The effect of prostaglandin synthetase inhibitors on renal function: studies in normal rats during sodium or water diuresis and in rats with chronic renal insufficiency

The effect of acute infusion of the prostaglandin synthetase inhibitors - meclofenamate or indomethacin - was examined in awake rats. Studies were performed in normal rats undergoing either sodium or water diuresis and in salt-replete rats with chronic renal insufficiency. Prostaglandin synthetase inhibitors had no effect on renal plasma flow, glomerular filtration rate or fractional excretion of sodium in any of the groups. Absolute urinary excretion rates for sodium and potassium decreased only in the normal, salt-replete rats. In contrast, prostaglandin synthetase inhibitors consistently decreased urinary flow and osmolar clearance under all experimental conditions studied. In the normal, salt-replete rats the fall in urine flow was preceded by an increase in urinary excretion of cyclic AMP. These results show that inhibitors of prostaglandin synthesis enhance the ability of the kidney to reabsorb water. This effect may be secondary to increased cyclic AMP generation and to increased urea recirculation resulting in higher urea accumulation in the renal medulla.     

The effect of suppression of prostaglandin synthesis on renal function in rats with intact and reduced renal mass

The present study was undertaken to assess the role of prostaglandin system in the compensatory response to reduced nephron population, respective to renal function and electrolyte excretion. Intact and nephrectomized rats were divided in 4 groups: 1) rats pretreated with indomethacin, 2) rats pretreated with the vehicle of indomethacin, 3) rats pretreated with sulindac, and 4) rats pretreated with the vehicle of sulindac.In normal rats, indomethacin administration resulted in a mild decrease in creatinine clearance and a significant reduction of the urinary Na excretion. In the rats with reduced renal mass treated with indomethacin, the creatinine clearance did not differ from that in the control group. The 24 h urinary sodium excretion and the fractional excretion of sodium, however, were significantly lower in the indomethacin treated animals than in the control rats. No change in the creatinine clearance or in the sodium excretion was observed in all groups pretreated with sulindac.The urinary PGE₂ and thromboxane excretion was significantly lower in the indomethacin treated intact rats and the rats with reduced renal mass. Sulindac induced a slight decrease in urinary excretion of PGE₂ in intact rats. No significant change in urinary excretion of PGE₂ or thromboxane was seen after sulindac in the rats with reduced renal mass.The antinatriuretic effect of indomethacin was dissociated from changes in urine flow in all groups of animals, suggesting that the increase in Na reabsorption tool place in a water impermeable segment of nephron.These results suggest that the compensatory increase in urinary Na excretion per nephron in rats with reduced nephron population at least partly depends on an intact prostaglandin synthesis.     

The effect of sodium intake on renal prostaglandin production

The effect of chronic alterations in dietary sodium intake on renal arachidonic acid (AA) metabolism was studied in male Wistar rats who were maintained for 14 days on a diet consisting of sodium-deficient food and either deionized water (low salt intake, LSI), 1% saline (normal salt intake, NSI), or 2% saline (high salt intake, HSI). 24 h Urinary Sodium (UNaV) and plasma renin activity (PRA) measurements were shown to validate the dietary protocol. Microsomal preparations from the cortices and medullae were incubated with radiolabeled exogenous AA, and endogenous urinary prostaglandin (PG) levels were assayed by RIA to quantify renal PG synthesis. Cortical PGF2 alpha and PGE2 synthesis was found to be the greatest following LSI. In contrast, medullary PGF2 alpha was shown to be the least following LSI and to increase with increased sodium intake. Likewise, urinary PGF2 alpha levels significantly increased with increasing sodium intake. Changes in urinary PGE2 levels showed the same trend as PGF2 alpha but did not achieve statistical significance. These data show that dietary sodium differentially affects renal cortical and medullary PG synthesis and may reflect physiological differences in the regulation of cyclooxygenase in these zones. These data further suggest that the major source of urinary PGs is the renal medulla since the relationship of urinary levels to sodium intake mimics that described for the synthesis of PGs by the medullary tissue.     

The effect of prolonged immobilization on diuresis and water intake in rats

Diuresis and water intake was determined in 20 male albino rats during 8 weeks of immobilization and in 10 rats in post-immobilization recovery phase. Increase of diuresis and water intake during the immobilization period have been observed. Neither changes in sodium and potassium excretion nor in Na/K ratio were found. As the immobilization of the rats did not cause any changes of their natural body position in relation to the direction of gravity forces, the effect of immobilization on diuresis and water intake could not be related to an ortostatic shift of blood or inhibition of the hypothalamo-hypophyseal antidiuretic system.     

The effect of reported prostaglandin synthetase inhibitors on estradiol - stimulated uterine prostaglandin biosynthesis in the ovariectomized rat

Aspirin, indomethacin and naproxen have been shown to inhibit the release of prostaglandins E and F (PGE and PGF) from the estradiol-stimulated uterus of progesterone-pretreated ovariectomized rats. Under the present experimental conditions indomethacin (1 mg/rat) was found to be a potent inhibitor of PGF and E biosynthesis, but the duration of action was less than 24 hours, after which a rebound above control levels was observed. The compounds were without effect on estradiol-stimulated increases in uterine wet weight. Δ′THC did not inhibit estradiol-stimulated PG biosynthesis but produced a significant rise (P<0.01) in PGE levels in uterine venous blood. A hypothesis is suggested to explain some of the pharmacological effects of Δ′THC.     

