Systemic administration of platelet activating factor (PAF; acetyl glyceryl ether phosphorylcholine) reduces renal blood flow, but the mechanism responsible for that effect has not been defined. To address that problem, we determined the effects on renal blood flow of PAF administered directly into the renal artery in pentobarbital (30 mg/kg)-anesthetized dogs. Bolus injections of PAF (0.2-0.8 microgram) caused transient renal vasoconstriction, reducing renal blood flow by 20 to 60% without altering systemic blood pressure; lyso-PAF (1 microgram) had no effect. The effects of PAF on renal blood flow were not altered by alpha-adrenergic blockade (phentolamine, 3 mg/kg) or by angiotensin II receptor blockade ([Sar1,Ala8]angiotensin II, 6 micrograms/kg/min), but they were increased in magnitude and duration by meclofenamate (5 mg/kg), a cyclooxygenase inhibitor. Methysergide (3 mg/kg), a serotonin antagonist, slightly reduced PAF effects, but a specific blocker of vascular serotonin receptors did not. Renal venous plasma platelet density was not altered by infusion of PAF into the renal artery at a dose (1-2 micrograms/min) that caused a sustained 20% renal blood flow decrease. Alprazolam, a benzodiazepine that competitively inhibited PAF-induced aggregation in canine platelet-rich plasma, also inhibited the renal vasoconstrictor action of PAF (0.8 mg/min, into the renal artery) but did not alter renal vasoconstrictor effects of norepinephrine or angiotensin II.

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

This study was designed to characterize the time course of the effects of dexamethasone (2.5 mg kg-1 week-1, sc) on the renal arachidonate-prostaglandin (PG) system and to define the effect of the steroid on the interstitial cells of the renal inner medulla (RIC). The RIC are rich in triglycerides, which, due to their high content of arachidonic acid, may be a source of arachidonate for PG synthesis during conditions of phospholipase inhibition. After 1 day of dexamethasone treatment, the urinary excretion of PGE2 and PGF2 alpha was reduced to about 50% of the control value (P less than 0.05), and angiotensin II-induced release of arachidonic acid and PGs from renal medulla slices was blunted (P less than 0.05). In contrast, dexamethasone treatment did not affect ionophore A23187-induced release of PGs and arachidonic acid from renal medulla slices. By day 3 of dexamethasone treatment, urinary excretion of PGE2 and PGF2 alpha had returned to control levels, and by days 5 and 14 the excretion rates of both were clearly increased (P less than 0.05). The rise in urinary PG excretion was accompanied by a reduction of renal 15-hydroxyprostaglandin dehydrogenase activity, augmentation of renal medulla microsomal PG synthetase activity, and diminution of renal medulla triglycerides, the latter associated with a reduction in the number of RIC and of RIC osmiophilic granules. This study demonstrates that the effects of dexamethasone on urinary PG are biphasic; this may reflect the changing balance between the opposing actions of the steroid on renal PG-synthesizing and catabolizing enzymes and the inhibitory effect on the synthesis of renal PG that is linked to activation of specific renal lipases by endogenous factors such as angiotensin II.

The effect of gonadectomy and treatment with sex-steroids on renal prostaglandin 9-ketoreductase activity in 10-11 week old male and female rats was determined. Rats were gonadectomized or subjected to sham operation at 3 weeks of age. During week 7, rats were injected s.c. twice over a 6-day interval with vehicle (peanut oil, 0.5 ml X kg-1) or with depot forms of testosterone (5 mg X kg-1), estradiol (0.02 mg X kg-1), progesterone (5 mg X kg-1), or estradiol and progesterone combined. Renal prostaglandin 9-ketoreductase activity was about 50% higher in female rats than in males. Gonadectomy decreased 9-ketoreductase activity in females, but not in males, and eliminated the gender difference in enzyme activity. Treatment with estradiol elevated 9-ketoreductase activity in males and females, while treatment with testosterone or progesterone was without effect. Progesterone did, however, antagonize the elevation in 9-ketoreductase activity produced by estradiol.

