title: Electropharmacological effects of a spironolactone derivative, potassium canrenoate, assessed in the halothane-anesthetized canine model.
abstract: While aldosterone receptor blockers improve survival of patients with congestive heart failure, spironolactone and its derivatives were recently shown to block ether-a-go-go-related gene (HERG) channels and native IKs and IKr currents in guinea pig ventricular myocytes. In this study, we examined in vivo electropharmacological effects of an active derivative of spironolactone, potassium canrenoate, using a halothane-anesthetized canine model. Potassium canrenoate was intravenously administered in three doses of 1, 10, and 100 mg/kg per 10 min with a pause of 20 min between doses (n = 5). The low dose hardly affected any of the cardiovascular parameters. The middle dose, a clinically recommended daily maximum i.v. dose, slightly inhibited the intraventricular conduction. The high dose decreased the heart rate, ventricular contraction and blood pressure, delayed the atrioventricular and intraventricular conduction, and prolonged the ventricular repolarization and refractory period. Increment in the refractoriness by the high dose was greater than that in the repolarization, resulting in the reduction of ventricular electrical vulnerability. This unique electrophysiological profile of potassium canrenoate may in part contribute to the favorable clinical results, whereas caution has to be paid on the cardiohemodynamic actions, particularly for patients with risk of elevated plasma drug concentration.
authors.affiliation: Department of Pharmacology, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Tamaho-cho, Nakakoma-gun, Yamanashi 409-3898, Japan. atsushis@yamanashi.ac.jp
authors.forename: Atsushi
authors.initials: A
authors.lastname: Sugiyama
authors.forename: Yoshioki
authors.initials: Y
authors.lastname: Satoh
authors.forename: Akira
authors.initials: A
authors.lastname: Takahara
authors.forename: Kentaro
authors.initials: K
authors.lastname: Ando
authors.forename: Kai
authors.initials: K
authors.lastname: Wang
authors.forename: Sachiko
authors.initials: S
authors.lastname: Honsho
authors.forename: Yuji
authors.initials: Y
authors.lastname: Nakamura
authors.forename: Keitaro
authors.initials: K
authors.lastname: Hashimoto
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000758:Anesthesia; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002191:Canrenoic Acid / Q000097:blood / Q000494:pharmacology*; D004285:Dogs; D004562:Electrocardiography / Q000187:drug effects; D005260:Female; D006221:Halothane / Q000494:pharmacology; D006321:Heart / Q000187:drug effects* / Q000502:physiology; D006339:Heart Rate / Q000187:drug effects; D008297:Male; D000451:Mineralocorticoid Receptor Antagonists / Q000494:pharmacology*; D012032:Refractory Period, Electrophysiological / Q000187:drug effects
chemical_list: D000451:Mineralocorticoid Receptor Antagonists; D002191:Canrenoic Acid; D006221:Halothane