Effect of timolol on autonomic neural discharge associated with ouabain-induced arrhythmia

Abstract

The purpose of this study was to determine the effect of the β-blocking agent timolol on postganglionic cardiac and preganglionic splanchnic sympathetic and vagal neural discharge, ouabain-induced arrhythmia, heart rate and mean arterial blood pressure. Cats were anesthetized with α-chloralose, given atropine, and pretreated with timolol (5 mg/kg, i.v. infused at a rate of 0.5 mg/kg/min for 10 min). Bolus injections of ouabain (25 μg/kg, i.v.) were given every 15 min until the animals died; the first injection was given 15 min after the end of the timolol infusion. When compared with cats (n = 13) receiving only ouabain, timolol (n = 11 cats) increased the time to ouabain-induced arrhythmia and death from 23 ± 3 to 48 ± 7 and 46 ± 3 to 76 ± 9 min, respectively (P < 0.05). Both heart rate and mean arterial blood pressure fell immediately after the onset of the timolol infusion. Eleven minutes later, the mean heart rate and blood pressure had decreased from 137 ± 3 to 104 ± 6 beats/min and 133 ± 6 to 103 ± 7 mm Hg, respectively (P < 0.05); ouabain did not reverse the decreases. Neural activity monitored from the vagus and from the postganglionic cardiac and preganglionic splanchnic sympathetic nerves was not significantly altered by the infusion of timolol. The administration of ouabain after timolol did not alter splanchnic nor vagal discharge. Most important was the observation that postganglionic cardiac sympathetic neural discharge exhibited both increases and decreases, i.e., a nonuniform neural discharge, at the time of ouabain-induced arrhythmia and that the ouabain-induced nonuniformity did not occur in the cats pretreated with timolol. Thus, the protective effect of timolol may be due, in part, to prevention of the nonuniform postganglionic cardiac sympathetic neural discharge and to the prevention of ouabain-induced increases in vagal discharge. The establishment of β-blockade and a direct negative inotropic action may also have contributed to the antiarrhythmic action of timolol.