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A D Cumming

Publications and source records attributed to A D Cumming.

At least 19 recordsLinked to original sources
PubMed1995

A genetic model of malignant phase hypertension in rats.

A genetic model of malignant phase hypertension in rats is described which closely parallels the natural history of untreated human malignant phase hypertension. Although the factors initiating transition from essential hypertension to the accelerated phase in humans remain unknown, we report the characteristics of a genetically determined and reproducible phenotype which was found to result from a cross between hypertensive transgenic Ren-2 rats and normotensive Sprague-Dawley (Edinburgh) rats. Male F1 hybrids developed malignant phase hypertension with a penetrance of 73.5% (95% confidence limits 65.7 to 81.3%) by 100 days of age. Phenotypic features included an accelerated rise in blood pressure, fibrinoid necrosis, activation of the renal renin-angiotensin system and microangiopathic hemolytic anemia. In an analytical cross no significant difference in blood pressure was observed between malignant phase and non-malignant phase animals prior to transition, implying that a factor in addition to hypertension appears necessary for inducing transition to the malignant phase phenotype. Segregation of the malignant phenotype suggested that susceptibility is determined by at most two genetic loci.

Alleles↗
PubMed1995

Endothelin in the kidney in malignant phase hypertension.

A role for endothelin in malignant phase hypertension has been suggested on the basis of reported increases of circulating plasma immunoreactive endothelins in animal models. Recently, a hypertensive rat model that exhibits a genetically determined tendency for developing spontaneous onset malignant hypertension has been described. Expression of the three genes endothelin-1, endothelin-2, and endothelin-3 was quantified in the kidney by specific RNase protection assays in rats with established malignant hypertension, in rats with benign hypertension with and without a genetic susceptibility to malignant hypertension, and in normotensive Sprague-Dawley rats. Endothelin-1 mRNA levels were significantly elevated in the group with malignant hypertension compared with the other three groups. For determination of whether endothelin-1-mediated effects were crucial in the transition from benign to malignant phase hypertension, an oral nonspecific combined endothelin-A and endothelin-B receptor antagonist (bosentan) was given to hypertensive rats susceptible to malignant hypertension. No hypotensive effects were observed, and no significant difference in the incidence of malignant hypertension was observed between treated and control groups. In conclusion, although increased endothelin-1 mRNA expression was found in kidney tissue from rats developing malignant hypertension, blockade of endothelin-1-mediated effects did not prevent the transition from benign phase hypertension. Hence, increased renal endothelin-1 expression in this model of malignant hypertension does not appear to have a causative role and may simply reflect cellular damage and ischemia.

Animals↗
PubMed1994

Spontaneous development of malignant phase hypertension in transgenic Ren-2 rats.

Spontaneous development of malignant phase hypertension in TGR(mREN2)27 heterozygotes occurs as a consequence of crossing TGR(mREN2)27 homozygotes with Edinburgh Sprague-Dawley rats. Similarities to human malignant phase hypertension are seen with an accelerated rise in blood pressure, fibrinoid necrosis of renal afferent arterioles, renal failure and evidence of renin-angiotensin system activation. It appears that introduction of an additional genetic factor or factors into a monogenic model of hypertension results in malignant phase hypertension.

Animals↗
PubMed1994

Effect of the serine protease inhibitor, aprotinin, on systemic haemodynamics and renal function in patients with hepatic cirrhosis and ascites.

1. Previous studies have documented activation of protease enzymes, such as the plasma kallikrein-kinin system, in hepatic cirrhosis. Increased plasma kinin generation could contribute to pathological systemic vasodilatation in cirrhosis, and reduced systemic vascular resistance has been suggested as a trigger to renal sodium retention in this disease. We investigated the effect of aprotinin, a protease inhibitor which binds to plasma kallikrein, on systemic haemodynamics and renal function in patients with hepatic cirrhosis and ascites. 2. Aprotinin was infused intravenously in high dosage (2 x 10(6) kallikrein inhibitory units loading, 1 x 10(6) kallikrein inhibitory units/h). 3. Of 13 patients, 10 had a low systemic vascular resistance (< 1200 dyn s cm-5) at baseline. In this group, eight showed an increase in systemic vascular resistance during aprotinin infusion. Overall, the increase in systemic vascular resistance was significant, and there was a small but significant increase in mean arterial pressure. In all patients, there were increases in renal plasma flow, glomerular filtration rate, and absolute and fractional urinary sodium excretion during aprotinin infusion. 4. Plasma renin activity, plasma angiotensin II and plasma aldosterone fell significantly during aprotinin infusion. Plasma prekallikrein, plasma noradrenaline and plasma atrial natriuretic peptide did not change. Plasma aprotinin concentration was 209 +/- 11 kallikrein inhibitory units/ml at the end of the infusion. 5. Before and during the infusion, there was a significant negative correlation between systematic vascular resistance and plasma renin activity. There was a positive correlation between the change in systemic vascular resistance and the change in renal plasma flow during aprotinin infusion.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1994

