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A study was set up to assess the effect on the clinical course of subarachnoid haemorrhage (SAH) of giving propranolol 80 mg eight-hourly plus phentolamine 20 mg three-hourly by mouth for three weeks. Out of the 90 patients studied, 14 died. Two of the deaths occurred in an open pilot study of 10 patients, the remaining 12 deaths occurring in patients in a randomised double-blind placebo-controlled study. Postmortem examination was carried out on 12 of the patients, six of whom had been receiving placebo and six propranolol plus phentolamine. Necrotic myocardial lesions were present in the hearts of all six patients (age range 30-59 years) who died while taking placebo (all had had abnormal electrocardiograms (ECGs). In contrast, no necrotic lesions were found in the hearts of the six patients (age range 28-59) who died while receiving the drugs (all had previously had normal ECGs). We conclude that the necrotic myocardial lesions were induced by catecholamines and that propranolol had a cardioprotective effect. While death from a further haemorrhage in cases of SAH is not affected by propranolol and phentolamine, propranolol may have a beneficial effect in other potentially lethal stresses.

The finding by several workers that biochemical responses to catecholamines are diminished in asthmatic patients during periods of active asthma as compared to normal subjects has led to the recognition of the beta-adrenergic blockade phenomenon, a common accompaniment of extrinsic bronchial asthma. Using an intact cell method to measure leucocyte adenyl cyclase activity, we have been able to show that there is a noticeably reduced responsiveness of this enzyme system (which is now identified with beta-receptor function) to isoprenaline in the leucocytes of patients suffering from acute bronchial asthma, but that asthmatic patients in remission could not be distinguished from normal persons in this respect. Evidently the defective beta-receptor function may be associated with overactivity of the alpha-receptors in acute bronchial asthma, since the responsiveness to isoprenaline stimulation could be restored towards normal by concomitant treatment of the leucocytes of these patients with alpha-receptor blocking drugs such as phentolamine or thymoxamine. Ouabain, though somewhat less potent, also enhanced responsiveness to isoprenaline stimulation. The relation of these results to the clinical observation of adrenaline resistance in active asthma suggests that alpha-receptor blocking drugs may be of value in restoring the sensitivity of beta-receptors to sympathomimetic amines.

One hundred and twenty five men with psychogenic or organic impotence used autoinjection of the penile corpora cavernosa with either papaverine or papaverine and phentolamine for a mean period of 10.5 months (range 1-24 months) to achieve penile erection for sexual intercourse. Prolonged (over four hours) painless erection resulted from 34 of the 3513 self administered injections. This seems to be a highly effective approach to treating impotence irrespective of the aetiology.

A total of 148 patients presenting within 48 hours of subarachnoid haemorrhage were assigned at random to receive standard management only or standard management and treatment with the adrenergic-blocking agents propranolol and phentolamine (or propranolol alone) for three weeks. One hundred and thirty-four patients completed the study. Assessment at four weeks showed a strong trend for less neurological deficit in the treated group, almost statistically significant (p=0.053) in the women. During the first month the treated group suffered fewer episodes of clinical deterioration consistent with cerebral arterial spasm: thus more treated patients underwent operation and those who did had a better outcome (p=0.030). At one year fewer were dead or disabled (unable to work) in the treated group; a significant difference for women (p=0.030). Possible mechanisms for these actions may include a reduction in pulmonary oedema, prevention of myocardial infarcts, a reduction in plasma renin activity, nd a reduction in cerebral oxygen requirements. It is concluded that early adrenergic blockade benefits patients (particularly women) with subarachnoid haemorrhage for up to one year in terms of lesser neurological deficit. Beta-blocker rather than alpha-blockade appears to be the useful component. A randomised, blind extension of the present study using long-acting propranolol and placebo has shown a significant (p=0.026) decrease in deaths and significantly (p=0.003) fewer poor results in the treatment group.

A severe rebound rise in blood pressure with agitation and insomnia had been noted in five patients when they had previously ceased clonidine (Catapres) This has been shown to be reproducible in these patients and to be associated with a significant increase in urinary catecholamine excretion. The blood pressure can be controlled and the symptoms alleviated promptly by alpha and beta adrenergic receptor blockade using intravenous phentolamine and propranolol.

Twenty patients with extrinsic type bronchial asthma are shown to have a significant fall in vital capacity (V.C.) and forced expiratory volume in 1 second (F.E.V.(1)) after an intravenous infusion of 50mug. of histamine dihydrochloride. In 10 of these subjects the fall in V.C. and F.E.V.(1) produced by intravenous histamine is inhibited by the alpha-receptor blocking drugs phentolamine and phenoxybenzamine injected before the histamine test. The inhalation of disodium cromoglycate in 10 subjects is also shown to inhibit the fall in V.C. and F.E.V.(1) produced by the intravenous infusion of histamine. It is suggested that bronchial smooth muscle in asthmatic subjects has alpha-adrenergic receptor sites, and that a possible mechanism for the action of disodium cromoglycate is that it stabilizes the cell membrane, thereby altering calcium ion transport.