Showing papers in "Clinical Science in 1971"

Leg Blood Flow during Exercise in Man

Abstract: 1. An indicator-dilution technique was used to determine human leg blood flow at rest and during exercise. The method is based on the infusion of Indocyanine Green into the femoral artery with blood sampling from the femoral vein at the level of the inguinal ligament. Evidence for mixing of dye and blood is presented, based on the finding of equal dye concentrations at two different sampling levels in the femoral vein. The minimum time of infusion required for equilibration at rest is 3 min and during exercise 1 min 20 s. 2. Leg blood flow was measured in eight healthy athletic subjects at rest and during upright exercise on a bicycle ergometer at 400, 800 and 1200 kpm/min. Linear relationships were found between blood flow on the one hand and work intensity and pulmonary oxygen uptake on the other. 3. Leg oxygen uptake was measured as the product of blood flow and femoral arterio-venous oxygen difference. Linear regressions were found for leg oxygen uptake in relation to both work intensity and pulmonary oxygen uptake. Leg mechanical efficiency during exercise averaged 34%. 4. A formula for the approximate calculation of leg blood flow is suggested, based on the pulmonary oxygen uptake and the femoral arterio-venous oxygen difference.

The Haemodynamic Consequences of Adaptive Structural Changes of the Resistance Vessels in Hypertension

Abstract: It is generally accepted that a rise in systemic flow resistance constitutes the essential background of the increased arterial blood pressure in well-established hypertension, though the early ‘labile’ phases of essential hypertension in particular may exhibit a pattern simulating a moderately intense defence reaction, with enhanced cardiac output and muscle blood flow as the most characteristic features, apart from the rise in blood pressure. With respect to the increased flow resistance in the well-established phase, it is accepted that the vessels respond readily, and apparently normally, to vasodilator substances, from which the correct conclusion has been drawn that the resistance increase cannot be ascribed to any sclerotic narrowing of the resistance vessels (Pickering, 1968). However, this observation has also generally led to the assumption that an increased smooth-muscle tone of the resistance vessels must be the explanation of the increased flow resistance and, despite the fact that there are numerous reports of medial hypertrophy in the precapillary resistance vessels for instance (Pickering, 1968), the possible haemodynamic consequences of such a type of structural vascular adaptation has hardly been considered at all. Instead the debate has mainly been concerned about whether the assumed increase of vascular tone is due to enhanced myogenic activity, to an increased neurogenic and/or hormonal exogenous stimulation of the vascular smooth muscles or whether these muscles might exhibit an enhanced sensitivity or ‘reactivity’ to such extrinsic stimuli. In other words, if summarized in a diagram relating the extent of active smooth-muscle shortening to the degree of resistance increase in an idealized resistance vessel (Fig. 1), an increased smooth muscle activity, whatever its background, would mean a shift from the normal resting equilibrium at point O to a point B along the curve N. However, one cannot safely deduce levels of vascular smooth-muscle activity between different individuals, or vascular beds, by simply assuming that they are proportional to the respective levels of current flow resistance. In each individual, or vascular bed, one must first relate the actual resistance level to that present when the vascular smooth muscles are completely inactive; i.e. when the resistance vessels are maximally dilated and exposed to the same amount of distending pressure. This latter resistance value provides the necessary ‘baseline’, or an equivalent of fully relaxed muscle length for a particular vascular bed, from which its current level of smooth muscle activity has to be judged in terms of the ratio between these two resistance values. This is simple and straightforward reasoning, but surprisingly enough studies along these lines were apparently not performed systematically until our group used this approach in analyses of the level of ‘basal tone’ in different vascular beds or individuals (Celander & Folkow, 1953; Lofving & Mellander, 1956; Folkow, 1956).

Cardio-respiratory response to exercise in normal children.

Abstract: 1. The results of studies during simple progressive exercise to exhaustion and steady-state submaximal exercise in 117 boys and girls aged 6–16 years are presented. 2. In the simple progressive exercise test, the highest work load achieved and the submaximal heart rate were related to size and sex. The maximum heart rate and submaximal ventilation were largely independent of size and sex. 3. Steady-state exercise was performed at one-third and two-thirds of the maximum work load achieved in the simple progressive test. The Indirect (CO 2 ) Fick method was used to measure cardiac output. 4. At any given level of steady-state work, tidal volume, dead space, heart rate and stroke volume were closely related to size, with girls having higher heart rates and smaller stroke volumes than boys. Minute ventilation and cardiac output were virtually independent of size and sex. The cardiac output in children was the same as that in the adult for any given oxygen consumption. Blood lactate was related to size at any given work load, but was independent of size at any given fraction of the maximum working capacity.

