J. G. G. Ledingham

Reduced Thirst after Water Deprivation in Healthy Elderly Men

To determine whether responses to dehydration are altered with age, we investigated the thirst, fluid and electrolyte responses, and hormonal responses to 24 hours of water deprivation in seven healthy active elderly men (67 to 75 years old) and seven healthy young men (20 to 31 years old) who were matched for weight loss during water deprivation. After water deprivation, the older men had greater increases in plasma osmolality, sodium concentration, and vasopressin levels. However, their urinary osmolality was lower and they were less thirsty and drank less after water deprivation, so that their plasma and urine were not diluted to predeprivation levels. Regression analysis indicated increased sensitivity of vasopressin osmoreceptors in the older group, although this difference was not statistically significant. We conclude that after 24 hours of water deprivation, there is a deficit in thirst and water intake in healthy elderly men, as compared with younger men, although vasopressin osmoreceptor responsiveness is maintained or even increased. Our findings also suggest that the well-known deficit in urinary concentrating ability that occurs with age reflects renal causes and not a lack of circulating vasopressin.

Skeletal muscle metabolism in patients with congestive heart failure: relation to clinical severity and blood flow.

We and others have previously demonstrated excessive phosphocreatine (PCr) depletion and acidosis in skeletal muscle during exercise in patients with congestive heart failure (CHF). In the present study, we performed serial measurements of PCr and pH during gradually incremental flexor digitorum superficialis exercise in 22 patients with CHF and 11 age-matched controls to determine: (1) whether abnormalities were present at the same relative workloads (a comparison that would at least partially compensate for differences in muscle mass), (2) the temporable course of the metabolic changes, (3) the relationship of the metabolic findings to clinical variables, and (4) the relationship of the metabolic abnormalities to forearm blood flow. The patients with CHF had significantly lower [PCr] and pH at all submaximal levels of exercise, and these abnormalities were apparent from the onset of low-level exercise. There was considerable heterogeneity among the patients with CHF with respect to the metabolic findings, with 14 of 22 exhibiting either PCr or pH values more than 2 SDs below normal. Patients whose capacity was more limited during the protocol had lower [PCr], and especially pH, at low loads than did other patients with CHF or the control subjects. The more symptomatic patients and those with more limited bicycle exercise tolerance also had lower pH values. In contrast, there were no significant differences in forearm blood flow between the patients and controls and no relationship between forearm blood and either clinical variables or the metabolic findings. These results indicate that skeletal muscle metabolic abnormalities are present in many patients with CHF and that they are not primarily due to either muscle atrophy or impaired blood flow. These changes may explain in part the marked heterogeneity of symptom status and exercise capacity of patients with similar degrees of cardiac dysfunction.

31P nuclear magnetic resonance evidence of abnormal skeletal muscle metabolism in patients with congestive heart failure

In patients with congestive heart failure (CHF), exercise limitation correlates poorly with central hemodynamic abnormalities, suggesting that additional abnormalities in skeletal muscle blood flow or metabolism play an important pathophysiologic role. Therefore, muscle metabolism was examined by 31P nuclear magnetic resonance (NMR) at rest and during repetitive bulb squeeze exercise in 11 patients with New York Heart Association class II to IV CHF and 7 age-matched control subjects. Serial spectra were obtained at rest, at 2 levels of exercise and during recovery. At rest, the only abnormal finding was an elevated inorganic phosphate (Pi) concentration (5.0 +/- 1.5 vs 3.6 +/- 0.4 mM, p less than 0.01). At the lower exercise level, phosphocreatine (PCr) utilization, which was followed as the ratio of [PCr]/[( PCr] + [Pi]), was greater (0.36 +/- 0.16 vs 0.53 +/- 0.10, p less than 0.02), and pH fell more rapidly and to a lower value (6.38 +/- 0.25 vs 6.85 +/- 0.17, p less than 0.001). At the higher level of exercise, the patients could not work effectively and the group differences narrowed. Compared with control subjects, acidification was disproportionately greater in relation to PCr depletion in patients, further suggesting excessive dependence on glycolytic metabolism. The Pi peak was prominently double in 5 patients, indicating presence of a population of muscle fibers undergoing unusually active glycolysis. PCr resynthesis, a reflection of oxidative phosphorylation, was delayed in 4 patients. These findings indicate that in many patients with CHF, exercising muscle has marked metabolic changes consistent with impaired substrate availability and altered biochemistry.

Changes in cerebral blood flow in patients with severe congestive cardiac failure before and after captopril treatment

The intravenous 133xenon injection method was used to estimate global cerebral blood flow before and after treatment with captopril in nine patients with severe heart failure. The pretreatment mean blood pressure was 94.9 mm Hg (S.D. 13.9) and fell to 85.1 mm Hg (S.D. 18.1) after treatment with captopril for between four and 15 days. The cerebral blood flow before captopril was 61.1 ml/100 g per minute (S.D. 6.9), which was less than the value of 75.8 ml/100 g per minute found in control subjects. After treatment with captopril the cerebral blood flow increased to 73.8 ml/100 g per minute (S.D. 11.8, p less than 0.01). The fraction of carbon dioxide in the expired air was not significantly different in the two studies (4.1 +/- 0.88 versus 3.97 +/- 0.65). It is concluded that cerebral blood flow is reduced in severe heart failure and can be restored by treatment with captopril, but the reasons for the reduced flow and its improvement after converting enzyme inhibition are not known.

