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
Gout, B.; Jean, J.; Bril, A.
Journal of Pharmacology and Experimental Therapeutics 262(3): 987-994
1992
ISSN/ISBN: 0022-3565 PMID: 1527735 Document Number: 404473
The effects of N-[4-(2-{2-[4-(methanesulphonamide)phenoxy]-N-methylethylamino}ethyl)phenyl]methanesulphonamide, free base (UK-68,798) (30- and 100 .mu.g/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-[3,4-dimethoxyphenyl]ethyl} methylamino-propyl]-2H-3-benzazepin-2-one, hydrochloride (UL-FS 49) (500 .mu.g/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 .mu.g/kg, respectively (P < .05). In normal area, both doses of UK-68,798 slightly increased regional function. In an ischemic area, the lower dose of UK-68,798 (30 .mu.g/kg) was without effect. At the higher dose (100 .mu.g/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 < .05). UL-FS 49 (500 .mu.g/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 .mu.g/kg) prolonged diastolic time significantly more than UK-68,798 (100 .mu.g/kg; P < .05). The present results show that although UK-68,798 and UL-FS 49 both reduced exercise-induced tachycardia, they exert a differential effect on ischemic function and suggest that prolongation of the diastolic period plays a major role in maintaining cardiac function during ischemia.