saralasin and Acute-Kidney-Injury

The roles of intrarenal angiotensin (A) and thromboxane (TX) in the vascular hypersensitivity to renal nerve stimulation (RNS) and paradoxical vasoconstriction to renal perfusion pressure (RPP) reduction in the autoregulatory range in 1 wk norepinephrine (NE)-induced acute renal failure (ARF) in rats were investigated. Renal blood flow (RBF) responses were determined before and during intrarenal infusion of an AII and TXA2 antagonist. Saralasin or SQ29548 alone partially corrected the slopes of RBF to RNS and RPP reduction in NE-ARF rats (P less than 0.02). Saralasin + SQ29548 normalized the RBF response to RNS. While combined saralasin + SQ29548 eliminated the vasoconstriction to RPP reduction, similar to the effect of renal denervation, appropriate vasodilatation was not restored. Renal vein norepinephrine efflux during RNS was disproportionately increased in NE-ARF (P less than 0.001) and was suppressed by saralasin + SQ29548 infusion (P less than 0.005). It is concluded that the enhanced sensitivity to RNS and paradoxical vasoconstriction to RPP reduction in 1 wk NE-ARF kidneys are the result of intrarenal TX and AII acceleration of neurotransmitter release to adrenergic nerve activity.

Topics: Acute Kidney Injury; Angiotensin II; Animals; Blood Flow Velocity; Bridged Bicyclo Compounds, Heterocyclic; Fatty Acids, Unsaturated; Hydrazines; Kidney; Norepinephrine; Rats; Rats, Inbred Strains; Renal Circulation; Saralasin; Sympathetic Nervous System; Thromboxane A2

Cadaver kidney donors were treated with Angiotensin II-Analogon-Saralasin before nephrectomy in order to reduce the rate of acute renal failure. Eighteen (64.3%) of the recipients of the 30 donor kidneys pretreated with Saralasin were primarily free from dialysis. Six recipients showed acute renal failure. Two donor kidneys never resumed their function and no reports could be obtained on two organs. In the control-group with no pre-treatment, acute renal failure appeared significantly more often (67.3%). Thus only 32.7% of the recipients needed no further dialysis. This difference is statistically significant.

Topics: Acute Kidney Injury; Adolescent; Adult; Cadaver; Humans; Kidney Function Tests; Kidney Transplantation; Nephrectomy; Postoperative Complications; Premedication; Renin-Angiotensin System; Saralasin

To estimate the renal ischemia-protective effect of saralasin, model studies were performed on rats and dogs. Acute ischemic renal failure was induced in rats by clamping off the vascular pedicle for 90 minutes. When the drug was prophylactically administered before the ischemia episode, a premature increase in post-ischemic plasma urea level and a shortening of survival time of the animals were observed compared with the untreated control. Following auto-transplantation of 24-hour cold-stored dog kidneys, the infusion of saralasin failed to improve renal blood flow (MRBF), glomerular filtration rate (KrCl) and fractional sodium excretion (FENa). On the other hand, the angiotensin blockade with captopril led to an increase in MRBF which was associated, however, with significant decreases in KrCl and FENa. This discrepancy was suggested to be due to a predominant postglomerular vasodilation. The results show that the application of saralasin before renal ischemia may aggravate the loss of renal function whilst the post-ischemic administration of the drug has no substantial effect on the acute failure of transplanted kidneys.

Topics: Acute Kidney Injury; Animals; Captopril; Dogs; Ischemia; Kidney; Kidney Function Tests; Kidney Transplantation; Organ Preservation; Rats; Rats, Inbred Strains; Renal Circulation; Saralasin; Vascular Resistance

Kidneys from cadaver donors who had been treated during the last 10 min before bilateral nephrectomy with an infusion of 10 micrograms/kg-1/min-1 (Sar1, Val5, Ala8)-angiotensin II had a remarkable, significantly lower percentage of acute renal failure (25%) after renal transplantation than untreated kidneys (58.3%). Anuria was seen in the treated group only in 4.2%, although it occurred in the untreated control group in 16.6%. The role of the activated renin-angiotensin system in postischemic acute renal failure is discussed.