The metabolism of isotopically labelled vitamin D3 in man: the influence of the state of vitamin D nutrition.

Abstract: SUMMARY 1. The metabolism of radioactive vitamin D, has been studied in individuals low or deficient in vitamin D (group I) and in vitamin D treated subjects (group 11). 2. In group I there was a smaller serum pool of vitamin D, turning over more rapidly than in group 11. The principal metabolite, peak IV, appeared more rapidly in the serum of group I; the level of radioactivity attained in this and in the more polar metabolites, peak V and VI, was also higher than in group 11. Peak VI was the major radioactive component in serum after 100 days. 3. Vitamin D treatment of individuals in group I converted the pattern of metabolism of radioactive vitamin D, to that characteristic of group 11. This effect was observed in healthy individuals and in patients with vitamin D deficiency or with chronic renal failure. 4. The metabolic disposal of vitaminD entering the body appears to be determined by the state of vitamin D nutrition in the individual. Reported changes of vitamin D metabolism in diseases such as renal failure could be determined by the nutritional state of the patients studied rather than by the primary disease. The metabolism in man of a test dose of isotopically labelled vitamin D has been studied by several groups of workers during the last few years. Administration of the radioactive vitamin was either by mouth (Thompson, Lewis & Booth, 1966; Avioli, Birge, Lee & Slatopolsky, 1968) or by intravenous injection (Avioli, Lee, McDonald, Lund & Deluca, 1967a; Mawer & Stanbury, 1968). The methods have involved serial sampling of serum after administration of the test dose with subsequent measurement of the radioactivity due to vitamin D and its metabolites. Separation of metabolites has been achieved on silicic acid columns; more components have been resolved as techniques have been refined (Haussler, Myrtle & Norman, 1968; Mawer & Backhouse, 1969; Ponchon & DeLuca, 1969).

Calcium oxalate crystalluria and urine saturation in recurrent renal stone-formers.

Abstract: 1. The degree of saturation with calcium oxalate has been determined in fresh urine samples from six patients with recurrent calcium oxalate-containing renal stones and six normal control subjects who were studied under the same conditions of diet and fluid intake. 2. The degree of saturation of urine with calcium oxalate was significantly higher in the group of stone-formers than in the control series and more often exceeded the amount needed for spontaneous crystallization of calcium oxalate (formation product). This was accounted for by the higher concentration of calcium and oxalate in the urine of the stone-formers. 3. Crystals of calcium oxalate were observed in all freshly examined urines in which the formation product of calcium oxalate was exceeded. Since the formation product of calcium oxalate was exceeded more often in the urines of stone-formers than in the urines of the control subjects, this accounted for the greater calcium oxalate crystalluria of the stone-formers. 4. Addition of a small quantity of sodium oxalate to the basal diets of the two groups resulted in a greater increase in the urine saturation and calcium oxalate crystalluria of the stone-formers, thus accentuating the difference observed between the two groups when they were given the basal diet. 5. Calcium oxalate crystalluria was related quantitatively to the degree of over-saturation of urine with calcium oxalate, although uric acid solubility may play a small role at low pH values. 6. The results are consistent with a ‘hyperexcretion—crystallization’ mechanism of stone formation.

Studies on the mechanism of hypernatriuresis in essential hypertension in relation to measurements of plasma renin concentration, body fluid compartments and renal function.

Abstract: SUMMARY 1. In twenty-two patients representing different stages of benign essential hyper­ tension, hyperosmotic saline was administered intravenously. Determinations of intra-arterial pressure, renal plasma flow, glomerular filtration rate and plasma renin concentration were carried out before and, in the majority, also during and after saline infusion. Changes in cardiac output were followed in ten patients. Plasma volume and extracellular volume were determined in the control period only, although haemodilution was assessed by haematocrit readings. 2. Excess ofsodiumexcretion showeda wide range andwas related to thepatient's age, as well as to a set ofparameters reflecting intrarenal pressure patterns; hypernatriuresis consistently occurred in older patients, in whom renal vascular resistance and filtration fraction were elevated and plasmarenin was suppressed. Itcould not be clarified whether hypernatriuresis togetherwithreninsuppressionwere determined by intrarenal pressure relationships or by an independent age-related factor in the hypertensive patient. 3. Excess of sodium excretion was not related to increments in arterial pressure, cardiac output, renal blood flow or glomerular filtration rate. 4. Plasma renin concentration failed to show consistent changes after hyperosmotic saline infusion. 5. It is concluded that natriuresis is not mediated by changes in the activity of the renin-angiotensin system. Hypernatriuresis appears to be a feature of progressive benign hypertension. Patients with uncomplicated essential hypertension characteristically respond to volume expansion by excreting salt in a more abrupt way than normal subjects (Farnsworth, 1946; Birchall, Tuthill, Jacobs, Trautman & Findley, 1953; Hollander & Judson, 1957; Baldwin, Biggs, Goldring, Hulet & Chasis, 1958; Cottier, Weller & Hoobler, 1958a, b; Hanenson, Taus­ sky, Polasky, Ransohoff & Miller, 1959; Cottier, 1960; Ulrych, Hofman & Hejl, 1964; Cannon, 1968; Buchalew, Puschett, Kintzel & Goldberg, 1969). Correspondence: Dr W. H. Birkenhllger, Zuiderziekenhuis, Groeneveld 15, Rotterdam, Netherlands. 219