Acute renal failure and sepsis: therapeutic approaches.

Previous studies of experimental sepsis suggested that excessive systemic vasodilatation might be the stimulus to renal hypofiltration and fluid retention in sepsis. Successful therapy for this syndrome requires agents that either act to improve systemic haemodynamics without adverse renal effects, or that act directly on the kidney without impairing circulatory homeostasis. The plasma kallikrein-kinin system is a potent vasodilator pathway, activated by endotoxin. We studied the effect of aprotinin (Trasylol), which inhibits plasma kallikrein, in an ovine model of surgically-induced intra-abdominal sepsis. Given either as an early or late intervention, aprotinin was associated with increased mean arterial pressure and systemic vascular resistance, improved glomerular filtration rate, and increased urinary sodium excretion. In further studies, treatment with the thromboxane synthetase inhibitor, U63,557A (Upjohn), either before or after the surgical induction of peritonitis, was associated with increased glomerular filtration rate and sodium excretion, without any effect on systemic haemodynamics. Logical use of specific antagonists, based on an understanding of the pathophysiology of the septic ARF syndrome, is a desirable strategy.

Acute Kidney Injury↗
PubMed1994

Intrarenal localization of interleukin-1 beta mRNA in crescentic glomerulonephritis.

Il-1 beta is a potent proinflammatory peptide, and induces expression of other cytokines which are involved in the immune response. Kidney biopsies from nine patients with crescentic GN were studied by in-situ hybridization to determine the site of expression of Il-1 beta mRNA. Biopsies from nine patients with nonproliferative renal disease were studied as negative controls, and tonsillar tissue was studied as a positive control. An Il-1 beta cDNA probe was 32P-labelled by random primers and hybridized to paraffin-embedded tissue sections after de-waxing. Il-1 beta mRNA was expressed in tonsil, but not in negative controls. Positive mRNA expression was seen in four of the nine crescentic biopsies. This was observed in interstitial cells with morphological characteristics of macrophages adjacent to tubular cells, in cells within the glomerular tuft, and in tubular epithelial cells. Il-1 beta mRNA is expressed in renal tissue in crescentic GN. Tubular and interstitial expression of Il-1 beta mRNA appears of equal prominence to glomerular expression. Intrarenal cytokine synthesis may be involved in the pathogenesis of crescentic glomerulonephritis.

Adult↗
PubMed1992

Effect of diclofenac on renal function and prostacyclin generation after surgery.

We have examined the effect of diclofenac on renal function after major surgery in a randomized, double-blind, controlled study of 20 patients undergoing oesophagogastrectomy. Diclofenac 75 mg or placebo was given i.m. 12-hourly for 2 days. I.v. fluid administration was standardized. Renal function was assessed by fluid balance and measurement of serum creatinine and electrolyte concentrations, creatinine and free water clearance, and urinary sodium and potassium excretion. Urinary 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha) was measured by radioimmunoassay to assess renal prostacyclin production. After surgery, 6-keto-PGF1 alpha production increased, but this did not occur with diclofenac. On the first day after surgery, use of diclofenac was associated with a decreased urine flow rate, decreased urinary sodium and potassium excretion and a tendency to hyperkalaemia. Frusemide was required more often in the diclofenac group. One patient was withdrawn from the diclofenac group because of impaired renal function. Urine flow rate and blood potassium concentration should be monitored if diclofenac is used after major surgery.