Topics: Acute Kidney Injury; Adolescent; Adult; Angiotensin II; Child; Diuresis; Female; Humans; Ischemia; Kidney; Kidney Transplantation; Male; Nephrectomy; Prospective Studies; Saralasin

In the present study 1 h of total occlusion of the left renal artery in conscious rats was chosen as experimental model of ischemic acute renal failure (ARF), while the contralateral kidney was left intact. Chronic high dietary sodium intake, acute isotonic saline infusion, or administration of saralasin did not protect from ARF. Furosemide, mannitol, and verapamil converted oliguric into non-oliguric ARF in 100%, 75%, and 60% of the animals, resp. Protection from oliguria and preservation of GFR inversely correlated with the depression of cortical ATP-concentration (control: 1.32 +/- 0.07 mumoles/g wet weight) 6 h after ischemia by 16%, 41%, and 58% in mannitol- and verapamil- treated rats and in untreated rats, resp. At this time, Na-K-ATPase enzyme activities in renal cortex and papilla were unaffected, while enzyme activity in outer medulla was suppressed from 15.4 +/- 1.4 to 9.4 +/- 1.0 mumoles Pi/mg protein h in all groups of animals. The results suggest that in this model of ARF renal ischemia not only affects cellular energy supply in renal cortex but also causes severe structural and functional impairment in the outer medulla, probably leading to tubular obstruction and depression of glomerular function. Pharmacological protection from ischemic oliguric ARF cannot be achieved by prior induction of high urine flow rates alone but depends on the degree of metabolic and functional reserve of the injured tubular epithelium.

Topics: Acute Kidney Injury; Animals; Female; Furosemide; Ischemia; Kidney; Mannitol; Rats; Rats, Inbred Strains; Saralasin; Urodynamics; Verapamil

Infusion of thrombin and the fibrinolysis inhibitor tranexamic acid during ether anaesthesia in the rat gives rise to fibrin deposition in the renal glomeruli. This resulted in renal insufficiency as indicated by an increase in the serum urea nitrogen, reduction in the renal blood flow and patchy cortical necrosis in the kidneys. The plasma renin activity was elevated initially probably due to the ether anaesthesia. Infusion of the angiotensin II antagonist saralasin prevented the renal insufficiency if it was given during the thrombin infusion but not if it was given afterwards. The deposition of fibrin in the kidneys was also reduced. The results indicate that angiotensin II is involved in the pathogenesis of the renal injury.

Topics: Acute Kidney Injury; Angiotensin II; Animals; Female; Fibrin; Rats; Rats, Inbred Strains; Renal Artery Obstruction; Renal Circulation; Renin; Renin-Angiotensin System; Saralasin; Thrombin

Many potential cadaveric kidney donors have been exposed to shock or hypotension before or during organ donation. Renin-mediated vasoconstriction has been implied in the pathogenesis of acute renal failure. High renin levels have been associated with poor graft survival under hypothermic pulsatile perfusion. An attempt was made to block renin effect with Saralasin (1-Sar-8-ala-angiotensin II), a competitive blocker. Eight conditioned mongrel dogs had their renal arteries exposed, and Saralasin, 100 microgram, was injected intra-arterially. Warm ischemia was then induced for 30 min. Thereafter, the kidney was removed and placed under hypothermic pulsatile perfusion for 24 hours, during which time Saralasin was given continuously at a rate of 1 microgram/min. The kidneys were reimplanted in the same animal on the contralateral iliac fossa, Saralasin, 100 microgram, was given intraarterially after implantation, and a contralateral nephrectomy was performed. Four control animals were given saline solution instead of Saralasin. No significant differences were noted in perfusion characteristics and postoperative creatinine values between treated and control groups. This apparent lack of protective effect of angiotensin II competitive blocker suggests that in the pathophysiology of acute renal failure other factors could be involved besides renin release.

Topics: Acute Kidney Injury; Angiotensin II; Animals; Blood Pressure; Creatinine; Dogs; Female; Ischemia; Kidney; Kidney Transplantation; Postoperative Complications; Saralasin; Transplantation, Autologous; Vascular Resistance

1. In rats deprived of food and water for 24 h acute renal failure was produced by the intramuscular injection of glycerol. Eight hours later plasma urea concentration had increased threefold despite a small rise in urine volume. Plasma concentrations of renin and renin substrate were elevated. 2. When saralasin, a competitive antagonist of angiotensin II, was infused for 8 h after glycerol injection, urine volume and plasma urea were similar to values in rats that had received an infusion of saline. 3. Administration of rat serum (4.5 ml h-1 kg-1) for 4 h suppressed plasma renin concentrations, but plasma urea increased to the same extent as in rats without serum. 4. When saralasin and serum were infused at the same time, urine volume, urine osmolality and solute excretion increased and the rise of plasma urea was diminished. 5. Saralasin has a protective effect against glycerol-induced acute renal failure only when volume is replaced concomitantly.

