SUMMARY A multicentre study of survivors of an anterior myocardial infarction is reported. The trial consisted of 720 patients and was a double-blind, placebo-controlled study with propranolol 40 mg three times a day. Trial entry was at two to 14 days (mean 8-5 days) and follow-up at one, three, and in most centres, six and nine months. The trial was designed to detect a 50 per cent reduction in mortality and this was not shown. The non-fatal reinfarction rate was similar in both groups. Subgroup analysis identified several prognostic risk factors for death, none of which interacted with treatment.

The effect of conventional propranolol and bendrofluazide tablets given twice daily has been compared with an equivalent dosage combined in a single capsule given twice daily in fourteen patients with essential hypertension. Good blood pressure control was achieved on both regimes in the majority of patients and there was no significant difference in treatment response between the two regimes. Use of the combined capsule is convenient and may improve patient compliance.

Summary1. The rabbit isolated superior cervical ganglion preparation has been used to measure the release of acetylcholine from the tissue at rest and during preganglionic nerve stimulation. 2. In the presence of physostigmine, the resting release of acetylcholine was 0-13+0±01 (nmol/g)/min (10 experiments) and that during stimulation with 300 shocks at 10 Hz was 3-1 +0-4 (pmol/g)/volley in 4 experiments (means+ S.E.M.). The volley output was independent of the frequency of stimulation over the range 1 to 10 Hz but was higher at 0 3 Hz.3. Tetrodotoxin, 0-8 /jM, had no effect on the resting release of acetylcholine but reduced the stimulated release below detectable levels (2 pmol). Lowering the temperature of the bathing fluid to 5°C reduced to below detectable levels both the resting release and that produced by nerve stimulation. 4. The resting release of acetylcholine was increased by a potassium-rich (494 mm K+) bathing solution and by replacing the sodium chloride in the solution with lithium chloride (113 mM Li+).5. (-)-Noradrenaline bitartrate, 3 um, and (±)-adrenaline bitartrate, 1-5 /LM, reduced by 70% the output of acetylcholine induced by stimulation at 0 3 Hz, but failed to reduce the resting release or that evoked by stimulation at 10 Hz. The inhibition was reversed by phentolamine. 6. It is concluded that the rabbit superior cervical ganglion in vitro is a suitable preparation for studying transmitter release and that the ganglion blocking effect of catecholamines is due to a reduction in transmitter release.

In an attempt to clarify the rǒle of the sympathetic neurone in the antihypertensive action of propranolol, the effect of this drug on responses to lumbar sympathetic nerve stimulation has been studied in the perfused hind‐limb of the dog. No consistent reduction of maximal or submaximal responses to nerve stimulation was produced by propranolol (10 to 100 μg/kg). In contrast, potentiation of nerve‐evoked responses, as well as those to injected noradrenaline, usually occurred. Dexpropranolol (50 μg/kg) had no effect. When neuronal uptake of noradrenaline was inhibited by desmethylimipramine or cocaine, no reduction in responses to sympathetic nerve stimulation was observed with propranolol. No evidence was found, using α‐adrenoceptor blocking drugs, that released transmitter stimulates β‐adrenoceptors in the blood vessels of the hind‐limb. No evidence has been found for the existence of an adrenergic neurone‐blocking action of propranolol that might contribute to the antihypertensive activity in man.

The introduction of one or more methyl substituents into the structure of choline phenyl ether bromide (TMl) may result in large changes, both qualitative and quantitative, in pharmacological action. Thus, whereas choline o-tolyl ether bromide (o-Me-TM1), and a-methylcholine phenyl ether bromide (a-Me-TMI) are potent ganglion stimulants, being respectively one half and twice as active as choline phenyl ether (Hunt & Renshaw, 1936), choline 2,6-xylyl ether bromide (xylocholine) and /8-methylcholine phenyl ether bromide (P-Me-TMl) are devoid of ganglion stimulant activity (Hey, 1952;Clark & Jana, 1966), and xylocholine possesses adrenergic neurone blocking activity.An examination of molecular models of xylocholine and choline phenyl ether suggested that the difference in biological action might be steric in origin. Xylocholine is very sterically hindered, rotation about its phenyl-oxygen bond is virtually completely inhibited, and the plane containing the oxygen valencies is orthogonal to the plane of the benzene ring. In contrast choline phenyl ether is completely flexible and able to adopt different conformations in which the angle between the plane of the benzene ring and the plane containing the oxygen valencies (" angle-of-twist") varies between 00 and 900. p-Me-TMl lies between these two extremes; some degree of rotation about the phenyloxygen bond is possible but steric hindrance occurs between the o-hydrogens and the ,B-methyl group, and the "angle-of-twist" is always >00. a-Me-TMl and o-Me-TM 1 on the other hand can both adopt conformations in which the " angle-of-twist" about the aryl-oxygen bond is 00. It might be inferred from these observations on molecular models that for nicotine-like stimulant activity in choline aryl ethers it is necessary for the aryl ring, ether oxygen and P-methylene group of the choline moiety to lie in the same plane (that is, "angle-of-twist "= 0) when interacting with the nicotinic receptor and that for adrenergic neurone blocking activity the " angle-of-twist " needs to be 90°. The observation by Exley (1957) that o-Me-TM1 possesses adrenergic neurone blocking activity as well as ganglion stimulant activity could then be explained by assuming that the molecule adopts different conformations at the two different sites of action. In order