The effect of acute or chronic administration of prolactin on renal function in feral chickens

The role of the hormone prolactin in avian osmoregulation has not been clearly defined. The increases in plasma prolactin concentrations which have been demonstrated in previous studies in response to osmotic stress are strongly suggestive of a role for prolactin in avian osmoregulation. The present study investigated the effects of either acute or chronic administration of ovine prolactin on plasma electrolytes and renal function in the feral chicken. The effect of acute administration of prolactin depended on the dose of prolactin used. All plasma concentrations of prolactin achieved by the infusions were greater than reported values for endogenous prolactin. Acute infusion of prolactin at the lower dose increased the fractional excretion of sodium and chloride significantly, whereas the higher dose of prolactin had no effect. However, chronic administration of ovine prolactin had no significant effects on plasma electrolytes and renal function. It is possible that the role of prolactin in avian osmoregulation is a combination of its effects on the kidneys and also on extrarenal tissues such as the intestine and nasal salt glands (where present). Accepted: 22 August 1997     

Effect of prostaglandin synthesis inhibitors on neurotensin and sodium salicylate-induced gastric cytoprotection in rats

Sodium salicylate (SA) has been reported to inhibit the formation of gastric ulcerations induced by aspirin, indomethacin, and absolute ethanol. In this study, SA dose-dependently inhibited gastric ulcers induced by three hours of cold-restraint stress (CRS); SA-induced cytoprotection was prevented by both acetylsalicylic acid (aspirin) and indomethacin pretreatment. Neurotensin (NT), which has previously been demonstrated to prevent the development of CRS-induced gastric ulcerations after intracisternal administration, was found to be ineffective in animals pre-treated with aspirin, and with indomethacin, as previously described. These data suggest that in the CRS model both NT- and SA-induced gastric cytoprotection require a functionally intact gastrointestinal prostaglandin synthetic pathway.     

肾素-血管紧张素系统在调节肾脏活动和慢性肾功能不全中的作用

一、肾内RAS的组成、生物学特征及肾内分布;(一)有关RAS的研究进展;(二)肾脏组织局部的RAS;(三)AngⅡ受体的亚型及其在肾内的分布;二、AngⅡ对肾脏血流动力学的影响;三、AngⅡ对肾脏的非血流动力学效应;(一)AngⅡ的促生长作用及促纤维生成效应;(二)AngⅡ作为促炎症因子的作用;四、有关RAS在肾功能不全中的临床研究     

Lack of prostaglandin effect on sodium balance and hyperreninemia in adrenalectomized rats

Glucocorticoids are known inhibitors of prostaglandin production. Prostaglandin E2 (PGE2) and prostacyclin (PGI2) are promoters of natriuresis and renin release. Excessive prostaglandin production, therefore, might contribute to the altered sodium balance and renin release observed in primary adrenal insufficiency. To test this hypothesis, sodium balance and prostaglandin production were measured in adrenalectomized rats and in animals receiving prostaglandin inhibitors or replacement dexamethasone. Compared to sham-operated controls, adrenalectomized rats had decreased two-day sodium balance and elevated plasma renin concentration (PRC), renal PGE2 production, and renal 6-ketoprostaglandin F1α (6kPGF1α, the nonezymatic metabolite of PGI2); however, no appreciable change in aortic 6kPGF1α production was observed. Dexamethasone given to adrenalectomized rats normalized PRC but had no effect on sodium balance or prostaglandin production. Likewise, prostaglandin inhibitors did not alter the sodium balance or decrease the PRC post adrenalectomy.These data confirm renal prostaglandin production is increased in adrenalectomized rats, but suggest that the elevation is not due directly to glucocorticoid deficiency. Further, PRC levels in adrenal insufficiency do not appear to be prostaglandin mediated. In conclusion, excessive renal prostaglandin production does not contribute to altered sodium balance or increased PRC in adrenalectomized rats.     

Vascular function in rats with adenine-induced chronic renal failure

The aim of the present study was to characterize the function of resistance arteries, and the aorta, in rats with adenine-induced chronic renal failure (A-CRF). Sprague-Dawley rats were randomized to chow with or without adenine supplementation. After 6-10 wk, mesenteric arteries and thoracic aortas were analyzed ex vivo by wire myography. Plasma creatinine concentrations were elevated twofold at 2 wk, and eight-fold at the time of death in A-CRF animals. Ambulatory systolic and diastolic blood pressures measured by radiotelemetry were significantly elevated in A-CRF animals from week 3 and onward. At death, A-CRF animals had anemia, hyperphosphatemia, hyperparathyroidism, and elevated plasma levels of asymmetric dimethylarginine and oxidative stress markers. There were no significant differences between groups in the sensitivity, or maximal response, to ACh, sodium nitroprusside (SNP), norepinephrine, or phenylephrine in either mesenteric arteries or aortas. However, in A-CRF animals, the rate of aortic relaxation was significantly reduced following washout of KCl (both in intact and endothelium-denuded aorta) and in response to ACh and SNP. Also the rate of contraction in response to KCl was significantly reduced in A-CRF animals both in mesenteric arteries and aortas. The media of A-CRF aortas was thickened and showed focal areas of fragmented elastic lamellae and disorganized smooth muscle cells. No vascular calcifications could be detected. These results indicate that severe renal failure for a duration of less than 10 wk in this model primarily affects the aorta and mainly slows the rate of relaxation.