To assess the concept of compartmentalization of renal prostaglandins (PG), we compared entry of PGE2 and the PGI2 metabolite 6-keto-PGF1 alpha into the renal vascular and tubular compartments, in sodium pentobarbital-anesthetized dogs. Renal arterial 6-keto-PGF1 alpha infusion increased both renal venous and urinary 6-keto-PGF1 alpha outflow. In contrast, renal arterial infusion of arachidonic acid (AA) or bradykinin (BK) increased renal venous 6-keto-PGF1 alpha outflow but had no effect on its urinary outflow. Both urinary and renal venous PGE2 outflows increased during AA or BK infusion. Ureteral stopped-flow studies revealed no postglomerular 6-keto-PGF1 alpha entry into tubular fluid. During renal arterial infusion of [3H]PGI2 and inulin, first-pass 3H clearance was 40% of inulin clearance; 35% of urinary 3H was 6-keto-PGF1 alpha, and two other urinary metabolites were found. During renal arterial infusion of [3H]6-keto-PGF1 alpha and inulin, first-pass 3H clearance was 150% of inulin clearance; 75% of urinary 3H was 6-keto-PGF1 alpha, and only one other metabolite was found. We conclude that in the dog PGE2 synthesized in the kidney enters directly into both the renal vascular and tubular compartments, but 6-keto-PGF1 alpha of renal origin enters directly into only the renal vascular compartment.

To determine whether chronic glucocorticoid excess influences the metabolism of arachidonic acid to prostaglandins (PGs) in the renal cortex, the authors investigated the effects of dexamethasone treatment (2.5 mg/kg/week) on the metabolism of arachidonic acid by renal cortex homogenates and microsomes and by isolated glomeruli, and on the release of immunoreactive prostanoids from isolated glomeruli incubated for 30 min in buffered salt solution at 37 degrees C. Glomeruli from dexamethasone-treated rats released, during basal incubation conditions, about twice (P less than .01) as much PGE2 and PGF2 alpha as did glomeruli from vehicle-treated rats. During incubation with arachidonic acid (33 microM) or calcium ionophore, A23187 (2.0 micrograms/ml), the release of PGE2 and PGF2 alpha from glomeruli of rats receiving dexamethasone also exceeded (P less than .01) the release from glomeruli of control rats. The rate of conversion of [1-14C]arachidonic acid to PGE2 and PGF2 alpha and to less polar metabolites having the chromatographic mobility of 5-hydroxyeicosatetraenoic acid and 12-hydroxyeicosatetraenoic acid, by isolated glomeruli and by renal cortex homogenates and microsomes from dexamethasone-treated rats, was higher (P less than .01) than the conversion by glomeruli and renal cortex homogenates and microsomes from control rats. The metabolism of arachidonic acid to the nonpolar metabolite(s) was not inhibited by indomethacin (10 microM), suggesting that it is not catalyzed by cyclooxygenase. The authors conclude that chronic dexamethasone treatment increases the release of glomerular PGE2 and PGF2 alpha and the metabolic transformation of arachidonic acid by glomeruli and by renal cortex homogenates and microsomes via both cyclooxygenase and noncyclooxygenase pathways.

Studies were conducted to determine whether prostaglandins are added to the urine during its passage through the rat urinary bladder in vivo. Control rats and rats with chronic streptozotocin-induced diabetes were anesthetized with Inactin, 100 mg/kg i.p., and urine was collected simultaneously from both kidneys. Urine from the left kidney was collected directly from the renal pelvis via a ureteral cannula, while urine from the right kidney was collected via a cannula in the urinary bladder. Prostaglandins in the urine were measured by radioimmunoassay. No difference in urinary concentration or rate of excretion of 6-keto-PGF1 alpha or PGE2 was seen between ureteral urine and bladder urine from either normal or diabetic rats. The results of this study indicate that in vivo there is no intralumenal addition of either 6-keto-PGF1 alpha or PGE2 to the urine by the ureteral bladder of rats.

