Effects of tedisamil (KC-8857) on cardiac electrophysiology and ventricular fibrillation in the rabbit isolated heart.
1. The direct cardiac electrophysiological and antifibrillatory actions of tedisamil (KC-8857) were studied in rabbit isolated hearts. 2. Tedisamil (1, 3, and 10 microM), prolonged the ventricular effective refractory period (VRP) from 120 +/- 18 ms (baseline) to 155 +/- 19, 171 +/- 20, and 205 +/- 14 ms, respectively. Three groups of isolated hearts (n = 6 each) were used to test the antifibrillatory action of tedisamil. Hearts were perfused with 1.25 microM pinacidil, a KATP channel activator. Hearts were subjected to hypoxia for 12 min followed by 40 min of reoxygenation. Ventricular fibrillation (VF) developed during hypoxia and reoxygenation in both the control and 1 microM tedisamil-treated groups (5/6 and 4/6, respectively). Tedisamil (3 microM) reduced the incidence of VF (0/6, P = 0.007 vs. control). 3. In a separate group of hearts, VF was initiated by electrical stimulation. The administration of 0.3 ml of 10 mM tedisamil, via the aortic cannula, terminated VF in all hearts, converting them to normal sinus rhythm. 4. Tedisamil (3 microM) reversed pinacidil-induced negative inotropic effects in rabbit isolated atrial muscle which were equilibrated under normoxia, as well as in atrial muscle subjected to hypoxia and reoxygenation. 5. The results demonstrate a direct antifibrillatory action of tedisamil in vitro. The mechanism responsible for the observed effects may involve modulation by tedisamil of the cardiac ATP-regulated potassium channel, in addition to its antagonism of IK and Ito.
Chi
L
L
Department of Pharmacology, University of Michigan Medical School, Ann Arbor 48109-0632, USA.
Park
J L
JL
Friedrichs
G S
GS
Banglawala
Y A
YA
Perez
M A
MA
Tanhehco
E J
EJ
Lucchesi
B R
BR
D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology* / Q000627:therapeutic use; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology* / Q000627:therapeutic use*; D003521:Cyclopropanes / Q000494:pharmacology* / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D004562:Electrocardiography / Q000187:drug effects*; D006146:Guanidines / Q000494:pharmacology; D006321:Heart / Q000187:drug effects* / Q000502:physiology; D066298:In Vitro Techniques; D020110:Pinacidil; D011817:Rabbits; D013237:Stereoisomerism; D014665:Vasodilator Agents / Q000494:pharmacology; D014693:Ventricular Fibrillation / Q000188:drug therapy
D000889:Anti-Arrhythmia Agents; D019086:Bridged Bicyclo Compounds, Heterocyclic; D003521:Cyclopropanes; D006146:Guanidines; D014665:Vasodilator Agents; D020110:Pinacidil; C059921:tedisamil