On the basis of a study of the activity of five sympathomimetic amines, Ahlquist in 1948 classified adrenoceptive receptors into two main types, which he designated alpha and beta. This classification has been vindicated by the development of drugs which specifically block the effects of stimulation of one type of receptor but not the other. Classical adrenergic blocking drugs such as phenoxybenzamine, dibenamine, phentolamine, tolazoline and dihydroergotamine block the effects of stimulation of alpha receptors but not beta receptors (Nickerson, 1949;Levy & Ahlquist, 1961 ;Moran & Perkins, 1961). These drugs are now described as adrenergic alpha receptor blocking agents. Recently several compounds have been described which block beta receptors but not alpha receptors. These, adrenergic beta receptor blocking agents, include dichloroisoprenaline (Powell & Slater, 1958) (Shanks, Wood, Dornhorst &Clark, 1966) and H 56/28 (Johnsson, Norrby, Solvell &Ablad, 1966). Structurally these compounds are closely related to each other and may be considered as derivatives of isoprenaline; in each case the side chain is identical with that of isoprenaline, or as in the last three compounds differs by the addition of an -OCH2 group. The blocking activity of these compounds is similar qualitatively, in that they block all beta receptors, but differs quantitatively. Another group of compounds, which block some but not all beta receptors, has recently emerged. These compounds include N-isopropylmethoxamine (Levy, 1964) which blocks beta receptors in the rat uterus; N tertiary butylmethoxamine (Levy, 1966a), and dimethyl isopropylmethoxamine (Levy, 1966b) which block beta receptors in the rat uterus, canine intestine and peripheral blood vessels. None of these compounds blocks the cardiac inotropic or chronotropic actions of catecholamines. Structurally these compounds are characterized by having a methyl group attached to the alpha carbon atom of the side chain. These observations suggest that beta receptors are not a homogenous group and may be capable of division into sub-groups. This hypothesis is further substantiated by the present paper in which

The intravenous infusion of I.C.I. 50172 in doses up to 20 mg reduced, although not significantly, the increase in heart rate produced by the infusion of isoprenaline in healthy volunteers; the response to adrenaline was significantly reduced. The infusion of 1 mg propranolol abolished these responses After the pre‐treatment of subjects with atropine or hexamethonium, I.C.T. 50172 produced a significant reduction in an isoprenaline tachycardia. This reduction was not competitive and did not exceed 50%. The intravenous injection of 4 mg I.C.I. 50172 reduced an exercise tachycardia; its effect was less than that of 4 mg propranolol. This difference became greater as the doses of the two drugs were increased. The dextro isomer of propranolol had no effect on the exercise tachycardia; I.C.I. 45763 reduced it to the same extent as propranolol. The intravenous injection of I.C.I. 50172 reduced the increase in heart rate produced by tilting a normal subject from the supine to 80° head‐up position. After the administration of atropine, I.C.I. 50172 almost abolished the response. In the presence of atropine, I.C.I. 50172 was as active as propranolol in reducing the increase in heart rate on tilting. The reason for the differences in the effects of I.C.I. 50172 on the increases in heart rate brought about by the three procedures is not clear. The increase in forearm blood flow produced by the infusion of isoprenaline into the brachial artery was not reduced by the intra‐arterial administration of I.C.I. 50172.

ICI 118,551, 5 to 80 mg orally, did not significantly alter resting heart rate or blood pressure. In doses less than 40 mg the reduction in exercise tachycardia was under 10 beats/min. ICI 118,551, 10 to 40 mg, did not appear to reduce the maximum rise in systolic pressure with isoprenaline but did attenuate the changes in diastolic pressure, forearm blood flow and finger tremor. It also attenuated the isoprenaline‐induced changes in serum glucose, insulin and potassium. On these observed changes, the effect of ICI 118,551 20 mg was similar to that of 40 mg and of propranolol 10 mg, but greater than that of atenolol 25 mg. An isoprenaline tachycardia was attenuated by all doses of ICI 118,551 studied. After atropine (0.04 mg/kg) ICI 118,551 20 mg still significantly reduced the effects of isoprenaline suggesting that functional beta 2‐adrenoceptors may be present in the human heart. In doses less than 40 mg, ICI 118,551 appears to be a selective and competitive antagonist of beta 2‐adrenoceptors in man.

1Mexiletine was given to 156 patients by intravenous or oral routes of administration. 2 There was great interpatient variation in kinetics and plasma concentrations with both routes of administration. 3 The mean volume of distribution was 6.63 1/kg. The mean plasma elimination half-life after chronic oral therapy was 11.31 h.4 Plasma concentrations between 0.75 and 2.00 gg/ml were usually effective. Within this therapeutic range severe side effects were uncommon. 5Plasma concentrations within this range were achieved in 72% of patients when doses of 10-14 mg-' kg-l day were given orally.

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