RESUMEN
We report microwave-assisted synthetic routes, the pharmacokinetic profile along with results from ulcerogenicity and mutagenicity studies of atenolol aspirinate, and an already described derivative, in which acetyl salicylic acid (aspirin) was connected to atenolol by an ester linkage. Atenolol aspirinate was stable towards aqueous hydrolysis but rapidly hydrolyzed in plasma (t(1/2) = 7.6 min). The results showed that the rapid and complete hydrolysis generates atenolol salicylate, which assumes a conformation stabilized by two intramolecular H-bonds, avoiding its further hydrolysis to salicylic acid and atenolol.
Asunto(s)
Antihipertensivos/farmacocinética , Aspirina/química , Atenolol/farmacocinética , Animales , Antihipertensivos/química , Antihipertensivos/metabolismo , Área Bajo la Curva , Atenolol/química , Atenolol/metabolismo , Mucosa Gástrica/efectos de los fármacos , Semivida , Humanos , Microondas , Modelos Moleculares , Pruebas de Mutagenicidad , Profármacos/química , Profármacos/metabolismo , Profármacos/farmacocinéticaRESUMEN
This study evaluated the effects of BAY 41-2272 (BAY), a specific activator of sGC NO-independent action on changes of mean arterial blood pressure, heart and left ventricle weight indexes, cardiomyocyte hypertrophy (Vv) and fibrosis area induced by chronic N-nitro-L-arginine methyl ester (L-NAME) treatment in rats. The animals were divided into (a) control group, (b) L-NAME group, (c) L-NAME+BAY group, and (d) BAY group. Eight weeks of L-NAME treatment caused a significant increase in mean arterial blood pressure when compared with untreated rats (173 +/- 11.1 and 109 +/- 5.0 mm Hg, respectively; P < 0.01). L-NAME + BAY cotreatment abolished the L-NAME-induced hypertension (112 +/- 5.1 mm Hg; P < 0.01). Significant increases in heart and left ventricle weight indexes and in Vv were observed in the L-NAME-treated animals compared with control group, and concomitant treatment with BAY significantly attenuated this hypertrophic effect. Treatment with L-NAME presented several areas of repairing fibrosis in left ventricles, and this effect was also abolished by BAY cotreatment. Our results demonstrate that BAY 41-2272 inhibits hypertension and prevents heart abnormalities (cardiac hypertrophy and increased fibrosis areas) induced by NO synthase inhibition.