The effect on work performance of a single oral dose of the cardio-selective beta-adrenoreceptor blocking agent, metoprolol, was compared with an equipotent dose of the non-selective agent, propranolol, in the same subjects. A number of biochemical and physiological variables including heart rate, oxygen consumption, ventilation, lactate, free fatty acid and glucose levels were measured. Following exercise in the presence of both active drugs, subjects complained of excessive leg fatique. For the group there was a significant reduction in the total work performed and the maximum heart rate achieved on both drugs. There was a significant correlation between plasma levels of metoprolol, reduction in total work performed and reduction in maximum heart rate. By contrast, after propranolol, there was a wide variation in work performed at a time when the reduction in maximum heart rate was similar for all subjects. This suggests for propranolol that a reduction in heart rate alone is an inappropriate guide to the impairment of work performance. There was a fail in the circulating level of free fatty acids at the end of exercise in the presence of both drugs and it is possible that this biochemical variable contributed to the decrease in work performance.

IN a recent paper [Theobald, 1934] it has been shown that water diuresis may be inhibited in the dog by afferent nerve stimuli associated with acupuncture in the lumbar area. We propose first, through the description of three related experiments, to offer proof that the renal nerves play no essential part in such inhibition, and second, through a consideration of the results of these experiments with others of cognate interest, to suggest its underlying cause. EXPERIMENTAL WORK.A bitch, on which a plastic operation to expose the urethral orifice had been performed some weeks previously, was anaesthetized with a mixture of chloroform and ether, the anaesthesia being continued with ether alone. After the abdomen had been opened with full surgical precautions the left renal artery and vein were defined and freed completely from the surrounding tissues. The numerous nerve fibres lying on the artery were then cut and the vessel itself cleaned with gauze. After the vein and ureter had been similarly cleaned the kidney was lifted forward and separated from all fascial connection with the body. At this stage the renal artery was painted for a distance of about a half an inch with phenol. After the kidney had been sutured to its bed, the right kidney was treated in a similar manner. The abdomen was then closed and the animal returned to its kennel.Three weeks later it was placed in a Pavlov stand, and the observations recorded in Fig. 1 were made. At C 250 c.c. of warm tap water were given by stomach tube, and when the diuresis was becoming estab-

BRIuiSH 123 MEDICAL JOURNAL ,close quantitative agreement with those obtained with sodium chloride. The assay of such response to sodium chloride is illustrated in Fig. 5. The response to the intracarotid infusion (black circles) lies for most of its course between the responses to 0.67 (black-and- Secondly, the results of the 40-minute infusions demonstrate that the induced change in the osmotic pressure of the arterial blood which is responsible for this degree of reduction in urine flow itself causes the release of postpituitary antidiuretic substance at an average rate of I juU/sec. (0.5 x 10-9 g./sec. in terms of the standard powder), this being the intermediating agency through which the change in osmotic pressure becomes effective.Thirdly, the recovery of urine flow when the intracarotid infusion is stopped (Fig. 5) shows that the secretion of postpituitary antidiuretic substance is now inhibited by the local fall in osmotic pressure and consequent depression of activity in the osmoreceptors, the progression of this recovery being attributable to the gradual destruction in the kidney, anid maybe in the blood, of the quantity of anti--diuretic substance which was maintaining the secretion of urine at a non-diuretic level. The latent period between the peak of the water-load curve and the maximum rate of urine secretion, to which I referred earlier and promised to return, is clearly to be attributed to the same proCess.Water diuresis, then, is fitly and accurately described as a condition of physiological diabetes insipidus, and there can be little doubt that the antidiuretic secretion of the neurohypophysis is a hormone in the physiological sense that its liberation is mainly and continually governed by the contemporary concentration of sodium chloride in the carotid arterial plasma. The physiological fitness of this control is emphasized by its quantitative aspects, in tha' changes within the range and of the order of 1% in the osmotic pressure of the arterial blood lead, through the intermediation of the antidiuretic hormone, to changes in the rate of water excretion within the range and of the order of 1,O000%: the maintenance of near constancy in the osmotic pressure of the internal environment is thereby achieved. (1947) have recently advocated the use of small amounts of post-pituitary extract in cases of prolonged labour. Reid advocates starting with one minim (0.06 ml.) and increasing the dosage to not more than five minims '(0.3 ml.), whereas Eastman is more cautious and starts with a half-minim (0.03 ml.), and never gives more than one minim. Both authors consider it wise to confine this method of treatment to obstetrically normal primigravidae whose progress in labour is tedious.In 1931 Burn described a method of estimating the antidiuretic activity of post-pituitary extract by injecting it subcutaneously into a number of rats. This method was accurate within certain limits, but the subcutaneous route of injection introduced unknown, incalculable, and avoidable errors. Using the method desc...

THE complexity and the fundamental nature of the issues involved in the regulation of the water content of the body and its partition have convinced most workers of the need for postulating some central control, but a wide divergence of opinion obtains as to its nature. Molitor and Pick have advanced the hypothesis that the control is vested in a centre situated in the neighbourhood of other vegetative centres in the midbrain, which when stimulated by a fall in the water content of the blood, causes the tissues to liberate water into the blood. On the other hand, an excess of water in the blood is dealt with by the kidneys. They are not, however, decided as to whether the water centre effects its control by nervous or hormonal means. Like the other vegetative centres the water centre is under the inhibiting control of the cerebral cortex, and if this restraining influence is removed either surgically or by optimum doses of such narcotics as paraldehyde or chloralose, the centre becomes overactive and water diuresis is no longer inhibited by posterior pituitary extract. This extract, in their view, has no direct action on the kidneys or the renal circulation, but acts, either directly or through the water centre, on the tissues, enabling them to hold more water.This hypothesis is based almost entirely on experiments devised to investigate the anti-diuretic action of posterior pituitary extract. Molitor and Pick [1924] found that the inhibition of water diuresis caused by this extract could not be overcome either by vaso-dilator substances such as amyl nitrite, sodium nitrite, nitroglycerine or papaverine or by diuretics such as caffeine, theobromine or theocin. On the PH. LXXXI. 16

& Hoffmann (1931), that ultrafiltrates from the blood of eclamptic women contained what they claimed to be excessive amounts of posterior pituitary substance.Theobald (1934 a, b) found that minimal inhibition of the diuretic response of the dog to 250 ml., of man to 1 1. and of pregnant women near term to 500 ml. of water was effected by the intravenous injection of the antidiuretic hormone (ADH) normally associated in the commercial preparation used with from 0-0005 to 0-01 of an oxytocin unit. Impressed by the fact that such consistent antidiuretic effects were caused by a commercial preparation standardized for its oxytocic content, he conjectured (Theobald, 1936a) that menstruation, ovulation, pregnancy and parturition were controlled by a centre or centres in the hypothalamus probably situated in 'two cell masses, named the paraventricularis and the supraopticus'. He thought that labour might be instituted and delivery effected by an amount of oxytocin in the blood of the same order as that of ADH which caused antidiuresis, and calculated that it would be necessary to deliver intravenously from 1 to 5 m-u./min of a commercial preparation of oxytocin.A wide range of stimuli can cause simultaneous release of both oxytocin and ADH, and it is generally held that the former is invariably secreted in greater amounts than the latter, the reported ratios varying from 4: 1 to 100: 1; but there is no accepted evidence of their separate release