Topics: Acute Kidney Injury; Angiotensin II; Animals; Blood; Glycerol; Male; Rats; Renin; Saralasin; Time Factors; Urea; Urodynamics

The effects of the competitive angiotensin II antagonist saralasin (1-sarcosine-8-alanine-5-isoleucine-angiotensin II) on renal function in healthy rats and in rats with myohemoglobinuric acute renal failure were studied. Acute renal failure was induced by an intramuscular injection of 50% glycerol (10 ml.kg-1). Functional impairment of the glycerol treated animals consisted in a decrease of renal blood flow (electromagnetic flowmeter) and GFR and in an increase of urine volume and arterial blood pressure. In healthy rats saralasin (6 microgram.kg-1.min-1 i.v.) had no renal effects by itself but antagonized the angiotensin II (200 ng.kg-1.min i.v.) induced fall of renal blood flow and GFR and the increase of arterial blood pressure. Given to glycerol treated animals saralasin did not induce any change of arterial blood pressure, renal blood flow, GFR or the urinary excretion of fluid and sodium.

Topics: Acute Kidney Injury; Angiotensin II; Animals; Blood Pressure; Glomerular Filtration Rate; Glycerol; Kidney; Male; Rats; Regional Blood Flow; Saralasin

Topics: Acute Kidney Injury; Angiotensinogen; Animals; Arginine Vasopressin; Blood Pressure; Glycerol; Hematocrit; Immune Sera; Male; Osmolar Concentration; Rats; Renin; Saralasin; Urea; Vasopressins

In the isolated perfused rat kidney, saralasin inhibits the vasoconstrictor effect of angiotensin II in a dose-dependent manner. At high infusion rates saralasin, by itself, increases renal vascular resistance and supresses renin release. Such an agonistic effect is not observed in the presence of high concentrations of angiotensin II. In acute renal failure induced by glycerol, saralasin has a beneficial effect on urine volume, solute excretion and plasma urea concentration only when it is administered together with an adequate volume of rat serum.

Topics: Acute Kidney Injury; Angiotensin II; Animals; Diuresis; In Vitro Techniques; Kidney; Male; Perfusion; Rats; Regional Blood Flow; Renin; Saralasin; Time Factors; Urea; Vascular Resistance

Acute renal failure was produced in rats by right nephrectomy and total occlusion of the left renal artery for 70 min. Angiotensin II competitive inhibitor, P113 (1-sar-8-ala-angiotensin II), was administered intravascularly for 100 min, starting 15 min before the clamping of the renal artery. A marked rise in plasma renin activity was observed 15 min after declamping and was significantly higher in the P113-treated rats than in saline-treated animals. The rise in plasma renin activity was observed 15 min after declamping and was similar in the two groups, indicating that P113 does not prevent the development of acute renal failure in this experimental model. It is suggested that the marked rise in plasma renin activity may be due to interruption of the normal feedback mechanisms which suppress renin release, as a result of occupation of the angiotensin II receptor sites by P113.

Topics: Acute Kidney Injury; Angiotensin II; Animals; Creatinine; Female; Ischemia; Kidney; Rats; Renin; Saralasin; Urea

The effectiveness of beta-adrenergic blockade in preventing acute renal failure (A.R.F.) in rats was studied in the hypoxia model produced by unilateral nephrectomy and clamping of the contralateral renal artery for 70 minutes. Beta-adrenergic blockade effectively reduced the severity of A.R.F. in this experimental model. Treatment with a combination of propranolol and a synthetic angiotensin-II competitive inhibitor (P113) produced no further improvement. These results are consistent with the view that intrarenal release of renin is to some extent involved in the pathogenesis of A.R.F.

Topics: Acute Kidney Injury; Animals; Blood Specimen Collection; Creatinine; Disease Models, Animal; Drug Therapy, Combination; Female; Kidney; Propranolol; Rats; Rats, Inbred Strains; Renin; Saralasin; Time Factors; Urea