Showing papers in "Clinical Science in 1983"

Pain and Fatigue after Concentric and Eccentric Muscle Contractions

Abstract: 1. Normal subjects performed a step test in which the quadriceps of one leg contracted concentrically while the contralateral muscle contracted eccentrically. 2. Maximal voluntary force and the force: frequency relationship were altered bilaterally as a result of the exercise, the changes being greater in the muscle which had contracted eccentrically. Recovery occurred over 24 h. 3. Electromyographic studies using three sites on each muscle showed an increase in electrical activation during the exercise only in the muscle which was contracting eccentrically. Recovery followed a time course similar to that of the contractile properties. 4. Pain and tenderness developed only in the muscle which had contracted eccentrically. Pain was first noted approximately 8 h after exercise and was maximal at approximately 48 h after exercise, at which time force generation and electrical activation had returned to pre-exercise values. 5. Eccentric contractions cause more profound changes in some aspects of muscle function than concentric contractions. These changes cannot be explained in simple metabolic terms, and it is suggested that they are the result of mechanical trauma caused by the high tension generated in relatively few active fibres during eccentric contractions.

Physical Exercise as Prophylaxis against Involutional Vertebral Bone Loss: A Controlled Trial

Abstract: Summary 1. The skeletal effects of physical training were studied in a controlled trial involving 31 healthy women (aged 50-73 years) with previous Colles’ fracture of the forearm. The bone mineral content of the lumbar spine and both distal forearms was measured by dual-photon (ls3Gd) absorptiometry. 2. The participants were allocated to either a physical exercise group or a control group. The former group followed a standardized exercise programme, exercising for 1 h twice weekly during 8 months. 3. Twenty-seven women completed the study. Lumbar spine bone mineral content of the exercise group increased by 3.5%, whereas that of the control group decreased by 2.7%. The rate of bone loss in the control group equalled that of age-matched normal women. 4. The changes in forearm bone mineral content appeared to be independent of the exercise. The bone mineral content of the previously fractured forearm remained nearly unchanged. The bone mineral content of the uninjured forearm decreased on average by 3.5%. 5. The data suggest that physical exercise can inhibit or reverse the involutional bone loss from the lumbar vertebrae in normal women. Physical exercise may prevent spinal osteoporosis.

Vertebral bone loss: an unheeded side effect of therapeutic bed rest.

Abstract: 1. The skeletal effects of simple bed rest and re-ambulation were studied in a consecutive series of 34 patients (aged 18-60 years) hospitalized with low backache due to protrusion of a lumbar intervertebral disc. The bone mineral content of the second, third and fourth lumbar vertebrae was determined by dual-photon (153Gd) absorptiometry immediately after admission to the hospital, at the end of the bed-rest period (mean 27 days, range 11-61 days) and approximately 15 weeks later (range 11-24 weeks). 2. During recumbency a mean decrease in lumbar spine bone mineral content of 0.9% per week was observed. 3. Re-ambulation resulted in bone mineral gain, and restoration of lumbar spine bone mineral content was nearly complete after 4 months. 4. The findings suggest that the simple therapeutic bed-rest regimen leads to excessive vertebral bone loss. Recurrent bed-rest periods may predispose to spinal osteoporosis.

The influence of different types of omega 3 polyunsaturated fatty acids on blood lipids and platelet function in healthy volunteers.

Abstract: 1. Five healthy subjects took a daily supplement of 20 ml of linseed oil for 2 weeks. After a break of at least 6 weeks, the same subjects took a similar amount of MaxEPA (a fish oil fraction) for 2 weeks. The linseed oil supplement provided 9.38 g of linolenic acid (18:3 ω3) and the MaxEPA supplement provided 3.03 g of eicosapentaenoic acid (20:5 ω3) and 2.93 g of docosahexaenoic acid (22:6 ω3). The effects of the supplements on plasma lipid concentrations and on the fatty acid composition of platelet phosphoglycerides were studied. 2. In a second experiment, five male subjects took 5, 10 and 20 g of MaxEPA/day in random order for 3 week periods; each experimental period was separated by a break of at least 6 weeks. These doses of MaxEPA provided 0.83, 1.67 and 3.33 g of 20:5 ω3 and 0.80, 1.61 and 3.22 g 22:6 ω3 respectively. The effects of these supplements on plasma lipid concentrations, the fatty acid composition of platelet phosphoglycerides, template bleeding time and platelet aggregation induced by collagen and the prostaglandin analogue compound U46619 were studied. 3. In the platelet lipids, the proportion of 20:5 ω3 was increased by the 20 ml linseed oil supplement but the increase was small compared with the increase brought about by even 5 g of MaxEPA/day. The proportion of arachidonic acid (20:4 ω3) was substantially decreased by the MaxEPA supplement but not by the linseed oil supplement. The ratio of 20:4 ω6/20:5 ω3 fell from 32:1 in the control periods to 11:1 with 5 g, 7:1 with 10 g and 5:1 with 20 g of MaxEPA/day. The MaxEPA supplement also led to increases in the proportions of 22:5 ω3 and 22:6 ω3 and decreases in those of 20:3 ω6 and 22:4 ω6. 4. Bleeding times tended to be prolonged with the MaxEPA supplement but did not follow any dose-dependent trend. Platelet aggregation induced by both collagen and compound U46619 was not inhibited in vitro . 5. Plasma triglyceride concentrations were lowered by the MaxEPA supplement but not by the linseed oil supplement. Plasma triglyceride concentrations were substantially lowered by 10 g and 20 g of MaxEPA/day. Total plasma cholesterol concentrations were slightly lowered and HDL cholesterol concentrations were slightly increased by 20 g of MaxEPA/day. No other significant differences were noted.

