title: Characterization of microminipigs as an in vivo experimental model for cardiac safety pharmacology.
abstract: We pharmacologically characterized microminipigs as an in vivo experimental model by assessing cardiovascular effects of pilsicainide, verapamil and E-4031, which can preferentially inhibit cardiac Na+, Ca2+and K+channels, respectively. Intravenous infusion of 1 mg/kg of pilsicainide (n = 4), 0.1 mg/kg of verapamil (n = 4) and 0.01 followed by 0.1 mg/kg of E-4031 (n = 5) over 10 min decreased the heart rate, mean blood pressure and ventricular contractility. Moreover, pilsicainide prolonged the PR interval, QRS width and QTc; verapamil prolonged the PR interval, but shortened the QRS width and QTc; and E-4031 prolonged the QTc, whereas no substantial change was detected in the PR interval or QRS width. Peak plasma concentrations of pilsicainide, verapamil and E-4031 in microminipigs were 1.7-4.8 times higher than those expected in humans and dogs, possibly due to smaller effective volume of drug distribution. The extent of the drug-induced cardiovascular responses was generally greater in microminipigs than in humans and dogs, which could be explained by the following possibilities; namely unique pharmacokinetic profile, less great reflex-mediated increase of sympathetic tone and/or smaller repolarization reserve in microminipigs. These information may make it feasible to apply this new-type animal to a tool for assessing cardiac safety profiles of new chemical entities.
authors.affiliation: Department of Pharmacology, Faculty of Medicine, Toho University, 5-21-16, Omori-nishi, Ota-ku, Tokyo 143-8540, Japan.
authors.forename: Suchitra
authors.initials: S
authors.lastname: Matsukura
authors.affiliation: Department of Pharmacology, Faculty of Medicine, Toho University, 5-21-16, Omori-nishi, Ota-ku, Tokyo 143-8540, Japan.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Nakamura
authors.affiliation: Department of Pharmacology, Faculty of Medicine, Toho University, 5-21-16, Omori-nishi, Ota-ku, Tokyo 143-8540, Japan.
authors.forename: Xin
authors.initials: X
authors.lastname: Cao
authors.affiliation: Department of Pharmacology, Faculty of Medicine, Toho University, 5-21-16, Omori-nishi, Ota-ku, Tokyo 143-8540, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Wada
authors.affiliation: Department of Pharmacology, Faculty of Medicine, Toho University, 5-21-16, Omori-nishi, Ota-ku, Tokyo 143-8540, Japan.
authors.forename: Hiroko
authors.initials: H
authors.lastname: Izumi-Nakaseko
authors.affiliation: Department of Pharmacology, Faculty of Medicine, Toho University, 5-21-16, Omori-nishi, Ota-ku, Tokyo 143-8540, Japan.
authors.forename: Kentaro
authors.initials: K
authors.lastname: Ando
authors.affiliation: Laboratory of Drug Metabolism and Pharmacokinetics, Showa Pharmaceutical University, 3-3165, Higashi-Tamagawa Gakuen, Machida, Tokyo 194-8543, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Yamazaki
authors.affiliation: Department of Pharmacology, Faculty of Medicine, Toho University, 5-21-16, Omori-nishi, Ota-ku, Tokyo 143-8540, Japan. Electronic address: atsushi.sugiyama@med.toho-u.ac.jp.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Sugiyama
mesh_terms: D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D001794:Blood Pressure; D002320:Cardiovascular Physiological Phenomena / Q000187:drug effects*; D004562:Electrocardiography; D006321:Heart / Q000187:drug effects; D006339:Heart Rate; D007262:Infusions, Intravenous; D008012:Lidocaine / Q000031:analogs & derivatives / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D013552:Swine; D013556:Swine, Miniature; D014700:Verapamil / Q000494:pharmacology
chemical_list: D000889:Anti-Arrhythmia Agents; D010880:Piperidines; D011725:Pyridines; C063968:E 4031; D008012:Lidocaine; C042288:pilsicainide; D014700:Verapamil
keywords: Cardiovascular effect; E-4031; Microminipig; Pilsicainide; Verapamil