Augmentation of renal response by magnesium lithospermate B

Magnesium lithospermate B and adenine were given simultaneously to rats p.o. in order to investigate their renal effects. In rats given magnesium lithospermate B at a dose of 5 mg/kg body weight/day for 12 or 24 days, glomerular filtration rate, renal plasma flow and renal blood flow were increased significantly. A significant increase in renal function parameters was also found in rats given 10 mg of magnesium lithospermate B. Urinary excretion of prostaglandin E2 was increased by administration of magnesium lithospermate B, while those of 6-keto-prostaglandin F1 alpha and thromboxane B2 were unaffected at a dose of 5 mg or 10 mg/kg body weight/day for 12 or 24 days. The activity of kallikrein in urine increased markedly and significantly in rats given 5 or 10 mg of magnesium lithospermate B for 12 or 24 days. From these results, it seems that magnesium lithospermate B increases renal function by improving the renal circulatory state through activation of kallikrein and promotion of prostaglandin E2 production.     

Effect of magnesium lithospermate B in rats with sodium-induced hypertension and renal failure.

To evaluate the antihypertensive effect of magnesium lithospermate B isolated from Salviae miltiorrhizae radix, determinations of blood pressure and urinary excretions of sodium, potassium, prostaglandin E2 (PGE2) and kallikrein, which have been proposed to play an important role in the regulation of blood pressure, were made in rats with sodium-induced hypertension and renal failure. In rats given magnesium lithospermate B, blood pressure was significantly decreased, whereas urinary excretion of electrolytes was significantly increased. Urinary PGE2 excretion following administration of magnesium lithospermate B increased as the dose of the compound was stepped up. The activity of kallikrein in urine was also increased by the treatment. From these results, the blood pressure-lowering action of magnesium lithospermate B may be due in part to enhancement of the kallikrein-prostaglandin system.     

Renal function and urinary prostaglandins in rats given an adenine diet

The glomerular filtration rate (GFR), renal plasma flow (RPF) and renal blood flow (RBF) were all markedly decreased in rats given an adenine diet as the period of adenine administration lengthened. Concurrently, the urinary excretions of prostaglandin E2 (PGE2) and 6-keto-prostaglandin F1 alpha(6-keto-PGF1 alpha) decreased gradually in parallel with the renal function parameters, whereas the urinary excretion of thromboxane B2 (TXB2) increased markedly. These findings suggest the involvement of prostaglandin in the renal circulation.     

Augmentation by aprotinin of the renal response to vasopressin

We contrasted the renal effects of vasopressin in Brattleboro rats with and without pretreatment with aprotinin (20,000 KIU kg-1). In both treatment groups, vasopressin injected at 3 mU kg-1 sec caused in conscious rats elevation of urine osmolality and reduction of urine flow and urinary excretion of total solutes. However, these effects of vasopressin were significantly greater in aprotinin pretreated rats than in rats without aprotinin treatment. In ketamine-pentobarbital-anesthetized rats without aprotinin pretreatment, vasopressin infused at 2 mU kg-1 hr-1 elevated urinary kinin excretion but did not affect urine flow rate or osmolality; in contrast, in aprotinin-pretreated rats, the same dose of vasopressin did not increase urinary kinins but caused elevation of urinary osmolality and reduction of urine flow, solute excretion, and glomerular filtration rate. Aprotinin pretreatment in anesthetized rats also blunted the rise in kinin excretion elicited by vasopressin at a higher dosage, 5 mU kg-1 hr-1, but did not potentiate the vasopressin-induced antidiuresis. We conclude that aprotinin facilitates the expression of the antidiuretic effect of vasopressin at a low, but not at a high dosage. This effect of aprotinin may be a consequence of: renal kallikrein inhibition which prevents augmentation of renal kinins in response to increased vasopressin levels, or other unrecognized properties of aprotinin.     

