Prostaglandin E2 Excretion Research Articles

Renal Hemodynamics and Natriuresis Induced by the Dopamine-1 Agonist, SKF 82526

The intrarenal infusion of dopamine (DA) during alpha- and beta-adrenergic blockade has been reported to increase renal blood flow (RBF) and sodium excretion by occupation of DA-1 receptors. In addition, DA may potentially influence renal function by occupation of DA-2 receptor subtypes. This study was designed to examine the hemodynamic and/or tubular mechanisms of the natriuretic effect of DA-1 in dogs anesthetized with pentobarbital. The intrarenal infusion of the DA-1 agonist, SKF 82526 (10−9, 10−8, 10−7M), resulted in dose related increases in RBF and absolute and fractional sodium excretion. These changes were not associated with alterations in urinary prostaglandin E2, F2 alpha, or kallikrein excretion. To determine the role of RBF in the natriuresis due to SKF 82526 infusion (10−7M), the renal artery was constricted to return RBF to control levels during continued SKF 82526 infusion. Although absolute and fractional sodium excretion decreased during this maneuver, they remained higher than control. These studies support both a hemodynamic and a tubular mechanism for the natriuretic effect of the DA-1 agonist, SKF 82526. These effects do not appear to be mediated by the renal prostaglandin or kallikrein systems.

Salsalate Exacerbation of Chronic Renal Insufficiency

Nonacetylated salicylates have not been reported to cause the hemodynamically mediated acute renal failure associated with nonsteroidal anti-inflammatory drug therapy. A 73-year-old woman with a creatinine clearance of 0.33 mL/s (20 mL/min), hypertension, and arteriosclerotic cardiovascular disease developed reversible renal insufficiency when her dose of salsalate was increased to 4.5 g/d (serum salicylate concentration, 2.22 mmol/L [30.7 mg/dL]). Under close observation the patient was re-treated with lower doses of salsalate while renal function and the urinary excretions of prostaglandins were monitored. The excretion of prostaglandin E2 decreased abruptly while the excretion of 6-keto-prostaglandin F1 alpha decreased more gradually as the dose of salsalate was increased. Renal function appeared to decline in parallel with the decrease in 6-keto-prostaglandin F1 alpha and recovered rapidly after discontinuation of salsalate therapy. Nonacetylated salicylates can cause a hemodynamically mediated acute renal failure in patients at risk for this nephropathy.

Aspirin enhances the antihypertensive effect of captopril in spontaneously hypertensive rats.

Activation of renal or vascular prostaglandin mechanisms (or both) has been proposed to contribute to the antihypertensive action of captopril. In conscious spontaneously hypertensive rats (SHR) studied in the established phase of hypertension, the blood pressure-lowering effect of captopril, 30 mg/kg/12 hr p.o. given for 7 days, was greatly enhanced by the addition of aspirin, 200 mg/kg/day s.c. Systolic blood pressure decreased from 185 +/- 6 and 182 +/- 4 to 135 +/- 3 mm Hg in rats treated, respectively, with captopril and aspirin or captopril alone, and was unaltered by either vehicle or aspirin alone. Water intake was inconsistently affected by captopril but was increased (p less than 0.01) by aspirin and was even higher after captopril-aspirin treatment (p less than 0.01). Urine volume was elevated in all 3 drug-treated groups, increasing threefold after captopril-aspirin treatment. Excretion of sodium and potassium was unchanged by any treatment regimen. In the vehicle group, prostaglandin F2 alpha excretion, measured by radioimmunoassay, ranged between 65 and 93 ng/8 hr and was twofold to fourfold higher than that of prostaglandin E2. Prostaglandin F2 alpha was unaffected during captopril treatment, whereas prostaglandin E2 excretion decreased to 12 +/- 2 ng/8 hr (p less than 0.01) by Day 7. Long-term aspirin treatment, either with or without captopril, did not cause sustained inhibition of renal prostaglandin excretion, although a transient effect occurred within the first four hours of administration. These results indicate 1) aspirin potentiates the blood pressure-lowering effect of captopril in SHR, an effect that is associated with a threefold increase in urine flow.(ABSTRACT TRUNCATED AT 250 WORDS)

