K-ATP channel blocker HMR 1883 reduces monophasic action potential shortening during coronary ischemia in anesthetised pigs

ATP-sensitive potassium channels (K-ATP) Open during myocardial ischemia. T he ensuing repolarising potassium efflux shortens the action potential. Acc umulation of extracellular potassium is able to partially depolarise the me mbrane, reducing the upstroke velocity of the action potential and thereby impairing impulse conduction. Both mechanisms are believed to be involved i n the development of reentrant arrhythmias during cardiac ischemia. The sul fonylthiourea HMR 1883 (1-[[5-[2-(5-chloro-o-anisamido)ethyl]-methoxyphenyl ]sulfonyl]-3-methylthiourea) was designed as a cardioselective K-ATP channe l blocker for the prevention of arrhythmic sudden death in patients with is chemic heart disease. The aim of this study was to show that this compound, which has already shown antifibrillatory efficacy in dogs and rats, is abl e to inhibit ischemic changes of the action potential induced by coronary a rtery occlusion in anesthetised pigs. Action potentials were taken in situ with the technique of monophasic action potential (MAP) recording. In a control group (n=7), three consecutive occlusions of a small branch of the left circumflex coronary artery resulted in reproducible reductions in MAP duration and a decrease in upstroke velocity. In a separate group (n=7 ), HMR 1883 (3 mg/kg i.v.) significantly (P<0.05) reduced the ischemia-indu ced shortening of the MAP: during the first and second control occlusion of the coronary artery in the HMR 1883-group, MAP(50) duration shortened from 218.5+/-3.0 ms to 166.7+/-3.3 ms and from 219.7+/-4.5 ms to 164.9+/-1.8 ms , respectively. After HMR 1883, during the third occlusion, MAP duration de creased from 226.9+/-3.6 ms to 205.3+/-4.3 ms only corresponding to 59% inh ibition. HMR 1883 also improved the upstroke velocity of the MAP, which was depressed by ischemia: in the two preceding control occlusions ischemia pr olonged the time to peak of the MAP, an index for upstroke velocity, from 1 0.83+/-0.43 ms to 39.42+/-1.60 ms and from 12.97+/-0.40 ms to 37.17+/-2.98 ms, respectively. With HMR 1883, time to peak during ischemia rose from 12. 42+/-0.51 ms to 25.53+/-2.51 ms only, corresponding to an average inhibitor y effect of 53.4%. The irregular repolarisation contour of the ischemic MAP was also improved. In conclusion, the present results indicate that HMR 1883 effectively block s myocardial K-ATP channels during coronary ischemia in anesthetised pigs, preventing an excessive shortening of the action potential and improving ex citation propagation.