The chronic effects of beta-adrenoreceptor antagonists on the efflux of tritiated noradrenaline from sympathetic nerves of the pithed rat.

The effect of chronic administration of two beta-adrenoreceptor blocking drugs, propranolol and timolol, on transmitter noradrenaline release from sympathetic nerves has been investigated in vivo using the pithed rat preparation. Oral treatment for 4 weeks with either propranolol (46.3 mg/kg/day) or timolol (7.1 mg/kg/day) significantly raised the stimulation frequency threshold for release of radioactivity on stimulation of the whole spinal outflow of the pithed rat after i.v. injection of 3H-NA. No differences in the stimulation-evoked rise in mean arterial pressure were observed between control or treated rats nor was the heart rate response to stimulation altered after timolol treatment. However, in propranolol treated rats the mean rises in heart rate were significantly higher with 3 and 30 Hz stimulation than in control rats. Timolol treatment significantly increased the blood concentration and lowered the heart content of 3H-NA whilst propranolol treatment did not significantly change either blood or heart levels. Log dose-response curves for mean rises in heart rate after i.v. isoprenaline were not shifted to the right in either propranolol or timolol treated pithed rats. With the lowest doses of isoprenaline (1 and 25 ng), the mean rises in heart rate in timolol treated rats were significantly greater than in the controls. Thus chronic administration of propranolol or timolol decreased the stimulation-induced increase in plasma 3H-NA but this change in release was not related to reduced rises in blood pressure or heart rate.