THE EFFECTS OF 4-AMINOPYRIDINE AND BAY-K-8644 ON VERAPAMIL-INDUCED CARDIOVASCULAR TOXICITY IN ANESTHETIZED RATS

Objective: To determine the effects of 4-aminopyridine and Bay K 8644 on mean arterial pressure and heart rate in an anesthetized rat model of verapamil toxicity. Methods: The study was a randomized, controlled animal study. Rats were anesthetized and the carotid artery was cannu lated for mean arterial pressure and heart rate measurements while bot h jugular veins were cannulated for drug administration. All animals w ere infused with verapamil (15 mg/kg/h IV) until 45-60% reduction of m ean arterial pressure and 30% reduction of heart rate were observed. A fter verapamil, control animals were given normal saline solution and the other groups received 4-aminopyridine (1 and 2 mg/kg/h) or Bay K 8 644 (0.3 and 0.6 mg/kg/h) for 60 minutes. Results: While 4-aminopyridi ne (1 mg/kg/h IV did not significantly increase mean arterial pressure (75.9 +/- 5.5%) when compared with the control group (64.3 +/- 5.1%, p > 0.05), 2 mg/kg/h IV of Lf-aminopyridine improved mean arterial pre ssure within 40 minutes (87.4 +/- 6.6%, p < 0.05, 95% CI 66.4-108.6%). Because the 2 mg/kg/h 4-aminopyridine produced side effects including seizures, secretions, and fasciculations at 35 +/- 5 minutes, the inf usion was stopped at that time. Only the 2 mg/kg/h LS-aminopyridine in fusion increased the heart rate at 10 and 20 minutes compared with the control group (p < 0.05, 95% CI 283.2-364.4). Bay K 8644 (0.3 and 0.6 mg/kg/h IV) significantly enhanced mean arterial pressure within 5 mi nutes (68.0 +/- 4.1% and 73.0 +/- 2.9%, respectively, p < 0.05), (95% CI 56.8-78.0% and 95% CI 64.9-81.1%, respectively) but no significant changes in mean arterial pressure were observed after 5 minutes. The 4 -aminopyridine (2 mg/kg/h) increased the heart rate at 10 and 20 minut es compared with the control group (p < 0.05, 95% CI 311.3-358.7). Bag . It 8644 did not produce a significant effect on heart rate (p > 0.05 ). Conclusions: 4-Aminopyridine improved mean arterial pressure and he art rate in a dose-dependent fashion; however, the higher infusion rat e (2 mg/kg/h) necessary to improve mean arterial pressure and heart ra te resulted in convulsions and excessive secretions. The reversal effe cts of Bay K 8644 on mean arterial pressure were transient and did not affect heart rate.