Human glomerular membrane porosity and filtration pressure: dextran clearance data analysed by theoretical models.

Abstract: 1. The renal clearance of dextran of different molecular sizes has been measured in normal humans from 6 days to 61 years of age. Gel chromatography of dextran has been used for determination of molecular weight distribution. 2. Information about the functional ultrastructure of the glomerular membrane has been deduced from the experimental clearance data in the light of theoretical models. The glomerular membrane was here visualized as a gel filter, localized in the basement membrane. The physical analogue of this membrane was interpreted as a somewhat heteroporous structure of quite well defined pore sizes: one system of smaller pores in the range of 20–28 A radius and an additional system of larger pores of radii up to 80 A. These larger pores are quite few in number with an approximate ratio of one large pore per 10 000 small pores. 3. The values obtained for the transglomerular pressure difference were low, about 1 cm of water or less. This supports the concept that tubular reabsorption may be the rate limiting factor in the process of urine formation and may also control the glomerular filtration rate. 4. The changes of the dextran clearance with ageing found in this investigation may be explained by an increase of the pore radii of the glomerular membrane and a concomitant decrease of the transglomerular pressure difference.

Depression of delta-aminolaevulic acid dehydrase activity by ethanol in man and rat.

Abstract: 1.β-Aminolaevulic acid (ALA) dehydrase activity has been measured in the blood of man and rats and in the tissues of rats intoxicated with ethanol. 2. ALA dehydrase activity was significantly depressed in the blood of man. This depression follows closely on the elevation of blood ethanol and returns to normal pari passu with the ethanol level. 3. In rats intoxicated with ethanol there is a significant depression of ALA dehydrase activity in blood, liver and kidney but not in heart or spleen. 4. A scheme is proposed whereby an increase in the intracellular redox potential by ethanol increases sulphydryl cofactor concentrations leading to an inhibition of enzyme activity.

The ability of man to detect added resistive loads to breathing

Abstract: 1. Resistive loads were added to the airways of patients with tracheostomies; the patients were blindfolded and the loads introduced without their knowledge. 2. The ability to detect the loads was the same in a patient with C3 transection (chest wall and diaphragm disconnected from the brain) as in a control group of patients with no neurological lesion. 3. It is concluded that receptors in the chest wall and diaphragm are not involved in the genesis of the sensation by which added resistive loads are detected.

Patterns of ventilatory response to carbon dioxide during recovery from severe asthma.

Abstract: SUMMARY i. Ventilatory response to CO 2 was measured regularly by a rebreathing technique in nineteen patients with severe asthma from the day of presentation to the time of clinical recovery. 2. Ventilatory response to CO 2 increased during recovery in sixteen patients and the increased ventilatory response correlated well with increase ofFEVr- Amongthese sixteen patients only one showed elevation of arterial CO 2 tension at the time of presentation. 3. Ventilatory response to CO2 failed to increase during recovery in three patients despite increasesin FEVr- All three patients showed elevation of arterial CO 2 tension at the time. of presentation. 4. In five patients (including three of the four with initial hypercapnia) ventilatory response to CO2 after recovery remained below the previously reported lower limit for normal subjects. The limits of normality were explored by examining ventilatory response to CO 2 in seventeen outstanding athletic performers. Values for ventilatory response to CO 2 both above and below the previously defined 'normal range' were found. The normal ventilatory response to CO2 covers a 14-fold range from 0'57 to 8'171 min"" mmfIg"! Pco2 • It is well known that ventilatory response to inhaled CO 2 is impaired in patients with chronic obstructive airways disease. Less is known of the patterns of ventilatory response to CO 2 when the airways obstruction is both acute and reversible. Read (1967) developed a 4 min rebreathing test suitable for serial studies of ventilatory response to CO 2 in sick patients. In the present study this rebreathing method has been used to study ventilatory response to CO2 in patients recovering from attacks of severe asthma. Each patient was studied day by day during the course of clinical recovery so that, as airways obstruction lessened, each patient served as his own control. The range of ventilatory response to CO2 in normal subjects was also further explored.