Aprotinin does not impair renal haemodynamics and function after cardiac surgery

Patients undergoing cardiac surgery with moderate hypothermic cardiopulmonary bypass (CPB) were allocated randomly to receive either saline (control group, n = 29) or a high-dose regimen of aprotinin (aprotinin group, n = 28). In both groups, CPB was associated with similar and transient increases in effective renal plasma flow (+54% in controls and +48% in aprotinin-treated patients) and in fractional excretion of sodium and potassium, but glomerular filtration rate remained unchanged. Plasma and urinary ratios of 6-keto-PGF1 alpha to thromboxane B2 (TxB2) increased significantly, indicating systemic and renal release of vasodilatory prostaglandins. Osmolar clearance correlated with urinary excretion of cyclic GMP (r = 0.79 and 0.86 in the control and aprotinin groups, respectively) and 6-keto-PGF1 alpha (r = 0.63 and 0.69 in the control and aprotinin groups, respectively). Compared with preoperative values, plasma atrial natriuretic peptide increased after weaning from CPB (+71% and +93% in the control and aprotinin groups, respectively). Aprotinin had no apparent adverse effect on renal function and it did not alter mechanisms involving prostanoids and atrial natriuretic peptide during cardiac surgery.      

Is thromboxane a potent antinatriuretic factor and is it involved in the development of acute renal failure?

Glycerol-treated rats exhibited significantly increased urinary thromboxane B2(TXB)2, prostaglandin E2 (PGE2) and 6-ketoprostaglandin F1 alpha (6kPGF1 alpha) excretion and urine volume (UV). These increases were associated with significant decreases in creatinine clearance (CCr), urinary sodium concentration (UNa), urinary sodium excretion (UNaV), and fractional excretion of sodium (FENa%), which is consistent with the development of the prerenal (reversible) phase of acute renal failure (ARF). When glycerol-treated rats were pretreated with a selective inhibitor of thromboxane A2 (TXA2) synthesis (imidazole), urinary PGE2 and 6kPGF1 alpha excretion and UV remained unchanged, whereas CCr, UNa, UNaV decreases were partially prevented. Additionally, FENa% was increased, indicating inhibition of sodium reabsorption. The findings indicate that inhibition of TXA2 synthesis increases UNaV and partially improves CCr in glycerol-treated rats. Further histologic observation and functional follow-up over longer periods of time are needed to clarify the role of TXA2 in the development of ARF.     

Role of renal sympathetic nerve activity in renal failure associated with obstructive jaundice in the rat.

The propensity for renal failure associated with obstructive jaundice and liver disease may be related to enhanced vasoconstriction of the renal vascular bed with resultant decreases in renal blood flow. Renal sympathetic nervous activity may be a mediator of this effect. The increased renal production of prostaglandins which has been observed in previous models of bile duct ligation may serve to counterbalance the effects of such vasoconstricting influences. This study was undertaken to assess the effect of bile duct ligation on renal function and prostaglandin production in the rat. Furthermore, this study was designed to determine if renal sympathetic nerve activity contributes to the development of renal failure after bile duct ligation. Sprague-Dawley rats underwent either sham operation (n = 8), bilateral renal denervation (n = 10), bile duct ligation alone (n = 11), or bile duct ligation and bilateral renal denervation (n = 10). Renal function was assessed before and 4 days after operation. Bile duct ligation resulted in a 46% decrease in creatinine clearance (p less than 0.01), a 33% decrease in urinary sodium excretion (p less than 0.01), a twofold increase in urine flow (p less than 0.01), and twofold increases in urinary excretion of PGE2, 6-keto-PGF1 alpha, and thromboxane B2 (p less than 0.01). Renal denervation did not prevent the decreases in creatinine clearance and sodium excretion seen after bile duct ligation and had no effect on the changes in urine flow and prostaglandin excretion. These findings demonstrate that bile duct ligation in the rat results in impaired renal function, accompanied by increases in renal prostaglandin production. In addition, this study indicates that the perturbations in renal function and renal prostaglandin production induced by bile duct ligation are not mediated by renal sympathetic nerve activity.     

Aprotinin decreases release of 6-keto-prostaglandin F1 alpha and increases release of thromboxane B2 in cultured human umbilical vein endothelial cells.

