Prostaglandin E2 Excretion Research Articles

Effects of prostaglandin inhibition on the renal function curve during ovine pregnancy

This study was designed to assess the influence of prostaglandins on the steady-state relationship of mean arterial pressure and urinary sodium excretion. Ten nonpregnant and nine pregnant ewes were chronically prepared with indwelling catheters and maintained in metabolism cages. All the ewes received a continuous intravenous infusion of indomethacin (5 mg/kg/day) for 24 days. Step increases in sodium intake (20, 100, 400, and 1200 mmol per day), each maintained for 6 days, were administered as a fixed dietary (20 mmol) component with the balance infused intravenously. Mean arterial pressure was continuously monitored. The renal function curves were constructed from the steady-state mean arterial pressure-urinary sodium excretion relationships after sodium balance was attained. Indomethacin inhibited urinary excretion of prostaglandin E2 by 62% +/- 4% in nonpregnant and 47% +/- 6% in pregnant ewes, and 6 keto-prostaglandin F1 alpha, the stable metabolite of prostaglandin I2, by 55% +/- 4% and 65% +/- 6% in nonpregnant and pregnant ewes, respectively. Blood volume was not affected by indomethacin or salt in either group. Plasma angiotensin II was suppressed less in pregnant ewes (60% vs 80%) by increases in salt intake. Chronic treatment with indomethacin did not alter the renal function curves of either nonpregnant or pregnant ewes. These results suggest that prostaglandins do not influence the steady-state relationship between mean arterial pressure and urinary sodium excretion in either nonpregnant or pregnant sheep.

Neurohormonal and Hemodynamic Changes in Severe Cases of the Ovarian Hyperstimulation Syndrome

To evaluate systemic hemodynamics, endogenous vasoactive neurohormonal factors (renin-angiotensin and sympathetic nervous systems, antidiuretic hormone, atrial natriuretic factor, and renal prostaglandins), and renal function in the severe ovarian hyperstimulation syndrome. Prospective longitudinal study. Assisted-reproduction unit of a tertiary care hospital in Barcelona, Spain. 31 consecutive patients having in vitro fertilization with development of ascites because of severe ovarian hyperstimulation syndrome. Mean arterial pressure; cardiac output; peripheral vascular resistance; hematocrit concentration; renal function; plasma renin activity; plasma aldosterone, norepinephrine, antidiuretic hormone, and atrial natriuretic peptide determinations; and urinary excretion of prostaglandin E2 and 6-keto-prostaglandin-F1 were measured during the syndrome and 4 to 5 weeks after recovery (baseline). During the syndrome, patients showed increased hematocrits (mean of the paired difference, 0.047; 95% CI, 0.029 to 0.064), decreased mean arterial pressure (-16.6 mm Hg; CI, -19.8 to -13.6), increased cardiac output (2.6 L/min; CI, 2.13 to 3.17), and reduced peripheral vascular resistance (-709 dyne/s.cm-5;CI, -792 to -627). This was accompanied by marked increases of plasma renin (14.4 ng/L.s; CI, 9.87 to 18.90), norepinephrine (1.857 nmol/L; CI, 0.533 to 3.161), antidiuretic hormone (3.3 pg/mL; CI, 1.89 to 4.71), and atrial natriuretic peptide levels (9.7 fmol/mL; CI, 6.1 to 13.2). Hemoconcentration developed in 16 patients (mean of the paired difference in hematocrit concentration, 0.082; CI, 0.063 to 0.101) but not in 15 others (0.009; CI, 0.003 to 0.021). Both groups showed similar values for arterial pressure, cardiac output, and peripheral vascular resistance, but patients with hemoconcentration had higher (P < 0.05) levels of renin (mean, 20.97 ng/L.s[CI, 13.3 to 28.63] compared with 7.83 ng/L.s[CI, 4.08 to 11.58]), norepinephrine (3.907 nmol/L [CI, 3.057 to 4.757] compared with 2.417 [CI, 2.035 to 2.799]), and antidiuretic hormone (6.0 pg/mL [CI, 4.1 to 7.9] compared with 2.4 [CI, 1.7 to 3.03]). In addition to increased capillary permeability, severe ovarian hyperstimulation syndrome is consistently associated with arteriolar vasodilation. The simultaneous occurrence of these disorders leads to hyperdynamic circulatory dysfunction with marked stimulation of the sympathetic nervous system, renin-angiotensin system, and antidiuretic hormone.