Hormones released into the circulation when the urinary bladder of the anaesthetized dog is distended

Abstract: 1. In anaesthetized dogs urinary bladder distension caused variable changes of mean blood pressure; these were unaffected by vagotomy. 2. Catecholamines were detected in the circulation during bladder distension in fourteen of seventeen dogs. The catecholamine concentration during bladder distension was greater after cervical vagotomy. 3. Vasopressin could not be detected in the blood during urinary bladder distension before or after section of the cervical vagus nerves. Cervical vagotomy itself resulted in a. transient release of vasopressin. 4. A prostaglandin-like material was sometimes detected in the circulation during or immediately after urinary bladder distension. The origin of this material was not determined; it was detected in arterial and venous blood. 5. Urine flow consistently decreased during urinary bladder distension. This decrease was due neither to circulating catecholamines nor to vasopressin; it was probably caused by renal sympathetic activity. Cervical vagotomy did not abolish the antidiuresis.

The reflex stimulation of catecholamine secretion during the acute stage of myocardial infarction in the dog.

Abstract: 1. The mechanism of catecholamine secretion after coronary occlusion was investigated in open-chest, anaesthetized dogs; the blood-bathed organ technique was used for continuous measurement of the changes in concentration of circulating catecholamines. 2. In dogs with increased output of adrenaline during the first hour after acute coronary occlusion, topical application of lignocaine to the infarcted area of the heart, spinal block at C 1 , bilateral section of thoracic splanchnic nerves, or ganglionic blockade virtually abolished adrenaline secretion. 3. Adrenaline secretion was abolished by bilateral vagotomy in 50% of the dogs, decreased in 28% and unchanged in the remaining 22%. Bretylium or guanethidine had no effect on adrenaline secretion in the early stages of myocardial infarction. 4. Seventeen of nineteen reserpinized dogs failed to secrete catecholamines during the first hour of coronary occlusion, even though the adrenal medulla responded to bradykinin, acetylcholine or nicotine. Noradrenaline infused either into the unoccluded carotid artery or intravenously restored adrenal medullary secretion. 5. When a sustained noradrenaline release occurred after coronary ligation, it was abolished by topical application of lignocaine to the ischaemic area of the heart or by ganglionic blockade. Neither bilateral vagotomy nor section of both thoracic splanchnic nerves suppressed noradrenaline liberation. 6. It is concluded that the adrenal medullary secretion of adrenaline which occurs in the early stages of myocardial infarction in the dog is induced reflexly from stimulation of cardiac receptors at the site and the boundary of the infarct. The reflex involves vagal as well as extra-vagal pathways and supraspinal structures. Enhanced liberation of noradrenaline in the early stage of infarction may reflect release from postganglionic sympathetic nerve endings in the heart.

The renal clearance of oxalate in normal subjects and patients with primary hyperoxaluria.

Abstract: SUMMARY 1. The renal clearance of oxalate was studied in six normal subjects and in two patients with primary hyperoxaluria utilizing a constant infusion of [14C]oxalic acid. 2. The [14C]oxalate clearance in normal subjects was between 101 and 217 ml/min with a range in the ratio ofp4C]oxalate clearance to creatinine clearance of 1,33-2,09. 3. The oxalate clearance in two patients with primary hyperoxaluria was within the range found in the normal subjects. 4. This study does not confirm the previous report of a low oxalate/creatinine clearance ratio in man nor the finding of an elevated oxalate clearance in patients with primary hyperoxaluria. 5. Estimates of serum oxalate concentration based on these clearance values suggest that the serum oxalate concentration in normal subjects is less than 100 jlg/loo ml. The diagnosis and pathogenesis of primary hyperoxaluria has been well delineated in several laboratories (Hockaday, Clayton, Frederick & Smith, 1964; Williams & Smith, 1968a, b; Wyngaarden & Elder, 1966; Hodgkinson & Zarembski, 1968). Despite these extensive investigations relatively little information is available about the renal clearance of oxalate in man. Cattell, Spencer, Taylor & Watts (1962) found that the renal clearance of infused sodium [14C]oxalate was 68 ml/min in the dog (mean of twenty-five observations on six dogs) with average ratio of oxalate clearance to inulin clearance and/or exogenous creatinine clearance of 1·28. In contrast with these studies Zarembski & Hodgkinson (1963) using a fluorimetric method for the determination of oxalate found that oxalate clear­ ance in normal subjects varied between 3'4 and 5'0 nil/min. In addition they noted an elevated renal clearance of oxalate in seven patients with primary hyperoxaluria. These discrepant results suggested a difference between the renal handling of oxalate in man and in the dog. We have infused p4C]oxalic acid, and determined the renal clearance of[ 14C]oxalate in normal

Mechanisms of dipeptide uptake by rat small intestine in vitro.