Use of the proteinase inhibitor aprotinin significantly improves hemostasis and reduces bleeding after operations in which extracorporeal circulation is used. The mechanism of action, however, has been only partially clarified. In this work we investigated whether aprotinin influenced the production and release of the eicosanoids prostacyclin, measured as the stable metabolite 6-keto-prostaglandin F1 alpha, and thromboxane A2, measured as the stable metabolite thromboxane B2, from endothelial cells. Human umbilical vein endothelial cells were incubated with different concentrations of aprotinin (5.5, 20, 55, and 100 mumol/L). The levels of 6-keto-prostaglandin F1 alpha and thromboxane B2 were measured at baseline and after thrombin stimulation. A concentration-dependent effect of aprotinin on 6-keto-prostaglandin F1 alpha synthesis was demonstrated. After incubation with 100 mumol/L of aprotinin, a 90% reduction in 6-keto-prostaglandin F1 alpha production was seen (31.69 versus 307.44 picograms per million cells; p less than 0.001). Conversely, thromboxane B2 production showed a 345% increase after incubation with aprotinin (287.80 versus 83.82 picograms per million cells; p less than 0.0001). Since 6-keto-prostaglandin F1 alpha inhibits and thromboxane B2 strongly enhances platelet aggregation, it appears that one mechanism of the clinically observed effectiveness of aprotinin lies in the altered ratio of 6-keto-prostaglandin F1 alpha: thromboxane B2 in endothelial cells, which leads to enhanced platelet aggregation and improved vessel sealing.     

Sulindac reduces the urinary excretion of prostaglandins and impairs renal function in cirrhosis with ascites

In 5 patients with cirrhosis and ascites the glomerular filtration rate (GFR), free water clearance (CH2O) and urinary excretion of prostaglandin E2(PGE2) and 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha) were measured before and after a 3-day treatment with sulindac (400 mg/day). The administration of sulindac induced a marked fall of urinary excretion of PGE2 (from 24.2 +/- 5.5 to 3.8 +/- 1.1 ng/h; p less than 0.05), 6-keto-PGF1 alpha (from 19.9 +/- 2.9 to 5.6 +/- 1.1 ng/h; p less than 0.02) GFR (from 111 +/- 15 to 67 +/- 10 ml/min; p less than 0.01) and CH2O (from 7 +/- 1.5 to 3.7 +/- 1.3 ml/min; p less than 0.02) in all patients studied. The plasma concentration of the active metabolite sulindac sulfide in cirrhotics was 400% of that found in 6 healthy volunteers (9.6 +/- 1.7 vs. 2.4 +/- 0.6 ng/ml). Our results indicate that sulindac, at a dose of 400 mg/day, inhibits the renal synthesis of prostaglandins and impairs renal function in cirrhotics with ascites. These effects are probably related to the marked alteration of sulindac kinetics that occurs in these patients.     

Acute effects of intravenous cyclosporine on blood pressure, renal hemodynamics, and urine prostaglandin production of healthy humans

The acute renal failure associated with cyclosporine may result from vasoconstriction of intrarenal arterioles. To evaluate the mechanism of cyclosporine-induced nephrotoxicity, we acutely administered cyclosporine to eight healthy female volunteers with normal blood pressure and renal function. Cyclosporine (4 mg/kg) in 250 ml of 5% dextrose in water (D5W) was administered as a steady intravenous infusion over 6 hr. Glomerular filtration rate and renal plasma flow were measured by serum disappearance of 99m TcDTPA and 131I hippuran, respectively, during the last 3 hr of the infusion. D5W was given to the patients on separate days before the cyclosporine infusion to obtain control data. Systolic and diastolic blood pressure measured every hour during the infusions and renal vascular resistance were slightly higher during cyclosporine administration, but the increases were not statistically significant. Renal plasma flow was not affected by cyclosporine, being 479.6 +/- 24.9 ml/min during the control infusion and 463.3 +/- 12.7 ml/min during the cyclosporine infusion. However, glomerular filtration rate was reduced by cyclosporine in all patients (control, 108.8 +/- 2.5 ml/min, vs. cyclosporine, 91.1 +/- 2.2 ml/min, P less than .01), except one who demonstrated no significant change. Urinary excretion of thromboxane B2 during cyclosporine administration was markedly increased in all patients, being 39.9 +/- 8.2 ng/hr in the control period and 85.8 +/- 22.3 ng/hr during cyclosporine infusion (P less than .05), except for the one patient in whom no decrease in GFR was noted. There was no significant change in the urinary excretion rate for 6-keto-prostaglandin F1a or prostaglandin E during cyclosporine infusion. Serum averaged levels of peripheral renin activity, angiotensin II, and aldosterone did not change during with the cyclosporine administration compared with the control. All patients demonstrated a decrease in 24-h urinary excretion of sodium and potassium on the day of the cyclosporine infusion. Verapamil SR (240 mg daily for 7 days prior to cyclosporine infusion) did not reverse the reduction in glomerular filtration rate induced by cyclosporine; however, a significant reduction in renal vascular resistance and an increase in renal plasma flow (P less than .05) were noted when the volunteers were treated with both verapamil and cyclosporine compared with cyclosporine alone. Intravenous infusion of Cremophor EL, the vehicle to dissolve cyclosporine, demonstrated no significant effects on blood pressure, renal hemodynamics or urinary prostaglandin excretion.(ABSTRACT TRUNCATED AT 400 WORDS)     

