saralasin and Ischemia

Topics: Adolescent; Adult; Age Factors; Animals; Arteriosclerosis; Bradykinin; Female; Fibromuscular Dysplasia; Humans; Hypertension, Renal; Hypertension, Renovascular; Ischemia; Kidney; Kidney Function Tests; Kidney Transplantation; Male; Prostaglandins; Radiography; Renal Artery; Renal Artery Obstruction; Renin; Renin-Angiotensin System; Saralasin; Sex Factors

We examined in anesthetized dogs the effects of left (L) intrarenal artery infusion of angiotensin II (AII) on renal hemodynamics, urinary concentration and Na excretion, and papillary plasma flow (PPF) (measured by the albumin accumulation technique) in both kidneys. Following AII infusion (0.5 ng/kg/min) into the L renal artery, urinary Na excretion decreased and osmolality increased slightly ipsilaterally, whereas Na excretion did not change significantly and osmolality decreased in the right (R) kidney. PPF was significantly lower in the L compared to the R kidney. When saline loading was superimposed on L intrarenal AII infusion, there was a blunted natriuretic response ipsilaterally with a significantly smaller decrease in urine osmolality compared with the R kidney. PPF increased significantly in the R, but not in the L kidney. Finally, AII blockade with saralasin prior to AII infusion and saline loading prevented the differences between the two kidneys, including PPF. In all groups GFR and renal blood flow did not differ between the two kidneys before or after AII. These data suggest that AII regulates regional blood flow in the medulla, and that the exogenously administered AII induces papillary ischemia, which serves to preserve medullary hypertonicity, preventing an increase in PPF during saline loading, and possibly contributing to the diminished natriuretic response.

Topics: Angiotensin II; Animals; Dogs; Glomerular Filtration Rate; Infusions, Intra-Arterial; Ischemia; Kidney Concentrating Ability; Kidney Medulla; Natriuresis; Renal Circulation; Saralasin

Intermittent patchy ischemia in the renal cortex during traumatic shock has previously been observed in dogs and rats. In recent experiments on rats a high rate of abrupt changes in local blood flow was observed after scalding. To try to reveal endogenous factors causing such ischemic episodes, we scalded six series of anesthetized rats (50% of body surface for 30 s in 80 degrees C water) and measured arterial pressure (AP), hematocrit (Hct), and local renal cortical blood flow (RCF). RCF was recorded by the local H2 washout technique. After scalding, RCF decreased markedly in all series whereas AP was relatively well preserved. In accordance with previous experiments, 11% of the washout curves recorded 0-75 min after scalding showed abrupt changes in local blood flow, rising to 27% during the next 60 min in drug-untreated rats. In contrast, blocking of serotonin S2 receptors with Ketanserin abolished the phenomenon. However, in rats treated with the prostaglandin synthesis blockers, indomethacin (general) or 3-ethyl pyridin (thromboxane A2 blocker), the phenomenon was observed in only 2-3% of the washout curves. Furthermore, after blocking the AngII receptors by saralasin or alpha receptors by phentolamine in separate series, the frequency of abrupt flow shifts was reduced in comparison to the frequency in untreated rats. The results indicate that intermittent, patchy vasoconstriction is mediated by serotonin and thromboxane A2 (TxA2), probably released from platelets. The occurrence of ischemic episodes also depends on the local AngII and alpha-adrenergic tonus present after scalding.

Topics: Animals; Blood Pressure; Burns; Indomethacin; Ischemia; Ketanserin; Kidney Cortex; Male; Phentolamine; Prostaglandins; Rats; Rats, Inbred Strains; Receptors, Adrenergic, alpha; Receptors, Angiotensin; Receptors, Serotonin; Regional Blood Flow; Saralasin; Shock, Traumatic; Thromboxane-A Synthase

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

By blocking the renin-angiotensin-system with saralasin or salt-loading the postischemic damage of the renal microcirculation is diminished. This can be realized in a markedly improved oxygenation of renal tissue. As a result of the improved microcirculation 60 minutes after a 120-minutes ischemic damage one can find a better filtration rate, i.e. tubular function in treated kidneys.