Abstract: 1. The uptake of l-methionine and glycine as free amino acids, and from their dipeptides by everted rings of rat small intestine in vitro has been investigated. The concentrations used covered a wide range, including values likely to be near those found in the lumen of the intestine. 2. Though no intact peptides were found in the mucosal cells, evidence was obtained which showed that hydrolysis of the peptides was cellular at all concentrations. Total hydrolysis of peptides by the intestine was very great in relation to amino acid uptake over very short incubation times, suggesting that much hydrolysis took place superficially. 3. Except at the lowest concentrations, the rates of uptake of amino acids from the peptides were more rapid than from the equivalent amino acid mixtures. Competition for uptake between glycine and methionine was avoided when they were presented in the form of l-methionylglycine. 4. Anoxia inhibited uptake of methionine from free l-methionine and from l-methionyl-l-methionine. It also inhibited hydrolysis of l-methionyl-l-methionine by intact intestine, but not by intestinal homogenates, suggesting that peptide uptake may be energy-dependent. The l-amino acid oxidase of snake venom, which destroys l-methionine but has no effect on glycine or on the peptides studied, inhibited methionine uptake from peptides when present at high concentrations, suggesting that a major site of hydrolysis is enzyme-accessible. 5. It is suggested that there may be two modes of uptake of amino acids from oligopeptides: (1) surface hydrolysis by mechanisms closely linked to the amino acid entry mechanisms, and (2) peptide entry into the mucosal cells by a special mechanism, followed by intracellular hydrolysis.

Lung mechanics during provocation of asthma.

Abstract: 1. The mechanical properties of the lungs of five symptom-free asthmatic subjects and two normal subjects were measured before and during provocation with nebulized methacholine. 2. Before provocation abnormalities of some aspects of the mechanical function of the lungs were found in four of the asthmatic subjects. 3. Pulmonary resistance increased within one breath of the methacholine inhalation and was the measurement of lung function which changed most in response to methacholine in both asthmatic and normal subjects. However, asthmatic subjects had a much greater response than normal subjects. 4. The results of the study suggest that both the large and the small airways respond to provocation with methacholine. The larger airways appear to respond faster than the smaller airways and the response of the smaller airways appears to be more prolonged.

Drug interactions with warfarin: studies with dichloralphenazone, chloral hydrate and phenazone (antipyrine).

Abstract: 1. Administration of dichloralphenazone, a complex of chloral hydrate and phenazone (antipyrine) caused a fall in steady-state plasma warfarin concentration and loss of anticoagulant control in five subjects. 2. This effect of dichloralphenazone is due to stimulation of the drug-oxidizing enzymes of the liver endoplasmic reticulum by antipyrine, the non-hypnotic part of the complex. Administration of antipyrine caused a fall in steady-state plasma warfarin concentration in five subjects, a shortening of the plasma warfarin half-life, with increased urinary excretion of the metabolites of 14 C-labelled warfarin in two subjects and increased urinary excretion of 6β-hydroxycortisol which is formed in the liver endoplasmic reticulum. 3. Administration of chloral hydrate, the hypnotic part of dichloralphenazone, caused no change in anticoagulant control but a fall in steady-state plasma warfarin concentration in five subjects. This is due to the accumulation of trichloroacetic acid which displaces warfarin from plasma protein binding sites. 4. Individual differences in the extent of enzyme induction have been shown to be related to the subjects9 rates of drug oxidation. 5. In the rat administration of dichloralphenazone and antipyrine, but not chloral hydrate, caused shortening of pentobarbitone sleeping time and of the plasma [ 14 C]pentobarbitone half-life, shortening of the zoxazolamine paralysis time and increase in the maximal velocity of N -demethylation of ethylmorphine.

Serum protein changes after injury.

Abstract: 1. By means of a quantitative immunoelectrophoretic technique, serum protein changes have been followed in seven patients before and during the week following inguinal herniorrhaphy, and in a single case of influenza. 2. The twenty proteins studied are grouped according to whether they rise (orosomucoid, α1-antitrypsin, Gc-globulin, caeruloplasmin, haptoglobin, β1A–C-globulin and proteins numbered 45, 99, 101 and X); fall (pre-albumin, α2HS-glycoprotein and protein No. 9); or show no significant change (α2-macroglobulin, haemopexin). α1-Lipoprotein fell in the case of influenza but did not change in the hernia patients; α1-easily-precipitable-glycoprotein increased in the hernia cases only. 3. The nature of the ‘acute phase reaction’ and the factors which elicit it are discussed.

