Cardioprotective Effects of the Novel Compound Vastiras in a Preclinical Model of End-Organ Damage.

Cardiac hypertrophy and renal damage associated with hypertension are independent predictors of morbidity and mortality. In a model of hypertensive heart disease and renal damage, we tested the actions of continuous administration of Vastiras, a novel compound derived from the linear fragment of ANP (atrial natriuretic peptide), namely pro-ANP31-67, on blood pressure and associated renal and cardiac function and remodeling. Of note, this peptide, unlike the ring structured forms, does not bind to the classic natriuretic peptide receptors. Dahl/Salt-Sensitive rats fed a 4% NaCl diet for 6 weeks developed hypertension, cardiac hypertrophy, and renal damage. Four weeks of treatment with 50 to 100 ng/kg per day of Vastiras exhibited positive effects on renal function, independent of blood pressure regulation. Treated rats had increased urine excretion, natriuresis, and enhanced glomerular filtration rate. Importantly, these favorable renal effects were accompanied by improved cardiac structure and function, including attenuated cardiac hypertrophy, as indicated by decreased heart weight to body weight ratio, relative wall thickness, and left atrial diameter, as well as reduced fibrosis and normalized ratio of the diastolic mitral inflow E wave to A wave. A renal subtherapeutic dose of Vastiras (25 ng/kg per day) induced similar protective effects on the heart. At the cellular level, cardiomyocyte size and t-tubule density were preserved in Vastiras-treated compared with untreated animals. In conclusion, these data demonstrate the cardiorenal protective actions of chronic supplementation of a first-in-class compound, Vastiras, in a preclinical model of maladaptive cardiac hypertrophy and renal damage induced by hypertension.

Diuretic effect of extracts, fractions and two compounds 2α,3ß,19α-trihydroxy-urs-12-en-28-oic acid and 5-hydroxy-3,6,7,8,4'-pentamethoxyflavone from Rubus rosaefolius Sm. (Rosaceae) leaves in rats.

Although diuretics have been widely used to treat hypertension along with others cardiovascular and renal disorders, no scientific data have been recorded to support the diuretic properties of Rubus rosaefolius Sm. (Rosaceae), a plant popularly used in Brazil to treat hypertension. Male Wistar rats were orally treated with: vehicle; hydrochlorothiazide; aqueous (AERR) and methanolic (MERR) extracts; dichloromethane (DCM), hexane (HEX) and ethyl acetate (EA) fractions; and the isolated compounds 2α,3ß,19α-trihydroxy-urs-12-en-28-oic acid (TUA) and 5-hydroxy-3,6,7,8,4'-pentamethoxyflavone (PMF). At the end of the experiment (after 8 or 24 h), urine volume and other urine or plasma parameters were measured. AERR and MERR, at 100 and 30 mg/kg, respectively, induced diuretic, natriuretic and kaliuretic effect. Additionally, the DCM and HEX, but not EA, at 10 mg/kg, also increased urine volume and Na+ and K+ excretion. Both active constituents, TUA and PMF, at doses of 1 and 3 mg/kg, showed an augmented diuretic and natriuretic index. While TUA revealed a kaliuretic action, PMF did not interfere with potassium excretion. The compounds increased urinary creatinine, but not urea, levels. TUA was able to decrease calcium excretion, as well as HCTZ, while PMF effect was associated with increased urinary prostaglandin E2 levels. The non-selective muscarinic receptor antagonist (atropine) prevented TUA-induced diuresis. In addition, indomethacin (a cyclooxygenase inhibitor) and atropine, exhibited the ability to block the diuretic effects prompted by PMF. Our study demonstrates the diuretic effect of extracts, fractions and two natural compounds obtained from R. rosaefolius leaves in rats.

Biomarkers for personalizing omega-3 fatty acid dosing.