Aged↗
PubMed1992

Hemodynamic, renal, and hormonal actions of aprotinin in an ovine model of septic shock.

BACKGROUND AND METHODS: Previous studies documented activation of protease enzymes such as the plasma kallikrein-kinin system in endotoxemia and sepsis, both in experimental animals and in patients. We investigated the actions of aprotinin (a protease inhibitor that binds to plasma kallikrein) on systemic hemodynamics and renal function, in an ovine model of septic shock. Aprotinin was infused intravenously in high dosage (1 x 10(6) kallikrein inhibitor units [KIU] loading, 200,000 KIU/hr), commencing 30 mins after surgical induction of sepsis (cecal ligation and puncture). RESULTS: In the control group (n = 6), there were significant decreases with time in BP and systemic vascular resistance, an increase in pulmonary artery pressure, reductions in creatinine clearance and sodium excretion, and an increase in plasma renin activity. In aprotinin-treated animals (n = 6), none of these changes occurred. There were significant between-group differences (controls vs. treatment) for mean arterial pressure, pulmonary artery pressure, and plasma renin activity. CONCLUSIONS: In this large animal model of septic shock, which reproduces the important features of clinical sepsis, treatment with aprotinin after the initiation of sepsis appears beneficial in relation to systemic hemodynamics, renal function, and hormonal stimulation, with no evidence of adverse effects.

Analysis of Variance↗
PubMed1992

Vasoactive effects of aprotinin.

The protease inhibitor aprotinin was given a) in experimental septic shock, and b) in patients with hepatic cirrhosis and ascites, since in both conditions, activation of the plasma kallikrein-kinin system is associated with pathological systemic vasodilatation, which may trigger reflex neuroendocrine activation and renal solute retention. Given early in experimental sepsis, aprotinin maintained the arterial pressure, systemic vascular resistance (SVR), creatinine clearance and sodium excretion, all of which fell in controls. Aprotinin also blocked increases in pulmonary artery pressure and plasma renin activity (PRA). Given late in sepsis, aprotinin caused a rapid rise in arterial pressure and SVR towards baseline levels. In cirrhosis, aprotinin increased SVR in patients with low baseline values, and improved glomerular filtration rate, renal plasma flow and sodium excretion in all subjects; PRA was suppressed by aprotinin. Aprotinin reverses pathological systemic vasodilatation in these two conditions, and this is associated with a reduction in renin release and improved renal function.

Animals↗
PubMed1992

Portal and systemic hemodynamics and humoral factors in cirrhosis with and without ascites.

The pathogenesis of salt and water retention in cirrhosis remains unclear. Systemic and portal hemodynamic parameters, including cardiac output, portal pressure gradient and systemic vascular resistance, were measured in six patients with untreated ascites and in six patients with hepatic cirrhosis with no history of ascites. Renal blood flow, urinary volume, and humoral factors, including plasma renin, aldosterone, angiotensin II, and urine kallikrein, were measured. Significant differences were seen between the two groups in urine volume, urine sodium and fractional sodium excretion, plasma angiotensin II, and the ratio between plasma renin activity and urinary kallikrein excretion (PRA:UKallV). A strong correlation existed between urinary sodium excretion and the PRA:UKallV ratio. No significant differences were detected between the groups in portal, renal, and systemic hemodynamics. The present results suggest that humoral changes occur early in ascites. Altered relationships between intrarenal hormone systems, such as the renin-angiotensin and kallikrein-kinin systems, may be important in salt and water retention.

Ascites↗
PubMed1991

Influence of the plasma protein concentration on renal function.

1. The effect of the plasma protein concentration on renal function remains controversial. Most, but not all, experimental studies suggest that a reduced plasma protein concentration perfusing the kidney may reduce tubular sodium reabsorption. Hypoproteinaemic disease states are usually associated with sodium retention, which is not always volume-dependent. 2. We induced a 21% and 24% reduction in plasma total protein and plasma albumin, respectively, in unanaesthetized sheep by acute extracorporeal plasmapheresis. Arterial pressure did not change, and changes in circulatory volume were minimised by infusion of crystalloid to maintain pulmonary artery occlusion pressure, measured using a Swann-Ganz pulmonary artery catheter. 3. After plasmapheresis, there was no significant change in creatinine clearance, sodium excretion, plasma renin activity or urinary kallikrein excretion. 4. After plasmapheresis, there was no significant reduction in plasma osmolality, increase in urine osmolality and fall in free water clearance. 5. The results suggest that in the absence of detectable changes in circulating volume or arterial pressure, acute hypoproteinaemia is associated with significant changes in renal water handling, but has no direct effect on sodium excretion or on renal release of renin and kallikrein.