The Use of 4-Aminobenzoic Acid as a Marker to Validate the Completeness of 24 H Urine Collections in Man

Abstract: 1. At the present time there is no method whereby the completeness of 24 h urine collections can be accurately assessed when clinical studies are undertaken. The suitability of 4-aminobenzoic acid (PAB) given with meals as a marker for completeness of urine collections was therefore investigated. 2. When a single dose of 80 mg of PAB was given to four volunteers 93% was recovered in the urine in 5 h. 3. Eight volunteers living in a calorimeter, where complete urine collection could be guaranteed, were given various doses of PAB divided up throughout the day. 88 +/- 5% was excreted in the urine over a 24 h period. Urine excretion and oral dose were directly related. 4. Thirty-three reliable free-living volunteers eating their normal diet took 80 mg of PAB with meals (240 mg/day). Mean urine recovery over the 24 h period was 223 +/- 9 mg, or 93 +/- 4% of the administered dose. The range in individual recovery from maximum to minimum was 15%, compared with 75% for creatinine excretion per kg fat-free mass. 5. PAB is a safe marker of the completeness of 24 h urine collections. Any collection containing less than 205 out of 240 mg (85%) of PAB, given as 80 mg with each of three meals, is probably incomplete.

Luxuskonsumption, diet-induced thermogenesis and brown fat: the case in favour

Abstract: The idea that the body can adapt to overnutrition, by activating energetically wasteful mechanisms to dispose of excess energy as heat, goes back to the turn of the century [ 1 I. Originally called ‘Luxuskonsumption’, the phenomenon is now described as an adaptive form of thermogenesis (diet-induced thermogenesis, DIT). In spite of its early beginnings, substantial quantitative evidence for DIT has been available only in the past 3-4 years, and this recent work has also suggested that a small and relatively obscure form of adipose tissue (brown fat) is the main effector of DIT. Therefore it is not altogether surprising to find a certain reluctance to accept what is for many a major revision of their understanding of energy metabolism. Nevertheless, we believe that the experimental evidence now available leaves little doubt about the importance of DIT in the regulation of energy balance in laboratory animals and that brown fat is the principal source of this form of heat production. Apparently we are not alone in this belief, and the high level of research activity now under way in the U.S.A. and Canada provides a marked contrast with the scene in this country, where only two or three groups are trying to maintain the impetus of what has been until now a uniquely British scientific advance. The evidence supporting this advance has already been published by ourselves and other workers, 1

Abnormalities of Calcium Metabolism in Essential Hypertension

Abstract: Calcium metabolism has been investigated in patients with essential hypertension and normal renal function to evaluate the renal calcium handling and the reported increase in renal calcium loss. In 55 hypertensive and 55 sex- and age-matched healthy normotensive subjects creatinine clearance, serum total and ionized calcium, plasma parathyroid hormone and 24 h urinary excretion of calcium, sodium and cAMP were measured. In a subgroup of 20 hypertensive patients and 20 controls the fasting calcium excretion rate was also measured. Both 24 h and fasting calcium excretion rates were higher in the hypertensive group; so also were plasma parathyroid hormone and urinary cAMP. Serum total and ionized calcium levels were not different in the two groups. After intravenous calcium infusion (15 mg 3 h-1 kg-1) in seven hypertensive patients and controls, the hypertensive patients excreted more calcium at all serum calcium concentrations. These results support the hypothesis of primary renal calcium leak in essential hypertension. Enhanced urinary calcium excretion rate may cause compensatory parathyroid overactivity.

Protein Synthesis, Bodily Renewal and the Sleep-Wake Cycle

Abstract: Dans la plupart des tissus, les taux maximaux de synthese des proteines et les taux maximaux de division des cellules coincident avec la periode du sommeil. A l'inverse, le catabolisme est plus grand au cours de l'etat de veille. Une explication en est ici fournie

3-Methylhistidine as a measure of skeletal muscle protein breakdown in human subjects: the case for its continued use.

