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Comparative effects of a potassium channel blocking drug, UK-68,798, and a specific bradycardic agent, UL-FS 49, on exercise-induced ischemia in the dog: significance of diastolic time on ischemic cardiac function

B Gout, J Jean and A Bril

SmithKline Beecham Laboratories Pharmaceutiques, Unite de Recherche, Saint Gregoire, France.

The effects of N-]4-(2-(2-[4-(methanesulphonamide)phenoxy]-N- methylethylamino)ethyl)phenyl]methanesulphonamide, free base (UK- 68,798) (30 and 100 micrograms/kg i.v.), a class III antiarrhythmic with potassium channel blocking activity, on regional ventricular function during exercise-induced ischemia in conscious dogs were compared to those of 1,3,4,5-tetrahydro-7,8-dimethoxy-3-[3-(]2-ad3,4- dimethoxyphenyl]ethyl)methylamino)propyl]-2H-3-benzazepin-2-one, hydrochloride (UL-FS 49) (500 micrograms/kg, i.v.), a specific bradycardic agent. Studies were performed in chronically instrumented dogs trained to run on a motor-driven treadmill. After stenosis of the left anterior descending coronary artery, dogs were submitted to a submaximal exercise. UK-68,798 did not change the resting heart rate, but reduced exercise heart rate by 6.5 and 13.5% at 30 and 100 micrograms/kg, respectively (P less than .05). In a normal area, both doses of UK-68,798 slightly increased regional function. In an ischemic area, the lower dose of UK-68,798 (30 micrograms/kg) was without effect. At the higher dose (100 micrograms/kg), the ischemic dysfunction was worsened, because the percent systolic shortening was reduced from 22.6 +/- 2.6% in the control exercise to 11.1 +/- 5.6% in the presence of UK-68,798 (P less than .05). UL-FS 49 (500 micrograms/kg) reduced heart rate before and during exercise. At rest, UL-FS 49 slightly increased systolic shortening in normal and ischemic areas. In the ischemic area, UL-FS 49 reversed the exercise-induced dysfunction. Before and during exercise, UL-FS 49 (500 micrograms/kg) prolonged diastolic time significantly more than UK-68,798 (100 micrograms/kg; P less than .05).(ABSTRACT TRUNCATED AT 250 WORDS)

Volume 262, Issue 3, pp. 987-994, 09/01/1992
Copyright © 1992 by American Society for Pharmacology and Experimental Therapeutics




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