Decrease In Sodium Excretion Research Articles

Acute effect of human recombinant insulin-like growth factor I on renal function in humans.

We examined the acute effects of insulin-like growth factor I (IGF-I) on renal function in 8 normal subjects who received a 3-hour intravenous infusion of IGF-I at a rate of 0.4 micrograms/kg.min. After starting the IGF-I infusion, the plasma IGF-I concentration rose quickly and achieved a plateau after 90 min that was threefold above the basal value. During IGF-I infusion, progressive rises in glomerular filtration rate (from 93 +/- 4 to 121 +/- 6 ml/173 m2.min; p < 0.01) and renal plasma flow (from 529 +/- 31 to 703 +/- 55 ml/1.73 m2.min; p < 0.01) were observed, with no change in filtration fraction. The plasma levels of potassium and phosphate decreased significantly during the last 90 min of the study, while the plasma sodium concentration remained unchanged. A significant decrease in the fractional excretion of sodium, potassium, and phosphate was observed during the last 90 min of the IGF-I infusion period. The heart rate rose modestly with no change in mean arterial pressure. These findings show that, when administered acutely, IGF-I is a potent renal vasodilator, but is antinatriuretic. IGF-I also enhances potassium and phosphate uptake by extrarenal tissues and reduces renal potassium and phosphate excretion.

Renal Endothelin System in Rats with Liver Cirrhosis

Rats with experimental liver cirrhosis have increased endothelin-1 (ET-1) plasma concentrations and show a tendency toward sodium and water retention. We therefore analyzed the renal ET system in cirrhotic rats and control rats, as the renal ET system is involved in the regulation of water and sodium excretion. Cirrhosis was induced by carbon tetrachloride (CCl4) administration. We analyzed the expression of ET receptor subtypes in the renal cortex and medulla using Scatchard analysis and receptor autoradiography, and measured plasma and renal tissue ET-1 concentrations using a specific radioimmunoassay. Furthermore, we analyzed the effects of the nonselective (A/B) ET receptor antagonist bosentan on water and sodium excretion and glomerular filtration rate. Our study revealed an overexpression of the ETB receptor in the renal medulla of rats with liver cirrhosis, whereas the density of ETB receptor in the cortex and the ETA receptor in the cortex and medulla were similar in both cirrhotic and control rats. Receptor autoradiography showed that the upregulation of medullary ETB in cirrhotic rats was due to an upregulation of ETB in the inner medullary collecting duct cells. The highest ET-1 concentrations were observed in the renal medulla of cirrhotic rats. Glomerular filtration rate decreased in cirrhotic rats but was not altered after bosentan treatment in cirrhotic and control rats. Bosentan decreased sodium excretion in both cirrhotic and control rats to a similar extent, whereas water excretion was reduced by bosentan only in cirrhotic rats. We therefore suggest that the upregulation of medullary ETB in cirrhotic rats is involved int he regulation of water excretion in rats with CCl4-induced cirrhosis.

Effects of endothelin-1 on renal function in humans: Implications for physiology and Pathophysiology

Elevated levels of the vasocontrictor peptide endothelin-1 have been demonstrated in various pathological conditions that are characterized by sodium retention and/or renal vasoconstriction, such as heart failure, hepatorenal syndrome, renal failure and during administration of cyclosporin and radiocontrast. In the present study we studied in seven healthy subjects the renal and endocrine effects of systemic administration of endothelin-1 (0.5, 1.0 and 2.5 ng/kg/min). During endothelin-1 infusion plasma levels rose from 3.2 +/- 0.5 to respectively 5.0 +/- 0.8, 6.2 +/- 0.5 and 8.5 +/- 1.1 pmol/liter, values that can also be observed in physiological and pathological conditions. Infusion of low dosages of endothelin-1, that result in a twofold increase in plasma levels, decreased sodium excretion by 36%, without a significant effect on systemic and renal hemodynamics. Infusion of 2.5 ng/kg/min of endothelin-1 further enhanced sodium retention and, in addition, increased renal vascular resistance by 37%. Blood pressure did not change significantly. Pretreatment with the calcium channel blocker nifedipine caused renal vasodilation, which compensated for the renal vasocontriction by endothelin-1 and prevented sodium retention. Apparently, endothelin-1 participates in volume homeostasis in human, whereas pathophysiological concentrations can contribute to renal vasoconstriction and sodium retention. Calcium channel blockers may protect against these effects of endothelin-1.