Comparison of paracentesis and diuretics in the treatment of cirrhotics with tense ascites: Results of a randomized study

To investigate whether paracentesis could be an alternative therapy for ascites, 117 cirrhotics with tense ascites were randomly allocated into two groups. Fifty-eight patients (group 1) were treated with paracentesis (4–6 L/day until disappearance of ascites) and intravenous albumin infusion (40 g after each tap). Fifty-nine patients (group 2) were treated with spironolactone (200–400 mg/day) plus furosemide (40–240 mg/day). Patients from group 2 not responding to diuretics were treated with a LeVeen shunt. After disappearance of ascites, patients from both groups were discharged from hospital and were instructed to take diuretics. Patients developing tense ascites during follow-up were readmitted to hospital and treated according to their initial schedule. Paracentesis was effective in eliminating the ascites in 56 patients from group 1 (96.5%) and did not induce significant changes in renal and hepatic function, plasma volume, cardiac index, peripheral resistance, plasma renin activity, plasma norepinephrine and antidiuretic hormone concentration, and urinary excretion of prostaglandin E2 and 6-keto-prostaglandin F1α. Diuretics were effective in eliminating the ascites in 43 patients from group 2 (72.8%) (p < 0.05). Ten patients in group 1 and 36 in group 2 developed complications during their first hospital stay (p < 0.001). This difference was due to the significantly higher incidence of hepatic encephalopathy, renal impairment, and electrolyte disturbances occurring in patients treated with diuretics. The duration of hospital stay was 11.7 ± 1.5 days for patients from group 1 and 31 ± 2.8 days for patients from group 2 (p < 0.001). The two groups did not differ significantly with respect to the probability of requiring readmission to hospital during follow-up, reasons for readmission, survival probability after entry into the study, and causes of death. These results indicate that paracentesis associated with intravenous albumin infusion is a fast, effective, and safe therapy for ascites in patients with cirrhosis.

Renal excretion of prostaglandin E2 and plasma renin activity in type I diabetes mellitus: relationship to normoglycemia achieved with artificial pancreas.

To determine the effect of normoglycemia on renal prostaglandin synthesis and renin-angiotensin system activity, prostaglandin E2 (PGE2) urinary excretion, plasma renin activity (PRA), and glomerular filtration rate (GFR) were studied in seven patients with insulin-dependent diabetes mellitus (IDDM) without complications, both in basal conditions and after a 20-h treatment with an artificial pancreas. Normoglycemia induced a significant reduction in PGE2 excretion (88 +/- 23 vs. 55 +/- 25 ng/12 h, P less than .05) and GFR (138 +/- 34 vs. 105 +/- 20 ml X min-1 X 1.73 m-2, P less than .05) and a nonsignificant increment of PRA (0.52 +/- 0.48 vs. 0.83 +/- 0.92 ng X ml-1 X h-1). The results enhance the hypothesis that renal prostaglandins play a role in the renal functional alterations observed in IDDM during hyperglycemia.

Immunohistochemical distribution of renal prostaglandin endoperoxide synthase and prostacyclin synthase: diminished endoperoxide synthase in the hepatorenal syndrome.

To evaluate possible causes of the diminished prostaglandin production in advanced hepatorenal syndrome, prostaglandin endoperoxide synthase and prostacyclin synthase were localized and semiquantitated by immunofluorescence in postmortem, biopsy and nephrectomy renal tissues. In normal kidneys, antiprostacyclin synthase serum caused intense staining in peritubular capillaries, in the adjacent renal interstitial cells and in glomerular mesangial regions. Antiprostaglandin endoperoxide synthase serum caused staining of collecting duct epithelial cells, cells of the thin ascending limb and possibly glomerular mesangial cells. Prostacyclin synthase-positive staining was graded 5+ (scale of 0+ to 5+) in all kidney samples. Medullary collecting tubule prostaglandin endoperoxide synthase-positive staining was graded 4+ or 5+ in kidney samples from patients with acute tubular necrosis or acute tubulointerstitial nephritis and from patients with liver failure without the hepatorenal syndrome. However, prostaglandin endoperoxide synthase-positive staining was markedly diminished or absent (average 1+) in patients with the hepatorenal syndrome. These data suggest that loss of the medullary prostaglandin endoperoxide synthase is the cause of diminished urinary prostaglandin E2 excretion in the hepatorenal syndrome.