Topics: Aminohippuric Acids; Animals; Dogs; Inulin; Ischemia; Kidney; Renin-Angiotensin System; Saralasin

Topics: Angiotensin II; Angiotensins; Blood Pressure; Captopril; Humans; Hypertension; Ischemia; Kidney; Peptidyl-Dipeptidase A; Posture; Renin; Saralasin; Teprotide

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

Topics: Angiotensin II; Animals; Dogs; Female; Ischemia; Kidney; Kidney Function Tests; Kidney Transplantation; Organ Preservation; Perfusion; Phentolamine; Prostaglandins E; Saralasin

1. Blood pressure and plasma renin activity were studied after bilateral nephrectomy in groups of rats with hypertension caused by unilateral renal ischaemia with the opposite kidney left intact. 2. Although blood pressure showed only a small fall in the first hour after bilateral nephrectomy, plasma renin activity fell rapidly with a half-life of 10 min. 3. Infusion of converting enzyme inhibitor (SQ20881) produced a 26-1% fall in blood pressure 1 h after nephrectomy, 24-% at 2 h and 4-6% at 6 h. 4. An angiotensin antagonist (Sar1-Ala8-angiotensin II) was infused into hypertensive rats 1 h after nephrectomy; this blocked the vasodepressor action of the converting enzyme inhibitor, indicating that the fall in blood pressure produced by the inhibitor was due to its action upon the renin-angiotensin system. 5. The renin-angiotensin system maintains blood pressure in this model even after plasma renin has fallen to insignificant levels. This supports the view that vascular renin activity has a longer half-life than circulating renin and is important in the control of blood pressure.

Topics: Angiotensin II; Animals; Arteries; Blood Pressure; Female; Hypertension; Ischemia; Kidney; Nephrectomy; Oligopeptides; Rats; Renin; Saralasin; Teprotide

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

Peripheral plasma renin activity (PRA) is not invariably elevated in patients whose ischemic renal lesion is causing hypertension. Infusions of an angiotensin II antagonist, 1-sar-8-ala-angiotensin II (P-113), have been used to determine whether the blood pressure responses might indicate angiotensin dependence in 221 consecutive hypertensive patients. In 32 patients P-113 infusion reversibly reduced blood pressure, and almost all of these "P-113 responders" had elevated renal vein and/or peripheral PRA levels, together with evidence of renal ischemia. Among the 189 "P-113 nonresponders," peripheral PRA was elevated in seven (3.8%), and renal vein PRA ratio was abnormal in two patients, who might represent exceptions to the otherwise successful record of the P-113 response in identifying "angiotensinoginic" hypertensives.

Topics: Adult; Aged; Angiography; Angiotensin II; Blood Pressure; Humans; Hypertension; Ischemia; Kidney; Middle Aged; Nephrectomy; Radioisotope Renography; Regional Blood Flow; Renal Veins; Renin; Saralasin; Urography

1. The acute reduction of renal blood flow following adrenalectomy in the rat, which had previously been shown to be associated with sequestration of blood volume in the splanchnic area, was further investigated. An attempt was made to define the role of the renal sympathetic nerves in causing the blood flow change. 2. The systemic and renal intra-arterial administration of phenoxybenzamine, isoprenaline and propranolol and denervation of the renal pedicle failed to re-establish normal renal function. 3. Infusion of P113 (sarcosyl1 alanine8), an angiotensin blocker, failed to improve renal function. 4. In contrast, volume replacement with high-molecular weight PVP caused a prompt increase of RPF and GFR without altering arterial pressure and central venous pressure. 5. Angiographic studies demonstrated that the calibre of the aorta of adrenalectomized rats was significantly smaller than that of the sham operated and increased after the administration of this plasma volume expander. 6. It was concluded that after adrenalectomy the major arteries readjusted their calibre to the reduced volume of blood in the arterial tree with maintenance of a constant pressure/volume relationship. Their contracted state in the case of the kidney then led to flow reduction.

Topics: Adrenalectomy; Animals; Aorta; Blood Pressure; Central Venous Pressure; Denervation; Glomerular Filtration Rate; Ischemia; Isoproterenol; Kidney; Male; Phenoxybenzamine; Plasma Substitutes; Propranolol; Rats; Regional Blood Flow; Saralasin; Sympathetic Nervous System