Renal effects of captopril and nitrendipine in transgenic rats with an extra renin gene.

We investigated the acute effects of captopril and nitrendipine on renal function and sodium excretion in hypertensive, male, heterozygous transgenic rats harboring a mouse renin gene [TGR (mRen-2)27]. Both drugs reduced blood pressure dose dependently in conscious transgenic rats. The oral ED20 for captopril was 0.5 mg/kg and 2.7 mg/kg for nitrendipine. In orally salt-loaded (20 mL/kg saline) transgenic rats captopril (0.3 to 3.0 mg/kg) reduced sodium excretion by approximately 90% in the 6 hours after administration, whereas equally antihypertensive doses of nitrendipine increased sodium excretion by approximately 100%. The antinatriuretic effect of captopril was accompanied by a reduction in creatinine clearance and a decrease in the excretion of cyclic GMP. In orally water-loaded (20 mL/kg water) transgenic rats captopril also reduced sodium excretion by more than 90%, and nitrendipine slightly increased sodium excretion. In control Sprague-Dawley rats the effects were opposite; namely, captopril tended to increase natriuresis, and nitrendipine caused a small but distinct decrease in sodium excretion. Intravenous captopril in anesthetized transgenic rats caused an antinatriuresis with a decrease in inulin clearance but not in Sprague-Dawley rats. To control for non-renin-related effects of captopril, we gave transgenic rats oral losartan. Losartan also decreased urinary sodium excretion. The results suggest a role for the renin-angiotensin system in the maintenance of glomerular filtration rate and sodium excretion in transgenic TGR (mRen-2)27 rats.

Altered pressure natriuresis in chronic angiotensin II hypertension in rats.

Angiotensin II (ANG II; 10 or 30 ng/min iv) was infused for 7-10 days in unilaterally adrenalectomized and nephrectomized Sprague-Dawley rats drinking 1% NaCl. The acute pressure-natriuresis relationship was studied under Inactin anesthesia in volume-expanded rats with fixed neurohumoral influences on the remaining kidney. Renal interstitial hydrostatic pressure (RIHP) was measured using a catheter implanted into the renal cortex. Arterial blood pressure before laparotomy was 149 +/- 3 (SE) mmHg (n = 6) and 152 +/- 6 mmHg (n = 16) for ANG II-infused rats (10 and 30 ng/min, respectively) and 123 +/- 5 mmHg (n = 6) and 123 +/- 7 mmHg (n = 16) for the respective control rats. Compared with values in control rats, ANG II-infused rats had significantly (P < 0.05) lower urine flow and absolute and fractional sodium excretion at renal artery pressures of 115-150 mmHg. There were no significant differences between RIHP measured in control and ANG II-hypertensive rats. The shift in the pressure-diuresis, pressure-natriuresis, and pressure-fractional sodium excretion relationships was similar with both doses of ANG II and was reversed by the acute administration of losartan (10 mg/kg iv). In all groups of rats, renal blood flow was autoregulated, whereas glomerular filtration rate was not autoregulated in ANG II-infused rats and was significantly lower than that in control rats at the lower level of renal artery pressure. The data indicate that rats with ANG II-induced hypertension have a rightward shift of the pressure-natriuresis curve caused primarily by a decrease in fractional excretion of sodium. The lack of effect of chronic ANG II infusion on filtration fraction and RIHP suggests that the increased tubular reabsorption was due to a direct action of ANG II on renal tubules. The reversal of these effects by losartan suggests that the shift in the pressure-natriuresis curve in ANG II-induced hypertension is mediated by the AT1-receptor subtype.

Role of renal interstitial pressure as a mediator of sodium retention during systemic blockade of nitric oxide.

