Halothane sensitizes the guinea-pig heart to pharmacological IKr blockade: comparison with urethane anesthesia.
Potential utility of halothane-anesthetized guinea pigs for detecting drug-induced repolarization delay was analyzed in comparison with urethane-anesthesia (n = 4 for both groups). Basal QT interval was significantly greater under halothane-anesthesia than urethane-anesthesia (192 +/- 7 vs 132 +/- 5 ms, respectively), whereas the reverse was true for the heart rate (190 +/- 7 vs 248 +/- 11 beats/min, respectively). The typical I(Kr)-blocker dl-sotalol (0.1 to 3 mg/kg, i.v.) induced dose-related bradycardia and QT interval prolongation under each anesthesia. The extent of maximum prolongation in the QT interval was greater under halothane-anesthesia than urethane-anesthesia (+101 +/- 15 vs +49 +/- 3 ms, respectively), whereas that of peak change in the heart rate was smaller under the former than the latter (-49 +/- 8 vs -63 +/- 5 beats/min, respectively). Pretreatment of the animals under urethane-anesthesia with the selective I(Ks) blocker chromanol 293B (n = 6) increased the extent of the dl-sotalol-induced QT interval prolongation to +57 +/- 8 ms, which was only 0.56 times of that under the halothane-anesthesia, whereas the pretreatment increased the peak change in the heart rate to -76 +/- 12 ms. These results indicate that the halothane-anesthesia may effectively sensitize the guinea-pig heart to pharmacological I(Kr) blockade.
Sakaguchi
Yasue
Y
Department of Pharmacology, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Tamaho-cho, Nakakoma-gun, Yamanashi 409-3898, Japan.
Sugiyama
Atsushi
A
Takao
Shuji
S
Akie
Yasuki
Y
Takahara
Akira
A
Hashimoto
Keitaro
K
D000200:Action Potentials / Q000187:drug effects; D018685:Anesthetics, Inhalation / Q000008:administration & dosage / Q000494:pharmacology*; D018686:Anesthetics, Intravenous / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D002839:Chromans / Q000494:pharmacology; D051668:Delayed Rectifier Potassium Channels / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004353:Drug Evaluation, Preclinical; D004562:Electrocardiography; D006168:Guinea Pigs; D006221:Halothane / Q000008:administration & dosage / Q000494:pharmacology*; D006339:Heart Rate / Q000187:drug effects; D008297:Male; D011188:Potassium / Q000378:metabolism; D026902:Potassium Channel Blockers / Q000494:pharmacology; D013015:Sotalol / Q000494:pharmacology; D013449:Sulfonamides / Q000494:pharmacology; D013997:Time Factors; D014520:Urethane / Q000008:administration & dosage / Q000494:pharmacology*
D018685:Anesthetics, Inhalation; D018686:Anesthetics, Intravenous; D002839:Chromans; D051668:Delayed Rectifier Potassium Channels; D026902:Potassium Channel Blockers; D013449:Sulfonamides; C103474:6-cyano-4-(N-ethylsulfonyl-N-methylamino)-3-hydroxy-2,2-dimethylchromane; D014520:Urethane; D013015:Sotalol; D011188:Potassium; D006221:Halothane