Effect of bimakalim (EMD 52692), an opener of ATP sensitive potassium channels, 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 sensitive potassium channels, can reduce infarct size in swine myocardium.


METHODS
Experiments were performed in open chest pigs subjected to a 60 min occlusion of a branch of the left anterior descending coronary artery and to 2 h reperfusion. Five groups of animals were studied. In seven animals bimakalim infusion (3 micrograms.kg-1 bolus over 5 min followed by 0.1 microgram.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 before occlusion and also ended at 60 min of reperfusion (group B). In a further seven animals bimakalim infusion was started 15 min before coronary 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.kg-1 over 15 min) was started 15 min before the occlusion and also terminated at the start of occlusion. The dose of hydralazine was chosen such that it lowered arterial pressure to the same extent as bimakalim. 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 risk region) was determined by incubating myocardium with p-nitrobluetetrazolium. Regional myocardial oxygen consumption (MVO2) was calculated as the product of coronary blood flow (electromagnetic flowmeter) and the difference in the oxygen contents of the aorta and the interventricular vein accompanying the left anterior descending coronary artery. Regional wall function was quantified with ultrasonic crystals aligned to measure wall thickening (% delta WT).


RESULTS
In all pigs in which bimakalim treatment was started prior to the 60 min coronary occlusion, 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 ischaemia only (p < 0.05); drug-induced potassium channel opening during reperfusion had no effect [A: 56.6(4.1)%]. Treatment with hydralazine did not reduce infarct size [59.4(4.3)%]. Neither drug altered % delta WT; however, they reduced MVO2 by 36.5% in B, by 27.1% in C, and by 14.6% in the hydralazine group.


CONCLUSIONS
Bimakalim treatment prior to the onset of a 60 min coronary occlusion increases the tolerance of pig myocardium to ischaemia. The data are consistent with the hypothesis that bimakalim reduces infarct size by activation of cardiac ATP sensitive potassium channels and not through unloading of the heart because of its vasodilator effects.
Rohmann
S
S
Department of Preclinical Cardiovascular Research, E Merck, Darmstadt, Germany.
Weygandt
H
H
Schelling
P
P
Soei
L K
LK
Becker
K H
KH
Verdouw
P D
PD
Lues
I
I
Häusler
G
G
D000818:Animals; D001578:Benzopyrans / Q000494:pharmacology*; D003326:Coronary Circulation / Q000187:drug effects*; D004095:Dihydropyridines / Q000494:pharmacology*; D006321:Heart / Q000187:drug effects*; D006830:Hydralazine / Q000494:pharmacology; D015640:Ion Channel Gating / Q000187:drug effects; D009203:Myocardial Infarction / Q000517:prevention & control*; D010101:Oxygen Consumption / Q000187:drug effects*; D015221:Potassium Channels / Q000187:drug effects; D013552:Swine; D014665:Vasodilator Agents / Q000494:pharmacology*
D001578:Benzopyrans; D004095:Dihydropyridines; D015221:Potassium Channels; D014665:Vasodilator Agents; D006830:Hydralazine; C061050:bimakalim