Abstract: Fifteen years ago 3-methylhistidine (3-MeH, NTmethylhistidine) was identified as a constituent of both actin [ l ] and myosin [2]. Young, Munro and their coworkers recognized the potential importance of these findings and suggested that the production rate of 3-MeH could potentially be used as an index of muscle protein breakdown [34] provided that: (a) the 3-MeH was present exclusively in muscle protein and at a constant amount, (b) 3-MeH released after protein degradation was neither re-utilized for protein synthesis nor metabolized, and (c) free 3-MeH was rapidly and quantitatively excreted in the urine. Initial experiments apparently confirmed all three conditions. Thus 3-MeH has not been found in any proteins other than actin and the myosin heavy chain from white fibres. In both proteins it is present at a constant proportion of 1 mol/mol of protein subunit [S] . Also some 90% of the total body pool of 3-MeH is in skeletal muscle (see below). Administration of radioactive 3-MeH to humans showed that the amino acid was not metabolized but was rapidly excreted in the urine [4]. Previous experiments had confirmed that 3-MeH was not a substrate for amino-acyl tRNA charging in vifro [3] and accordingly could not be reutilized for protein synthesis.

Thermic response to isoenergetic protein, carbohydrate or fat meals in lean and obese subjects.

Abstract: The thermic response of five lean and five obese subjects was measured by indirect calorimetry before, and for 157.5 min after a meal of protein, carbohydrate or fat, each of which provided 1.25 MJ. The change in plasma glucose, insulin and (in the case of the carbohydrate meal) the rate of exogenous glucose oxidation was also measured. There was no significant difference between the lean and obese groups in the magnitude of the thermic response to any of the three meals. In both weight groups the response was largest and most prolonged after the protein meal (P less than 0.01). The obese group showed a higher concentration of fasting plasma insulin (P less than 0.01) and a larger increase in plasma glucose (P less than 0.05) after the carbohydrate meal, but there was no significant difference in the oxidation of exogenous glucose when compared with the lean group. Previous studies on dietary-induced thermogenesis in lean and obese subjects have given conflicting results. In general reports of decreased thermogenesis in obese subjects are characterized by either (a) high pre-meal metabolic rates in the obese group, especially in diabetic subjects, or (b) a group classified as 'normal' who have been selected for their high thermogenic capacity.

Effect of pH, viscosity and ionic-strength changes on ciliary beating frequency of human bronchial explants

Abstract: 1. Ciliary activity is significantly influenced by chemical and physical properties of the liquid medium in which the cilia beat. 2. We studied the effect of changes in pH, ionic strength and viscosity on the ciliary beat frequency (CBF) of explants of human respiratory mucosa. 3. Optimal CBF was elicited at pH 7 . 0-9 . 0, with a marked reduction of CBF outside these limits. The CBF was well preserved at NaCl concentrations between 5 g/l (80 mmol/l) and 12 g/l (200 mmol/l), but there was rapid loss at concentrations below 0 . 5 g/l (10 mmol/l). The cilia beat best at viscosities below 1 . 0 centipoises (1 mN s m-2). Increase of the viscosity gradually decreases CBF with a significant drop at viscosities above 87 millipoises. 4. It is concluded that the above limits may fairly accurately indicate the actual physical characteristics of the periciliary environment ('sol layer') in vivo.

Effects of Free Radical Scavengers on Renal Circulation after Ischaemia in the Rabbit

Abstract: The intrarenal erythrocyte distribution, total renal blood flow and renal vascular resistance were studied before and during recirculation after 60 min of warm ischaemia in three groups of rabbits. One group was pretreated with superoxide dismutase, another with catalase and the third group was not pretreated at all. In non-pretreated ischaemic kidneys there was a significant trapping of labelled erythrocytes in the outer stripe of the medulla. This trapping was not seen in non-ischaemic control kidneys and was completely prevented by pretreatment with either superoxide dismutase or catalase. In non-pretreated ischaemic kidneys there was a transient increase in total renal blood flow during the first 5 min of recirculation, after which it returned to preischaemic values. After pretreatment with catalase the postischaemic increase in blood flow was more pronounced but again the blood flow returned to preischaemic values within 30 min. Pretreatment with superoxide dismutase resulted in a rapid postischaemic increase in blood flow which remained high throughout the 30 min period studied. The renal vascular resistance decreased initially during recirculation after ischaemia in both pretreated and non-pretreated kidneys. In the latter it returned to pre-ischaemic values within 10 min whereas a slower increase was observed after catalase pretreatment. After pretreatment with superoxide dismutase the resistance remained low during the 30 min recorded.

