Biomedical subjects
Publications and source records attributed to J G Ledingham.
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The malignant phase of hypertension is invariably fatal unless treated, and rapid reduction of arterial pressure is thought to be the treatment of choice. Ten patients with accelerated hypertension are described in whom abnormal neurological signs developed following the rapid reduction of arterial pressure. Three patients died without recovering from the neurological damage. A fourth died of an unrelated cause a month later. Areas of ischaemic damage were found in the brains of three of these cases. Of the six survivors, four were left with some permanent neurological disability. It is likely that these changes resulted from the inability of the cerebral circulation in patients with severe hypertension to autoregulate blood flow to the brain, so that a rapid reduction in arterial pressure led to ischaemia, especially of the watershed areas of the brain. Cerebrovascular autoregulation is likely to be compromized in patients with cerebral oedema, stenosis of major cranial vessels or in those patients with long-standing severe hypertension. It is suggested that the blood pressure in patients with accelerated hypertension should be lowered gently over a period of several hours or even days in order to allow time for the cerebrovascular autoregulatory mechanisms to recover.
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The apparent suppression of plasma renin activity in essential hypertensive patients compared to normotensive controls prompted an examination of factors which might be responsible for this difference in people taken from a blood pressure screening survey. Plasma renin activity was lower in 89 previously untreated "hypertensive" subjects than in an equal number of age- and sex-matched "controls" from the same community. The rise in plasma renin activity on standing or after frusemide was proportional to the resting level, and it was generally less in hypertensives, but small or absent responses were also seen in those with normal blood pressure. There was no evidence for a "low renin sub-group" among the hypertensives. Plasma renin activity fell with both increasing age and increasing arterial pressure. A low renin activity is more likely to be a consequence of hypertension than to be associated with its cause.
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1. Total renal blood flow and its cortical distribution were measured by the microsphere technique before and after haemorrhage in conscious rabbits, and after haemorrhage in rabbits anaesthetized with pentobarbitone, chloralose-urethane or ether. 2. The average blood loss necessary to achieve a fall in systolic blood pressure to about 65 mmHg was 101 ml in conscious rabbits and 38, 90 and 118 ml in weight-matched groups of rabbits anaesthetized with pentobarbitone, chloralose-urethane and ether respectively. 3. After haemorrhage in conscious rabbits total renal blood flow fell by 25%, this fall being confined to the superficial renal cortex. 4. In rabbits subject to haemorrhage under pentobarbitone anaesthesia renal blood flow fell by a further 23% when compared with the conscious bled rabbits. This reduction in blood flow was confined to the superficial cortex. 5. Haemorrhage in the rabbits subjected to chloralose-urethane anaesthesia caused no significant change in renal blood flow, as compared with conscious bled rabbits. 6. Haemorrhage under ether anaesthesia was associated with a further 33% fall in total renal blood flow, as compared with conscious bled rabbits. This was associated with a fall of 32% and 34% in superficial and deep cortical blood flow respectively. 7. Animals subjected to general anaesthesia may be particularly susceptible to the renal haemodynamic effects of haemorrhage.
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Successful treatment of osteitis fibrosa with 1alpha-hydroxycholecalciferol (1alpha-OHD3) in 9 patients with end-stage chronic renal failure was associated with a significant increase in plasma levels of immunoreactive calcitonin (iCT) independently of changes in plasma calcium, and a decrease in levels of parathyroid hormone (iPTH). In 9 further patients whose plasma alkaline phosphatase activity failed to suppress with 1alpha-OHD3, changes in iPTH were associated with proportionate changes in iCT. This suggests that a rise in endogenous calcitonin (CT) secretion contributes to the success of treatment with 1alpha-OHD3. In 13 further patients, injections of salmon CT induced a fall in plasma calcium and phosphate which was proportional to the prevailing level of plasma alkaline phosphatase. These data provide further evidence that bone resorption can be effectively inhibited when CT levels are raised either by exogenous CT or its endogenous stimulation.
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We studied the effects of bilateral nephrectomy on bone metabolism in 27 patients on maintenance hemodialysis. After nephrectomy plasma alkaline phosphatase fell rapidly in 10 patients whose preoperative plasma levels had been higher than normal. This fall was associated with a transient decrease in osteoblast counts of iliac-bone biopsies. A fall in plasma phosphate and a rise in plasma immunoreactive calcitonin also occurred, but calcium and immunoreactive parathyroid hormone levels did not change. Alkaline phosphatase levels remained unchanged in a control group of 17 patients on dialysis who had undergone an operation other than nephrectomy. In 26 nonsurgical patients on dialysis, immunoreactive calcitonin was inversely related to osteoblast counts. Rises in immunoreactive calcitonin may be partly responsible for the transient decreases in bone turnover after bilateral nephrectomy. Low levels of endogenous calcitonin may allow an increase in bone turnover in chronic renal failure.