The contribution of sex steroids to sex-related differences in renal prostaglandin dehydrogenase activity and urinary prostaglandin excretion was examined in 7–8-week-old male and female rats subjected to sham-operation or gonadectomy at 3 weeks of age. Rats were injected subcutaneously twice over a 6-day interval with vehicle (peanut oil, 0.5 mg/kg) or with depot forms of testosterone (10 mg/kg), estradiol (0.1 mg/kg), progesterone (5 mg/kg), or with estradiol and progesterone combined (0.1 and 5 mg/kg). After the second injection, 24-h urine samples were collected for prostaglandin measurement by radioimmunoassay; the rats were killed, and renal and pulmonary prostaglandin dehydrogenase activities were determined by radiochemical assay. Renal prostaglandin dehydrogenase activity was 10-times higher in intact male rats than in intact females. Gonadectomy increased renal prostaglandin dehydrogenase activity 4-fold in females, but had no effect in males; estradiol, alone or combined with progesterone, markedly suppressed renal prostaglandin dehydrogenase activity in both sexes, while testosterone or progesterone alone had no effect. Pulmonary prostaglandin dehydrogenase did not differ between the sexes and was unaffected by gonadectomy or sex-steroid treatment. Intact female sham-operated rats excreted 70–100% more prostaglandin E2, prostaglandin F2α, and 6-keto-prostaglandin F1α in urine than did males; gonadectomy abolished the difference in urinary prostaglandin E2 excretion. Estradiol decreased urinary prostaglandin E2 in females but not in males; treatment with other sex steroids did not alter urinary prostaglandin excretion.

This study was designed to investigate relationships between dietary potassium and the renal prostaglandin system in rats. The potassium content of the diet was 0.162 mmol/g during the control period and 0.004, 0.162, 1.351, or 2.702 mmol/g during the experimental period. Relative to control data in rats fed a 0.162 mmol/g potassium diet, the urinary excretion of 6-keto-PGF1 alpha was not affected by high potassium intake but increased (P less than 0.05) by 25% in rats fed a low potassium diet for 13 days and was associated with reduction of plasma potassium and with elevation of both plasma renin and net release of 6-keto-PGF1 alpha from renal inner medulla slices incubated in Krebs solution. The excretion of PGF2 alpha was not affected by low potassium intake but increased (P less than 0.05) by about twofold in rats fed a potassium-rich diet (1.351 and 2.702 mmol/g) for 13 days and was associated with elevation of plasma potassium concentration, renal prostaglandin 9-keto-reductase activity, and urinary excretion of kallikrein and vasopressin. The urinary excretion of PGE2 was not altered in rats fed either low or high potassium diets. Altogether, these results indicate selective influence of dietary potassium on the urinary excretion of prostaglandins in the rat.

We have found, in normal Wistar rats 10-11 weeks old, that the plasma vasopressin concentration (PADH) and the 24-h urinary excretion of vasopressin (UADHV) were higher in males than in females (P less than 0.01). In rats that were gonadectomized when they were 3 weeks old and studied when they were 10-11 weeks old, PADH and UADHV were reduced in males (P less than 0.01) and increased in females (P less than 0.01 for UADHV; PADH not significant) compared to those in intact males and females, respectively. Treatment of castrated male rats with testosterone tended to increase PADH, but estradiol, progesterone, or a combination of estradiol and progesterone were without effect; UADHV was increased by testosterone (P less than 0.01) and lowered by estradiol plus progesterone (P less than 0.01). In ovariectomized rats, PADH was unaffected by either testosterone or estradiol, but was decreased by progesterone alone (P less than 0.05) or in combination with estradiol (P less than 0.05). In these ovariectomized rats, UADHV was unaffected by testosterone and was decreased by estradiol and progesterone individually or in combination (P less than 0.01). These findings suggest that the gonadal steroid hormones can act either centrally to affect ADH release or peripherally to affect ADH metabolism. Compared to intact male rats, the lower PADH in intact female rats was accompanied by lower urine osmolality and greater urine volume, but further study will be required to appreciate fully the physiological significance of the differing PADH in males and females.

