EFFECT OF BIMAKALIM (EMD-52692), AN OPENER OF ATP-SENSITIVE POTASSIUMCHANNELS, ON INFARCT SIZE, CORONARY BLOOD-FLOW, REGIONAL WALL FUNCTION, AND OXYGEN-CONSUMPTION IN SWINE

Objective: The aim was to assess whether bimakalim, an opener of ATP s ensitive potassium channels, can reduce infarct size in swine myocardi um. Methods: Experiments were performed in open chest pigs subjected t o a 60 min occlusion of a branch of the left anterior descending coron ary artery and to 2 h reperfusion. Five groups of animals were studied . In seven animals bimakalim infusion (3 mu g.kg(-1) bolus over 5 min followed by 0.1 mu g.kg(-1).min(-1)) was started at 45 min of coronary occlusion and continued until 60 min of reperfusion (group A), while in seven other animals the bimakalim infusion was started 15 min befor e occlusion and also ended at 60 min of reperfusion (group B). In a fu rther seven animals bimakalim infusion was started 15 min before coron ary occlusion, but was stopped at the onset of ischaemia (group C). In the fourth group of animals (n = 7), a hydralazine infusion (0.2 mg.k g(-1) over 15 min) was started 15 min before the occlusion and also te rminated at the start of occlusion. The dose of hydralazine was chosen such that it lowered arterial pressure to the same extent as bimakali m. A fifth group of animals (n = 7) received the vehicle and served as controls. At the end of the protocol, infarct size (as percent of ris k region) was determined by incubating myocardium with p-nitrobluetetr azolium. Regional myocardial oxygen consumption (MVO(2)) was calculate d as the product of coronary blood flow (electromagnetic flowmeter) an d the difference in the oxygen contents of the aorta and the intervent ricular vein accompanying the left anterior descending coronary artery . Regional wall function was quantified with ultrasonic crystals align ed to measure wall thickening (%Delta WT). Results: In all pigs in whi ch bimakalim treatment was started prior to the 60 min coronary occlus ion, infarct size was significantly reduced [B: 22.4(SEM 4.5)%; C: 35. 3(6.6)%] compared with 60.4(5.2)% in pigs subjected to 60 min of ischa emia only (p < 0.05); drug-induced potassium channel opening during re perfusion had no effect [A: 56.6(4.1)%]. Treatment with hydralazine di d not reduce infarct size [59.4(4.3)%]. Neither drug altered %Delta WT ; however, they reduced MVO(2) by 36.5% in B, by 27.1% in C, and by 14 .6% in the hydralazine group. Conclusions: Bimakalim treatment prior t o the onset of a 60 min coronary occlusion increases the tolerance of pig myocardium to ischaemia. The data are consistent with the hypothes is that bimakalim reduces infarct size by activation of cardiac ATP se nsitive potassium channels and not through unloading of the heart beca use of its vasodilator effects.