Prostaglandin E2 (PGE2) has been linked to a higher risk of colorectal cancer. PGE2 in colon tissue can be reduced by increasing dietary eicosapentaenoic acid (EPA). The dose-dependent relationships between dietary EPA, serum EPA:arachidonate (AA) ratio, urinary PGE2 metabolites, and colonic eicosanoids were evaluated to develop biomarkers for prediction of colonic PGE2. Male rats were fed diets containing EPA:ω6 fatty acid ratios of 0, 0.1, 0.2, 0.4, or 0.6 for 5 weeks. Increasing the dietary EPA:ω6 fatty acid ratio increased EPA:AA ratios in serum and in the proximal, transverse, and distal colon (P < 0.001). The urinary PGE2 metabolite was reduced (P = 0.006). EPA-rich diets reduced colonic tissue PGE2 concentrations by 58% to 66% and increased PGE3 by 19- to 28-fold. Other AA-derived eicosanoids were reduced by 35% to 83%. The changes were not linear, with the largest changes in eicosanoids observed with the lower doses. A mathematical model predicts colonic tissue eicosanoids from the EPA:AA ratio in serum and the EPA dose. Every 10% increase in serum EPA:AA was associated with a 2% decrease in the (geometric) mean of PGE2 in the distal colon. These mathematical relationships can now be applied to individualized EPA dosing in clinical trials.

Dietary intake of PUFAs and colorectal polyp risk.

BACKGROUND: Marine-derived n-3 (omega-3) PUFAs may reduce risk of developing colorectal cancer; however, few studies have investigated the association of n-3 PUFA intakes on colorectal polyp risk. OBJECTIVE: The objective of this study was to examine the associations of dietary PUFA intake on risk of colorectal adenomatous and hyperplastic polyps. DESIGN: This was a colonoscopy-based case-control study that included 3166 polyp-free control subjects, 1597 adenomatous polyp cases, and 544 hyperplastic polyp cases. Dietary PUFA intake was calculated from food-frequency questionnaires and tested for association by using unconditional logistic regression. The urinary prostaglandin E(2) metabolite, which is a biomarker of prostaglandin E(2) production, was measured in 896 participants by using liquid chromatography and tandem mass spectrometry. RESULTS: n-6 PUFAs were not associated with adenomatous or hyperplastic polyps in either men or women. Marine-derived n-3 PUFAs were associated with reduced risk of colorectal adenomas in women only, with an adjusted OR of 0.67 (95% CI: 0.47, 0.97) for the highest quintile of intake compared with the lowest quintile of intake (P-trend = 0.01). Dietary intake of α-linolenic acid was associated with an increased risk of hyperplastic polyps in men (P-trend = 0.03), which was not seen in women. In women, but not in men, dietary intake of marine-derived n-3 PUFAs was negatively correlated with urinary prostaglandin E(2) production (r = -0.18; P = 0.002). CONCLUSION: Higher intakes of marine-derived n-3 PUFAs are associated with lower risk of adenomatous polyps in women, and the association may be mediated in part through a reduction in the production of prostaglandin E(2). This trial was registered at clinicaltrials.gov as NCT00625066.

[Changes in nitric oxide, prostaglandins and myeloperoxidase activity in acrolein-induced cystitis in rats]. / Cambios en el oxido nitrico, las prostaglandinas y en la actividad de la mieloperoxidasa, inducidos por la acroleína en vejiga urinaria de rata.

To investigate the role of substance P (sP), nitric oxide (ON) and prostaglandins (PGs) in acrolein (ACR)-induced cystitis, we studied the changes induced by ACR on bladder inducible nitric oxide synthase (iNOS) and mieloperoxidase (MPO) activities, along with PGs and NO metabolites levels. Sprague-Dawley male rats received i.p. ACR (5 mg/Kg) plus one of the following treatments: Group 1: saline 0.10 mL/100g i.p.; Group 2: Win-51.708 (WIN) 25 mg/Kg i.p.; Group 3: S-metilisothiourea (MITU) 35 mg/Kg i.p.; Group 4: Rofecoxib(ROF) 20 mg/Kg o.p.; Group 5: Meloxicam(MEL) 25 mg/Kg i.p.; Group 6: combination MITU+MEL. ACR-induced mortality was partially prevented by WIN (NK1 antagonist) and MITU (iNOS inhibitor). Animals that survived after 24h of ACR exposure, had histological inflammatory changes in bladder along with increased MPO activity. There was augmentation of nitrates+nitrites and of PGs. WIN didn't prevent any of these effects. ROF and MEL (COX-2 inhibitors) partially protected against bladder inflammation; MITU pre-treatment was able to prevent these changes and those of NO metabolites levels. The MITU+MEL combination produced the highest protection against ACR-induced damage. These results suggest that NO produced via iNOS and PGs produced by COX-1/COX-2, have an important role in the pathogenesis of cystitis induced by ACR. ACR could stimulate iNOS and COX-1/COX-2, producing lymphocyte migration and increases of NO and PGs.

