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.

No abstract

1 Plasma levels of propranolol were measured at intervals after the oral administration of 160 mg propranolol and 160 mg L.A. propranolol in ten subjects who received both drugs on separate occasions.2 Mean peak plasma concentration of propranolol occurred 2 h after propranolol and 10 h after the L.A. formulation; the peak concentration with the former was four times that with the latter. At 24 h the plasma level was significantly higher after L.A. propranolol. 3 Observations were made in nine healthy volunteers who exercised before and at intervals after the oral administration of 160 mg propranolol and 160 mg L.A. propranolol.4 Propranolol produced a maximum reduction (27.84 + 2.4%) in the exercise tachycardia at 3 h and L.A. propranolol a maximum reduction (22.00 + 1.73%) at 6 h. The effects at 24 h were 9.24 + 1.55 and 16.79 + 2.16% respectively.5 Five subjects were given 160 mg propranolol as a single dose daily for 8 days and on a separate occasion similar treatment with L.A. propranolol. Subjects were exercised and blood samples were taken before and 3 h after each dose on days 1 to 5 and on day 8. propranolol were 12.5 to 17.5 (trough values) and 18.4 to 50.0 (peak values) ng/ml. 8 These observations show that the new long acting formulation of propranolol produces a significant reduction of an exercise tachycardia throughout a 24 h period without a very high initial effect during single and multiple dosing. This formulation should be suitable for once a day administration.

No abstract

The mechanism causing renal vascular flow to vary less than proportional to changes in arterial-venous pressure gradient, was studied in isolated dog kidneys perfused with whole blood and with cell-free colloidal solutions. This autoregulation of renal flow rapidly deteriorated along with vascular reactivity to drugs when oxygenated polyvinyl-pyrrolidone-Locke solution was used for perfusion. This deterioration was prevented by the addition of plasma to the colloidal perfusate. During the first 2 seconds of suddenly raised arterial pressure, renal flow normally increased proportionately or slightly more than proportionately to the increase in arterial pressure; intrarenal venous pressure, needle tissue pressure and kidney weight rose simultaneously. During the next 4 seconds, increasing vascular resistance upstream from the intrarenal veins caused parallel reductions in renal flow, intrarenal venous pressure, needle tissue pressure and at times kidney weight. After brief rhythmical changes in prevenous segmental resistance, flow became steady to show intense autoregulation, while intrarenal venous pressure and needle tissue pressure remained relatively low. This genuine autoregulation of renal flow was abolished by cooling kidneys to 3 to 10 C, and by treatment with chloral hydrate and with procaine in concentrations rendering the smooth muscle of the renal blood vessels relatively inert to direct drug stimulants. On the other hand, at temperatures of 3 to 10 C., and usually with chloral hydrate treatment, a factitious and passive type of flow autoregulation was observed, caused by the effects of abnormally high tissue pressures. Renal flow autoregulation was not appreciably impaired by anesthetization of the intrarenal nerves by procaine in concentrations which did not simultaneously depress vascular smooth muscle reactivity. Yohimbine induced sympatholysis did not impair autoregulation, and Dibenzyline treatment to intrarenal sympatholysis depressed only slightly autoregulation of renal flow. It was not inhibited by γ-aminobutyric acid. Anoxic perfusion which did not appreciably depress the reactivity of intrarenal autonomic ganglia, impaired autoregulation moderately. The loss of autoregulation of renal flow, accompanied by vasoconstriction following severe hemorrhage in the kidney donor dog, was slowly reversible upon perfusion of the subsequently isolated kidney and was related to smooth muscle contracture within the arterial-arteriolar vasculature. It is concluded, that myogenic vasomotion in the renal arterial-arteriolar tree in response to the level of transmural vascular pressure is the fundamental cause of genuine renal circulatory autoregulation. It is furthermore suggested that the myocytes of the juxtaglomerular apparatus may act as myogenic pacemakers in the vasomotion responsible for the essentially perfect autoregulation of the normal kidney.