The combined effects of infection and malnutrition on protein metabolism in children.

Abstract: Twenty-two children were studied as inpatients at a Nigerian Hospital. They were divided into four groups on the basis of weight for age: I, adequately nourished, acutely infected; II, moderately under weight, acutely infected; III, malnourished, chronically infected; IV, malnourished, uninfected. Urinary nitrogen excretion was highest in group I and lowest in groups III and IV. Urinary creatinine was highest in group I, but did not differ significantly in groups II, III and IV. The excretion of 3-methylhistidine closely paralleled that of creatinine. It is suggested that the high rates of creatinine and methylhistidine excretion in group I resulted in part from destruction of muscle. Rates of whole body protein turnover were measured by administration of a single dose of [15N]glycine with measurement of the excretion of 15N in urinary NH3 for the next 9 h. Rates of protein synthesis and breakdown were very high in infected children of groups I and II. Although rates were lower in the malnourished groups, in infected children of group III they were nearly twice as high as in the uninfected group IV. The net balance of protein (synthesis minus breakdown) was negative in group I, less negative in group II, zero in group III and positive in group IV. Repeat measurements in group I during recovery from infection showed a decline in rates of excretion of nitrogen, creatinine and 3-methylhistidine. Rates of protein synthesis and breakdown declined and the protein balance became less negative, but these changes were not statistically significant. Multiple regression analysis of the results of all groups taken together showed independent contributions to rates of protein metabolism from infection and nutritional state, especially plasma albumin. It was concluded that infection caused a rise in protein breakdown which was larger than the concomitant rise in synthesis, leading to net loss of protein, and that these responses were reduced by malnutrition.

The effects of cardioselective and non-selective beta-adrenoceptor blockade on the hypokalaemic and cardiovascular responses to adrenomedullary hormones in man

Abstract: 1. Adrenaline was infused intravenously in nine normal volunteers to plasma concentrations similar to those found after myocardial infarction. This study was undertaken on three occasions after 5 days9 treatment with placebo or the β-adrenoceptor antagonists, atenolol or timolol. 2. Adrenaline increased the systolic pressure by 11 mmHg, decreased the diastolic pressure by 14 mmHg, and increased the heart rate by 7 beats/min. These changes were prevented by atenolol. However, after timolol the diastolic pressure rose (+19 mmHg) and heart rate fell (− 8 beats/min). 3. Adrenaline caused the corrected QT interval (QT c ) to lengthen (0.36 ± 0.02 s to 0.41 ± 0.06 s). No significant changes were found in the QT c when subjects were pretreated with atenolol or timolol. 4. The serum potassium fell from 4.06 to 3.22 mmol/l after adrenaline. Serum potassium fell to a lesser extent to 3.67 mmol/l after atenolol and actually increased to 4.25 mmol/l after timolol. Adrenaline-mediated hypokalaemia appears to result from the stimulation of a β 2 -adrenoceptor linked to membrane Na + /K + -ATPase causing potassium influx.

Biochemical analysis of hepatic lipid in alcoholic and diabetic and control subjects.

Abstract: 1. Percutaneous needle biopsy specimens of liver were obtained from alcoholic, diabetic and control patients. Micro-methods of lipid separation and quantification were employed to determine the detailed nature of hepatic lipid. 2. Triglyceride is the major accumulating liver lipid in both alcoholic and diabetic patients. Cholesteryl ester levels were raised in both alcoholic and diabetic patients but only diabetic patients had significantly increased free cholesterol and phospholipid levels. Determination of phospholipid/free cholesterol ratios revealed a significant decrease in alcoholic cirrhosis compared with controls. 3. Fatty acid ester analysis of hepatic phospholipid and triglyceride revealed significant differences between alcoholic patients and controls but not between diabetic patients and controls. An increased ratio of non-essential/essential fatty acids was found in the patients with alcoholic liver disease whereas those of diabetic patients were similar to the controls.

Purine Transport and Metabolism in Man: The Effect of Exercise on Concentrations of Purine Bases, Nucleosides and Nucleotides in Plasma, Urine, Leucocytes and Erythrocytes

Abstract: 1. After decreasing muscle ATP by a 2 min period of intense exercise, we have studied purine metabolism by using high-pressure liquid chromatography. 2. A major increase in hypoxanthine concentration in plasma and urine was found with increases in xanthine and, in plasma, inosine. Erythrocyte hypoxanthine rose with the level in plasma, but there was no corresponding rise in IMP, the first intracellular metabolite of hypoxanthine. No rises in uridine or urate were found in plasma. 3. Plasma adenosine did not rise and fall significantly after exercise, but a small rise and fall in adenine nucleotide concentrations in plasma was found. 4. Running, swimming and games, which tended to be at the weekend, were associated with a rise in hypoxanthine and xanthine excretion; exercise was probably the cause of the higher excretion during the day than at night. Such activities do not produce changes in concentrations of ATP in muscle, although turnover must rise. 5. The results are consistent with widespread purine exchange between tissues and a ‘circulating hypoxanthine pool’.