Acute Disease↗
PubMed1989

Sheep-acquired severe Chlamydia psittaci infection in pregnancy.

There have been five confirmed cases of severe Chlamydia psittaci infection during pregnancy, three having been treated in Edinburgh, Scotland. The most recent case is presented and previous experience is reviewed. The illness usually causes thrombocytopenia with disseminated intravascular coagulation, renal failure and hepatic dysfunction during the late second and early third trimester. The outcome for the fetus is usually fatal and the infection only resolves after delivery or abortion. The main hope is for education to prevent infection occurring in susceptible populations.

Abortion, Incomplete↗
PubMed1989

The protective effect of thromboxane synthetase inhibition on renal function in systemic sepsis.

To study the role of thromboxane in systemic sepsis and renal failure, peritonitis was induced surgically in 22 sheep, leading to local and systemic sepsis. A selective thromboxane synthetase inhibitor, U63,557A (Upjohn Co, Kalamazoo, MI) was given before surgery in five animals and 30 minutes after surgery in five animals. A typical picture of volume-loaded, normotensive, vasodilated septic shock developed in all animals. Twenty four hours after induction of sepsis, the control group showed a marked reduction in glomerular filtration rate (GFR), urine volume, and urinary sodium excretion. Pretreated animals showed no change in GFR and a smaller reduction in urine volume and sodium excretion. The posttreatment group showed no change in any parameters of renal function. Plasma renin activity, urinary TXB2 excretion, and urinary 6-keto PGF1 alpha excretion increased after 24 hours only in the control group. Urinary TXB2 excretion was reduced by 80% in animals given U63,557A before surgery. The results indicate a significant protective effect of U63,557A on renal function during septic shock, probably related to reduced thromboxane synthesis, with no apparent deleterious systemic effects. The results support a role for thromboxane in the pathogenesis of acute renal failure in systemic sepsis.

Animals↗
PubMed1989

The kallikrein-kinin and renin-angiotensin systems in nephrotic syndrome.

We previously found that virtually all patients with nephrotic syndrome (NS) excrete supranormal amounts of urinary kallikrein; it is known that activity of the renin-angiotensin system (RAS) is increased in some such patients. We therefore studied the relationship between urinary kallikrein excretion (UKa) and plasma renin activity (PRA) in 16 patients with NS. Compared with healthy controls, PRA was normal in 8 subjects and elevated in 8; UKa was elevated in the high-renin group (40.4 +/- 5.2 nkat/24 h, normals 12.0 +/- 1.1). UKa was also elevated in the normal renin group (25.7 +/- 2.4 nkat/24 h) but to a significantly lesser degree. Significant activity in plasma against a specific substrate of glandular and renal kallikreins was observed in 8 of 10 patients with NS. Such activity was not found in plasma of 17 patients with glomerulonephritis without NS, or in 10 healthy controls. The results are in keeping with previous suggestions of a functional link between the renal kallikrein-kinin system (KKS) and the RAS, but indicate that the renal KKS is activated in NS, in some cases independently of the RAS. It is possible that renal kallikrein reaches the systemic circulation in some patients with NS.

Adult↗
PubMed1988

The acute renal haemodynamic and endocrine response to felodipine in normal man.

Felodipine (0.075 mg/kg p.o.), a calcium antagonist, was given to 9 male volunteers, with and without indomethacin pretreatment. Diuresis and natriuresis occurred after felodipine without significant change in effective renal plasma flow or glomerular filtration rate. There was no significant change in urinary 6 keto PGF 1 alpha or urinary kallikrein excretion and indomethacin did not inhibit the natriuretic or diuretic response to felodipine. The felodipine induced diuresis and natriuresis appears most likely to be mediated by an action of the drug on renal tubules.

Adult↗