Protection of CGS 10078B against Ouabain-Induced Arrhythmia in the Cat

Abstract

CGS 10078B (CGS; l-[2,3-dihydro-l,4-(2S)-benzodioxm-2-yl]-5-[2,3-dihydro-1,4-(2i?)-benzodioxin-2-yl]-3-(1R,55)-aza-1,5-pentanediol methane sulfonate) is an agent with α- and β-receptor and calcium channel blocking actions. To study its antiarrhythmic activity, cats were anesthetized with α-chloralose, ventilated, and given atropine and gallamine. CGS (10 or 20 mg/kg, i.v.) was infused 15 min prior to ouabain. Bolus injections of ouabain (25 μg/kg, i.v.) were given every 15 min until death (D). Some cats were pretreated with reserpine (R; 5 mg/kg, i.p.) 24 h prior to the experiment. In other cats 6-hydroxydopamine (6-OHDA; 20 mg/kg, i.v.) was administered 3 days prior to CGS 20 mg/kg and ouabain. Data were compared with those of Lathers [Eur. J. Pharmacol. 64: 95, 1980], i.e., with 12 cats who received only ouabain and with 11 pretreated with timolol (T; 5 mg/kg, i.v.) prior to ouabain. After CGS (10 or 20 mg/kg, i.v.), but just prior to the first dose of ouabain, the blood pressure (BP) was decreased (p < 0.05) from control (165 ± 6 vs. 96 ± 7, and 136 ± 5 vs. 90 ± 10 mm Hg, respectively). Comparable heart rate (HR) values were also decreased (p < 0.05) from 225 ± 17 to 166 ± 14 and from 193 ± 8 to 152 ± 6beats/min. 11 min after T, BP and HR had decreased (p < 0.05) from 133 ± 6 to 103 ± 7 mm Hg and from 134 ± 4 to 104 ± 6 beats/min, respectively. Ouabain did not influence these decreases in BP and HR. CGS (10 or 20 mg/kg, i.v.) increased (p < 0.05) the time to ouabain-induced arrhythmia (AR) and D. The magnitude of the protection appeared to be similar to that afforded by T. R given prior to CGS (20 mg/kg, i.v.) also increased the time to ouabain-induced AR and D while 6-OHDA increased the time to AR. The CGS protection against ouabain-induced AR was still present in animals pretreated with R or 6-OHDA. This indicates that the antiarrhythmic affect is not dependent upon adrenergic neuronal blockade.