Systemic haemodynamics, renal and platelet function during chronic propranolol administration in patients with compensated cirrhosis.

Chronic propranolol administration is followed by some haemodynamic alterations, which may impair renal function. It has also been suggested that it may reduce platelet production of proaggregatory thromboxane (TX) A2. We therefore evaluated cardiac index (CI), systemic vascular resistance (SVR), creatinine clearance, daily sodium excretion under controlled sodium intake, platelet aggregation and platelet TXA2 production during whole blood clotting in eight patients with cirrhosis, portal hypertension and no ascites, before and after 3 months of propranolol administration. Liver function was also assessed by evaluating the galactose elimination capacity (GEC) and galactose clearance (Cgal). The expected, significant reduction of CI and increase of SVR was observed. Creatinine clearance and sodium balance were unchanged throughout the study. Furthermore, the renal prostaglandin system, as reflected by urinary prostaglandin E2 and TXB2 excretion, was also unaffected by the drug. No modification of platelet aggregation, platelet TXA2 production during whole blood clotting, GEC and Cgal was observed. We conclude that chronic propranolol administration is followed by alterations of CI and SVR, but it does not impair renal function and platelet aggregation in patients with cirrhosis, portal hypertension and no ascites. The maintenance of renal function during beta-adrenergic blockade is not due to an increased renal production of vasodilating prostaglandins.

Systemic and renal hemodynamic consequences of manipulation of serum calcium and/or parathyroid hormone in the intact conscious mongrel dog.

Studies were undertaken in conscious mongrel dogs to separate the systemic and renal hemodynamic effects of alterations in serum calcium (Ca) from those of parathyroid hormone (PTH) in an intact conscious animal. Blood pressure was measured intra-arterially, cardiac output was determined by dye-dilution or thermodilution, total peripheral resistance (TPR) was calculated from standard formulae, and renal hemodynamics were estimated by the clearance of inulin and para-aminohippurate. Measurements were made before and after a 2 hour calcium chloride (CaCl2) infusion in 10 dogs (group 1). These animals had previously received a dose of PTH to prevent suppression of PTH during the CaCl2 infusion. Ionized calcium (Ca++) and TPR increased significantly. Blood pressure increased but not significantly. Administration of EDTA did not significantly change any systemic hemodynamic variable in eight thyroparathyroidectomized dogs (group 2). Chelation in seven dogs with intact parathyroid glands (group 3) reduced mean arterial blood pressure and total peripheral resistance. Renal hemodynamic measurements were not affected. Isolated acute elevation of serum Ca++, independent of suppression of PTH, increased total peripheral resistance. Decreased serum Ca++ required normal activity of parathyroids to reduce total peripheral resistance. The renal circulation was resistant to acute manipulation of ionized serum calcium and PTH. CaCl2 infusion to intact dogs (group 1) decreased serum magnesium significantly, increased urine flow rate, and decreased urinary PGE2 excretion. Comparisons between group 2 and group 3 revealed a greater decline in serum Mg and urinary prostaglandin E2 excretion in group 2 vs group 3. Elevation of peripheral resistance due to acute Ca elevations was accompanied by decreased serum Mg and decreased renal prostaglandin excretion.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of urinary pH and urine flow rate on prostaglandin E2 and kallikrein excretion by the conscious dog.