A Case of Familial Central Diabetes Insipidus: The Response of Urinary Prostaglandins to 1-Deamino-8-D-Arginine Vasopressin

A case of familial central diabetes insipidus and dilatation of the urinary tract is reported. Administration of desmopressin for 1 year improved urinary tract dilatation with a concomitant reduction in urine volume. Urinary cyclic adenosine monophosphate and prostaglandin E2 excretion increased after treatment.

Increased thromboxane mediates the adverse renal effects of interleukin-2 in rats.

The capillary leak syndrome with decreased GFR and renal water and sodium retention after recombinant interleukin-2 (IL-2) administration may arise from endothelial activation via an increase in prostaglandin synthesis. This study was undertaken to better define the role of the prostaglandin system in the renal and metabolic effects of IL-2 administration in rats. The chronic administration of IL-2 (100,000 U/kg, thrice daily, ip) resulted in a significant increase in body weight, a decrease in GFR and in the urinary excretion of sodium and potassium, and an increase in the urinary excretion of thromboxane (TXB2). After combined IL-2 and low-dose indomethacin (1.7 mg/kg per day po), a significant decrease in body weight with normalization of GFR, of the urinary excretion of Na, and of urinary TXB2 was noted in animals receiving combined therapy as compared with those receiving IL-2 alone. In contrast, high-dose indomethacin administration (33.3 mg/kg po for the last 3 days of the study) was associated with a further decrease in GFR, enhancement of the sodium and potassium retention, and suppression of prostaglandin E2 excretion. The administration of the thromboxane receptor antagonist SQ 29548 in IL-2-treated rats led to a reversal of the fall in GFR induced by the lymphokine without significant changes in urinary sodium excretion. These results support the hypothesis that thromboxane is an important mediator of the renal and systemic effects of IL-2. These effects are reversed at least partly by low-dose indomethacin, which selectively suppresses thromboxane A2 (TXA2) synthesis, or by TXA2 receptor antagonism.

Systemic and Uteroplacental Hemodynamics and the Prostaglandin System in Pregnancy-Induced Hypertension and Normal Pregnancy

Objective: The aim of this prospective study was to establish whether or not there is any relationship between activation of the prostaglandin system and changes in systemic and uteroplacental hemodynamics in pregnancy.Methods: Urinary excretion of prostaglandin E2 (PGE2) and the main metabolites of prostacyclin (PGI2) and thromboxane A2 (TXA2) was determined, and indices of the vascular resistance of the uteroplacental bed were measured in 10 normotensive women studied in each trimester of pregnancy and in 15 women with pregnancy-induced hypertension in the third trimester. None of these subjects presented renal insufficiency or coagulation disorders, and all were monitored up to delivery to assess the outcome of pregnancy. Urinary excretion of prostanoids was measured by radioimmunoassay after purification of samples with high-pressure liquid chromatography. Blood pressure was measured and vascular resistance indices were calculated, using ultrasonography to measure the amplitude of systolic and diastol...

Effects of swim training on blood pressure, catecholamines and prostaglandins in spontaneously hypertensive rats.