Marginal zinc deficiency increases magnesium retention and impairs calcium utilization in rats.

An experiment with rats was conducted to determine whether magnesium retention is increased and calcium utilization is altered by a marginal zinc deficiency and whether increased oxidative stress induced by a marginal copper deficiency exacerbated responses to a marginal zinc deficiency. Weanling rats were assigned to six groups of ten with dietary treatment variables of low zinc (5 mg/kg for 2 weeks and 8 mg/kg for 7 weeks), low copper (1.5 mg/kg), adequate zinc (15 mg/kg), and adequate copper (6 mg/kg). Two groups of rats were fed the adequate-zinc diet with low or adequate copper and pair-fed with corresponding rats fed the low-zinc diet. When compared to the pair-fed rats, marginal zinc deficiency significantly decreased the urinary excretion of magnesium and calcium, increased the concentrations of magnesium and calcium in the tibia, increased the concentration of magnesium in the kidney, and increased the urinary excretion of helical peptide (bone breakdown product). Marginal copper deficiency decreased extracellular superoxide dismutase and glutathione, which suggests increased oxidative stress. None of the variables responding to the marginal zinc deficiency were significantly altered by the marginal copper deficiency. The findings in the present experiment suggest that increased magnesium retention and impaired calcium utilization are indicators of marginal zinc deficiency.

Urinary prostaglandins and the effect of indomethacin on phosphate excretion in children with hypophosphatemic rickets.

We recently reported the urinary prostaglandin E(2)/creatinine ratio (PGE(2)/Cr) was markedly elevated in Hyp mice, the animal model for X-linked hypophosphatemia, compared with control mice. We provided evidence for altered prostaglandin production mediating the phosphaturia and that indomethacin decreases urinary phosphate excretion in Hyp mice but not control mice. To determine the levels of urinary PGE(2)/Cr, the safety and efficacy of indomethacin on phosphate excretion in children with hypophosphatemic rickets (HPR), a prospective clinical trial was performed in 16 children with HPR and 16 age- and gender-matched healthy controls. Urinary PGE(2)/Cr excretion was determined on a 24 h timed urine collection. A randomized cross over, placebo versus indomethacin, clinical trial was performed in the 16 children with HPR. There was no difference in urinary PGE(2)/Cr excretion between controls and patients with HPR. In children with HPR, indomethacin treatment for 3 mo had no significant effect on serum phosphorus or urinary phosphate excretion. In conclusion, urinary prostaglandin excretion is similar in children with HPR compared with controls. Indomethacin had no significant effect on serum phosphorus or urinary phosphate excretion in children with HPR.

Lithium treatment inhibits renal GSK-3 activity and promotes cyclooxygenase 2-dependent polyuria.

