Endogenous and exogenous agonist regulation of responses to beta-adrenoceptor stimulation in patients with chronic autonomic failure.

1. Two patients with orthostatic hypotension due to peripheral autonomic neuropathy were studied. The diagnosis was based on severe hypotension during 60 degrees head-up tilting and absence of the systolic pressure overshoot in phase IV of the Valsalva response. Plasma noradrenaline levels were 50 and 90 pg/ml in the two patients. Noradrenaline was unresponsive to head-up tilting. Heart rate did not change after atropine, 1 mg i.v. Thus the patients had combined efferent sympathetic and parasympathetic lesions. 2. Infusion of isoprenaline in these patients showed supersensitivity for the chronotropic and vascular effects of this drug. Similar cardiac and vascular supersensitivity was observed for salbutamol. The patients were treated with pindolol, 15 mg daily divided in three doses. After 4 weeks treatment pindolol was stopped and the infusion of isoprenaline and salbutamol were repeated 72 h after the last dose of pindolol, 5 mg. The isoprenaline dose-heart rate response curve was shifted to the right by a factor of 9 and 14 in the two patients. The salbutamol dose-heart rate response curve was shifted by a factor of 61 in both patients. 3. The observed chronotropic effects of salbutamol provides evidence for the existance of cardiac beta 2-adrenoceptors in man. Comparison between the cardiovascular responses to the non-selective beta-adrenoceptor agonist isoprenaline and the beta 2-selective agonist salbutamol suggest preferential beta 2-adrenoceptor sensitization in chronic autonomic failure, which can be reversed by treatment with the non-selective partial beta-adrenoceptor agonist pindolol.