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 cannulated for mean arterial pressure and heart rate measurements while both jugular veins were cannulated for drug administration. All animals were infused with verapamil (15 mg/kg/h i.v.) until 45-60% reduction of mean arterial pressure and 30% reduction of heart rate were observed. After verapamil, control animals were given normal saline solution and the other groups received 4-aminopyridine (1 and 2 mg/kg/h) or Bay K 8644 (0.3 and 0.6 mg/kg/h) for 60 minutes.


RESULTS
While 4-aminopyridine (1 mg/kg/h i.v.) 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 i.v. of 4-aminopyridine improved mean arterial pressure 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 infusion was stopped at that time. Only the 2 mg/kg/h 4-aminopyridine infusion 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 i.v.) significantly enhanced mean arterial pressure within 5 minutes (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 minutes compared with the control group (p < 0.05, 95% CI 311.3-358.7). Bay K 8644 did not produce a significant effect on heart rate (p > 0.05).


CONCLUSIONS
4-Aminopyridine improved mean arterial pressure and heart rate in a dose-dependent fashion; however, the higher infusion rate (2 mg/kg/h) necessary to improve mean arterial pressure and heart rate resulted in convulsions and excessive secretions. The reversal effects of Bay K 8644 on mean arterial pressure were transient and did not affect heart rate.
Dokuz Eylul University Medical Faculty, Department of Pharmacology, Balcova, Izmir, Turkey. tuncoky@cs.med.deu.edu.tr
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Tuncok
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Apaydin
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Gelal
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Ates
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Guven
D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester / Q000494:pharmacology*; D015761:4-Aminopyridine / Q000494:pharmacology*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D001919:Bradycardia / Q000139:chemically induced / Q000188:drug therapy; D002120:Calcium Channel Agonists / Q000494:pharmacology*; D002121:Calcium Channel Blockers / Q000633:toxicity*; D002319:Cardiovascular System / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D006339:Heart Rate / Q000187:drug effects; D007022:Hypotension / Q000139:chemically induced / Q000188:drug therapy; D008297:Male; D011897:Random Allocation; D051381:Rats; D017208:Rats, Wistar; D014700:Verapamil / Q000633:toxicity*
D002120:Calcium Channel Agonists; D002121:Calcium Channel Blockers; D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester; D015761:4-Aminopyridine; D014700:Verapamil