The epidemiology of plasma renin.

Abstract: 1. The epidemiological characteristics of plasma renin activity (PRA) were established in 1999 members of occupational groups in North and West London. 2. The main finding was that PRA was inversely associated with systolic blood pressure in men, the percentage fall in PRA (on a log scale) being 8.4% for each increase of one standard deviation in systolic blood pressure. There was a less obvious inverse relationship in women. 3. However, blood pressure accounted for less than 1% of the variance in PRA. 4. Mean PRA in both smokers and ex-smokers was about 20% higher than in non-smokers. 5. PRA fell with increasing age, was lower in women than in men and considerably lower in blacks (of either sex) than whites. 6. PRA was lower in the first quarter of the menstrual cycle than in the rest of the cycle. 7. Haemoglobin, blood cholesterol, leucocyte count and Factor VIII were positively correlated with PRA. 8. PRA was lower in men with diagnosed hypertension than in those without; there was no significant difference in the women. 9. PRA was lower in those who had had myocardial infarcts in the past than in those who had not. 10. The data as a whole suggest that it may be low, not high, levels of PRA which are associated with increased risks of cardiovascular disease in which hypertension is a predisposing factor. 11. The explanation may be a homoeostatic fall in PRA in response to a rise in blood pressure rather than a major causal role for PRA in the pathogenesis of essential hypertension and target-organ damage.

Formation of Hydroxyl Radicals from Hydrogen Peroxide and Iron Salts by Superoxide- and Ascorbate-Dependent Mechanisms: Relevance to the Pathology of Rheumatoid Disease

Abstract: 1. Superoxide and hydrogen peroxide are formed by activated phagocytes and react together in the presence of iron salts to form the hydroxyl radical, which attacks hyaluronic acid. Ascorbic acid also interacts with hydrogen peroxide and iron salts to form hydroxyl radical in a reaction independent of superoxide. Since iron salts, ascorbate and activated phagocytes are present in the rheumatoid joint, experiments were designed to see whether ascorbate-dependent or superoxide-dependent formation of hydroxyl radicals would be more important in vivo. 2. in the present study, addition of ascorbate to a superoxide-generating system at concentrations of 100 μmol/l provoked a superoxide-independent formation of hydroxyl radicals for a short period. Lower concentrations of ascorbate did not do this. It is therefore suggested that the superoxide-dependent reaction is probably more important. 3. It is further suggested that destruction of ascorbate by oxygen radicals formed by activated phagocytes accounts for the previously reported low concentrations of this compound in the serum and synovial fluid of rheumatoid patients.

Release of intracellular enzymes from an isolated mammalian skeletal muscle preparation.

Abstract: An isolated skeletal muscle preparation is described which has been used to study the efflux of enzymes in response to contractile activity, metabolic poisons and detergent treatment. In both fast and slow muscles contractile activity caused a release of lactate dehydrogenase and creatine kinase that reached a peak 1-2 h after the end of stimulation. There was very little release during the 30 min stimulation period whether the muscles were under aerobic or hypoxic conditions. Incubation of the muscles with cyanide and iodoacetate caused a similar delayed release of enzyme. Disruption of cell membranes with detergent treatment caused an entirely different and very rapid pattern of enzyme release. Enzyme release from the fatigued isolated muscle preparations appears to be initiated as a consequence of phosphorylcreatine or ATP depletion. The relevance of this to release of muscle enzymes after activity in vivo is discussed.

Effects of Ingested Steak and Infused Leucine on Forelimb Metabolism in Man and the Fate of the Carbon Skeletons and Amino Groups of Branched-Chain Amino Acids