The use of LiCl in clinical psychiatry is routinely complicated by overt nephrogenic diabetes insipidus (NDI), the mechanism of which is incompletely understood. In vitro studies indicate that lithium can induce renal medullary interstitial cell cyclooxygenase 2 (COX2) protein expression via inhibition of glycogen synthase kinase-3beta (GSK-3beta). Both COX1 and COX2 are expressed in the kidney. Renal prostaglandins have been suggested to play an important role in lithium-induced polyuria. The present studies examined whether induction of the COX2 isoform contributes to LiCl-induced polyuria. Four days after initiation of lithium treatment in C57 BL/6J mice, urine volume increased in LiCl-treated mice by fourfold compared with controls (P < 0.0001) and was accompanied by decreased urine osmolality. This was temporally associated with increased renal COX2 protein expression and increased urinary PGE(2) excretion, whereas COX1 levels remained unchanged. COX2 inhibition significantly blunted lithium-induced polyuria (P < 0.0001) and reduced urinary PGE(2) levels. Lithium-associated polyuria was also seen in COX1-/- mice and was associated with increased urinary PGE(2). COX2 inhibition completely prevented polyuria and PGE(2) excretion in COX1-/- mice, suggesting that COX2, but not COX1, plays a critical role in lithium-induced polyuria. Lithium also induced renal medullary COX2 protein expression in congenitally polyuric antidiuretic hormone (AHD)-deficient rats, demonstrating that lithium-induced COX2 protein expression is not secondary to altered ADH levels or polyuria. Lithium also decreased renal medullary GSK-3beta activity, and this was temporally related to increased COX2 expression in the kidney from lithium-treated mice, consistent with a tonic in vivo suppression of COX2 expression by GSK-3 activity. In conclusion, these findings temporally link decreased GSK-3 activity to enhanced renal COX2 expression and COX2-derived urine PGE(2) excretion. Suppression of COX2-derived PGE(2) blunts lithium-associated polyuria.

Pathophysiology of vascular dysfunction in a rat model of chronic joint inflammation.

The impact of chronic joint inflammation on articular vascular function in rats was investigated to address whether joint swelling and the associated vascular dysfunction are dependent upon a common prostanoid mechanism. Urinary nitrate/nitrite (NO(x)) and PGE(2) excretion, knee joint diameter and body weight were measured following induction of adjuvant-induced arthritis (AIA). Ten days postinduction of AIA, joint vascular reactivity was assessed by measuring the perfusion response using a laser Doppler imager (LDI) to topical application of acetylcholine (ACh) and sodium nitroprusside (SNP). Four groups were compared: a non-inflamed control group and three AIA groups treated i.p. with vehicle, indomethacin or SC-236 (at equimolar doses). The selective cyclooxygenase-2 (COX-2) inhibitor (SC-236) was used to differentiate between COX-1 and -2-derived prostaglandins. Urinary NO(x) and PGE(2) levels increased substantially during the early phase of AIA but decreased thereafter. Toxicity to indomethacin but not SC-236 was observed, as indicated by a marked decrease in body weight. Joint swelling was similarly attenuated by indomethacin and SC-236 (P= 0.0001 cf. vehicle-treated AIA; n= 5-6 per group), indicating that this is due to COX-2 and not COX-1 inhibition. The AIA-induced changes in urinary NO(x) and PGE(2) were corrected by both COX inhibitors. While vascular reactivity to ACh and SNP was significantly attenuated by AIA (P < 0.002; n= 5-10 per group), the perfusion responses to these vasodilating agents were similar in all three AIA groups, demonstrating that the vascular dysfunction was not corrected by inhibition of either COX-1 or COX-2 enzymes. Furthermore, the attenuation of both ACh and SNP-induced responses in AIA suggest that vascular dysfunction was not exclusively endothelial in nature. In conclusion, the joint swelling and vascular dysfunction associated with AIA appear to be mediated, at least in part, by independent mechanisms. While COX-1/COX-2 inhibition reduced joint swelling, vascular dysfunction in AIA is independent of constitutive or inducible prostanoid mechanisms, and appears not to be solely endothelial-derived, but to involve other components such as the vascular smooth muscle.

Beneficial effects of a diet rich in a mixture of n - 6/n - 3 essential fatty acids and of their metabolites on cyclosporine - nephrotoxicity.

