Attenuation of KATP channel-opener induced shortening of repolarization time by alpha 1-adrenoceptor antagonist during ischemia in canine heart.
The purpose of the study was to determine whether a new KATP channel opener, Y 26763 (Y), can influence the electrophysiological properties in the ischemic myocardium as well as to determine whether the blunting effect of the alpha 1-adrenoceptor antagonist bunazosin (BN) on an ischemia-induced shortening of repolarization time can be related to the KATP channel activity. The anterior descending branch of the left coronary artery was ligated four times for 5 minutes, separated by 15 minutes of reperfusion (stages 1-4) to test the dose-dependent effect of drugs on repolarization. Dogs received either vehicle (n = 9), Y (0.4, 2.0, and 4.0 micrograms/kg at stages 2, 3, and 4, respectively, with 0.4 microgram/kg/min drip infusion at each of stages 2-4, n = 7), BN (0.1 mg at each of stages 2-4, n = 8), or a combination of these two drugs (BN + Y, the same dose of BN and Y in groups BN and Y, respectively, n = 9). Drugs were administered into the left atrium. The monophasic action potential (MAP) and regional electrograms were recorded. The MAP90 and the duration of the slow deflections (DSD) of the regional electrogram were used as markers of repolarization. The Vmax of the MAP and the rapid deflections (DRD) of the regional electrogram were used as markers of conduction. Y augmented an ischemia-induced shortening of MAP90 and DSD in proportion to an increase in the dose given and the plasma concentration (P < .05-.01), especially at the epicardial site. BN and BN + Y blunted the ischemia-related shortening of MAP90 and DSD, causing a reduction in repolarization time dispersion between the ischemic and normal zones. There were no significant changes in the Vmax or DRD in the ischemic zone between periods before and after an increase in each drug dose in the four groups. None of the seven dogs developed ventricular tachycardia (VT)/ventricular fibrillation (VF) in the Y group, whereas two of the eight dogs in the BN group, three of the nine dogs in the BN + Y group, and three of the nine dogs in the control group developed VT/VF. These results suggest that the alpha 1-adrenergic blocker bunazosin blunts the shortening effect of KATP channel activator on repolarization time, and that the KATP channel opener Y may be antiarrhythmic, although the repolarization time dispersion during myocardial ischemia is increased.
Department of Cardiovascular Medicine, School of Medicine, Tokai University, Isehara, Japan.
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Tanabe
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Aikawa
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Deguchi
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Yoshioka
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Handa
D018528:ATP-Binding Cassette Transporters; D000200:Action Potentials / Q000187:drug effects; D058668:Adrenergic alpha-1 Receptor Antagonists; D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology*; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D000959:Antihypertensive Agents / Q000494:pharmacology*; D001578:Benzopyrans / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects; D004285:Dogs; D004562:Electrocardiography / Q000187:drug effects; D004594:Electrophysiology; D006321:Heart / Q000187:drug effects*; D066298:In Vitro Techniques; D054086:KATP Channels; D015428:Myocardial Reperfusion Injury / Q000188:drug therapy / Q000503:physiopathology; D015221:Potassium Channels / Q000819:agonists*; D024661:Potassium Channels, Inwardly Rectifying; D011799:Quinazolines / Q000494:pharmacology
D018528:ATP-Binding Cassette Transporters; D058668:Adrenergic alpha-1 Receptor Antagonists; D000317:Adrenergic alpha-Antagonists; D000889:Anti-Arrhythmia Agents; D000959:Antihypertensive Agents; D001578:Benzopyrans; D054086:KATP Channels; D015221:Potassium Channels; D024661:Potassium Channels, Inwardly Rectifying; D011799:Quinazolines; C092520:uK-ATP-1 potassium channel; C018176:bunazosin; C074338:Y 26763