Renal hemodynamics and urinary excretion of 6-keto-prostaglandin F1 alpha and thromboxane B2 in newly diagnosed type I diabetic patients

We have studied the functional importance of renal eicosanoids in renal hemodynamics of seven newly diagnosed insulin-dependent diabetes mellitus (IDDM) patients by treatment with two structurally unrelated inhibitors of cyclooxygenase (i.e., piroxicam and sulindac). Glomerular filtration rate (GFR), renal plasma flow (RPF), daily urinary excretion of 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha, the stable hydrolysis product of prostacyclin), and thromboxane B2 (TXB2, the stable hydrolysis product of thromboxane A2) were measured before, during, and after piroxicam (all patients) or sulindac (3 patients) treatment. Urinary excretion of 6-keto-PGF1 alpha was significantly increased (P less than .01) in diabetic patients compared with seven healthy subjects, whereas urinary excretion of TXB2 was unchanged. The baseline value of GFR was significantly (P less than .01) higher in diabetic compared with normal volunteers, whereas baseline RPF was comparable in both groups. Piroxicam (20 mg/day) reduced urinary excretion of 6-keto-PGF1 alpha and TXB2 by 65.7 +/- 26 and 64.6 +/- 33%, respectively. These biochemical changes were temporally associated with the approximately 19% decrease in GFR (P less than .01). A week after discontinuation of the drug, GFR and urinary excretion of 6-keto-PGF1 alpha were still significantly (P less than .05) reduced, whereas urinary excretion of TXB2 returned to control values. In contrast, urinary excretion of eicosanoids and renal function were not affected by sulindac (0.4 g/day) treatment. No functional changes were detected in healthy subjects despite a similar suppression of renal cyclooxygenase activity when they were treated with piroxicam.(ABSTRACT TRUNCATED AT 250 WORDS)     

Urinary excretion of vasoactive substances in chronic renal failure

To investigate the pathophysiological role of vasoactive substances in the progression of chronic renal disease, we measured the 24-hour urinary excretion of prostaglandin 6-keto F1alpha, thromboxane B2, NOx, cGMP and ET-1 in 26 patients with chronic renal failure under conservative treatment and in 40 control subjects. Urinary 6-keto PgF1alpha, TxB2 and cyclic GMP were evaluated by RIA, and ET-1 was assayed by EIA. NOx were evaluated using a colorimetric assay as nitrate/nitrite. Urinary excretion of prostaglandin 6-keto F1alpha averaged 18.1 +/- 20.9 ng/g Ucreat in patients vs. 240.9 +/- 257.3 in controls (p < 0.0001), thromboxane B2 422 +/- 374 ng/g Ucreat in patients vs. 967 +/- 589 in controls (p < 2x 10(-5)), NOx 7.07 +/- 5.54 mg/g Ucreat in patients vs. 9.79 +/- 3.77 in controls (p < 0.01), cGMP 310 +/- 200 pg/g Ucreat in patients vs. 488 +/- 241 in controls (p < 0.001). In contrast, ET-1 urinary excretion was almost doubled in patients (13.45 +/- 5.84 ng/g of Ucreat) in comparison with controls (6.84 +/- 2.81 p < 1x10(-5)). While in control subjects significant correlations between urinary excretions of prostaglandin 6-keto F1alpha and thromboxane B2 (r = 0.69, p < 0.001) or NOx and ET-1 (r = 0.54, p < 0.001) were present, in patients only the relationship between urinary excretions of prostaglandin 6-keto F1alpha and thromboxane B2 (r = 0.53, p < 0.01) was retained. Our data suggest that in the normal kidney a balance between prostaglandin I2 and thromboxane A2, or nitric oxide and endothelin-1 is present, which contributes to hemodynamic regulation and protects this organ from ischemic damage. This balance is abolished in CRF, where a large increment of vasopressor agent endothelin is present, which, joined to a prevalent decrease of prostaglandin I2 synthesis, could contribute to the ischemic and fibrogenetic damage of the kidney, leading to progression of renal disease.     