In this study we investigated the role of a mixture of n-6/n-3 essential fatty acids, in the cyclosporine model nephrotoxicity. Administration of cyclosporine in rats decreased creatinine clearance and provoked body weight loss, but it did not induce proteinuria and did not alter the urine volume. These changes were associated with decreased urinary ratios of prostaglandin E/thromboxane B and prostaglandin I/thromboxane B excretions. Light microscopic sections showed that 100% of the animals were affected by histological tubular lesions on their kidneys. Administration of cyclosporine to animals fed for 3 months on standard chow containing a mixture of n - 6/n - 3 essential fatty acids, restored creatinine clearance, augmented urine volume and prevented body weight loss. The improvement of renal function was accompanied by increased urinary ratios of prostaglandin E/thromboxane B and prostaglandin I/thromboxane B excretions. Light microscopic sections showed that only 40% of the animals demonstrated histological tubular lesions, of minor importance, to their kidneys. Our results suggest that the metabolites of arachidonic acid can play important role in the development of cyclosporine-nephrotoxicity because they increase the levels of thromboxane A and that the enhanced synthesis of prostaglandins (E) and (I) induced by a mixture of n - 6/n - 3 essential fatty acids, could play a beneficial role in the prevention of this renal dysfunction.

Beneficial effects of a diet rich in a mixture of n - 6/n - 3 essential fatty acids and of their metabolites on cyclosporine - nephrotoxicity.

In this study we investigated the role of a mixture of n-6/n-3 essential fatty acids, in the cyclosporine model nephrotoxicity. Administration of cyclosporine in rats decreased creatinine clearance and provoked body weight loss, but it did not induce proteinuria and did not alter the urine volume. These changes were associated with decreased urinary ratios of prostaglandin E/thromboxane B and prostaglandin I/thromboxane B excretions. Light microscopic sections showed that 100% of the animals were affected by histological tubular lesions on their kidneys. Administration of cyclosporine to animals fed for 3 months on standard chow containing a mixture of n - 6/n - 3 essential fatty acids, restored creatinine clearance, augmented urine volume and prevented body weight loss. The improvement of renal function was accompanied by increased urinary ratios of prostaglandin E/thromboxane B and prostaglandin I/thromboxane B excretions. Light microscopic sections showed that only 40% of the animals demonstrated histological tubular lesions, of minor importance, to their kidneys. Our results suggest that the metabolites of arachidonic acid can play important role in the development of cyclosporine-nephrotoxicity because they increase the levels of thromboxane A and that the enchanced synthesis of prostaglandins (E) and (I) induced by a mixture of n - 6/n - 3 essential fatty acids, could play a beneficial role in the prevention of this renal dysfunction.

Pathophysiological basis of acute inflammatory hyperaemia in the rat knee: roles of cyclo-oxygenase-1 and -2.

The role of different isoforms of cyclo-oxygenase (COX) in mediating the acute (0-6 h) and late (24 h) phases of inflammation was investigated in the rat knee joint following intra-articular injection of carrageenan. The hyperaemic response was assessed transcutaneously using laser Doppler imaging (LDI). Samples were taken at corresponding time points for detection of synovial COX-1, COX-2 and inducible nitric oxide synthase (iNOS) mRNA, and measurement of urinary prostaglandin (PG) and nitric oxide metabolites (NO(x)). A non-selective COX inhibitor (indomethacin, 15 mg kg(-1) I.P.), a selective COX-2 inhibitor (SC-236, 16.8 mg kg(-1) I.P.) or vehicle were administered 1 h prior to carrageenan in the acute phase study. LDI scans were taken hourly for 4 h post-induction. Inflammatory hyperaemia in the vehicle group was attenuated in the indomethacin- (P < 0.001, two-way ANOVA) and SC-236-treated groups (P < 0.0001), with no difference between these treatments. At 24 h, I.V. infusion of indomethacin (0.1 mg min(-1)), increased vascular resistance (24 +/- 7.1 %; P < 0.05) compared to vehicle infusion, whereas SC-236 (0.11 mg min(-1)) did not. Resistance changes to indomethacin also differed from SC-236 (P < 0.05). Knee joint diameter progressively increased over 24 h (P < 0.0001, one-way ANOVA). Urinary PG levels increased by 6 h (P < 0.05), but returned to baseline by 24 h. COX-1 mRNA was detectable at all time points; COX-2 mRNA only at 3 h. Urinary NO(x) levels increased progressively over 24 h (P < 0.05), paralleled by induction of iNOS in the 3 and 24 h samples. Prostaglandin production via COX-2 appears to mediate the development of acute inflammatory hyperaemia, but nitrergic mechanisms may supervene subsequently. COX-1 but not COX-2 contributes to the maintenance of basal blood flow in the hyperaemic joint at 24 h.

