Anticonvulsant and antiarrhythmic actions of the beta blocking agent timolol.

Cats were anesthetized with alpha-chloralose and pentylenetetrazol, 10 and/or 20 mg were administered intracerebroventricularly (i.c.v.) to elicit epileptiform activity, including both interictal and ictal discharges. Timolol, 10, 100, 500 micrograms/kg i.c.v. and 1, 5, 10 and/or 20 mg/kg i.v., was administered at 5 min intervals to determine whether it suppressed the epileptiform activity. Mean arterial blood pressure and heart rate increased after the administration of pentylenetetrazol; these increases were associated with the development of epileptiform activity and cardiac arrhythmias. All doses of timolol caused a decrease in the blood pressure and heart rate elevated by pentylenetetrazol and suppressed the epileptiform activity. Similar findings were obtained in cats that received the same doses of timolol administered at different time intervals. The data indicate that the central administration of timolol reverses the epileptiform activity of pentylenetetrazol in the brain and suppresses the associated increases in blood pressure, heart rate and cardiac arrhythmias.

The relationship of the lock-step phenomenon and precipitous changes in mean arterial blood pressure.

The lock-step phenomenon (LSP) is the occurrence of postganglionic cardiac sympathetic discharge (PCSD) and cortical epileptiform activity (EA) in a time-locked fashion. The relationship between the LSP and precipitous changes in blood pressure (PCBP: greater than 23 mm Hg in 10 sec) was determined in 9 cats after EA was induced with pentylenetetrazol following pretreatment with phenobarbital (20 mg/kg, i.v.). Electrocorticogram (ECoG), PCSD, lead II EKG, and mean arterial blood pressure (MAP) were monitored. Since an interspike interval of 2.8 sec was frequently found to exist between ECoG spikes when the LSP was present, 4 categories of LSP were defined: LSP absent; stable LSP with 2.8 sec interval; stable LSP without 2.8 sec interval; and unstable LSP with increasing or decreasing rates of discharge. The duration of each LSP pattern and the proportion of time spent in PCBP were determined. A one-way repeated measures ANOVA and the Newman-Keuls post-hoc test showed that a higher mean proportion of time spent in PCBP was associated with the unstable LSP pattern (P less than 0.05). The LSP and associated patterns as related to precipitous changes in MAP are indicators of changes in autonomic function. Autonomic dysfunction with EA, causing cardiac arrhythmias, has been postulated as a cause of sudden unexplained death (SUD) in persons with epilepsy. Thus, an understanding of the autonomic changes, as indicated by PCBP associated with LSP, may contribute to the understanding and prevention of SUD in persons with epilepsy.