The intramedullary connections of the area postrema involved in the central cardiovascular response to angiotensin ii

Abstract: SUMMARY 1. The intramedullary connections of the area postrema involved in the central cardiovascular response to angiotensin were studied in the chloralose-anaesthetized greyhound. 2. In the intact animal the response to vertebral arterial infusions of angiotensin (32 ng/min for 5 min) was decreased by unilateral ablation of the area postrema suggesting that both areas postrema contribute to this response. 3. In the animal in which both vagiwere blocked by cooling, the residual sympatheti­ cally mediated pressor response was unmodified by unilateral ablation of the area postrema suggesting that each area postrema can mediate the central sympathetic component of the response to angiotensin. 4. In the animal in which one vagus only had been blocked, unilateral ablation of the area postrema, irrespective of side, did not abolish the central cardiovascular response to angiotensin demonstrating that each area postrema can influence both vagi. 5. Midcollicular transection of the midbrain did not significantly alter the response to vertebral arterial infusions of angiotensin. This demonstrated that the central cardio­ vascular response to angiotensin is not dependent on connections with centres above the midbrain. 6. These results are consistent with the concept that the angiotensin-area postrema system is a neuro-humoral vasomotor centre afferent pathway. There is much evidence that angiotensin has a direct constrictor effect on arterioles (Bumpus, Schwartz & Page, 1957, 1958; Page & Bumpus, 1961; Peart, 1965) but other, autonomic, sites of action have been demonstrated including the adrenal medulla (Feldberg & Lewis, 1964), the autonomic ganglia (Lewis & Reit, 1965), the post-ganglionic nerve terminals

Rates of absorption by rat intestine of pancreatic hydrolysates of proteins and their corresponding amino acid mixtures.

Abstract: 1. Though the occurrence of intestinal mucosal uptake of intact peptides, with cellular hydrolysis to amino acids, has been established, the importance of this mode of absorption in protein absorption is not known. This paper describes a comparison of the rates of intestinal absorption of pancreatic hydrolysates of four proteins with those of the corresponding acid hydrolysates or amino acid mixtures. 2. The results show that the absorption of pancreatic hydrolysates, consisting largely of small peptides of two to six amino acid residues, is substantially more rapid than that of the corresponding mixtures of free amino acids. This shows that the small intestine has a high capacity for absorption from mixtures of small peptides such as might be produced during protein digestion, and supports the hypothesis that mucosal uptake of intact oligopeptides is an important mode of protein absorption.

Diuretics in chronic renal disease: a study of high dosage frusemide.

Abstract: SUMMARY 1. The efficacy and mode of action of frusemide (100-750 mg) have been studied acutely in thirty-four investigations on twenty-four water-loaded subjects with stable, non-oedematous chronic renal disease (GFR 2,3-26'0 ml/min) of varying aetiology (fourteen 'tubular', ten 'glomerular'). 2. Water loading alone resulted in a slight increase in urine flow rate, a flow­ dependent rise in electrolyte excretion and a small fall in urine osmolality. 3. Basal fractional excretion of fluid and electrolytes was closely related to GFR, increasing as this fell, so that at a GFR of 3·0 ml/min 80% of the fluid filtered, 50­ 60% ofthe filtered load of sodium and chloride and 400% of potassium was excreted. 4. After oral or intravenous frusemide, up to 93% of the filtered load of chloride, 87% of sodium and apparently all of the glomerular filtrate could be excreted; the magnitude ofthe response depended on dose, GFR and basal fractional sodium excre­ tion, being greatest at higher GFR and lowest fractional excretion. Free water clearance increased. 5. No significant change in inulin clearance was found after frusemide and no differ­ ence in the response of 'tubular' as opposed to 'glomerular' subjects. 6. Long-term treatment of nineteen patients with 'resistant' oedema and chronic renal disease has shown high dosage frusemide (0,12-2,0 gJday) to be an effective diuretic, although significant side effects were found in five patients.

The effect of changes in lactate uptake on the intracellular pH of the perfused rat liver.

Abstract: 1. Mean intracellular pH (pH i ) and lactate have been measured simultaneously in the isolated perfused rat liver on two successive occasions separated by an interval of 20 min. In some experiments extra lactate was added to the perfusion medium immediately after the first measurement of pH i . 2. There was a direct relationship between the change in pH i over this interval and the simultaneous change of lactate uptake. 3. This finding is consistent with the hypothesis that lactate enters the liver cell at least partly in the ionized form and that its metabolism is accompanied by the effective production of hydroxyl ions. 4. These observations are discussed in terms of a possible control mechanism for lactate uptake by the liver.

Plasma renin in idiopathic orthostatic hypotension: differential response in subjects with probable afferent and efferent autonomic failure.