The present study was designed to investigate the effect of dexamethasone treatment for 2 weeks (2.5 mg/kg/week, subcutaneously) on the level of unesterified fatty acids, particularly arachidonic acid, in the renal medulla of rats, and to relate the observed effect to changes in the tissue concentration and the fatty acid composition of renal medulla phospholipids and triglycerides. Dexamethasone treatment caused an increase in the renal inner medulla level of unesterified fatty acids, including arachidonic acid, that was associated with a reduction of triglycerides and of arachidonic acid esterified into triglycerides, and with an increase in the rate of fatty acids esterification into triglycerides. In contrast, dexamethasone treatment did not affect the renal medulla concentration of phospholipids, the arachidonic acid content of renal medulla phospholipids, or the rate of esterification of fatty acids into renal medulla phospholipids. In the face of increased fatty acid esterification into triglycerides, the finding of reduced triglyceride levels in the renal medulla of dexamethasone-treated rats suggests excessive triglyceride breakdown. If so, fatty acids including arachidonic acid liberated from triglycerides may contribute to elevation of unesterified fatty acid levels in the renal medulla during dexamethasone treatment. The increased level of free arachidonic acid in the renal medulla of dexamethasone-treated rats may explain in part the reported effect of this steroid in increasing urinary prostaglandins.

Male Wistar rats were used to examine whether renal prostaglandins (PG) contribute to functional compensatory changes in the remaining kidney after uninephrectomy. Total urinary excretion of PGE2, PGF2 alpha and 6-keto-PGF1 alpha, a metabolite of PGI2, was measured before and during 11 days after surgery in uninephrectomized (UNX, n = 8) and sham-operated control (S, n = 9) rats. Urine volume was increased for the UNX rats on days 2-8 after surgery, but not thereafter, and urine osmolality for UNX was decreased on post-surgery days 1-9; total urinary sodium excretion did not differ between the two groups. Urinary PGE2 excretion was decreased in the UNX rats to 50% of S rat values, except on post-surgery days 2 and 3, when values for the two groups were not significantly different. Urinary PGF2 alpha excretion by the UNX rats was reduced to 50% of S rat values throughout the post-surgery period. In contrast, the urinary excretion of 6-keto-PGF1 alpha by the UNX rats did not differ significantly from that by the S rats, except on a single day. Chronic renal functional adaptation to renal mass reduction does not depend on increased renal prostaglandin systems activity; however, increased intrarenal PGE2 activity in the remaining kidney might be a factor in compensatory adjustments during the first days after surgery.

In various models of experimental and genetic hypertension in rats, blood pressure is markedly reduced during late pregnancy. The period during which the blood pressure reduction occurs is also the period when plasma progesterone is maximally elevated, and administration of progesterone to renal hypertensive rats has been reported to reduce blood pressure (J. Armstrong, 1959, Proc. Soc. Exp. Biol. Med. 102:452-455). To test the possibility that elevated plasma progesterone is responsible for the blood pressure reduction in late pregnancy, on Day 14 of pregnancy a group of New Zealand genetically hypertensive (NZGH) rats was ovariectomized and implanted with progesterone-filled capsules, to maintain plasma progesterone at low levels just sufficient to maintain pregnancy, and compared with intact, pregnant NZGH. Ovariectomy did not alter the characteristic course of blood pressure reduction seen in late-pregnant intact NZGH rats. In addition, daily administration of progesterone (15 mg/kg, sc) for 14 days did not alter blood pressure of either nonpregnant NZGH rats or New Zealand normotensive rats with chronic 1-kidney, 1-clip hypertension. It is concluded that blood pressure of NZGH rats is reduced to near normotensive levels in late pregnancy, as reported for other models of rat hypertension, but that elevated plasma progesterone levels are not requisite for that reduction and do not reduce blood pressure of renal hypertensive rats.

Anterior pituitaries of New Zealand genetically hypertensive and normotensive rats were compared for their content of glandular kallikrein-like activity. Anterior pituitary homogenates were assayed for their ability to cleave a chromogenic peptide substrate for glandular kallikrein (H-D-val-leu-arg-p-nitroanilide) at pH 8.0. Anterior pituitaries of both male and female New Zealand genetically hypertensive rats contained significantly less glandular kallikrein-like activity than their normotensive counterparts (-55% for females and -31% for males).