Abstract: 1. The effects of ingested grilled beef steak (250 g raw weight of lean meat) and infusion of leucine (3.8 g) on human forelimb metabolism were studied by monitoring the concentrations of various metabolites in arterial (A) and venous (V) blood of four overnight fasted and rested men. 2. The mean basal A—V for branched-chain 2-oxo acid (BCOA) was small (−3.6 μmol/l). After ingestion of steak or administration of leucine there were large positive increases in the A—V for branched-chain amino acid (BCAA) but increase in the negative A—V for BCOA was relatively small. 3. Within 2 h of ingestion of steak, BCAA accounted for approx. 50% of those amino acids with a positive A—V and glutamine for up to 75% of those with a negative A—V; the negative A—V for alanine decreased to 10% of its basal value. Infusion of leucine produced a large positive A—V for leucine by forelimb, a doubling in the negative A—V for glutamine and a rise in the blood glutamine concentration; the negative A—V for alanine was virtually unchanged and the blood alanine concentration showed a late significant decrease. 4. After ingestion of steak there was a two- to three-fold rise in the arterial insulin concentration, little change in the positive A—V for glucose and a decreased negative A—V for ‘glycolytic products’ (alanine + lactate + pyruvate), suggesting increased utilization of glucose carbon. Infusion of leucine doubled the arterial insulin concentration; the A—V for glucose decreased, that for lactate, pyruvate and alanine remained unchanged, suggesting decreased utilization of glucose carbon. 5. Circulating BCOA was distributed almost entirely in the plasma space. 6. in a variety of clinical conditions (insulin-dependent diabetes, cirrhosis, muscular dystrophy and starvation), the basal plasma concentrations of BCOA correlated well with those of BCAA ( r = 0.989). Infusion of leucine increased the plasma BCAA/BCOA ratio to the same extent (about 40%) in each clinical condition despite considerable variations in the rate of leucine clearance. 7. The observations indicate that both ingested steak and infused leucine produce important changes in the selection of respiratory fuels by the human forelimb, that BCOA is preferentially oxidized rather than released from human limb tissues, and that glutamine, not alanine, is the major amino group carrier leaving the forelimb both after a protein meal and after leucine administration. Changes in cellular uptake or transamination of leucine appear not to be responsible for the varied rates of leucine clearance in a variety of clinical conditions.

Effect of Adrenergic and Vagal Blockade on the Normal Human Airway Response to Exercise

Abstract: Ten normal, non-asthmatic subjects performed an 18 min graduated exercise test on a static exercise bicycle on 3 separate days. They received either no medication, or propranolol 80 mg orally 2 h before, or ipratropium bromide 0.216 mg by inhalation 30 min before, the start of exercise. With no medication, transpulmonary index (TPI), a measure of airway resistance, fell linearly during exercise from a resting value of 0.269 +/- 0.024 to 0.170 +/- 0.014 kPa X 1(-1) X s by the end of exercise. This returned to baseline between 2 and 4 min after stopping exercise. Propranolol elevated baseline TPI slightly from 0.270 +/- 0.024 to 0.294 +/- 0.024 before exercise and during exercise this fell linearly to 0.185 +/- 0.016 kPa X 1(-1) X s. The fall in TPI during exercise after propranolol was not significantly different from the fall seen with no medication. Six minutes after exercise stopped TPI rose to 0.336 +/- 0.035 kPa X 1(-1) X s after propranolol. All values for TPI from 4 min to 16 min after exercise were significantly higher after propranolol than the corresponding values found after no medication (P less than 0.05). Ipratropium bromide decreased baseline TPI from 0.264 +/- 0.024 to 0.163 +/- 0.013 kPa X 1(-1) X s (P less than 0.001) and this did not change significantly further either during or after exercise. Normal subjects show considerable airway dilatation during exercise and this appears to result from inhibition of resting vagal tone. The sympathetic system does not appear to mediate the airway dilatation during exercise, but it may be important in protecting against post-exercise bronchoconstriction.

Proteolytic enzymes, their inhibitors and lung diseases.

Abstract: The pathogenesis of many acute and chronic lung diseases remains a mystery. However, recent years have seen a rapidly increasing interest in the role of proteolytic enzymes and their inhibitors in modifying the inflammatory, destructive and reparative changes that occur in the lung. Much of this interest owes its existence to two observations in the early 1960s: firstly, the recognition that subjects with an inherited deficiency of α 1 -antitrypsin (α 1 -AT; the main serum inhibitor of proteolytic enzymes) had a high incidence of pulmonary emphysema [1], and secondly the demonstration by Gross et al. [2] that a proteolytic enzyme (papain) was capable of producing lesions similar to emphysema in experimental animals. These observations ultimately led to the proteinase—anti-proteinase theory of emphysema, which predicts that a state of balance occurs in the healthy lung in which the proteolytic enzyme inhibitors functionally equal or exceed the enzymes. Destructive lung disease occurs when the enzymes functionally exceed the inhibitors such that they remain active within the lung, resulting in digestion of connective tissue. This general concept of a disturbed proteinase—anti-proteinase balance within the lung has been recently applied to many other lung diseases, and some will be mentioned later. However, it is in the study of chronic bronchitis and emphysema that the concept has become most well established.

Clearance and non-invasive determination of the hepatic extraction of indocyanine green in baboons and man.

