Biomedical subjects
D J Warren
Publications and source records attributed to D J Warren.
Vagal function in patients with chronic renal failure.
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Haemodynamic effects of noradrenaline and isoprenaline in chronic renal failure.
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Autonomic neuropathy.
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Effects of high-dose intravenous methylprednisolone on circulation in humans.
We describe four patients who suffered asystole, myocardial infarction (in two cases) and supraventricular tachycardia at the time of high-dose methylprednisolone infusion. One patient died during infusion. We measured the effects of methylprednisolone and placebo infusion on heart rate, blood pressure, and cardiac output in six stable renal allograft recipients. A significant rise in arterial pressure, caused by an increase in total peripheral resistance, occurred during methylprednisolone infusion. Possible mechanisms include potentiation by methylprednisolone of the vascular effects of the high plasma noradrenaline levels that are found in renal allograft recipients. We suggest that electrocardiograms and blood pressure measurements should be monitored during methylprednisolone infusion, especially in patients with preexisting cardiovascular disease.
Increased vascular sensitivity to noradrenaline in hypertensive renal transplant recipients.
We have studied several factors that may cause hypertension in renal transplant recipients. Cardiac output measurements suggest that hypertension is maintained by an increase in total peripheral resistance. Plasma noradrenaline concentration was significantly higher in both normotensive and hypertensive patients than in matched normal subjects. Plasma noradrenaline rose significantly in response to head-up tilt in normotensive, but not in hypertensive, patients. Resting plasma renin activity was significantly higher in both groups of patients than in normal subjects, but there was no relationship between plasma renin activity and blood pressure. Plasma renin activity did not change in response to head-up tilt or isoprenaline infusion in the patients. The rise in arterial pressure during noradrenaline infusion was significantly greater in hypertensive than in normotensive patients. Regression analysis showed a significant relationship between the combination of total exchangeable sodium and the rise in mean arterial pressure during noradrenaline infusion with resting mean arterial pressure.
Acebutolol pharmacokinetics in renal failure.
Acebutolol was administered orally in a single dose of 200 mg to 17 individuals whose renal function varied markedly. The plasma half-life and elimination rate constant for acebutolol showed a four-fold variation but these did not correlate with the degree of renal impairment. However, there was a good correlation between the renal clearance of creatinine and that of acebutolol (P less than 0.001). The half-life and elimination rate of the acetyl metabolite, diacetolol, were subject to 10-fold inter-individual variability which correlated significantly with the creatinine clearance and serum creatinine concentration. The AUC for the acetyl metabolite showed a 40-fold individual variation which also correlated with renal function. It is concluded that renal elimination is the principal route of excretion for diacetolol but not the parent compound, acebutolol.
Effect of acute oral beta adrenergic blockade on muscle blood flow in man.
We have determined the effect of beta blocking drugs in man to ascertain whether cardioselectivity or intrinsic sympathomimetic activity influence muscle blood flow response to exercise. Exercise muscle blood flow was determined using a miniaturised lightweight cadmium telluride detector attached to the skin surface. Mean exercise muscle blood flow for the six subjects, during a constant work load, did not differ significantly either for predosing values on the six separate study days or at 2, 4 and 6 h after dosing with placebo. All the beta blocking agents caused a reduction in exercise muscle blood flow. Propranolol caused significant reduction in muscle blood flow at 2 h only. Metoprolol and atenolol produced the greatest and most prolonged effect and oxprenolol the smallest effect on exercise muscle blood flow. Intrinsic sympathomimetic activity may protect against reduction in exercise muscle blood flow in man.
Diagnosing autonomic neuropathy.
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Uric acid crystal-induced nephropathy: evidence for a specific renal lesion in a gouty family.
Gout is principally a disease of middle-aged men. There has been a lot of discussion over the cause of the renal lesion, whether it is age, hypertension or crystal induced, as single factors or in combination. We have recently been able to study renal biopsies from three related young women with an hereditary gout, and another girl with 2,8-dihydroxyadenine crystal nephropathy. All were normotensive. These findings were compared with the findings of a crystal-induced nephropathy in pigs. In the renal biopsies many stages of acute and chronic nephritis were found which were similar to the crystal nephropathy in pigs. We concluded that the cause of the original lesion in the women was crystal deposition in the tubules, that crystals were not necessary to keep a non-specific nephritis active and that age and hypertension need not be contributory factors.
Cardiovascular and autonomic reflexes in haemodialysis patients.