1. The effects of urine flow rate and urinary pH on renal prostaglandin E2 (PGE2) and kallikrein excretion were investigated in conscious dogs during water deprivation followed by rehydration and under conditions which altered urine pH, but caused similar change in salt and water excretion. 2. When water-restricted dogs were rehydrated in two steps by gavage giving the animals tap water, urine flow increased by 22- and 63-fold with a concomitant increase in PGE2 excretion by 100 and 318%, respectively; whereas urinary kallikrein excretion and urine pH did not change significantly. 3. Oral administration of isotonic sodium chloride solution increased urine flow as well as electrolyte excretion without altering urine pH (6.90 +/- 0.26) and PGE2 excretion. 4. When urine was made alkaline (pH 7.79 +/- 0.09) by oral sodium bicarbonate, urine flow and electrolyte excretion were similar to those observed after oral sodium chloride, while renal PGE2 excretion increased by 66% (P less than 0.05). 5. When urine was made acidic (pH 5.31 +/- 0.14) by oral ammonium chloride, urine flow and electrolyte excretion were similar to the values seen after oral sodium chloride. Urinary PGE2 excretion, however, was reduced by 46% (P less than 0.05). 6. After oral fluid loads a positive correlation could be detected between urine pH and urinary PGE2 excretion (r = 0.854, P less than 0.001). 7. Urinary kallikrein excretion was not significantly altered by any of the three interventions mentioned above. 8. The present results suggest that, in conscious dogs, urine flow as well as urine pH are important determinants of urinary PGE2 excretion rates, but not of kallikrein excretion.

Altered furosemide pharmacokinetics in chronic alcoholic liver disease with ascites contributes to diuretic resistance

Some patients with chronic alcoholic liver disease and ascites have an impaired natriuretic response to furosemide. To elucidate the mechanism of this diuretic resistance, we measured para-aminohippurate and inulin clearances and urinary excretion of electrolytes, prostaglandin E2, and furosemide after intravenous administration of 80 mg of furosemide in 26 patients. The natriuretic response was variable (3.3–172 mEq/h) and was unrelated to basal sodium excretion, renal clearances, or urinary prostaglandin E2. Natriuresis correlated negatively with plasma aldosterone (r = −0.54, p < 0.01), and strongly with urinary furosemide (range 5.5–76 mg/h, r = 0.71, p < 0.001). As urinary furosemide excretion reflects the amount of furosemide reaching the active site on the luminal side of the tubule, the data demonstrate markedly reduced amounts of furosemide at its primary site of action in patients with diuretic resistance. Plasma furosemide was higher in patients with reduced furosemide excretion and impaired natriuresis, suggesting that the defect was an impairment of furosemide transport into the tubule. Thus, a major factor in diuretic resistance is altered furosemide pharmacokinetics.

The effect of propranolol on urinary prostaglandin E2 after frusemide administration in healthy subjects.

We have evaluated the effect of propranolol on urinary prostaglandin E2 (PGE2) excretion after frusemide administration in 8 healthy subjects. Urine was collected for 60 min after frusemide administration (20 mg intravenously) with or without propranolol pretreatment, and urinary excretion of PGE2, frusemide, and sodium were determined. Plasma renin activity (PRA) was also measured before and 60 min after frusemide administration. Urinary PGE2 excretion after frusemide administration and frusemide-stimulated PRA were reduced after propranolol pretreatment. However, urine volume and the urinary excretion of frusemide and sodium were not influenced by propranolol pretreatment. These results suggest that urinary PGE2 excretion after frusemide administration may be reduced by propranolol and that the mechanism responsible for the effect of propranolol on the frusemide-induced renal PGE2 production may be, at least in part, secondary to inhibition of the renin-angiotensin system.

No Evidence on Significant Roles of the Prostaglandin-Thromboxane and Kallikrein-Kinin System in the Antihypertensive Effect of MK 421 in Rats Made Hypertensive by Norepinephrine or Vasopressin

Inhibition of angiotensin converting enzyme by MK 421 (6 mg/kg/day ip) induced a significant increase in urinary kinin excretion in norepinephrine-infused rats (1.8 mg/kg/day ip), whereas it had no effect on urinary prostaglandin E2 excretion. In contrast, MK 421 did not induced any significant changes in urinary kinin and prostaglandin E2 excretion in vasopressin-infused rats (7.2 U/kg/day ip). The simultaneous administration of indomethacin (10 mg/kg/day sc), OKY 046 (12 mg/kg/day sc) or aprotinin (100,000 units/kg/day sc) did not affect the antihypertensive effect of MK 421 in rats made hypertensive by chronic infusion of norepinephrine or vasopressin. The present results suggest that the hypotensive effect of MK 421 may depend on a reduced sensitivity of the vasculature to vasoconstrictor substances. In addition, it is also suggested that neither the prostaglandin-thromboxane or kallikrein-kinin systems are essential for the antihypertensive effect of MK 421 in these models of hypertension.