The role of renal interstitial pressure was examined in mediating the sodium retention induced by blockade of nitric oxide synthesis. The effects of intravenous NG-nitro-L-arginine-methyl ester (L-NAME), a synthesis inhibitor, on renal hemodynamics, renal interstitial hydrostatic pressure, and sodium and lithium excretion were determined. L-NAME (50 micrograms/kg per minute) was infused for 75 minutes in Sprague-Dawley rats (n = 7) in which renal perfusion pressure was permitted to rise in parallel with systemic arterial pressure and in rats (n = 8) in which renal perfusion pressure was serocontrolled constant at basal levels. Infusion of L-NAME raised renal perfusion pressure from 122 +/- 6 to 157 +/- 4 mm Hg in the nonservocontrolled group but not in the servocontrolled group (118 +/- 3 mm Hg). L-NAME decreased renal plasma flow and glomerular filtration rate to the same level in both rat groups. L-NAME significantly decreased sodium excretion (1.38 +/- 0.41 to 0.36 +/- 0.14 microEq/min and 1.19 +/- 0.46 to 0.30 +/- 0.05 microEq/min, respectively), fractional excretion of lithium (25.7 +/- 1.7% to 16.7 +/- 2.3% and 25.6 +/- 4.0% to 18.2 +/- 1.7%), and renal interstitial hydrostatic pressure (6.4 +/- 1.4 to 3.2 +/- 0.9 mm Hg and 6.3 +/- 1.8 to 2.7 +/- 0.9 mm Hg) in servocontrolled and nonservocontrolled groups. However, there was no significant difference in the renal hemodynamic and excretory responses to L-NAME between the servocontrolled and nonservocontrolled groups. In summary, reductions in sodium excretion during inhibition of nitric oxide synthesis are associated with significant reductions in renal interstitial hydrostatic pressure.(ABSTRACT TRUNCATED AT 250 WORDS)

Erythropoietin-induced antinatriuresis mediated by angiotensin II in perfused kidneys.

Erythropoietin (EPO)-induced hypertension is a common complication of EPO usage. The hypothesis that erythropoietin is antinatriuretic and that the sodium retention is mediated by intrarenal angiotensin II production was tested. Experiments were performed in Wistar rat kidneys perfused for 60 min in an isolated system. A dose-response curve was performed for EPO at 0, 10, 100, 1,000, and 10,000 mU/mL. EPO administration resulted in a dose-dependent decrease in sodium excretion to a maximum of 50% at the 1,000 mU/mL dose. In a second experiment, kidneys from five groups were perfused: controls, EPO (100 mU/mL), captopril (50 ng/mL), captopril (50 ng/mL) plus EPO (100 mU/mL), and the angiotensin receptor antagonist losartan (1 nM) plus EPO (100 mU/mL). The administration of EPO resulted in an immediate decrease in average sodium excretion (30%) with no change in GFR or other renal function parameters. Pretreatment with captopril or losartan blocked the effect of EPO. Captopril alone had no effect on renal function. A final experiment demonstrated the ability of losartan (10 nM) to block the pressor effects of angiotensin II (0.01, 0.1, and 1 nM). It was concluded that EPO acts within the kidney to cause the production of angiotensin II, which mediates the increased reabsorption of sodium.

Adaptation to increased dietary salt intake in the rat. Role of endogenous nitric oxide.

Previous studies have suggested that nitric oxide (NO) plays a role in regulation of renal vascular tone and sodium handling. We questioned whether the effects of NO synthase inhibition on renal function are direct or due to increased renal perfusion pressure (RPP) and whether stimulation of endogenous NO activity plays a role in adaptation to increased dietary salt intake. Intrarenal arterial infusion of the NO synthase inhibitor NG-monomethyl-L-arginine (L-NMMA) in control rats resulted in decreased glomerular filtration rate, renal vasoconstriction, natriuresis, and proteinuria. When RPP was held at basal levels with suprarenal aortic snare, L-NMMA had similar hemodynamic effects but decreased sodium excretion and did not induce proteinuria. Exposure of rats to high salt intake (1% NaCl drinking water) for 2 wk induced increased serum concentration and urinary excretion of the NO decomposition products, NO2 + NO3. Urinary NO2 + NO3 and sodium excretion were significantly correlated. Compared with controls, chronically salt-loaded rats also demonstrated enhanced renal hemodynamic responses to NO synthase inhibition. We conclude that the endogenous NO system directly modulates renal hemodynamics and sodium handling and participates in the renal adaptation to increased dietary salt intake. Enhanced NO synthesis in response to increased salt intake may facilitate sodium excretion and allow maintenance of normal blood pressure.

