RESUMO
BACKGROUND: Depression of myocardial contractility as a result of isoflurane appears to be greater in myocardial hypertrophy, and the cellular basis for this difference in susceptibility is not clear. In this study we examined the effects of isoflurane and sevoflurane on contractility and intracellular calcium in an animal model of pressure-overload hypertrophy. METHODS: Pressure-overload hypertrophy was established in young male ferrets by banding the main pulmonary artery for 1 month and the effects of isoflurane and sevoflurane on contractility and intracellular calcium ([Ca]i) were examined in isolated right ventricular papillary muscles, trabeculae, and myocytes. Intracellular calcium was measured with the bioluminescent photoprotein aequorin in isolated papillary muscles, and also with the fluorescent indicator fluo-3 in isolated ventricular myocytes. In addition, Ca sensitivity was assessed in isolated trabeculae after disruption of the surface membrane with a nonionic detergent (skinned fibers). RESULTS: In the presence of isoflurane and sevoflurane, papillary muscles from banded animals exhibited a greater depression of contractility and isolated ventricular myocytes showed a greater decrease in peak [Ca]i. Furthermore, baseline calcium sensitivity was decreased and the slope of the relationship between [Ca] and force was increased in skinned trabeculae from banded animals. Isoflurane decreased calcium sensitivity in trabeculae from both normal and banded animals. CONCLUSIONS: These results suggest that changes in [Ca]i and altered calcium sensitivity are both responsible for the exaggerated effects of some volatile anesthetics on contractility in pressure-overload hypertrophy.
Assuntos
Anestésicos Inalatórios/farmacologia , Cálcio/metabolismo , Hipertrofia Ventricular Direita/fisiopatologia , Isoflurano/farmacologia , Éteres Metílicos/farmacologia , Contração Miocárdica/efeitos dos fármacos , Equorina/farmacologia , Animais , Pressão Sanguínea/fisiologia , Western Blotting , Estimulação Elétrica , Eletroforese em Gel de Poliacrilamida , Furões , Hipertensão/fisiopatologia , Técnicas In Vitro , Contração Isométrica/efeitos dos fármacos , Masculino , Contração Muscular/efeitos dos fármacos , Músculo Liso Vascular/efeitos dos fármacos , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/fisiologia , Músculos Papilares/efeitos dos fármacos , Músculos Papilares/fisiologia , Artéria Pulmonar/fisiologia , SevofluranoRESUMO
We describe herein the design, syntheses, and biological evaluation of new series of P4 tetrazole and adipic acid, ester, amide capped tetrapeptidyl alpha-ketoamide based HCV protease inhibitors.
