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HMR 1883
HMR 1883 (1-sulfonyl-3 methylthiourea) and its sodium salt HMR 1098, are experimental anti-arrhythmic drugs classified as sulfonylthiourea compounds.〔Heinrich C. Englert, Uwe Gerlach, Heinz Goegelein, Jens Hartung, Holger Heitsch, Dieter Mania, and Sabine Scheidler. 2001. Cardioselective KATP Channel Blockers Derived from a New Series of m-Anisamidoethylbenzenesulfonylthioureas J. Med. Chem. 44 (7):1085–1098〕 Their main purpose is to treat ventricular fibrillation caused by myocardial ischemia. They were synthesized via structural modifications to glibenclamide, an antidiabetic drug.〔 Both HMR 1883 and glibenclamide act by inactivating the ATP-sensitive potassium channels (KATP) responsible for potassium efflux.〔Billman, G. E., Englert, H. C., & Schoelkens, B. A. (1998) HMR 1883, a novel cardioselective inhibitor of the ATP- sensitive potassium channel; Part II: effects on susceptibility to ventricular fibrillation induced by myocardial ischemia in conscious dogs. J Pharmacol Exp Therap 286, 1465−1473〕 Unlike glibenclamide, HMR 1883 has been suggested to target selectively the Kir6.2/SUR2A KATP subtype, found mostly in the membranes of cardiac cells.〔Suzuki, M., Li, R. A., Miki, T., Uemura, H., Sakamoto, N., Ohmoto-Sekine, Y., Tamagawa, M., Ogura, T., Seino, S., Marban, E., & Nakaya, H. (2001). Functional roles of cardiac and vascular ATP-sensitive potassium channels clarified by Kir6.2-knockout mice. Circ Res 88, 570−577.〕 However, data showing that HMR 1098 inhibits the Kir6.2/SUR1 KATP subtype found in insulin-secreting pancreatic beta cells challenges this view.〔Hai Xia Zhang, Alejandro Akrouh, Harley T Kurata, Maria Sara Remedi, Jennifer S Lawton, Colin G Nichols. 2011. HMR 1098 is not an SUR isotype specific inhibitor of heterologous or sarcolemmal KATP channels. J. Mol. Cell. Cardiol. 50(3):552-560〕
== Mechanism ==
Hypoxia provokes potassium efflux from cardiac muscles cells via the activation of ATP-sensitive potassium channels (KATP).〔Wilde, A. A. M. (1993). Role of ATP-sensitive K+ channel current in ischemic arrhythmias. Cardiovasc Drugs Ther 7, 521−526.〕 Potassium efflux from cardiac cells decreases action potential duration and results in non-uniform repolerization of the cardiac cells.〔Harris, A. S., Bisteni, A., Russell, R. A., Brigham, J. C., & Firestone, J. E. (1954). Excitory factors in ventricular tachycardia resulting from myocardial ischemia: potassium a major excitant. Science 119, 200−203〕 The heterogeneous repolarization of the cardiac tissue permits reentry of action potentials into conducting pathways, which manifests as malignant arrhythmias in the heart.〔 HMR 1883 is a cardioselective ATP-sensitive potassium channel antagonist that prevents the potassium efflux, hence corrects the non-uniform refractory period in the ischemic tissue. A uniform refractory period corrects the conductance problems in the heart and prevents the re-entry arrhythmias.
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