Abstract: 1 The disposition of an intravenous bolus of indocyanine green (ICG) has been studied in healthy man and baboons using a novel analysis of a two compartment pharmacokinetic model 2 This analysis enabled the hepatic extraction ratio (ER) of dye to be determined solely from the plasma disappearance curve, and the ER determined did not differ from that measured by hepatic vein catheterization 3 When compared with clearance measured at steady state, the two compartment model gave a significantly more accurate determination of plasma clearance than did the conventional one compartment model 4 It is concluded that, in health, liver blood flow may be calculated accurately and non-invasively after a single intravenous injection of ICG

The effects of nutrition and trauma on whole-body protein metabolism in man.

Abstract: Whole-body protein metabolism was determined by a primed constant-rate infusion of L-[ 1-14C ]leucine in patients before and after elective surgery, the nutritional intake being carefully controlled and the surgical stress in individuals being assessed. Pre-operatively, whole-body protein flux (P less than 0.05) and synthesis (P less than 0.05), along with amino acid oxidation (P less than 0.01), increased with nutritional intake whereas protein breakdown remained unaltered. Whole-body protein balance also correlated with intake (P = 0.001). Postoperatively, whole-body protein metabolism was determined with patients either fasted (group 1) or fed (group 2) and the change in metabolism in each individual from a pre-operative study, carried out in the fed state, was calculated. Whole-body protein breakdown increased in both groups (group 1, + 0.91 +/- 0.74 g day-1 kg-1; mean +/- SD, n = 7: group 2, + 0.47, + 0.63 and + 1.01 g day-1 kg-1, n = 3), the change being significant in those fasted after surgery (P less than 0.05). However, the pattern of change in whole-body protein synthesis was entirely different in each group, rising in those fed throughout (+ 0.32, + 0.41 and + 0.66 g day-1 kg-1, n = 3) but falling in those fasted after surgery (-0.38, -0.80 and -1.33 g day-1 kg-1, n = 3). The changes in metabolism appeared more marked in those undergoing greatest surgical stress. Some of the factors involved in the calculations are discussed and their effects on the overall conclusions are considered. A concept of whole-body protein metabolism in the metabolic response to trauma is advocated whereby protein breakdown is largely obligatory to the response, whereas synthesis responds to substrate availability.

Interaction of diuretics and non-steroidal anti-inflammatory drugs in man

Abstract: 1. The influence of four diuretics on renal prostaglandins was investigated in a study designed in two parts (A and B): A, 24 normal subjects on a constant sodium intake received frusemide (80 mg daily), or hydrochlorothiazide (100 mg), or triamterene (200 mg) or spironolactone (300 mg); B, the same subjects were pretreated for 3 days with indomethacin (150 mg daily), which was continued during the 3 day administration of the respective diuretics and during a 2 day post-diuretic period. 2. In study A, only triamterene provoked a rise in urinary prostaglandins E2 and F2 alpha (+ 474 +/- SEM 92%, P less than 0.01, and + 192 +/- 7%, P less than 0.01). In study B, prostaglandins were significantly inhibited in all subjects. After indomethacin, the natriuretic effect of frusemide and spironolactone was reduced by 80 +/- 12% (P less than 0.01) and 54 +/- 11% (P less than 0.001), whereas the natriuresis induced by hydrochlorothiazide and triamterene was unchanged. No correlation was found between urinary PGE2 and F2 alpha and natriuresis. 3. When triamterene was associated with indomethacin, two subjects developed reversible acute renal failure. 4. Plasma renin activity and urinary aldosterone were stimulated by the four diuretics in study A, but their response was blunted in study B. Urinary antidiuretic hormone was not modified by diuretics but was suppressed by indomethacin. 5. Diflunisal, a structurally unrelated nonsteroidal anti-inflammatory drug, given to 12 of the subjects provoked similar interactions with frusemide, hydrochlorothiazide and spironolactone. 6. The results suggest that prostaglandins contribute to the natriuretic effects of frusemide and spironolactone, but not to those of hydrochlorothiazide and triamterene.

Myocardial Exchanges of Glutamate, Alanine and Citrate in Controls and Patients with Coronary Artery Disease

Abstract: 1. Myocardial exchanges of plasma alanine, glutamate, citrate, lactate, glucose and free fatty acids were determined in 17 patients with coronary artery disease and in seven control subjects during rest, atrial pacing and recovery. 2. Myocardial release of alanine was demonstrated in all subjects. The amount released was higher in patients with coronary artery disease than in controls. In the patients alanine release was related to severity of coronary artery stenosis. 3. All subjects showed myocardial uptake of glutamate, higher in patients than in controls at rest and during recovery. During atrial pacing myocardial glutamate extraction remained unchanged in controls but decreased in patients. 4. Citrate was released by the heart in all controls and patients. During recovery citrate output was higher in patients than in controls. 5. Myocardial alanine and citrate release during recovery were positively correlated. Both were positively related to myocardial uptake of glutamate during recovery and to the decrease in glutamate extraction during pacing. 6. The results indicate changed myocardial citrate and amino acid metabolism in coronary artery disease. Measurement of myocardial exchanges of glutamate, alanine and citrate in addition to lactate is suggested as a sensitive biochemical test in assessing myocardial ischaemia in man.

