EFFECTS OF SELECTED BETA-ADRENERGIC BLOCKING-AGENTS ON SLEEP STAGES IN SPONTANEOUSLY HYPERTENSIVE RATS

The effects on sleep of six beta-adrenergic blockers (propranolol, dilevalol, pindolol, metoprolol, celiprolol and atenolol) which differ in their pharmacological characteristics were studied in spontaneously hypertensive rats. Electroencephalographic activity was recorded for 6 hr after p.o. administration of drugs or vehicle, and the stages of wakefulness, rapid eye movements (REM) sleep and non-REM sleep (non-REM) were classified thereafter. In separate experiments antihypertensive activity of each drug was assessed by the tail-cuff technique. The most common effect of the beta-blockers examined was a decrease of the duration of REM. The effect was marked for propranolol (10-100 mg/kg), celiprolol (10-100 mg/kg) and pindolol (1-10 mg/kg), whereas it occurred at low doses, but not at high doses for metoprolol (10 mg/kg) and atenolol (3 and 10 mg/kg). Dilevalol induced a moderate REM decrease at 30 mg/kg only. For the beta-1 antagonists, the dose reducing REM substantially (ED30) was slightly above (1.4- to 3.7-fold) that effective on blood pressure (ED10), whereas the separation was high for pindolol (17.4-fold) and dilevalol (22.4-fold). Conversely, propranolol displayed a weak antihypertensive activity in this model and was more potent on REM than in reducing blood pressure. Propranolol, celiprolol and atenolol also increased duration of wakefulness. Considering the pharmacological characteristics of the beta-blockers examined, it is suggested that selective beta-1 antagonism and interaction with other neurotransmitters, such as serotonin, are relevant to the potential effects of this class of antihypertensive drugs on sleep function. Other properties such as lipophilicity or partial agonist activity appear to be less important as a determinant of sleep disturbances and, in turn, of other central nervous system side effects.