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Adenosine triphosphate-sensitive potassium channel blocking agent ameliorates, but the opening agent aggravates,
1School of Medicine, University of Connecticut Health Center, Farmington 06030-1110.
Insights
Glibenclamide, a potassium channel blocker, reduced reperfusion-induced arrhythmias and improved cardiac function in guinea pig hearts. ATP-sensitive potassium channel openers like cromakalim did not show these protective effects, suggesting glibenclamide
Area of Science:
- Cardiovascular Physiology
- Pharmacology
- Cellular Electrophysiology
Background:
- ATP-sensitive potassium channels (KATP) play a role in ischemia/reperfusion injury, with openers potentially reducing damage.
- Hypothesis: KATP openers might be arrhythmogenic, while blockers interfering with potassium loss could be antiarrhythmic.
Purpose of the Study:
- To investigate the role of glibenclamide (KATP channel blocker) and cromakalim (KATP channel opener) in reperfusion-induced cardiac injury.
- To determine the effects of these agents on myocardial function and arrhythmias post-ischemia.
Main Methods:
- Isolated working guinea pig hearts subjected to global normothermic ischemia (30-50 min) followed by reperfusion.
- Treatment groups included control, glibenclamide, and cromakalim.
- Assessment of myocardial function, arrhythmias, and high-energy phosphorus compounds using 31P-NMR spectroscopy.
Main Results:
- Glibenclamide dose-dependently reduced the incidence of ventricular fibrillation and tachycardia post-reperfusion.
- Cromakalim did not reduce reperfusion-induced arrhythmias.
- Glibenclamide improved recovery of coronary blood flow, aortic flow, contractility, and tissue ATP/creatine phosphate levels; cromakalim did not.
Conclusions:
- Glibenclamide preserves myocardial potassium ions and phosphorus compounds, enhancing recovery of post-ischemic function.
- Caution is advised for KATP channel openers in post-infarction patients at high risk for sudden cardiac death.
Objectives:
This study was conducted to elucidate the role of the adenosine triphosphate (ATP)-sensitive potassium channel blocking agent glibenclamide and the opener cromakalim in the mechanism of reperfusion-induced injury.
Background:
Recently, ATP-sensitive potassium channel openers have been proposed to reduce ischemia/reperfusion-induced injury, including arrhythmias and heart function. Thus, one might hypothesize that pharmacologic agents that enhance the loss of potassium ions in the myocardium through ATP-sensitive potassium channels would be arrhythmogenic, and agents that interfere with tissue potassium ion loss would be antiarrhythmic.
Methods:
Isolated "working" guinea pig hearts and phosphorus-31 nuclear magnetic resonance spectroscopy were used to study the recovery of myocardial function and phosphorus compounds after 30, 40 and 50 min of normothermic global ischemia followed by reperfusion in untreated control and glibenclamide- and cromakalim-treated groups.
Results:
After 30 min of ischemia, 1, 3, 10 and 30 mumol/liter of glibenclamide dose-dependently reduced the incidence of reperfusion-induced ventricular fibrillation (total) from its control value of 92% to 75%, 33% (p < 0.05), 33% (p < 0.05) and 42% (p < 0.05), respectively. The incidence of ventricular tachycardia followed the same pattern. A reduction of arrhythmias was also observed after 40 and 50 min of ischemia followed by reperfusion in the glibenclamide-treated hearts. Cromakalim, at the same concentrations, did not reduce the incidence of reperfusion-induced arrhythmias. During reperfusion, glibenclamide (3 and 10 mumol/liter) improved the recovery of coronary blood flow, aortic flow, myocardial contractility and tissue ATP and creatine phosphate content, but cromakalim failed to ameliorate the recovery of postischemic myocardium compared with that in the drug-free control hearts.
Conclusions:
The preservation of myocardial potassium ions and phosphorus compounds by glibenclamide can improve the recovery of postischemic function, but the use of ATP-sensitive potassium channel openers as antihypertensive or antiarrhythmic agents may be of particular concern in those postinfarction patients who are known to be at high risk for sudden cardiac death.