Beta-adrenergic receptor blocking drugs in spontaneous hypertension

Abstract

Eleven beta-adrenergic receptor blocking agents and derivatives were evaluated for their ability to affect systolic arterial blood pressure and pulse rate in unanesthetized, male spontaneously hypertensive rats (SHRs) and normotensive Wistar Kyoto (WKY) controls. Animals ranged from 7 to 76 weeks of age. The subcutaneous injection of 5 and 45 mg/kg metoprolol in 52 to 64 week old SHRs and 45 mg/kg twice a day to 26 to 29 week old SHRs produced a significant decrease in blood pressure. The subcutaneous injection of pindolol (0.1 and 1.0 mg/kg) produced a greater and more consistent depressor effect in mature SHRs. The subcutaneous administration of sotalol (100 mg/kg) and alprenolol (20 mg/kg) resulted in a depressor action which was significant 120 minutes after injection of the drug. In the doses used, propranolol, oxprenolol, 4-hydroxypropranolol and KO-1366 produced pressor effect in SHRs. Propranolol did not cause this pressor effect in prehypertensive (seven week old) SHRs. Practolol, dextro-propranolol and KO-1313 had no effect on blood pressure in the doses used. Propranolol, pindolol, metoprolol, dextro-propranolol, 4-hydroxypropranolol, practolol, oxprenolol, KO-1366 and KO-1313 produced no significant effects on blood pressure in normotensive WKY controls in the doses tested. Placing oral doses of 160 mg/kg/day of metoprolol in the drinking water for seven days significantly lowered blood pressure in 14 week old SHRs previously exposed to ineffective doses of 77 mg/kg/day for 24 days. The administration of oral doses of oxprenolol (40 mg/kg/day) in drinking water for three weeks had a slight but insignificant pressor effect. Smaller doses of metoprolol (15 and 39 mg/kg/day for three to four weeks) and practolol (70 to 85 mg/kg/day for two weeks) had no effect on 52 week old SHRs. Oral doses of pindolol, metoprolol, practolol and oxprenolol had no significant effect on blood pressure in WKY controls. There was no clear relationship between the effects of the drugs on blood pressure and their ability to affect the pulse rate. Similarly, there did not appear to be any consistent relationship between the potency of the beta-blocking drug and the blood pressure lowering action. In addition, neither cardioselective beta-blockade nor sympathomimetic properties allowed the prediction of blood pressure responses to the administration of those agents possessing these features. Although SHRs provide a valuable model of human essential hypertension, the variable effects reported here and elsewhere in the literature require caution as to the applicability and usefulness of testing and evaluating beta-adrenergic blocking drugs for their potential antihypertensive effects in this particular form of experimental hypertension.