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HMR 1883 (1-
-[2-(5-chloro-o-anisamido)ethyl2-methoxyphenyl">-(5-chloro-o-anisamido)ethyl.html" ;"title="-
-[2-(5-chloro-o-anisamido)ethyl2-methoxyphenylulfonyl-3 methylthiourea) and its Salt (chemistry)">sodium salt
Sodium salts are salt (chemistry), salts composed of a sodium cation and the conjugate base anion of some Inorganic compound, inorganic or Organic compound, organic acids. They can be formed by the Neutralization (chemistry), neutralization of su ...
HMR 1098, are experimental
anti-arrhythmic drugs classified as sulfonylthiourea">Antiarrhythmic agent">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 Anti-diabetic medication, antidiabetic drug.
Both HMR 1883 and glibenclamide act by inactivating the
ATP
ATP may refer to:
Companies and organizations
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* American Technical Publishers, employee-owned publishing company
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-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
A membrane is a selective barrier; it allows some things to pass through but stops others. Such things may be molecules, ions, or other small particles. Membranes can be generally classified into synthetic membranes and biological membranes. Bi ...
of cardiac cells. 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). Potassium efflux from cardiac cells decreases action potential duration and results in non-uniform repolarization of the cardiac cells.
[Harris, A. S., Bisteni, A., Russell, R. A., Brigham, J. C., & Firestone, J. E. (1954). Excitory factors in ]ventricular tachycardia
Ventricular tachycardia (V-tach or VT) is a fast heart rate arising from the lower chambers of the heart. Although a few seconds of VT may not result in permanent problems, longer periods are dangerous; and multiple episodes over a short period ...
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 correcting 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.
Side effects
HMR 1883 attenuates is chemically induced arrhythmias with little to no side effects as a result of having a higher affinity for the cardiac tissue KATP subtype than any other subtype found in the body.
In contrast, glibenclamide interacts with many KATP channels throughout the body resulting in many side effects. In particular its interaction with coronary smooth muscle cells and pancreatic-β cells cause decreased coronary blood flow, hyperinsulinemia, and hypoglycemia.
Since KATP channels only become activated during periods of low ATP and High ADP, HMR 1883 only affects hypoxic tissue and has no negative effect on the normal tissue.
Activation of the KATP channels on cardiac mitochondria is involved in ischemic preconditioning that results in protection for the heart. It was shown that HMR 1883 did not interfere with the mitochondrial protective mechanisms in both rat and rabbit models. By not inhibiting the mitochondrial KATP channel subtype, HMR 1883 can treat cardiac arrhythmias while permitting mitochondrial protective mechanisms.
Research
HMR 1883 has been shown to attenuate and decrease ventricular fibrillation in anesthetized pigs,
[Bohn, H., Englert, H. C., & Schoelkens, B. A. (1998). The KATP channel blocker HMR 1883 attenuates the effects of ischemia on MAP duration and improves survival during LAD occlusion in anesthetized pig. Br J Pharmacol 124, 23P.] rats and conscious dogs.
Its sodium salt, HMR 1098, has been shown to decrease ventricular fibrillation in rabbit hearts, anesthetized rats and dogs.
[Zhu, B. M., Miyamoto, S., Nagawa, Y., Wajima, T., & Hashimoto, K. (2003). Effect of sarcolemmal K-ATP blocker HMR 1098 on arrhythmias induced by programmed electrical stimulation in canine old myocardial infarction model: comparison with glibenclamide. J Pharmacol Sci 93, 106−113.]
References
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Potassium channel blockers