Effects of intracoronary glyburide on cesium-induced arrhythmias in anesthetized dogs.
Intracellular calcium plays an essential role in regulation of many cellular processes, but increases in internal calcium levels can also exacerbate pathophysiologic or pharmacologic responses, in particular myocardial arrhythmias. Pharmacologic increases in intracellular calcium may be obtained by opening calcium channels, either directly or indirectly, or by increasing calcium release from intracellular stores. In this study, cesium chloride administered intracoronarily (i.c.) through the left anterior descending coronary artery (LAD) dose-dependently elicited ventricular arrhythmias. Glyburide (3 micrograms/kg/min i.c.), clofilium (1 micrograms/kg/min i.c.) or ryanodine (0.03 micrograms/kg/min i.c.) exacerbated arrhythmias. Specifically, the ED50 values for cesium were shifted from 0.56 mM in the vehicle group to 0.17, 0.27, and 0.20 mM in the glyburide, clofilium, and ryanodine groups, respectively. Coronary blood flow (CBF) and blood pressure (BP) did not change significantly in any treatment group. Effects of glyburide were not mediated by either insulin or decreased glucose levels, since infusions of insulin (decreasing blood glucose to 20 mg/dl) did not exacerbate arrhythmias. In vitro electrophysiologic studies showed that glyburide (1 microM) and ryanodine (1 microM) did not significantly affect action potential durations (APD). In contrast, clofilium (1 microM) significantly prolonged APD. These results demonstrate that glyburide, clofilium, and ryanodine tend to exacerbate cesium-induced arrhythmias. We suggest that glyburide and ryanodine may exacerbate arrhythmias by increasing internal calcium from intracellular stores, whereas clofilium may increase internal calcium by increasing influx of calcium across the sarcolemma.
D'Alonzo
A J
AJ
Department of Pharmacology, Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, New Jersey 08543-4000.
Hess
T A
TA
Darbenzio
R B
RB
Sewter
J C
JC
D000758:Anesthesia; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology; D001145:Arrhythmias, Cardiac / Q000139:chemically induced* / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D002586:Cesium; D003326:Coronary Circulation / Q000187:drug effects; D003331:Coronary Vessels / Q000187:drug effects; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004594:Electrophysiology; D005110:Extracellular Space / Q000378:metabolism; D005260:Female; D005905:Glyburide / Q000008:administration & dosage / Q000494:pharmacology*; D006168:Guinea Pigs; D066298:In Vitro Techniques; D007269:Injections, Intra-Arterial; D007328:Insulin / Q000494:pharmacology; D008297:Male; D000644:Quaternary Ammonium Compounds / Q000494:pharmacology; D012433:Ryanodine / Q000494:pharmacology; D012519:Sarcoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism
D000889:Anti-Arrhythmia Agents; D007328:Insulin; D000644:Quaternary Ammonium Compounds; D012433:Ryanodine; D002586:Cesium; C022799:clofilium; D005905:Glyburide; D002118:Calcium