Z Yao1, G J Gross. 1. Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee 53226.
Abstract
BACKGROUND: The major purpose of the present study was to determine the effect of the potassium channel opener bimakalim, administered intracoronary only during the initial 10 minutes of ischemia, on myocardial infarct size in anesthetized dogs. A second aim was to test the possibility that bimakalim mediates its cardioprotective effects by accelerating the rate of myocyte action potential shortening during early ischemia. A third aim was to determine the relative potency of bimakalim to open coronary vascular ATP-regulated potassium (KATP) channels versus myocyte KATP channels. METHODS AND RESULTS: Barbital-anesthetized open-chest dogs were used. In the initial studies, bimakalim (0.1 to 10 micrograms/min) was infused into the left anterior descending coronary artery (LAD), and changes in coronary blood flow and monophasic action potential duration (MAPD) were used as indexes of coronary vascular KATP channel and myocyte KATP channel activity, respectively. In subsequent infarct studies, dogs were subjected to 60 minutes of LAD occlusion followed by 4 hours of reperfusion. Based on preliminary studies, two doses of bimakalim that did not shorten MAPD during nonischemic conditions (0.1 and 0.3 microgram/min) and one that markedly shortened MAPD during nonischemic conditions (3.0 micrograms/min) or an equal volume of vehicle were infused into the LAD during the initial 10 minutes of coronary artery occlusion. Transmural myocardial blood flow was measured at 5 and 30 minutes of occlusion by the radioactive microsphere technique, and infarct size was determined at the end of 4 hours of reperfusion by triphenyltetrazolium staining. The monophasic action potential duration at 50% repolarization (MAPD50) was measured by an epicardial probe placed in the center of the ischemic area. Bimakalim had an approximately 10-fold greater affinity for the coronary vascular than the myocardial KATP channel (ED50 coronary, approximately 0.3 microgram/min; ED50 myocyte, approximately 3.0 micrograms/min). Three doses of bimakalim (0.1, 0.3, and 3.0 micrograms/min) all markedly reduced infarct size expressed as percent of the area at risk (12.6 +/- 3.3%, 14.5 +/- 2.2%, and 14.2 +/- 5.3%, respectively, versus 27.2 +/- 5.7% in controls) to nearly equal extents. Subsequently, we found that the two higher doses of bimakalim (0.3 and 3.0 micrograms/min) markedly accelerated yet the 0.1-microgram/min dose of bimakalim did not significantly affect the ischemia-related shortening of the action potential during the initial 5 minutes of occlusion. In addition, 0.1 and 0.3 microgram/min bimakalim did not increase the incidence of ventricular fibrillation during the 60 minutes of occlusion (0 of 7 and 0 of 8 dogs, respectively), whereas 3.0 micrograms/min bimakalim had a profibrillatory effect (6 of 6) compared with the control group (1 of 8). There were no significant differences between groups in systemic hemodynamics, myocardial oxygen demand, ischemic bed size, or collateral blood flow to the ischemic region. CONCLUSIONS: The results of the present study clearly reveal that a small dose (0.1 or 0.3 microgram/min) of the KATP channel opener bimakalim administered only during the initial 10-minute period of ischemia markedly reduced myocardial infarct size to an extent equal to that of a higher profibrillatory dose in barbital-anesthetized dogs. These data also suggest that bimakalim and other potassium channel openers may partially exert their cardioprotective effects by accelerating KATP channel activation during early ischemia as evidenced by an enhanced rate of ischemic myocyte action potential shortening. However, the results also suggest that other cellular mechanisms may be involved in mediating the cardioprotection produced by a low dose of bimakalim (0.1 microgram/min) because it did not significantly accelerate the shortening of the action potential duration, yet it had an efficacy to redu BACKGROUND: The major purpose of the present study was to de
BACKGROUND: The major purpose of the present study was to determine the effect of the potassium channel opener bimakalim, administered intracoronary only during the initial 10 minutes of ischemia, on myocardial infarct size in anesthetized dogs. A second aim was to test the possibility that bimakalim mediates its cardioprotective effects by accelerating the rate of myocyte action potential shortening during early ischemia. A third aim was to determine the relative potency of bimakalim to open coronary vascular ATP-regulated potassium (KATP) channels versus myocyte KATP channels. METHODS AND RESULTS: Barbital-anesthetized open-chest dogs were used. In the initial studies, bimakalim (0.1 to 10 micrograms/min) was infused into the left anterior descending coronary artery (LAD), and changes in coronary blood flow and monophasic action potential duration (MAPD) were used as indexes of coronary vascular KATP channel and myocyte KATP channel activity, respectively. In subsequent infarct studies, dogs were subjected to 60 minutes of LAD occlusion followed by 4 hours of reperfusion. Based on preliminary studies, two doses of bimakalim that did not shorten MAPD during nonischemic conditions (0.1 and 0.3 microgram/min) and one that markedly shortened MAPD during nonischemic conditions (3.0 micrograms/min) or an equal volume of vehicle were infused into the LAD during the initial 10 minutes of coronary artery occlusion. Transmural myocardial blood flow was measured at 5 and 30 minutes of occlusion by the radioactive microsphere technique, and infarct size was determined at the end of 4 hours of reperfusion by triphenyltetrazolium staining. The monophasic action potential duration at 50% repolarization (MAPD50) was measured by an epicardial probe placed in the center of the ischemic area. Bimakalim had an approximately 10-fold greater affinity for the coronary vascular than the myocardial KATP channel (ED50 coronary, approximately 0.3 microgram/min; ED50 myocyte, approximately 3.0 micrograms/min). Three doses of bimakalim (0.1, 0.3, and 3.0 micrograms/min) all markedly reduced infarct size expressed as percent of the area at risk (12.6 +/- 3.3%, 14.5 +/- 2.2%, and 14.2 +/- 5.3%, respectively, versus 27.2 +/- 5.7% in controls) to nearly equal extents. Subsequently, we found that the two higher doses of bimakalim (0.3 and 3.0 micrograms/min) markedly accelerated yet the 0.1-microgram/min dose of bimakalim did not significantly affect the ischemia-related shortening of the action potential during the initial 5 minutes of occlusion. In addition, 0.1 and 0.3 microgram/min bimakalim did not increase the incidence of ventricular fibrillation during the 60 minutes of occlusion (0 of 7 and 0 of 8 dogs, respectively), whereas 3.0 micrograms/min bimakalim had a profibrillatory effect (6 of 6) compared with the control group (1 of 8). There were no significant differences between groups in systemic hemodynamics, myocardial oxygen demand, ischemic bed size, or collateral blood flow to the ischemic region. CONCLUSIONS: The results of the present study clearly reveal that a small dose (0.1 or 0.3 microgram/min) of the KATP channel opener bimakalim administered only during the initial 10-minute period of ischemia markedly reduced myocardial infarct size to an extent equal to that of a higher profibrillatory dose in barbital-anesthetized dogs. These data also suggest that bimakalim and other potassium channel openers may partially exert their cardioprotective effects by accelerating KATP channel activation during early ischemia as evidenced by an enhanced rate of ischemic myocyte action potential shortening. However, the results also suggest that other cellular mechanisms may be involved in mediating the cardioprotection produced by a low dose of bimakalim (0.1 microgram/min) because it did not significantly accelerate the shortening of the action potential duration, yet it had an efficacy to redu BACKGROUND: The major purpose of the present study was to de