Body fluid changes, thirst and drinking in man during free access to water.

To investigate whether human thirst and drinking during ad lib access to water occur in response to body fluid deficits, we obtained blood samples and visual analog scale thirst ratings from five healthy, volunteer, young men at hourly intervals and when they were thirsty during a normal working day. Although there were significant increases in ratings of thirst, pleasantness of drinking water, mouth dryness and unpleasantness of the taste in the mouth when subjects were thirsty enough to drink compared with intervening intervals, there were no concomitant changes in body fluid variables (microhematocrit, plasma osmolality and plasma sodium, potassium, protein and angiotensin II concentrations). Subjects drank mainly in association with eating and were not overhydrated as indicated by constantly hypertonic urine and significant tubular reabsorption of free water over the experimental period. The results indicate that during free access to water humans become thirsty and drink before body fluid deficits develop, perhaps in response to subtle oropharyngeal cues, and so provide evidence for anticipatory thirst and drinking in man.

Clinical experience with captopril in the treatment of severe drug-resistant hypertension

Thirty-three patients aged 12 to 77 years with severe hypertension uncontrolled on maximal combination therapy (mean arterial pressure on treatment 149 +/- 4 mm Hg) were treated with captopril, 45 to 450 mg daily for up to 30 months. Renovascular lesions were present in 11 and other renal disease in a further 15, of whom 8 had undergone renal transplantation. Good control (mean blood pressure less than 110 mm Hg) was achieved in 11 patients and moderate control (mean blood pressure 110 to 130 mm Hg) in 13. Captopril was given with a diuretic agent in 13 patients, with a diuretic agent and a beta-adrenoreceptor blocker in 13, and with three or more other agents in 7, of whom 4 had undergone renal transplantation. Side effects of rash, fever and gastrointestinal symptoms were observed, but there were no adverse effects on renal function or leukocyte counts. Severe hyperkalemia (potassium level greater than 6.0 mmol/liter) occurred in four patients despite the use of furosemide and low potassium diet. There was no significant correlation between the long-term hypotensive response and the initial decrease in blood pressure during captopril therapy.

Timing of the onset of changes in renal energetics in relation to blood pressure and glomerular filtration in haemorrhagic hypotension in the rat.

The timing and circumstances of changes in renal energetics during the gradual induction of haemorrhagic hypotension were studied in anaesthetised rats by phosphorus-31 nuclear magnetic resonance. Animals were bled at a constant rate of 0.1 ml/min via the femoral artery. Whenever changes in renal energetics were seen, a similar pattern was observed. A decrease in adenosine triphosphate occurred rapidly and was always associated with accumulation of inorganic phosphate and tissue acidosis. Profound oliguria, reflecting a markedly decreased rate of glomerular filtration preceded the changes in metabolite levels. Such a fall in glomerular filtration rate and consequently in the energy requirement for tubular reabsorption could be viewed as a mechanism by which energy demands of the kidney are reduced before a critical limitation of energy supply is reached. During uncomplicated haemorrhage in Wistar rats, mean arterial pressures as low as 25-40 mm Hg were reached before changes in renal energetics developed. In contrast, spontaneously hypertensive rates subjected to uncomplicated haemorrhage, and Wistar rats subjected to haemorrhage during concurrent stimulation of the ipsilateral sciatic nerve, developed changes in renal energetics at higher and more variable blood pressures and in response to the withdrawal of lesser but more variable quantities of blood. The sudden onset and severe degree of energy depletion at varying blood pressures during bleeding and its more ready occurrence in animals in which sympathetic nervous activity could be expected to be increased, suggests that sudden renal vasoconstriction is responsible for the unpredictable occurrence of tubular ischaemia in haemorrhagic hypotension.

Chronic left atrial catheterisation in the rabbit

SummaryA technique for chronic left atrial catheterisation in the rabbit is described and its advantages over other methods of access to the systemic circulation are discussed, particularly in relation to studies of cardiac output measurement and distribution. Evidence is presented which suggests that this procedure does not cause endocarditis and is followed by normal body growth and a rapid return to haemodynamic normality. Endothelialisation of the catheter within the atrium eliminates the risk of embolisation during implantation for several months. The uses of such a catheter in other areas of physiology are discussed.

31Phosphorus NMR Studies of Mercuric Chloride Nephrotoxicity in the in Vitro Perfused Rat Kidney

31P Nuclear Magnetic Resonance (NMR) studies of the effect of hypoxia on ATP levels in the isolated perfused rat kidney have shown that a step-wise decrease in oxygen delivery is associated with a step-wise decrease in ATP to a new plateau level (1). The decrement in ATP was closely correlated with the volume extent of cellular necrosis determined from morphometric analysis of the same kidneys at the end of the perfusion period.