title: Antiarrhythmic agent, MS-551, protects against pinacidil + hypoxia-induced ventricular fibrillation in Langendorff-perfused rabbit isolated heart.
abstract: We studied the electrophysiologic and antifibrillatory effects of the class III agent MS-551 in a rabbit isolated heart model in which ventricular fibrillation (VF) occurs reproducibly under conditions of hypoxia/reoxygenation in the presence of the ATP-dependent potassium channel opener, pinacidil. Ten minutes after MS-551 or vehicle administration, addition of pinacidil (1.25 microM) to the buffer was followed by a 12-min hypoxic period and 40-min reoxygenation. At a low concentration of MS-551 (1.0 microM), VF occurred in 5 of 6 hearts, the same incidence as in the control group (5 of 6). In contrast 0 of 6 hearts treated with 15 microM MS-551 developed VF (p < 0.05 vs. vehicle). Ventricular effective refractory period (VERP) was determined in a separate group of isolated hearts (n = 13). Pinacidil alone, during normoxic perfusion, decreased VERP 48 +/- 11% (p < 0.05) 15 min after exposure. Five minutes of hypoxia alone also decreased VERP (57 +/- 8%, p < 0.05). Under normoxic conditions, MS-551 increased ERP 31 +/- 10% (p < 0.05 vs. baseline). VERP prolongation by MS-551 was reduced in the presence of pinacidil but remained 22 +/- 6% (p < 0.05) above baseline. The results suggest that VERP shortening owing to pinacidil-mediated ATP-dependent K+ channel opening is associated with development of VF in isolated heart. MS-551 attenuates the pinacidil-mediated decrease in VERP and prevents pinacidil+hypoxia-reoxygenation-induced VF. Because pinacidil and hypoxia open myocardial KATP channels, putatively decreasing VERP, MS-551 may exert its antifibrillatory effect through partial blockade of KATP channels.
authors.affiliation: Department of Pharmacology, University of Michigan Medical School, Ann Arbor 48109-0626.
authors.forename: G S
authors.initials: GS
authors.lastname: Friedrichs
authors.forename: L
authors.initials: L
authors.lastname: Chi
authors.forename: S C
authors.initials: SC
authors.lastname: Black
authors.forename: P J
authors.initials: PJ
authors.lastname: Manley
authors.forename: B R
authors.initials: BR
authors.lastname: Lucchesi
mesh_terms: D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology / Q000627:therapeutic use*; D004195:Disease Models, Animal; D004285:Dogs; D006146:Guanidines / Q000633:toxicity; D006321:Heart / Q000187:drug effects*; D006325:Heart Atria / Q000187:drug effects; D000860:Hypoxia / Q000503:physiopathology; D066298:In Vitro Techniques; D020110:Pinacidil; D011744:Pyrimidinones / Q000494:pharmacology / Q000627:therapeutic use*; D011817:Rabbits; D014665:Vasodilator Agents / Q000633:toxicity; D014693:Ventricular Fibrillation / Q000209:etiology / Q000517:prevention & control*
chemical_list: D000889:Anti-Arrhythmia Agents; D006146:Guanidines; D011744:Pyrimidinones; D014665:Vasodilator Agents; C076259:nifekalant; D020110:Pinacidil