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1. The initial blood pressure response to saralasin (Sar1-Ala8-angiotensin II) infusion was examined in 15 normal subjects, eight patients with untreated essential hypertension and 65 patients established on chronic haemogialysis (including six anephric patients), and related to measurements of plasma renin activity (PRA), angiotensin II, plasma catecholamines (noradrenaline and adrenaline), blood volume and extracellular fluid volume ([35S]sulphate space or exchangeable sodium). 2. A transient rise in arterial pressure, maximum after 5-6 min, occurred in all normal subjects, patient with essential hypertension and anephric patients, and in 41 of the 59 dialysis patients with kidneys. 3. In the normal subjects, saralasin infusion resulted in a significant rise in plasma noradrenaline (mean increase 360%, P less than 0-02) without change in plasma adrenaline concentration. The change in noradrenaline was significantly related to the change in mean blood pressure (P less than 0-05) and was similar to the response to 5 min of a 40 degree head-up tilt. 4. An increase in plasma noradrenaline also occurred in dialysis patients (P less than 0-005) but the change in mean blood pressure with saralasin in this group was inversely related to PRA (P less than 0-001) and angiotensin II (P less than 0-001), directly related to blood volume (P less than 0-001), but unrelated to the change in plasma noradrenaline. 5. The pressor response to saralasin may be mediated not only by angiotensin-like action on vascular receptors but also by an action on the central or peripheral autonomic nervous system.
1. The metabolic effects of p-aminophenol have been compared with those of paracetamol and other analgesics in studies of rat liver and kidney in vitro. 2. p-Aminophenol injected into rats inhibited gluconeogenesis from lactate in renal cortical tubules, but not in isolated hepatocytes, and reduced kidney ATP content without affecting the ATP content of liver. Perfused kidneys from rats previously injected with p-aminophenol showed a 50% reduction of ATP content, severe inhibition of Na+ reabsorption and reduction of inulin clearance without significant inhibition of gluconeogenesis from lactate. 3. Paracetamol, p-phenetidine, phenazone and aspirin, when given intravenously to rats, had no effect on renal tubular glucose synthesis from lactate or pyruvate. Paracetamol and aspirin both slightly inhibited renal glucose synthesis from several different substrates when added directly to tubules. 4. Paracetamol (4 mmol/l) inhibited glucose synthesis from lactate and other substrates by 50% or more in isolated hepatocytes. Glucose synthesis from lactate was inhibited 30% by concentrations of paracetamol as low as 0.5 mmol/l. 5. These results indicate that p-aminophenol is a potent inhibitor of proximal tubular function, with its main site of action the inhibition of ATP synthesis and energy production, and they confirm the primary hepatotoxic effect of paracetamol.
Thirty-five patients with bone disease and chronic renal failure (twenty-four on maintenance haemodialysis) were treated for 7--39 months with 1alpha-hydroxyvitamin D3, 2--2.5 microgram daily by mouth. Symptoms (bone pain and muscle weakness) and radiographic appearances improved and plasma alkaline phosphatase returned to normal in the majority of patients (87, 76 and 75% respectively). In contrast, histological appearances in bone improved in only 46% twenty-three patients from whom paired biopsies were available, and this change was not greatly different from that seen in a comparable group of untreated patients. Significant correlations were noted in individual patients between the changes in symptoms, X-rays, plasma alkaline phosphatase and immunoreactive parathyroid hormone and these, in turn, were related to histological changes in bone, although these latter changes were often small. It is concluded that 1alpha-hydroxyvitamin D3 is a useful new drug in the treatment of renal bone disease, but that the evaluation of the response depends critically on the method of assessment used.
The effects of small oral doses (1-2 microgram/day) of 1alpha-hydroxycholecalciferol, given for 1 to 2 years, have been examined in four nondialysed adolescents with chronic renal failure and bone disease. Treatment increased calcium retention and plasma calcium, and decreased plasma levels of alkaline phosphatase, hydroxyproline, and immunoreactive parathyroid hormone. X-ray abnormalities of bone regressed, and 2 patients underwent successful surgical correction of knock-knees; bone histology in these 2 was normal at the time of operation. 2 patients developed hypercalcaemia which promptly reversed when 1alpha-hydroxycholecalciferol was withdrawn. In one patient treatment was initially successful, but later there was biochemical, radiographic, and histological evidence of relapse. Long-term treatment of such patients with 1alpha-hydroxycholecalciferol may be effective and facilitate the surgical correction of deformities, but this is not invariable. Toxic effects are similar to those of vitamin D itself, but are more readily reversible.