Effects of dietary polyunsaturated fatty acid supplementation in early renal insufficiency in dogs.

Dietary supplementation with polyunsaturated fatty acids (PUFAs) alters the course of experimental kidney disease in dogs. In particular, supplementation with omega-6 PUFAs hastens the decline of kidney function, and omega-3 PUFAs are renoprotective. We investigated the early stages of renal insufficiency to determine whether PUFA supplementation altered the magnitude of hypercholesterolemia or glomerular hemodynamics. Two months after 11/12 nephrectomy, dogs were randomly divided into three groups of 6 animals each. Each group of dogs was then fed a low-fat basal diet supplemented with one of three sources of lipid to achieve a final concentration of 15% added fat. Fat sources were rich in omega-3 PUFAs (menhaden fish oil, group FO), omega-6 PUFAs (safflower oil, group SO), or saturated fatty acids (beef tallow, group C). Early in renal insufficiency, before significant kidney damage, group FO had a lower (P<.05) serum cholesterol concentration and tended to have a lower urinary prostaglandin E2 (PGE2) and thromboxane A2 (TxA2) excretion than group C. In contrast, group SO had a higher mean glomerular capillary pressure (P<.05) and more glomerular enlargement (P<.05) and tended to have higher eicosanoid excretion rates than group C. These differences in lipid metabolism, glomerular hypertension and hypertrophy, and urinary eicosanoid metabolism could explain, in part, the beneficial effects of omega-3 PUFAs and the detrimental effects of omega-6 PUFAs when administered on a long-term basis in this model of renal insufficiency.

Therapeutic and diagnostic potential of a vasopressin-2 antagonist for impaired water handling in cirrhosis.

OBJECTIVE: Progressive cirrhosis is associated with increasing difficulty to handle free water. We examined the therapeutic potential of an orally active nonpeptide vasopressin-2 receptor antagonist (OPC-31260) in the management of edema and ascites in patients with cirrhosis. By means of its chemical blockade of the vasopressin-2 receptor in the kidney, we also assessed the ability of renal water handling in the early stage of cirrhosis. METHODS: A single 30 mg dose of OPC-31260 was administered orally to eight biopsy-proven patients with cirrhosis who had ascites or peripheral edema. The aquaretic responses were compared with those in six healthy subjects. RESULTS: In the patients with cirrhosis, OPC-31260 significantly (p < 0.01) increased the urinary excretion rate at 0 to 2 hours, and significantly (p < 0.01) lowered urine osmolality at 2 to 4 hours after administration. Free water clearance increased from -0.48 +/- 0.14 to +0.19 +/- 0.21 ml/min (p < 0.05) at 0 to 4 hours after administration. However, these aquaretic responses in the patients with cirrhosis were only approximately half the responses observed in the healthy subjects. A significant (p < 0.05) inverse relationship was observed between indocyanine green retention at 15 minutes after administration and the maximal free water clearance after administration to the patients with cirrhosis. Urinary sodium excretion did not change significantly in the patients, whereas it increased twofold in the healthy subjects. Urinary vasopressin excretion tended to increase in the patients, whereas it increased twofold to threefold (p < 0.01 to 0.05) from the baseline in the healthy subjects. Urinary prostaglandin E2 excretion was not increased, and serum sodium and plasma vasopressin levels were elevated only slightly in both groups. CONCLUSIONS: Even though a hyporesponsiveness was observed in the group of patients with cirrhosis compared with the healthy group, the novel vasopressin-2 antagonist induced hypotonic diuresis in patients with cirrhosis, suggesting a therapeutic potential in managing water excess. This drug response may be a new index to assess impairment of water handling in patients with cirrhosis.

Effect of sairei-to on prostaglandin E2-induced phosphatidylinositol breakdown in aminonucleoside nephrotic rat.