Effect of Urea and Indomethacin Intake on Solute Excretion in the Syndrome of Inappropriate Secretion of Antidiuretic Hormone

Our purpose was to compare the effect of urea and indomethacin on solute excretion in hyponatremic patients with inappropriate secretion of antidiuretic hormone (SIADH). In 6 patients (serum Na: 126 +/- 3 mmol/l), the intake of urea (0.1 g/kg) induced a decrease in sodium excretion while urine osmolality, urine flow and osmotic clearance (Cosm) did not change. In the control group, the urinary flow and Cosm were increased as expected, while sodium excretion tended to increase. In the SIADH group, the decrease in the fractional excretion (FE) of Na+ (FE.Na+) (or FE.Cl-) after urea intake was negatively correlated with urinary urea concentration while the FE.K+ was positively correlated with FE.Na+ (or FE.Cl-), which suggests that the effect of urea on sodium excretion takes place proximally to the distal tubule, probably at the thin ascending limb. After indomethacin intake, FE.Na+ (or FE.Cl-), FE.K+, Fe.osm and Fe.urea decreased in the normal and hyponatremic groups. The mean free water reabsorption relatively to osmolar delivery was lower in SIADH (p < 0.05), and did not change significantly after indomethacin intake. The fact that the decrease of FE.Na+ (or FE.Cl-) after indomethacin was associated with a decrease in FE.K+ suggests that the increase in sodium (or chloride) reabsorption occurred more proximally to the distal tubule (probably a the medullary segment of the thick ascending limb of the loop of Henle).

Deficient production of nitric oxide induces volume-dependent hypertension

To study the influence of nitric oxide on renal function. Nitric oxide synthesis was inhibited and the effects on renal parameters were determined. Nitric oxide synthesis was progressively blocked by the intravenous administration of increasing doses of NG-nitro-arginine methylester (L-NAME) and then (c)GMP was administered. The blockade of nitric oxide synthesis first induced a marked fall in urinary sodium excretion, and later, a sustained increase in mean arterial pressure. These effects were reversed by 8-bromide cGMP. Nitric oxide-dependent cGMP formation was higher in the inner medulla than in any other part of the renal parenchyma, and the inhibition of nitric oxide synthesis significantly decreased both pressure- and volume expansion-induced natriuresis. Both the natriuretic and vasodilator tone maintained by nitric oxide are ultimately due to the production of cGMP. Nitric oxide-induced formation of cGMP appears to be the major factor that links changes in renal medullary circulation to those of sodium excretion. Sufficient inhibition of nitric oxide synthesis to decrease sodium excretion without altering blood pressure induces volume-dependent hypertension because blood pressure is elevated by an increased sodium intake.

Prostaglandin E2 in renal transplant recipients.

The concentrations of prostaglandin E2 (PGE2), sodium, potassium and creatinine were determined in the blood and urine of 50 renal transplant recipients treated with cyclosporine A or azathioprine, as immunosuppressive agents, for at least one year post transplantation. Fourteen healthy subjects served as control group. The urinary PGE2 excretion was significantly decreased in all treated renal transplant recipients and this reduction was associated with significant decrease in urinary excretion of sodium and potassium. On the other hand, a high elevation in blood PGE2 concentration was observed while no significant changes were seen in sodium and potassium levels in the blood of these renal transplant recipients. The observations suggest an association between urinary PGE2 reduction and immunosuppressive treatments in renal transplant recipients; also, PGE2 may regulate intra-renal haemodynamics and influence the renal tubular electrolyte excretion. Moreover, urinary PGE2 can be used as an indicator of successful renal transplantation.

Cardiovascular and renal actions of C-type natriuretic peptide.