A 6-month program of exercise with a daily swimming time of 30 minutes 3 times a week was carried out in female spontaneously hypertensive rats (SHR) to assess the roles of catecholamine and prostaglandin metabolism in the antihypertensive effect of chronic exercise conditioning. Swim training resulted in a significant reduction of mean blood pressure in SHR by 13.3 mmHg as compared with sedentary controls (158.8 +/- 5.0 versus 172.1 +/- 3.3 mmHg, p < 0.05). The increase in plasma levels of norepinephrine and epinephrine after acute blood loss of 2% of body weight were smaller in trained than control SHR. The daily urinary excretion of thromboxane B2, a stable metabolite of thromboxane A2, was significantly decreased by 33% in swim trained SHR as compared with control SHR (p < 0.01), while there was no difference in urinary excretion of prostaglandin E2 or 6-keto-prostaglandin F1 alpha, a stable metabolite of prostacyclin. These findings indicate that both the suppression of the sympathoadrenal system and decrease in vasoconstrictory prostaglandins in the kidney may have shared in the antihypertensive effect of exercise training in SHR.

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.

Unchanged noradrenaline reactivity and blood pressure after corrective surgery in primary hyperparathyroidism

Jespersen B, Brock A, Charles P, Danielsen H, Sørensen SS, Pedersen EB. Unchanged noradrenaline reactivity and blood pressure after corrective surgery in primary hyperparathyroidism. Scand J Clin Lab Invest 1993; 53: 479-486.In order to evaluate the role of the hyperparathyroid state for blood pressure and volume homeostasis, eight patients with primary hyperparathyroidism were studied before and after corrective surgery. Neither noradrenaline induced blood pressure changes nor basal blood pressure were affected by the operation, and the values were the same as in an age- and sex-matched control group. Noradrenaline infusion induced an increase in PTH(1-84) values before (72-86ngl−1, medians, p < 0.02), in contrast to a decrease after (28 to 19ngp−1, p < 0.05) operation for primary hyperparathyroidism. Basal plasma atrial natriuretic peptide was lower before than after removal of adenomata (3.2 vs. 4.8pmoH−1, medians, p < 0.02). Cyclic 3′-5′-guanosine monophosphate was not significantly changed (4.7 vs. 5.5nmoll_1). Aldosterone was higher before than after surgery (139 vs. 71pmoll−1, p < 0.02), whereas angiotensin II was unaltered (20 vs. 9pmoH−1). Arginine vasopressin was higher before than after the operation (0.9 vs. 0.7pmoir', p < 0.05), but urinary excretion of prostaglandin E2 was unchanged.In conclusion primary hyperparathyroidism was not associated with changes in noradrenaline reactivity or basal blood pressure despite derangements of hormones adjusting sodium and water homeostasis. It is suggested that the hormonal changes may be secondary to a relative volume depletion.

HUMORAL DETERMINANTS OF Na+ EXCRETION AFTER INTRAVENOUS NaCl LOADING IN NORMAL VOLUNTEERS

1. Twelve healthy volunteers maintained on a 100 mmol/day Na+ diet, were given an intravenous infusion of 2L saline (0.9%) between 10.00 h on 2 study days at least 1 week apart. Urine collections (90 min) were made from 08.30 to 16.00 h. Either carbidopa 100 mg or indomethacin 50 mg was given orally at 07.45 h on one study day and placebo was given on the other (in random order). 2. On the placebo day, saline infusion caused significant decreases in plasma albumin concentration, plasma renin activity (PRA), plasma aldosterone concentration and urinary aldosterone excretion, with 2 to 3-fold increases in plasma atrial natriuretic peptide (ANP) concentration and urinary dopamine: noradrenaline ratio (DA:NA), whereas mean urinary kallikrein and prostaglandin E2 (PGE2) excretion rates were unchanged. Carbidopa decreased urinary DA:NA and indomethacin decreased urinary PGE2 excretion, compared with the placebo day. Excretion of sodium (Na+) decreased below baseline in two out of six carbidopa-treated subjects and in three out of six indomethacin-treated subjects, but showed little or no change in the remainder. 3. These preliminary observations suggest that some subjects in the early phase of natriuresis after an intravenous Na+ load can be identified as having prostaglandin-dependent or dopamine-dependent mechanisms for Na+ excretion.