Influence of age on pulmonary haemodynamics at rest and during supine exercise

Abstract: 1. To determine the effects of age on the pulmonary circulation at rest and on exercise we analysed the results of right heart catheterization studies performed in 125 asymptomatic subjects aged 14-68 years, who were healthy or had indispositions which did not impair cardiac or pulmonary function. 2. Age accounted for less than 10% of total variation in resting values of right atrial, pulmonary artery and wedge pressures, and of cardiac output. 3. The pulmonary artery-wedge pressure gradient and flow resistance at rest significantly increased with age. 4. On exercise there were significant increases with age in right atrial, pulmonary artery and wedge pressures, pulmonary to wedge pressure gradient and flow resistance, but cardiac output was not influenced by age. 5. Pulmonary circulation variables at rest are mainly influenced by sex and size, but during exercise significant effects of age are apparent.

The importance of the renin-angiotensin system in the development and maintenance of hypertension in the two-kidney one-clip hypertensive rat.

Abstract: 1. Blood pressure, renin concentration and angiotensin II were measured in unanaesthetized two-kidney one-clip hypertensive rats at 1 and 2 days, at weekly intervals up to 10 weeks and at 15 and 20 weeks after clipping. 2. Compared with values in sham-operated rats, renin and angiotensin II were initially increased at 1-2 days but were then suppressed between 2 and 4 weeks to levels similar to that found in sham-operated rats. Between 5 and 20 weeks renin and angiotensin II increased again to high levels. 3. There was a significant correlation between angiotensin II and blood pressure in acute rats 1-2 days after clipping (P less than 0.05) and in chronic rats 8-20 weeks after clipping (P less than 0.001). There was no difference in the slope of the regression lines but the regression line for the chronic rats was shifted upwards in a parallel manner. 4. The acute hypotensive response (-20.3 +/- SD 24.9 mmHg) in 26 chronic rats given converting enzyme inhibitor was related to the basal renin and angiotensin II levels and followed the slope of the angiotensin II/blood pressure regression line for all chronic rats. Only one out of 26 rats reduced its blood pressure to normal levels. 5. In 12 rats at 4 weeks after clipping, when blood pressure was elevated but angiotensin II was suppressed, there was only a small fall in blood pressure (-7.1 +/- SD 7.2 mmHg). This also followed the angiotensin II/blood pressure regression line for chronic rats but at the lower end. Blood pressure again was not reduced to normal. 6. These results suggest that renin and angiotensin II are increased up to 20 weeks after clipping, that there is no change in the net vascular responsiveness to endogenous angiotensin II at any stage in this experimental model and that the acute effect of angiotensin II is determined solely by its position in the same dose-response curve. Also with the exception of 1-2 days immediately after clipping the acute effect of angiotensin II plays only a minor, though variable, role in the hypertension and that some other mechanism, as yet undetermined, is of greater importance and begins to have an effect as early as 2 weeks after clipping.

Nocturnal hypoxaemia in chronic obstructive pulmonary disease.

Abstract: 1. Day and night arterial oxygen saturation (Sao2) has been measured in forty-one patients with chronic obstructive pulmonary disease (COPD), mean FEV1 0.84 (range 0.4-1.4)litres, and with a range of daytime Sao2 values of 67-95%. 2. The mean and biggest falls in Sao2 at night were much greater in the patients with lower daytime saturations. However, when falls in arterial oxygen tension (Pao2) were estimated from the decreases in Sao2, there was no correlation between the estimated biggest fall in Pao2 and daytime Sao2 and only a weak correlation between estimated mean fall in Pao2 and daytime Sao2. 3. Measurement of ventilation in four hypoxaemic patients with COPD (range 60-90% Sao2) by respiratory inductance plethysmography showed that nocturnal hypoxaemic dips were accompanied by diminished ventilation, which was not always shown by nasal thermistors. 4. Because nocturnal hypoxaemic dips are transient the ideal alveolar-arterial oxygen difference, which assumes a constant respiratory exchange ratio, cannot be used to assess the mechanism of hypoxaemia. 5. Erythrocyte mass was strongly correlated with daytime Sao2 but this correlation was not significantly improved by including nocturnal hypoxaemia in the regression. 6. The results suggest that greater falls in Sao2 at night are related to lower initial Sao2 values and that the cause may be a reduction in ventilation.