Studies were performed in two groups of anesthetized dogs (n = 5 per group) to determine the cardiovascular and renal actions of synthetic C-type natriuretic peptide (CNP). Systemic infusion of CNP (group 1; 10 and 50 ng.kg-1.min-1 iv) resulted in marked cardiovascular hemodynamic effects characterized by a decrease in mean arterial pressure, cardiac output, and atrial pressures in association with a decrease in sodium excretion. Bolus administration of CNP (group 2; 5 micrograms/kg iv) to minimize cardiovascular hemodynamic changes resulted in only a transient decrease in arterial pressure. Sodium excretion decreased despite a return of arterial pressure to baseline. These biological responses were associated with increases in plasma guanosine 3',5'-cyclic monophosphate (cGMP) in both groups but with no change in urinary cGMP. With both systemic infusion or bolus administration of CNP, significant increases in plasma aldosterone were observed in association with increases in distal nephron sodium reabsorption. This study demonstrates that CNP exhibits profound systemic hemodynamic actions and is indirectly, or perhaps directly, antinatriuretic.

Stress-Induced Renal Functional Alterations in Normotensives

This study was performed to assess changes in renal function accompanying cardiovascular responses to mental stress. Glomerular filtration rate (GFR, inulin clearance), renal plasma flow (RPF, PAH clearance), filtration fraction (FF), sodium excretion, and segmental sodium tubular reabsorption (lithium clearance) were measured in 15 normal volunteers during rest and stress. The psychological stress test used is based on a computerized version of the Stroop word color conflict test. Stress induced a significant (P less than .05) and sustained increase in blood pressure and heart rate. During stress, GFR and RPF did not change whereas FF increased significantly (P less than .05) and sodium excretion tended to decrease. The decrease in sodium excretion was due to a significant (P less than .05) increase in proximal reabsorption, which may be mediated by renal hemodynamic changes. The observed significant increase in FF suggests an increase in postglomerular arteriolar resistances, which may account for the increase in proximal sodium reabsorption through an alteration in peritubular Starling forces. In the long run, the stress-associated increase in sodium reabsorption may contribute to the development of hypertension.

EFFECTS OF OPIATES ON SODIUM EXCRETION IN THE ISOLATED PERFUSED RAT KIDNEY

1. A rat isolated perfused kidney preparation was utilized to define clearly a renal site of action. The variables measured were perfusate pressure and flow, glomerular filtration rate, urine volume, sodium excretion and potassium excretion. 2. Dextromethorphan (3 nmol/L) and dextrorphan (10 nmol/L) reduced sodium excretion in kidneys from rats on either control or high K+ diet, in the absence of any other measured renal effects. Dextromethorphan (10 nmol/L) produced a decrease in glomerular filtration rate as well as a decrease in sodium excretion. Naloxone (1 mumol/L) inhibited the effect of dextromethorphan on sodium excretion but had no effect when administered alone. 3. The levorotatory opiates levorphanol and levomethorphan, the kappa agonist ketocyclazocine and a range of other opiates had no effect on sodium excretion. 4. The results suggest a renal action specific for dextrorotatory opiates. This renal action is consistent with earlier binding studies suggesting preferential recognition of dextrorotatory opiates.

Acute and sustained changes in sodium balance during nifedipine treatment in essential hypertension

purpose: To assess the changes in sodium excretion and sodium balance after initiation of nifedipine treatment and after withdrawal of nifedipine. patients: Eight patients with uncomplicated mild to moderate essential hypertension were entered in a single-blind, placebo-controlled study of 39 days' duration. methods: Two 7-day periods while on a fixed sodium intake of 150 mmol/day approximately 3 weeks apart. After 4 days of a placebo and fixed sodium intake, patients were given nifedipine GITS (gastrointestinal therapeutic system) once a day and carefully studied for the following 4 days. Thereafter, patients continued to receive nifedipine GITS, and approximately 3 weeks later they were studied again for a week while on a fixed sodium intake. Nifedipine administration was stopped and changes occurring after withdrawal were studied. results: Nifedipine caused a significant increase in sodium excretion with a cumulative loss of sodium of 38 mmol per subject within the first 4 days of treatment. The withdrawal of nifedipine treatment caused a significant decrease in sodium excretion and a cumulative retention of sodium of 42 mmol per subject within the first 4 days of withdrawal. conclusions: Nifedipine causes an acute and a sustained reduction in sodium balance in patients with essential hypertension. This prolonged effect may contribute to the mechanism whereby nifedipine lowers blood pressure.