Abstract: 1. The changes of peripheral venous plasma renin concentration (PRC) induced by head-up tilting were studied in four patients with orthostatic hypotension. 2. Two of the patients had the Holmes—Adie syndrome and tests of autonomic function suggested that they had an afferent block from baroreceptors with intact efferent pathways; the others had no evidence of the Holmes—Adie syndrome and investigations suggested that they had interruption of efferent sympathetic pathways. 3. In the two patients in whom lesions of the afferent side of baroreceptor reflexes were suspected, a marked increase in PRC occurred with upright tilting, whereas no change in PRC occurred in the two patients thought to have an efferent sympathetic block. 4. During repeated tilting, supine blood pressure and PRC increased progressively in the two patients with suspected afferent block, but not in the two patients with suspected efferent block. 5. It is suggested that an increase in plasma renin may contribute to the supine hypertension sometimes observed in patients with orthostatic hypotension. 6. It is also suggested that renin release does not require intact autonomic reflexes although certain components of efferent sympathetic pathways, not dependent on baroreceptor reflexes, may be important.

Abnormal excretion of the isomers of urinary coproporphyrin by patients with Dubin-Johnson syndrome in Israel.

Abstract: 1. The urinary excretion of isomers I and III of coproporphyrin by fifty-nine patients with Dubin—Johnson syndrome has been examined, and compared with the results obtained for normal control subjects and patients with various types of jaundice. 2. The control subjects (with one exception) excreted less than 45% of the coproporphyrin as isomer I. Fifty-six patients with the Dubin—Johnson syndrome excreted more than 65% isomer I (mode, 87%). In three cases the relative content of isomer I was normal. These exceptional patients differed also in some other characteristics from typical cases of the Dubin—Johnson syndrome. 3. Patients with obstructive jaundice or infectious hepatitis showed an intermediate pattern of the isomer distribution. In Gilbert9s disease the isomer pattern was normal (six cases). In Rotor syndrome the relative content of isomer I was increased (three cases). 4. The abnormal urinary excretion of coproporphyrins in the various types of jaundice is probably caused by different mechanisms. In obstructive jaundice and infectious hepatitis the absolute excretion of isomer I is raised and isomer III is normal or elevated. This pattern may be explained by a shift from the biliary to the urinary route of excretion affecting mainly isomer I. On the other hand, in Dubin—Johnson syndrome an increased excretion of isomer I was accompanied by a significant decrease of isomer III excretion in the urine. It is suggested that this abnormal pattern might be a result of a deficiency or inhibition of uroporphyrinogen isomerase (uroporphyrinogen III co-synthetase) in the liver of patients with the Dubin—Johnson syndrome.

Seasonal influence on insulin secretion in man.

Abstract: 1. The seasonal variation of fasting blood glucose, peroral glucose tolerance, fasting plasma insulin and triglycerides and the sum of insulin values during glucose tolerance test was studied in 100 patients who had suffered a myocardial infarction. These patients comprised a population of all men who had suffered a myocardial infarction below the age of 55 years and had survived. 2. The material was divided into four numerically equal groups covering two dark, cold periods and two warm, light periods of the year. 3. Lower fasting blood glucose and insulin values during glucose tolerance test as well as a trend to higher glucose tolerance were found during the warm, light part of the year in comparison with winter. Triglycerides and fasting insulin values did not vary significantly in these infarction patients. The variation could not be explained by a difference in age or body weight between the groups. 4. It is suggested that glucose tolerance and insulin secretion are subjected to seasonal variation in man as has previously been shown in laboratory animals.

Measurement of interstitial 'fluid' pressure by means of a cotton wick in man and animals: an analysis of the origin of the pressure.