Effect of demeclocycline on renal function and urinary prostaglandin E2 and kallikrein in hyponatremic cirrhotics

8 cirrhotics with hyponatremia were given demeclocycline (DMC) 900 mg/day to investigate its effect on renal function, plasma renin activity, aldosterone and urinary excretion of prostaglandin E2 and kallikrein. In 7 patients DMC induced an increase of free water clearance (from -0.36 +/- 0.06 to 0.13 +/- 0.06 ml/min) and serum sodium concentration (from 125.4 +/- 0.09 to 131.1 +/- 1.0 mEq/l, mmol/l). In 5 of these patients DMC also induced a marked reduction of glomerular filtration rate (from 72.2 +/- 6.2 to 31,2 +/- 4.7 ml/min) and renal plasma flow (from 468 +/- 98 to 195 +/- 55 ml/min) which could not be explained on the basis of hypovolemia. In each case this renal impairment was not associated with changes in urinary concentration of beta 2-microglobulin, urinary casts excretion, fresh urine sediment or urine protein content and disappeared after discontinuation of the drug. DMC induced a marked increase in the urinary excretion of prostaglandin E2 (from 0.82 +/- 0.27 to 6.16 +/- 1.91 ng/min) in 6 out of the 7 patients who responded to DMC and a marked reduction in urinary kallikrein (from 16.1 +/- 4.4 to 4.2 +/- 1.6 pkat/min) in the 5 patients who developed renal insufficiency. The serum DMC concentration was greater than 5 micrograms/ml in all patients who responded to DMC, greater than 8 micrograms/ml in all cases who developed renal insufficiency and of 3 micrograms/ml in the case not responding to DMC. (ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of thromboxane inhibition on renal blood flow in dogs with complete unilateral ureteral obstruction

The effect of the thromboxane synthetase inhibitor OKY-046 on renal blood flow and ureteral pressure in awake dogs during 18 hours of complete unilateral ureteral obstruction was studied. OKY-046 was infused continuously throughout the period of obstruction and post-release. Renal blood flow and ureteral pressure were constantly monitored during the study. Urinary thromboxane B2 and prostaglandin E2 excretion served as markers for inhibition of renal thromboxane A2 synthesis. The triphasic relationship between ipsilateral renal blood flow and ureteral pressure previously found following unilateral ureteral obstruction was observed despite OKY-046 infusion. Inhibition of ipsilateral urinary thromboxane B2 excretion was greater than 90% compared to control while ipsilateral urinary prostaglandin E2 excretion was not consistently decreased showing specific thromboxane inhibition. These results suggest that urinary thromboxane B2 may serve as a useful marker for determining the effects of inhibition on renal thromboxane A2 production. At the level of inhibition of thromboxane synthesis achieved we did not observe any change in the late decrease in renal blood flow which is typically seen with chronic unilateral ureteral obstruction.     