We describe the effects of Sairei-to, a Chinese herbal medicine, on aminonucleoside-induced nephrotic rats (ANNR), and analyze the urinary excretion of protein and phosphatidylinositol (PI) turnover via prostaglandin E2 (PGE2) receptors in isolated glomeruli. Sairei-to suppressed urinary excretion of protein and PGE2 in ANNR, and inhibited acceleration of PI turnover in isolated nephrotic glomeruli. The affected responsiveness of the PI turnover system to PGE2 in a nephrotic state was presumed to be normalized by Sairei-to. These findings suggest that Sairei-to restores abnormal changes in the PI turnover system in ANNR kidneys, and thereby inhibit excretion of protein into the urine.

Aquaretic effects of the nonpeptide V2 antagonist OPC-31260 in hydropenic humans.

The antidiuretic action of arginine vasopressin (AVP) is mediated by interaction with renal V2 receptors. A nonpeptide V2 receptor antagonist, OPC-31260, has recently been developed. In this study, the effects of OPC-31260 on the excretion of water and electrolytes were investigated in normal subjects who were under water restriction. Since the clinical circumstances in which a V2 antagonist would be useful generally would be in patients with concentrated urine, a hydropenic state with nearly maximally concentrated urine was selected as the experimental condition. Intravenous injection of OPC-31260 caused an increase in urine volume and a decrease in urine osmolality in a dose dependent manner without any significant changes in the excretion of sodium and other electrolytes. A high dose of OPC-31260 (1 mg/kg body wt) caused free water excretion equivalent to that obtained during maximum diuresis after water loading, followed by an increase in plasma sodium and AVP concentration. Excretion of urea increased transiently during diuresis. Thus, OPC-31260 is demonstrated to be the first V2 antagonist which exhibits water diuresis (aquaresis) in hydropenic humans with endogenous AVP secretion and maximally concentrated urine. The drug will be useful as an aquaretic in the treatment of some types of hyponatremia where there is excess AVP and water retention.

Alteration of cyclosporine (CsA)-induced nephrotoxicity by gamma linolenic acid (GLA) and eicosapentaenoic acid (EPA) in Wistar rats.

Administration of cyclosporine (CsA), 37.4 microM (45 mg)/Kg, per day for 7 days, to Wistar rats, induced decreased creatinine clearance (Ccr) and body weight loss (BWL), but it did not induce proteinuria. These changes were associated with enhanced urinary thromboxane B2 (TXB2) and diminished 6-keto-PGF1 alpha (6kPGF1 alpha) and prostaglandin E2 (PGE2) excretions. The augmentation in TXB2 and the decrease in PGs highly diminished the ratios of 6kPGF1 alpha/TXB2 and PGE2/TXB2. In microscopic sections all of the kidneys were affected to variable degrees. When CsA was administered to animals fed for 70 days, prior to the experiment, on standard chow (SC) containing evening primrose oil (EPO) or fish oil (FO), 1% and 10% respectively (EPO contained 9% gamma-linolenic acid (GLA) and FO 5.6% eicosapentaenoic acid (EPA)), the nephrotoxic effect of CsA was partially prevented. These changes were accompanied by increased ratios of urinary 6kPGF1 alpha/TXB2 and PGE2/TXB2 excretions. Light microscopic (LM) studies showed that rats' kidneys fed on SC containing EPO or FO were not always affected and the lesions were of minor importance. In conclusion, these results suggest that EPO (GLA) and FO (EPA) could play a beneficial role in the development or the modulation of the renal syndrome induced by CsA.

Stimulation by interleukin-1 of renal calcium reabsorption in thyroparathyroidectomized rats.

