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Biomedical subjects

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

Renal expression of interleukin-2 receptor mRNA in patients with crescentic glomerulonephritis.

We studied paraffin sections of renal biopsies from 7 patients with crescentic glomerulonephritis (CGN) by in situ hybridisation, to detect sites of interleukin-2 receptor (IL-2R) mRNA expression. Frozen sections from a further patient with CGN were studied by immunohistochemistry with a monoclonal antibody to CD25, to detect IL-2R protein. Positive control sections were taken from biopsies of acute cellular renal transplant rejection and negative controls from biopsies of membranous glomerulonephritis. No autoradiographic signal was detected in negative controls. IL-2R mRNA expression was seen in rejected transplants and in sections from 4 to 7 patients with CGN. Expression was seen in cortical interstitial cells, renal tubular epithelial cells, cells within glomerular crescents and in one glomerulus at the margin of Bowman's capsule. Tubular cell expression of IL-2R protein was confirmed by immunohistochemistry. We have confirmed that IL-2R mRNA expression occurs locally within the kidneys in CGN and have identified expression in tubular epithelial cells. The results suggest that local activation of immunocompetent cells occurs in the kidney and may be of significance in the pathogenesis of CGN.

Adult↗
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

Expression of tissue kallikrein in human kidney.

1. We studied the distribution of human tissue kallikrein mRNA in normal and diseased kidney, using in situ hybridization, together with immunohistochemical localization of renal kallikrein protein. Materials studied were (a) normal tissue from kidneys removed because of localized renal carcinoma, (b) kidneys removed because of post-traumatic haemorrhage and (c) renal biopsy specimens from patients with membranous glomerulonephritis and nephrotic syndrome. 2. A 1.35 kb EcoRI fragment of human tissue kallikrein cDNA was labelled with [32P]dCTP using the random-primer technique, and used for in situ hybridization. A specific rabbit antibody to active human urinary kallikrein was employed for immunocytochemistry, using a peroxidase-antiperoxidase method. 3. By in situ hybridization, no tissue kallikrein gene expression was seen in the carcinoma nephrectomy specimens. Positive expression was seen in the trauma nephrectomy tissue, and in four of five nephrotic syndrome biopsies. In all kidneys, expression was confined to the renal cortex. The dominant site of gene expression was the distal tubule. Apart from one area of positive signal related to an epithelial cell of Bowman's capsule, expression was not observed in glomeruli. Expression was also seen in the walls of large- and medium-sized blood vessels. 4. By immunohistochemistry, the dominant site of immunoreactivity was the distal tubule. Dense staining was also seen in granular peripolar cells and in isolated parietal epithelial cells close to the vascular pole. Isolated immunoreactive cells were seen in the media of large- and medium-sized arteries. 5. The tissue kallikrein gene in the kidney may not be constitutively expressed, but is expressed in response to physiological or pathological stimuli.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
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

Changes in plasma calcium during septic shock.

Previous studies have documented a decrease in plasma calcium occurring early after trauma, haemorrhage and cardiac arrest. Therefore, changes in plasma calcium in an ovine experimental model of septic shock due to intraperitoneal sepsis were investigated. Subjects were volume-loaded with Ringer's lactate solution. Plasma calcium and albumin were measured before and 24 h after surgical induction of sepsis. Subjects were divided into two groups according to the severity of shock. Group 1 (n = 8) developed severe hyperdynamic sepsis with renal failure. Group 2 (n = 8) showed no change in blood pressure, cardiac output or renal function. Plasma calcium fell significantly in both groups, and was lower in Group 1 during sepsis (Group 1: 2.36 +/- 0.19 to 1.84 +/- 0.14 mmol l-1; Group 2: 2.34 +/- 0.12 to 2.01 +/- 0.13 mmol l-1; mean +/- SD; both P < 0.001). Plasma albumin fell during sepsis, and the reduction was greater in Group 1. The plasma calcium, corrected for albumin, was still significantly reduced and was similar in each group during sepsis (Group 1: 2.55 +/- 0.13 to 2.23 +/- 0.12 mmol l-1; Group 2: 2.50 +/- 0.08 to 2.27 +/- 0.09 mmol l-1; both P < 0.001). In this large animal model of septic shock, which reproduces the important features of clinical sepsis, there were significant decrements in uncorrected and corrected plasma calcium 24 h after the surgical induction of intraperitoneal sepsis. These changes may contribute to the pathophysiology of this condition.

Animals↗
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↗