Effects of angiotensin converting enzyme inhibitors MK 421, SA 446 and captopril on renal prostaglandin E and kinins in conscious normotensive rats.

Angiotensin converting enzyme inhibition by MK 421, SA 446 or captopril (6 mg/kg/day ip) for up to 6 days induced significant fall in systolic blood pressure and plasma angiotensin II concentration. The hypotensive effect was greater in sodium depleted rats than in sodium repleted rats. The hypotensive effect was also accompanied by increased excretion of urinary prostaglandin E2, however the levels of urinary prostaglandin E2 in sodium repleted rats were not different from those in sodium depleted rats. Urinary kinin excretion was increased during infusion of MK 421, SA 446 or captopril in sodium depleted rats, whereas no significant change was found in sodium repleted rats. Thus the present results suggest that renal prostaglandin E system may not be essential for the hypotensive effect of these inhibitors. In addition, the greater hypotensive effect of these inhibitors in sodium depleted rats may be in part due to stimulated renal kinin system.

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.

Rabbit nephrotoxic nephritis: effect of a thromboxane synthetase inhibitor on evolution and prostaglandin excretion.

Accelerated anti-glomerular basement membrane nephritis was induced in rabbits, and the immunological, clinical and histological evolution studied in relation to urinary immunoreactive thromboxane B2 (i-TXB2) and immunoreactive prostaglandin E2 (i-PGE2) excretion. In control nephritic animals, urinary i-TXB2 increased 5-fold on day +1, but was normal again by day +5. The urinary i-TXB2 showed a positive correlation with creatinine clearance (CCr), proteinuria and anti-sheep immunoglobulin antibody. Urinary i-PGE2 excretion increased by 50% on day +1, but was indistinguishable later from controls. The effects of the specific thromboxane synthetase inhibitor OKY-046 on this model was studied. In non-nephritic control animals, OKY-046 did not affect the CCr, the urinary protein excretion or the number of monocytes in glomeruli but reduced the excretion of i-TXB2. Although OKY-046 markedly inhibited the i-TXB2 excretion throughout the experiment in nephritic animals, the creatinine clearances were significantly worse, the proteinuria greater, and the number of infiltrating monocytes greater at day +5; by day +10 there was no difference from controls. There was no evidence that TXB2 is involved in the induction of proteinuria, and increased PGE2 synthesis did not protect against later proteinuria and fall in creatinine clearance. Inhibition of thromboxane synthetase appears to make this model of nephritis worse, rather than better.

Role of the prostaglandin-thromboxane system in the development and maintenance of spontaneous hypertension in the rat.

In spontaneously hypertensive rats (SHR) between the ages of 6 and 8 weeks before the development of established hypertension, repeated daily subcutaneous administration of indomethacin, an inhibitor of cyclo-oxygenase, at a dose of 5 mg/kg/day enhanced significantly the development of spontaneous hypertension, but repeated daily subcutaneous administration of OKY 046, an inhibitor of thromboxane (TX)A2 synthetase, at a dose of 12 mg/kg/day did not alter the development of spontaneous hypertension. In SHR between the ages of 15 and 18 weeks with established hypertension, indomethacin or OKY 046 did not alter the high blood pressure as compared with the injection of vehicle. In both young and adult SHR, indomethacin decreased significantly urinary prostaglandin (PG)E2 and TXB2 excretion but not PGE2. These results indicate that cyclo-oxygenase products other than TXA2 may play a protecting role in the development of spontaneous hypertension in the rat whereas their contribution to the maintenance of hypertension may be unlikely. In addition, it is suggested that TXA2 may not be involved in the development and maintenance of spontaneous hypertension in the rat.

