Posgrado e Investigación, Escuela Superior de Medicina, I.P.N. Plan de San Luis y Díaz Mirón, Col. Casco de Sto. Tomás, México.
authors: J S
authors: JS
authors: López-Canales
authors: P
authors: P
authors: López-Sanchez
authors: V M
authors: VM
authors: Perez-Alvarez
authors: I
authors: I
authors: Wens-Flores
authors: A C
authors: AC
authors: Polanco
authors: E
authors: E
authors: Castillo-Henkel
authors: C
authors: C
authors: Castillo-Henkel
mesh_terms: D000818:Animals; D001011:Aorta / Q000187:drug effects* / Q000201:enzymology; D003513:Cycloheximide / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000187:drug effects*; D005464:Fluorobenzenes / Q000737:chemistry / Q000494:pharmacology*; D006903:Hydroxymethylglutaryl CoA Reductases / Q000187:drug effects*; D008297:Male; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology*; D052247:Nitric Oxide Synthase Type II / Q000494:pharmacology; D011743:Pyrimidines / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D000068718:Rosuvastatin Calcium; D013449:Sulfonamides / Q000737:chemistry / Q000494:pharmacology*; D019789:Tetraethylammonium / Q000494:pharmacology; D014664:Vasodilation / Q000187:drug effects* / Q000502:physiology; D014665:Vasodilator Agents / Q000494:pharmacology*
chemical_list: D005464:Fluorobenzenes; D011743:Pyrimidines; D013449:Sulfonamides; D014665:Vasodilator Agents; D019789:Tetraethylammonium; D000068718:Rosuvastatin Calcium; D003513:Cycloheximide; D006903:Hydroxymethylglutaryl CoA Reductases; D052247:Nitric Oxide Synthase Type II; D019331:NG-Nitroarginine Methyl Ester