Recombinant human interleukin-1 (rhIL-1) can induce an elevation in calcium that has been ascribed exclusively to the stimulation of bone resorption. In the present study, we investigated whether rhIL-1 could also enhance the renal tubular reabsorption of calcium. The chronic influence of recombinant human rhIL-1 on renal calcium transport was investigated in thyroparathyroidectomized rats. Administration of rhIL-1 at the dose of 1.5 micrograms/day sc for 6 days induced a significant elevation in plasma calcium that was associated with a slight but significant decrease in the urinary excretion of calcium. Recording of the urinary calcium excretion expressed per ml glomerular filtrate at various plasma calcium levels, as achieved by acutely infusing calcium gluconate, indicates that rhIL-1 enhanced the tubular reabsorption of calcium. The calculated index of the tubular reabsorption of calcium (TRCal) was significantly increased by rhIL-1 (2.18 +/- 0.14 versus 1.79 +/- 0.07 mmol/l GFR, p < 0.05, in vehicle-treated rats). The change in the renal handling of calcium was not associated with stimulation of the tubular reabsorption of magnesium. Acute administration of a large dose (24 micrograms given in a bolus IV injection) of rhIL-1 enhanced within minutes the urinary excretion of prostaglandin E2. This effect was followed by a significant increase in urinary cAMP excretion and associated with a lower urinary calcium excretion. In conclusion, the results presented in this study indicate that rhIL-1 administered chronically selectively stimulated the tubular reabsorption of calcium. Experimental evidence suggests that this effect is mediated by prostaglandin-induced cAMP generation. These data strongly suggest that changes in the tubular handling of calcium could contribute to rhIL-1-induced hypercalcemia.

Effects of starvation on the urinary contents of primary thromboxane and prostacyclin metabolites and a possible selenium-dependent role of prostacyclin in the renal handling of ketone bodies.

The aim of this study was to investigate whether urinary prostanoids, as an index of renal synthesis of these compounds, are affected in selenium (Se) deficiency and, if so, whether such changes could add to our understanding of the high excretion of ketone bodies in Se-deficient rats (p < 0.005 vs Se-adequate rats). Male rats were fed a Se-deficient diet with less than 0.01 mg Se/kg or the same diet supplemented with 0.2 mg Se/kg. The urinary contents of prostaglandin E2 (PGE2), PGF2 alpha and 6-keto PGF1 alpha were not significantly affected by the Se status. However, there was a positive correlation between the urinary contents of ketone bodies and 6-keto PGF1 alpha in Se deficiency (with p < 0.02 for acetaoacetate and p < 0.05 for 3-hydroxybutyrate). In contrast, only negative (nonsignificant) relationships were observed between these same parameters in Se-adequate rats. No correlations between urinary contents of ketone bodies and PGE2, PGF2 alpha or thromboxane B2 (TXB2) were obtained. Compared to fed rats, starvation caused a 4-fold increase in the urinary TXB2 content in Se-adequate, as well as in Se-deficient rats (p < 0.001). Starvation had an opposite effect on the content of 6-keto PGF1 alpha, which decreased (to 64% that of fed animals p < 0.001) in Se-adequate rats and, nonsignificantly (to 93% that of fed animals) in the Se-deficient group. It is concluded that starvation profoundly affects the urinary contents (and thus, probably renal synthesis) of TX and prostacycline (PGI2).(ABSTRACT TRUNCATED AT 250 WORDS)

Dietary modification of omega 6 fatty acid intake and its effect on urinary eicosanoid excretion.

A group of women were fed two separate diets in a crossover study and urinary eicosanoids were quantified. One diet contained 3.1% of total energy (en%) as polyunsaturated fatty acids (3.0 en% linoleic acid) and the other contained 8.4 en% polyunsaturated fatty acids (8.3 en% linoleic acid). Carbohydrate replaced fat in the low-polyunsaturated-fat diet. No changes were observed in the urinary excretion of 6-oxo-prostaglandin F1 alpha, its 2,3-dinor metabolite or thromboxane B2 by subjects on either of the diets. Urinary 2,3-dinor-thromboxane B2 excretion was lower (206.5 ng/24 h) when subjects were fed the high-omega 6 polyunsaturated fatty acid diet when compared with the lower-omega 6 polyunsaturated fatty acid diet (275.3 ng/24 h). Conversely, urinary prostaglandin E2 was higher (139.2 ng/g creatinine) during the higher-omega 6 polyunsaturated fatty acid diet when compared with the lower-omega 6 polyunsaturated fatty acid diet (94.4 ng/g creatinine).