Vasoactive hormones in the renal response to systemic sepsis

The pathophysiology of renal dysfunction in generalized sepsis remains unknown. In this study, 24 hours after surgical induction of peritonitis in 20 volume-loaded sheep, three patterns of renal function were seen. In group 1 (n = 8), glomerular filtration rate (GFR) decreased by 70%, urine volume by 85%, absolute sodium excretion by 95%, and fractional sodium excretion by 83%. Group 2 (n = 4) exhibited similar sodium retention but GFR did not fall. Group 3 (n = 8) showed no change in GFR or urine volume and only minimally reduced sodium excretion. Mean arterial pressure fell 17% in group 1 only; central venous pressure, pulmonary capillary wedge pressure, and plasma volume were maintained at or above presepsis values in all groups. Cardiac index was either increased or unchanged, and renal plasma flow was maintained in all groups; there was thus no hemodynamic evidence to suggest volume contraction. Histologic examination showed only minor changes with no consistent pattern. Renal functional changes correlated with other manifestations of severe sepsis--GFR and sodium retention correlated significantly with increased cardiac index, decreased systemic vascular resistance, pulmonary arterial hypertension, leukopenia, hypoproteinemia, and hypoglycemia. All of these changes were most marked in group 1. In groups 1 and 2, plasma renin activity (PRA) increased and urinary kallikrein excretion decreased. PRA correlated inversely with GFR, urine volume, and sodium excretion; urinary kallikrein excretion correlated positively with urine volume and sodium excretion. Urinary excretion of 6-keto-PGF1 alpha was increased in groups 1 and 2 and correlated inversely with mean arterial pressure in group 1 animals. During sepsis, urinary thromboxane B2 excretion continued at presepsis values in all groups. The results suggest that unusual reciprocal changes in activity of the renin-angiotensin and renal kallikrein-kinin systems may play a role in the renal response to sepsis. PGI2 synthesis is increased and may affect systemic hemodynamics and renal function; the role of thromboxane A2 in this context is unknown.     

Possible role of prostaglandins in pathogenesis of nocturnal enuresis in children

OBJECTIVE: To compare excretion of ions and prostaglandins by the kidney in children with noctural enuresis. MATERIAL AND METHODS: Thirty-two children with primary nocturnal enuresis and 23 normal children were examined. Osmolality and sodium and potassium concentrations were measured in their urine and blood serum. Prostaglandins E2, E1, and F2alpha were determined using kits for immunoenzyme analysis. Luminal and contraluminal prostaglandin secretions were studied in frog urinary bladder. RESULTS: Children with nocturnal enuresis have increased nocturnal diuresis and renal sodium excretion, but no increase was found in excretion of prostaglandins E2, E1, and F2alpha. Administration of sodium diclofenac before bed-time eliminated episodes of nocturnal enuresis in 37% of children; intranasal administration of Adiuretin SD had a positive effect in 69% of enuretics. In children with nocturnal enuresis there is a correlation between renal excretion of PGE2 and sodium ions; this correlation is absent in the control group children, and disappears in enuretics treated with desmopressin. To evaluate the representativeness of the data on prostaglandin secretions to urine as compared with their release to extracellular fluid, experiments on frog urinary bladder were performed: a correlation was found between prostaglandin secretion to the urinary bladder lumen and to the extracellular fluid. CONCLUSIONS: The results of the study suggest that changes in renal function are due not to a higher secretion of prostaglandins in nocturnal enuresis but to the relative dominance of their effect as compared with other physiologically active substances that simultaneously act on renal tubular cells.     

Effects of sulfinpyrazone on renal function and prostaglandin formation in man

Sulfinpyrazone (800 mg/day for 6 days) significantly reduced the excretion of the main urinary prostaglandin E metabolite by 54% in 6 healthy female volunteers. While sulfinpyrazone did not affect inulin clearance, clearances of creatinine and PAH were significantly diminished by 18.0 and 44.7%, respectively. In the anaesthetized dog sulfinpyrazone decreased PAH clearance and PAH extraction concomitantly without affecting renal blood flow. These results show that clearances of creatinine and PAH do not reliably reflect glomerular filtration and renal perfusion, respectively, during sulfinpyrazone administration. Whereas sodium balance and body weight were not significantly different between the first control period and sulfinpyrazone administration, net sodium excretion significantly increased from 121.6 +/- 5.4 mEq/day during sulfinpyrazone treatment to 139.3 +/- 6.6 mEq/day during the following control period, while body weight significantly decreased indicating modest sodium retention during drug administration. Plasma renin activity, vascular sensitivity to angiotensin II, and urinary excretion of the enzymes N-acetylglucosaminidase and alanineaminopeptidase were not affected by sulfinpyrazone administration. In summary, sulfinpyrazone caused a decrease of total body prostaglandin E formation in healthy female volunteers together with a moderate sodium retention. Despite inhibition of prostaglandin synthesis, glomerular filtration rate, plasma renin activity, or pressor effects of angiotensin II were not altered.     