Role of prostaglandin and angiotensin II in ANP-induced natriuresis.

The aim of the present study was to examine if the natriuresis induced by a dose of ANP that does not alter glomerular filtration rate (GFR) or mean arterial pressure (MAP) is accompanied by changes in renin release urinary excretion of prostaglandins and intrarenal blood flow distribution. It was found that the intrarenal infusion of ANP (8-33) at a dose of 0.05 micrograms/kg min in seven anaesthetized dogs did not produce any change in GFR or MAP, but its natriuretic effect was similar to that induced by a larger dose (0.3 micrograms/kg min, n = 5) that produces significant changes in both MAP and GFR. The natriuresis induced by the lower dose of ANP was associated with a redistribution of RBF to the deep cortical nephrons and with an increase (p less than 0.05) in urinary excretion of prostaglandins E2 and 6 keto-F1 alpha. Renin secretion rate decreased by a 54% (p less than 0.05). The role of angiotensin II (AII) suppression on the natriuresis induced by ANP was examine in another experimental group (n = 6). It was found that the infusion of ANP during fixed intrarenal levels of AII produced a natriuretic effect that was significantly lower (38%) than that produced by the infusion of ANP alone. The results of this study show that the natriuresis induced by ANP is not necessarily produced by an increase in GFR and is associated with a redistribution of RBF to the deep cortex an increase in urinary excretion of prostaglandins and a decrease of renin release. These results also suggest that the natriuretic effect of ANP is partly mediated by the intrarenal suppression of AII.

Role of renal nerves and dopamine on prostaglandin E release from the kidney of rats.

The aim of the study is to investigate the role of renal nerves and dopamine (DA) on urinary excretion of prostaglandin E (PGE) released from kidney with or without salt loading in rats. After excessive intake of high Na, urinary excretions of PGE and DA enhanced as compared with those of basal Na. In rats with renal denervation, urinary excretion of PGE and norepinephrine decreased in salt loading, and urinary Na excretion increased. Urinary PGE excretion was also enhanced by treatment of bromocriptine accompanying with augmented natriuresis. Urinary PGE excretion was suppressed by treatment of carbidopa, which also suppressed the urinary excretion of DA. These results suggest that the renal adrenergic nerve and tubular DA in kidney play an important role on the release of PGE and that these mechanisms in PGE release from kidney augment in salt loading.

Is urinary prostaglandin E2 excretion correlated to urinary excretion of calcium, sodium and potassium?

Is urinary prostaglandin E2 excretion correlated to urinary excretion of calcium, sodium and potassium?

Long-term effects of aldosterone on kallikrein, prostaglandin E2 and sodium in rats.

To assess the long-term effects of mineralocorticoids on the regulation of the synthesis or release of kallikrein and prostaglandin E2 in the renal kallikrein-kinin-prostaglandin E system, we studied the effects of chronic infusion of aldosterone (50 micrograms/kg/day) on urinary excretion of total and active kallikrein, and prostaglandin E2 for 10 days in conscious rats on regular intakes of sodium and on sodium loading with 1% NaCl as a drinking water. Chronic infusion of aldosterone induced a prompt and transient decrease in the ratio of sodium to potassium and a sustained increase in urinary prostaglandin E2 excretion in rats on regular diets, whereas urinary total and active kallikrein excretion did not increase significantly until the 4th day of aldosterone infusion. In rats loaded with sodium, aldosterone did not induce any changes in urinary total and active kallikrein excretion, whereas it induced similar changes in the ratio of sodium to potassium and urinary prostaglandin E2 excretion to those in rats on regular diets. Thus, the present results suggest that aldosterone might stimulate the synthesis or release of renal prostaglandin E2 independent of sodium balance. Furthermore, it is also suggested that aldosterone might stimulate the synthesis or release of kallikrein, at least partly, via the same pathway as sodium loading does.