title: Pharmacological characterization of microminipig as a model to assess the drug-induced cardiovascular responses for non-clinical toxicity and/or safety pharmacology studies.
abstract: We tried to establish the halothane-anesthetized microminipigs as an alternative animal model for non-clinical toxicity and/or safety pharmacology studies. In order to characterize the halothane-anesthetized microminipigs, we firstly clarified the effects of halothane anesthesia on their cardiovascular system (n = 5). Then, we examined the cardiovascular effects of dl-sotalol in doses of 0.1, 0.3 and 1 mg/kg, i.v. on the halothane-anesthetized microminipigs (n = 6). Induction of the halothane anesthesia by itself prolonged the QT interval as well as QTcF, suggesting that the halothane anesthesia can reduce the cardiac repolarization reserve in microminipigs like in dogs. dl-Sotalol showed more potent negative chronotropic, dromotropic and hypotensive effects together with repolarization delay in microminipigs than in dogs, although each cardiovascular response to dl-sotalol was directionally similar between them, suggesting greater basal sympathetic tone and/or smaller volume of distribution of the drug in microminipigs than in dogs. Analyses of proarrhythmic surrogate markers indicate that Tpeak-Tendand short-term variability of QT interval may be more sensitive to detect the dl-sotalol-induced direct electrophysiological changes in microminipigs than in dogs, but its reverse will be true for J-Tpeakc. Thus, these results may help better understand the drug-induced cardiovascular responses in microminipigs.
authors.affiliation: Department of Pharmacology, Faculty of Medicine, Toho University.
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Yokoyama
authors.forename: Yuji
authors.initials: Y
authors.lastname: Nakamura
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Saito
authors.forename: Yukitoshi
authors.initials: Y
authors.lastname: Nagayama
authors.forename: Kiyotaka
authors.initials: K
authors.lastname: Hoshiai
authors.forename: Takeshi
authors.initials: T
authors.lastname: Wada
authors.forename: Hiroko
authors.initials: H
authors.lastname: Izumi-Nakaseko
authors.forename: Kentaro
authors.initials: K
authors.lastname: Ando
authors.forename: Yasuki
authors.initials: Y
authors.lastname: Akie
authors.forename: Atsushi
authors.initials: A
authors.lastname: Sugiyama
mesh_terms: D000319:Adrenergic beta-Antagonists / Q000494:pharmacology*; D000758:Anesthesia; D018685:Anesthetics, Inhalation / Q000494:pharmacology*; D000818:Animals; D004562:Electrocardiography / Q000187:drug effects*; D006221:Halothane / Q000494:pharmacology*; D008133:Long QT Syndrome / Q000139:chemically induced; D008297:Male; D023421:Models, Animal; D013015:Sotalol / Q000494:pharmacology*; D013552:Swine; D013556:Swine, Miniature; D018675:Toxicity Tests / Q000379:methods
chemical_list: D000319:Adrenergic beta-Antagonists; D018685:Anesthetics, Inhalation; D013015:Sotalol; D006221:Halothane