Prostaglandin synthesis associated with renal allograft rejection in the dog

Vasospasm and intrarenal thrombosis are characteristics of acute renal allograft rejection. A possible mediator of these phenomena is thromboxane A2. Single kidneys were exchanged between nonimmunosuppressed mongrel dogs. At intervals after transplantation, rejecting and normal kidneys were removed and slices of cortex and medulla were prepared for incubation. The in vitro release of thromboxane B2 (TxB2), prostaglandin E2 (PGE2), and 6-keto-prostaglandin F1a (6-keto-PGF1 alpha) into the incubation media was measured by radioimmunoassay. Within 72 hr of transplantation the cortex of rejecting kidneys synthesized 10 to 30 times as much PGE2 and TxB2 as normal controls. A similar increase was not observed for 6-keto-PGF1 alpha synthesis. In the medulla there was a selective reduction in 6-keto-PGF1 alpha production within five days of transplantation. In both cortex and medulla there was a significant increase in the ratio of TxB2 to 6-keto-PGF1 alpha production. Reversal of the normal TxB2:6-keto-PGF1 alpha ratio could induce the widespread intrarenal thrombosis and vasospasm that characterizes acute renal allograft rejection.     

Obstructive jaundice and renal failure in the rat: the role of renal prostaglandins and the renin-angiotensin system

We have previously noted that bile duct ligation (BDL) in the rat results in decreased creatinine clearance (Ccr) and decreased urinary sodium excretion (UNaV) as well as increased renal prostaglandin (PG) production. This study was undertaken to assess the role of increased renal PG production in the change in renal function after BDL and to determine if these changes are mediated by the renin-angiotensin system. After baseline measurement of renal function, Sprague-Dawley rats underwent either sham operation (SO) or BDL. Four days later animals received a single intraperitoneal injection of either 0.9% saline, 0.5 ml/kg (SO, n = 10; BDL, n = 10), or indomethacin, 5 mg/kg (SO + Indo, n = 10; BDL + Indo, n = 10), and renal function was reassessed. Plasma renin activity was measured at the end of the second study period. BDL resulted in a 40% decrease in Ccr (p = 0.000), a 38% decrease in UNaV (p = 0.002), a twofold increase in urinary 6-keto-PGF1 alpha excretion (p = 0.005), and fourfold increases in urinary excretion of PGE2 (p = 0.006) and thromboxane B2 (p = 0.000). Indomethacin prevented the increase in urinary PG excretion otherwise seen with BDL and resulted in an additional 41% reduction in UNaV (p = 0.018). Further reductions in Ccr by indomethacin, however, were minimal and nonsignificant. Plasma renin activity did not differ among any of the groups. These findings indicate that the sodium retention associated with BDL is attenuated by the concomitant rise in renal PG production. This elevation in PG production, however, does not protect against the adverse effects of BDL on Ccr. Furthermore, the changes in renal function that occur after BDL do not appear to be mediated by the renin-angiotensin system.     

Isolated hypoaldosteronism and abnormalities in renin, kallikrein, and prostaglandin

To further define the pathophysiology of the syndrome of acquired isolated hypoaldosteronism, we determined plasma concentrations of active and inactive renin and urinary kallikrein and prostaglandin E2 excretion rates in 11 patients with the syndrome, 12 patients with similar serum creatinine levels, but without hyperkalemia, and in 12 normotensive patients with normal renal function and low plasma renin activities (PRA). Ten of 11 patients with the syndrome had low baseline PRA, and, unlike the control groups, six of 11 failed to double their PRA after furosemide stimulation. There were also consistent abnormalities in the percentage of inactive renin, no patient having a value less than and no control subjects having a value greater than 65%. Seven of 11 patients had prostaglandin E2 excretion rates lower than either control groups. Urinary kallikrein excretion rates in the patients with isolated hypoaldosteronism were significantly lower than in the control groups, but increased in response to therapy with fludrocortisone.