1. Blood pressure and heart rate responses to head-up tilt, standing, the Valsalva manoeuvre, sustained handgrip and cutaneous cold were measured in 27 haemodialysis patients (10 of whom had episodes of haemodialysis-induced hypotension) and 15 control subjects to assess autonomic nervous function. Plasma noradrenaline levels were measured at rest and during head-up tilt. 2. Mean resting supine blood pressure, heart rate and plasma noradrenaline levels were higher in haemodialysis patients than in the control subjects. There was no fall in blood pressure during head-up tilt or standing. The ratio of the R--R intervals of the thirtieth and the fifteenth heart beat after standing (30:15) was lower in the patients; this may be related to their higher resting heart rate. Head-up tilt raised plasma noradrenaline levels in both groups. Heart rate responses to the Valsalva manoeuvre were similar in the patients and control subjects. 3. Systolic blood pressure and heart rate responses to sustained handgrip were similar in both groups. Diastolic and mean blood pressure changes, however, were lower in the patients. The blood pressure and heart rate responses to cutaneous cold were similar in the patients and control subjects. 4. We conclude that generalized autonomic nervous dysfunction does not appear to cause haemodialysis-induced hypotension in patients with chronic renal failure on maintenance haemodialysis.
Adrenergic components of hypertension after renal transplantation.
1. Blood volume, total exchangeable sodium and the effects of head-up tilt on plasma noradrenaline were studied in 10 normotensive and 11 hypertensive renal transplant recipients. The blood pressure and heart rate responses to infused noradrenaline and isoprenaline were measured. 2. Blood volume and total exchangeable sodium were significantly greater in hypertensive than in normotensive patients. 3. Resting plasma noradrenaline was significantly higher in both groups of transplantees than in normal subjects, but was similar in normotensive and hypertensive patients. 4. Plasma noradrenaline rose in normotensive but not hypertensive patients in response to head-up tilt. 5. The rise in blood pressure in response to infused noradrenaline was significantly greater in hypertensive than in normotensive transplantees. Both groups of patients showed similar responses to infused isoprenaline. 6. Extracellular fluid volume expansion associated with increased alpha-receptor sensitivity to noradrenaline may contribute to hypertension in renal transplant recipients.
Assessment of cadmium telluride detector system for measurement of muscle blood flow during dynamic exercise in man.
We have used a miniature cadmium telluride detector in the assessment of muscle blood flow during dynamic exercise in man following local injection of 133Xenon. The results obtained were compared with those using a conventional sodium iodide detector. There was no significant difference between the results obtained with the two detectors. The reproducibility of results was greater with cadmium telluride than with sodium iodide. The cadmium telluride system has the advantage of being small, lightweight and portable and enables measurements to be made during dynamic exercise.
Familial gout and renal failure.
Clinical gout and renal failure was seen in a 9-year-old girl. The family tree showed that 9 out of 11 young females in three generations suffered from hyperuricaemia and normal (n = 1), or impaired (n = 8), renal function. One set of twins occurred in each generation and there is only one living male subject. In members with renal failure there was no improvement in renal function after treatment of hyperuricaemia, and in 2 sisters oral contraceptives appeared to precipitate hypertension. This clinical picture may be more common than is generally realised because of failure to compare blood uric acid values with suitable age- and sex-matched controls. The evidence from this family suggests that hyperuricaemia preceded the development of renal failure.
Inappropriate renin secretion and abnormal cardiovascular reflexes in coarctation of the aorta.
The response of the renin-angiotensin system to high and low sodium diets, to standing, and to saralasin infusion was assessed before and after surgical correction of aortic coarctation in a 27-year-old man. The cardiovascular responses to tests of autonomic function were measured. The heart rate responses to the Valsalva manoeuvre and standing were abnormal before operation, and plasma renin levels were high and renin secretion responded poorly to changes in dietary sodium, to standing, and to saralasin. Renin responsiveness and cardiovascular reflexes returned to normal after operation. The results are consistent with the hypothesis that there is a high level of sympathetic efferent activity in coarctation of the aorta and that factors other than increased activity of the renin-angiotensin system may cause high blood pressure.
Continuous monitoring of renal transplant function by external forearm counting.
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The role of the adrenergic system in hypertension after renal transplantation.
Heart rate and blood pressure responses to head up tilt in renal transplant recipients were the same as in normal subjects. Resting plasma noradrenaline was higher in transplantees compared to normal subjects but did not differ between normotensive and hypertensive patients. Plasma noradrenaline rose normally in normotensive patients but did not rise in hypertensive patients in responses to head up tilt. The rise in blood pressure during noradrenaline infusion was significantly greater in hypertensive than in normotensive transplantees. The responses to infused isoprenaline were the same in both groups. Total exchangeable sodium was significantly greater in hypertensive than in normotensive patients. Extracellular fluid volume expansion associated with increased alpha receptor sensitivity to noradrenaline may cause hypertension in renal transplant recipients.
Effect of nicotinic acid and dipyridamole on tissue blood flow in peripheral vascular disease.
The effect of 2-weeks' treatment with daily doses of 150 mg nicotinic acid, 300 mg dipyridamole and placebo, in random order, on muscle blood flow and skin temperature gradient in the legs was measured in 6 patients with advanced arteriosclerotic peripheral vascular disease. Mean resting skin temperature gradient and muscle blood flow were uninfluenced by any of these treatments. Dipyridamole, but not nicotinic acid, caused a significant increase in exercise muscle blood flow compared to placebo (p less than 0.01). This improvement was maintained after 2-months' continuous treatment at the end of the trial. It is concluded that dipyridamole may be of value in the medical management of peripheral vascular disease.