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Selective block of delayed rectification (Ik) in feline ventricular myocytes by Wy 48,986, a novel Class III antiarrhythmic agent
J Mol Cell Cardiol 21 (Supplement 553
II) (1989)
FE Kuhn, RA THE EFFECT OF COCAINE ON THE CANINE CORONARY CIRCULATION. Departments of Medicine and Pharmacology, Gillis, R Virmani, GL Schaer. Georgetown University School of Medicine, Washington, DC. The association of cocaine abuse and myocardial infarction led us to study the effect of cocaine (2 mg/kg IV) on hemodynamics, diameter of the left anterior descendins (LAD) coronary artery (auantitative anaiosraohv) and coronary vascular r&.&a&e (CVR,-microsphe&es) in sufenta&il-sedatl ed dogs (n=7). Cocaine produced a 19+3% reduction in LAD diameter (pc.02) This was associated with signifand a-55+20% increase in CVR (pc.05). icant (pc.05) increases in heart rate (7629 to 100+14 beats/min), mean arterial pressure (106+6 to 148+10 mm Hg) and cardiac output (3.7kO.7 to A second group (N=5) was pretreated with the alpha5.421.7 L/min). adrenoceptor antagonist phentolamine (2.5 mg/kg) which prevented cocaine In a third group (n=7) the LAD endoinduced coronary vasoconstriction. thelium was denuded in vivo with an angioplasty balloon prior to cocaine Despite successful denudation, cocaine produced nearly (2 mg/W IV). identical effects on LAD diameter (+19+3%) and CVR (+65-&32%). conclusions: 1) Cocaine produces constriction of epicardial and coronary resistance vessels despite a marked increase in myocardial oxygen demand. 2) These deleterious effects are mediated by alpha-adrenoceptor stimulation and are not potentiated by prior endothelial injury.
554 SELECTIVE
BLOCK OF DELAYED RECTIFICATION (Ik) IN FELINE VENTRICULAR MYOCYTES BY WY 48,986, A NOVEL CLASS III ANTIARRHYTHMIC AGENT. Christopher II. Follmer, Maria T. Poczobutt, Thomas J. Colatsky. Div. of Experimental Therapeutics, Wyeth-Ayerst Research, Princeton, NJ 08543. Wy 48,986 (WY)is an orally active an&rhythmic agentwithClassIIIelectrophysiologicproperties and efficacy against re-entrant arrhythmias. The mechanism by which WY uniformly prolongs cardiac refractory periods was investigated using whole-cell suction pipette voltage clamp techniques on single feline ventricular myocytes. Tail currents elicited upon repolarization from selected test potentials (0 - +60mV, 1 set, Vh=-4OmV, T=32OC) were used to assessblock of the delayed rectifier current Ik. 3pM WY completely blocked tail currents at all test potentials after 30-60 min exposure. Clamp steps to more negative potentials (-100 to -40mV) from a holding potential of -4OmV were used to elicit the inward rectifier current, Ikl. External application of 100 FM WY was required to observe effects on the magnitude and/or kinetics of Ikl. Concentrations as high as 3OOpM had no effect on the inward sodium current (INa) measured under conditions favoring clamp control (T=17uC, reduced Na+ gradient). In conclusion, WYis a potent and selective blocker of the delayed outward potassium current in cardiac tissue,aresultwhichcanexplainthe Class IIIprofile observedinisolated tissues andinvivo.
S.185
II) (1989)
FE Kuhn, RA THE EFFECT OF COCAINE ON THE CANINE CORONARY CIRCULATION. Departments of Medicine and Pharmacology, Gillis, R Virmani, GL Schaer. Georgetown University School of Medicine, Washington, DC. The association of cocaine abuse and myocardial infarction led us to study the effect of cocaine (2 mg/kg IV) on hemodynamics, diameter of the left anterior descendins (LAD) coronary artery (auantitative anaiosraohv) and coronary vascular r&.&a&e (CVR,-microsphe&es) in sufenta&il-sedatl ed dogs (n=7). Cocaine produced a 19+3% reduction in LAD diameter (pc.02) This was associated with signifand a-55+20% increase in CVR (pc.05). icant (pc.05) increases in heart rate (7629 to 100+14 beats/min), mean arterial pressure (106+6 to 148+10 mm Hg) and cardiac output (3.7kO.7 to A second group (N=5) was pretreated with the alpha5.421.7 L/min). adrenoceptor antagonist phentolamine (2.5 mg/kg) which prevented cocaine In a third group (n=7) the LAD endoinduced coronary vasoconstriction. thelium was denuded in vivo with an angioplasty balloon prior to cocaine Despite successful denudation, cocaine produced nearly (2 mg/W IV). identical effects on LAD diameter (+19+3%) and CVR (+65-&32%). conclusions: 1) Cocaine produces constriction of epicardial and coronary resistance vessels despite a marked increase in myocardial oxygen demand. 2) These deleterious effects are mediated by alpha-adrenoceptor stimulation and are not potentiated by prior endothelial injury.
554 SELECTIVE
BLOCK OF DELAYED RECTIFICATION (Ik) IN FELINE VENTRICULAR MYOCYTES BY WY 48,986, A NOVEL CLASS III ANTIARRHYTHMIC AGENT. Christopher II. Follmer, Maria T. Poczobutt, Thomas J. Colatsky. Div. of Experimental Therapeutics, Wyeth-Ayerst Research, Princeton, NJ 08543. Wy 48,986 (WY)is an orally active an&rhythmic agentwithClassIIIelectrophysiologicproperties and efficacy against re-entrant arrhythmias. The mechanism by which WY uniformly prolongs cardiac refractory periods was investigated using whole-cell suction pipette voltage clamp techniques on single feline ventricular myocytes. Tail currents elicited upon repolarization from selected test potentials (0 - +60mV, 1 set, Vh=-4OmV, T=32OC) were used to assessblock of the delayed rectifier current Ik. 3pM WY completely blocked tail currents at all test potentials after 30-60 min exposure. Clamp steps to more negative potentials (-100 to -40mV) from a holding potential of -4OmV were used to elicit the inward rectifier current, Ikl. External application of 100 FM WY was required to observe effects on the magnitude and/or kinetics of Ikl. Concentrations as high as 3OOpM had no effect on the inward sodium current (INa) measured under conditions favoring clamp control (T=17uC, reduced Na+ gradient). In conclusion, WYis a potent and selective blocker of the delayed outward potassium current in cardiac tissue,aresultwhichcanexplainthe Class IIIprofile observedinisolated tissues andinvivo.
S.185