Potassium Depletion Exacerbates Essential Hypertension

To determine the effect of potassium depletion on blood pressure in patients with essential hypertension. Double-blind, randomized, crossover study, with each patient serving as his or her own control. Clinical research center at a university hospital. Twelve patients with hypertension. Patients were placed on 10-day isocaloric diets providing a daily potassium intake of either 16 mmol or 96 mmol. The intake of sodium (120 mmol/d) and other minerals was kept constant. On day 11 each patient received a 2-litre isotonic saline infusion over 4 hours. Blood pressure; urinary excretion rates for sodium, potassium, calcium, and phosphorous; glomerular filtration rate; renal plasma flow; and plasma levels of vasoactive hormones. With low potassium intake, systolic blood pressure increased (P = 0.01) by 7 mm Hg (95% CI, 3 mm Hg to 11 mm Hg) and diastolic pressure increased (P = 0.04) by 6 mm Hg (CI, 1 mm Hg to 11 mm Hg), whereas plasma potassium concentration decreased (P less than 0.001) by 0.8 mmol/L (CI, 0.4 to 1.0 mmol/L). In response to a 2-litre isotonic saline infusion, the mean arterial pressure increased similarly on both diets but reached higher levels on low potassium intake (115 +/- 2 mm Hg compared with 109 +/- 2 mm Hg, P = 0.03). Potassium depletion was associated with a decrease in sodium excretion (83 +/- 6 mmol/d compared with 110 +/- 5 mmol/d, P less than 0.001). Plasma renin activity and plasma aldosterone concentrations also decreased in patients during low potassium intake, but concentrations of arginine vasopressin and atrial natriuretic peptide, glomerular filtration rate, and renal plasma flow were unchanged. Further, low potassium intake increased urinary excretion of calcium and phosphorus and of plasma immunoreactive parathyroid hormone levels. Dietary potassium restriction increases blood pressure in patients with essential hypertension. Both sodium retention and calcium depletion may contribute to the increase in blood pressure during potassium depletion.

Chronic intrarenal hyperinsulinemia does not cause hypertension

Hyperinsulinemia has been postulated to link obesity and hypertension via the antinatriuretic actions of insulin. The main goal of this study was to quantitate the importance of the direct intrarenal actions of insulin, independent of systemic effects, in altering blood pressure and renal function. This was accomplished by determining the responses to chronic intrarenal insulin infusion in uninephrectomized, chronically instrumented conscious dogs maintained on a 74 meq/day sodium intake. Insulin was infused at rates calculated to raise intrarenal, but not systemic, insulin to levels similar to those observed in obese hypertensive dogs. Intrarenal insulin infusion (0.6 mU.kg-1.min-1) for 7 days caused transient decreases in sodium excretion but no significant changes in potassium excretion. Mean arterial pressure did not change during 7 days of insulin infusion, averaging 93 +/- 4 mmHg during control and 93 +/- 3 mmHg during insulin infusion. Intrarenal insulin caused small increases in GFR but no significant changes in effective renal plasma flow or renal vascular resistance. These results demonstrate that insulin causes transient decreases in sodium excretion, but chronic intrarenal hyperinsulinemia does not elevate blood pressure in normal dogs. Additional factors other than the direct sodium-retaining effects of insulin may be important in raising blood pressure in obesity-associated hypertension.

The beneficial effects of thyroxine on nephrotoxic acute renal failure in the rat.