Abstract: 1. A method for measuring interstitial ‘fluid’ pressure by using a wick consisting of long-stranded cotton wool at the interface of the tissue is described. 2. A correct measurement of hydrostatic fluid pressure was obtained when the wick, connected to a suitable transducer, was applied to filter paper in which the channels contained fluid at a known subatmospheric pressure. 3. A mean subatmospheric pressure of −1.6 cmH 2 O was recorded in the subcutaneous tissue of the normally hydrated frog; pressure fell with dehydration and rose with overhydration. 4. A mean subatmospheric pressure of −2.8 cmH 2 O was recorded in the subcutaneous tissues of the abdominal wall and scalp of the normally hydrated rat. Simultaneous measurements made at symmetrical sites showed a high degree of correlation. 5. A comparison of interstitial ‘fluid’ pressure in the subcutaneous tissues of the scalp (measured by a wick) and the abdominal wall (measured by a Guyton capsule), in both anaesthetized and conscious rats showed some degree of correlation. There was, however, a wide scatter of values. 6. The interstitial ‘fluid’ pressure in the rat, measured by both wick and capsule, became more negative when the animals underwent frusemide diuresis; the capsule pressures fell more rapidly for a given degree of fluid loss. 7. The wick method was applied to the subcutaneous tissues of the arm in normal man; a mean atmospheric pressure of −3.4 cmH 2 O was recorded in five subjects. There were no untoward sequelae. 8. The forces responsible for the measured pressure have been analysed. The recorded subatmospheric interstitial ‘fluid’ pressure in the rat rose towards atmospheric pressure and sometimes became positive when the wick was removed, soaked in increasing concentrations of hyaluronic acid, and reinserted in the tissues. This did not happen in similar experiments in which the wick was soaked in bovine albumin, rat plasma or saline. The large macromolecules of hyaluronic acid therefore exert a force which opposes the forces responsible for the subatmospheric interstitial pressure. 9. It is suggested that the apparent subatmospheric hydrostatic pressure is due to the osmotic forces developed by the hyaluronic acid molecules in the interstitial tissues trapped by their mutual entanglement in a sieve of collagen fibrils acting as a semipermeable membrane.

A reinvestigation of methylguanidine concentrations in sera from normal and uraemic subjects.

Abstract: (Received 15 Apri/197l) SUMMARY 1. A cation-exchange-chromatographic method for the determination of methyl­ guanidine in serum is described. 2. In ten normal subjects, the mean serum methylguanidine concentration was 0·055 (SE 0'019) mg/ 100 ml and in ten uraemic patients it was 0·175 (SE 0,038) mg/ 100 ml. This difference is significant (P<0·02). 3. Recent claims that methylguanidine is present in uraemic serum in much higher concentrations are shown to be due to artifactual conversion of creatinine when methods involving charcoal chromatography are employed. 4. The results of intoxication experiments, in which blood concentrations of methylguanidine similar to those found by charcoal-chromatographic methods have been reproduced, must be interpreted with caution.

Quantitative Changes in Plasma Amino Acids Induced by Oral Contraceptives

Abstract: Plasma samples from 6 regularly menstruating women (ages 20-30) and 7 women (same age range) who had been using Gynovlar (0.05 mg ethinyl estradiol and 3.0 mg norethisterone acetate) were taken to study the effect of oral contraceptives on amino acid concentrations. Samples were drawn from all individuals between days 2 and 5 and again between days 19 and 22 of the same cycle. An additional sample was drawn 1 or 2 days before the new course of tablets in those taking contraceptives. In the control group total plasma amino acid concentration was significantly higher between days 2 and 5 than between days 19 and 22 (p less than 0.01). The corresponding difference in the contraceptive group was also significant (p less than 0.01). In the controls there were significant decreases in concentrations of serine glutamate and ornithine in the second half of the cycle. Among the contraceptors there were also significant decreases in concentrations of proline glycine alanine valine leucine and tyrosine in the second half. In the interval between pill courses however there is a normal plasma amino acid concentration with a significant decrease in plasma glycine. It is apparent that these plasma changes are influenced by both endogenous and exogenous sex hormones but the exact mechanism of action of oral contraceptives on amino acid metabolism is not yet known. It is likely that they influence the activity of enzymes concerned with the metabolism of many free amino acids in both the liver and peripheral tissues.

Reactions of Arterial and Venous Vessels in the Human Forearm and Hand to Deep Breath or Mental Strain

Abstract: 1. Arterial and venous reactions in forearm and hand to a deep breath or to mental strain (a 50 s period of arithmetic) were measured in fourteen individuals. Blood flow and tissue volume change were measured by venous occlusion plethysmography, and venous tone by the occluded limb technique. 2. A deep breath caused cutaneous vasoconstriction which was short-lasting in resistance (arterial) vessels and long-lasting in capacitance vessels. 3. Mental strain caused cutaneous venous constriction and muscular arterial dilatation with a similar time-course, while the cutaneous arterial reaction was variable.

The effect of long-term mestranol administration on calcium and phosphorus homeostasis in oophorectomized women.

Abstract: To study the effect of long-term mestranol administration on calcium and phosphorus metabolism in oophorectomized women 32 women 44-58 years old were given daily either mestranol in a dose of 20-40 mcgm or a placebo. After 1 year the mestranol group had significantly lower serum calcium (9.54 mg/100 ml compared with 9.99 mg/100 ml)(p less than .01); calcium excretion (.055 mg/100 ml compared with .093 mg/100 ml; p less than .02); and serum phosphorus (2. 98 mg/100 ml compared with 3.67 mg/100 ml; p less than .001) than the control group. The index of phosphorus excretion was significantly higher (p less than 0.02 in the mestranol- treated women.