We were able to confirm previous studies demonstrating that administration of thyroxine is capable of ameliorating the severity of acute nephrotoxic renal failure in the rat. Nephrotoxic acute renal failure was induced by the subcutaneous injection of potassium dichromate (6.25 mg/kg) into Sprague-Dawley rats. Twenty-four hours after this injection, rats received an intraperitoneal injection of either thyroxine (80 micrograms/kg body wt) or normal saline. Forty-eight hours after the potassium dichromate injection, renal clearance studies were performed. Inulin clearance was significantly higher in the thyroxine-treated than in the saline-treated acute renal failure rats: 1.12 +/- 0.13 (SEM) mL/g versus 0.75 +/- 0.07 mL/min/g kidney wt (P = 0.025). Thyroxine treatment also effected an increase of p-aminohippuric acid extraction from 0.23 +/- 0.03 to 0.33 +/- 0.02 (P = 0.011) and a decrease in the fractional excretion of sodium from 0.38 +/- 0.21 to 0.11 +/- 0.03% (P = 0.037 by Mann-Whitney U test). In order to investigate one potential mechanism of the beneficial effect of thyroxine we studied renal tubular regeneration in this model of acute renal failure. Renal cortical uptake of labeled thymidine into DNA was significantly increased 48 h after the injection of potassium dichromate, and thyroxine administration further enhanced this repair process: 53.9 +/- 3.6 versus 81.4 +/- 5.3 dpm/200 pg of DNA (P = 0.0033).

Role of prostaglandins in the natriuresis of head-out water immersion in humans

1. Prostaglandins may play a role in the natriuresis seen after acute circulatory challenges. To assess this role in head-out water immersion, we compared, in clearance studies, the effects of acute (24 h) and chronic (7 days) administration of indomethacin, an inhibitor of prostaglandin synthesis, on the renal response to head-out water immersion in six healthy subjects on a 200 mmol of sodium/day diet and on a 40 mmol of sodium/day diet. 2. Indomethacin caused a similar degree of sodium retention on each of these two diets. 3. During the 40 mmol of sodium/day diet, acute administration of indomethacin decreased sodium excretion before, as well as during, head-out water immersion; however, the relative increase caused by head-out water immersion was normal. After chronic administration of indomethacin, both baseline sodium excretion and the natriuresis induced by head-out water immersion were similar to those in control studies. 4. During the 200 mmol of sodium/day diet, indomethacin had no effect on baseline sodium excretion, nor on the natriuretic effect of head-out water immersion. 5. Head-out water immersion decreased tubular lithium reabsorption and increased diluting segment delivery. Despite opposite effects of indomethacin on these parameters, indomethacin did not prevent the tubular effects of head-out water immersion on either diet. However, indomethacin did prevent the marked increase in estimated renal plasma flow and the fall in filtration fraction that were observed during head-out water immersion in the absence of indomethacin (control). 6. Head-out water immersion was not associated with an increase in urinary excretion of prostaglandins.(ABSTRACT TRUNCATED AT 250 WORDS)

THE RELATIONSHIP OF URINARY THROMBOXANE EXCRETION TO CYCLOSPORINE NEPHROTOXICITY

Alterations in renal prostaglandin production have recently been postulated to modulate the decrease in renal blood flow associated with cyclosporine nephrotoxicity. In particular, increases in renal production of the potent vasoconstrictor thromboxane A2 have been implicated in the pathogenesis of this disorder. The present study was undertaken to explore the relationship between alterations in urinary thromboxane B2 excretion (UTxB2V) and CsA nephrotoxicity in two rat models. Male Sprague-Dawley (SD) rats were treated for 14 days with CsA 50 mg/kg/day (n = 8) or olive oil (C) (n = 9) by gavage. Creatinine clearance (Ccr), urine flow (V), and urinary excretion rates of sodium, N-acetyl-beta-D-glucosaminidase (NAG), glucose, and TxB2 were determined before and after treatment. A similar study was conducted using Fischer rats (CsA: n = 10, C: n = 13). In Fischer rats, CsA caused a 35% decrease in Ccr (P = 0.01), a 33% decrease in sodium excretion (P = 0.02), and a greater than 2-fold increase in NAG excretion (P = 0.03), while V, glucose excretion, and UTxB2V did not change. Although similar changes in sodium and NAG excretion were seen after CsA administration in SD rats, Ccr was not affected. Additional findings in SD rats included a 3-fold increase in V (P less than 0.01), a 24-fold increase in glucose excretion (P = 0.03), and a 5-fold increase in UTxB2V (P = 0.04). Thus, Fischer rats developed CsA nephrotoxicity in the absence of increased UTxB2V. In contrast, SD rats failed to develop nephrotoxicity despite a marked increase in UTxB2V. We conclude that changes in renal TxA2 production are unrelated to the development of CsA nephrotoxicity.