Rapid and Selective Inhibition of Platelet Aggregation and Thromboxane Formation by Intravenous Low Dose Aspirin in Man

1. One of the major problems in the clinical use of low dose aspirin for the prevention of vascular occlusion is that it takes about 3-5 days to become effective, a time too long for patients with unstable angina or coronary thrombolysis. Intravenous aspirin may be expected to exert a more rapid effect, but its influence on endothelial prostacyclin synthesis is uncertain. 2. In a single-blind, randomized, prospective study, we compared the effects of a single intravenous low dose (50 mg) or high dose (500 mg) of aspirin or placebo infused over a 60 min period on platelet aggregation, platelet thromboxane A2 production and whole-body prostanoid synthesis in 10 healthy male subjects by gas chromatography-tandem mass spectrometry. 3. Before the study, blood flow rates in the basilic and subclavian veins were determined by sonographic colour velocity imaging; the infusion rate for low dose aspirin was calculated to avoid biologically effective plasma levels of aspirin in the systemic circulation. 4. Platelet aggregation induced by 1 mmol/l arachidonic acid was similarly inhibited by > 85% within 30 min after the start of the infusion of high dose or low dose aspirin, respectively, and remained suppressed for 24 h. Platelet thromboxane A2 release declined gradually after low dose aspirin, reaching a minimum of 93% inhibition after 60 min. High dose aspirin suppressed platelet thromboxane A2 release to below the detection limit after 10 min. 5. Urinary excretion of the major urinary metabolite of thromboxane A2 (2,3-dinor-thromboxane B2) was equally suppressed by both dosages of aspirin [no significant difference between high dose (-83.2%) and low dose (-67.4%)].(ABSTRACT TRUNCATED AT 250 WORDS)

Chronic kinin receptor blockade induces hypertension in deoxycorticosterone-treated rats.

1. The contribution of endogenous kinins to the regulation of blood pressure and renal function of Wistar rats was evaluated by use of the new B2-receptor antagonist, Hoe 140, (D-Arg[Hyp3,Thi5,D-Tic7,Oic8]-bradykinin). 2. Neither Hoe 140 (4 micrograms h-1 s.c., for 6 weeks), nor vehicle altered systolic blood pressure (SBP, tail-cuff plethysmography) or renal function in rats, under normal conditions. 3. Chronic administration of deoxycorticosterone (DOC, 25 mg kg-1 s.c., weekly) increased SBP slightly only after 6 weeks (from 124 +/- 2 to 133 +/- 3 mmHg, P < 0.05). An earlier and greater rise in SBP (P < 0.01) occurred when DOC was combined with chronic infusion of Hoe 140 (from 125 +/- 1 to 154 +/- 3, P < 0.01). The hypertensive effect of Hoe 140 was confirmed by direct measurement of mean blood pressure (143 +/- 2 vs 122 +/- 2 mmHg in controls, P < 0.01). 4. DOC caused an initial fall, followed by a transitory increase in urinary volume and sodium excretion; thereafter, both parameters returned to baseline. The initial antidiuretic and antinatriuretic effects were enhanced by Hoe 140 (P < 0.05). 5. Urinary prostaglandin E2 excretion was increased by DOC (from 106 +/- 3 to 153 +/- 4 ng 24 h-1, P < 0.01) and this effect was prevented by Hoe 140 (from 95 +/- 3 to 104 +/- 3 ng 24 h-1, NS). By contrast, the high urinary vasopressin excretion and suppressed plasma renin activity found in DOC-treated rats were not altered by Hoe 140. 6. These data suggest that endogenous kinins play an important role in the regulation of arterial blood pressure under conditions of mineralocorticoid excess.

Peripheral vs. Central Blockade of the Renin-Angiotensin System in Spontaneously Hypertensive Rats: Comparison of Novel AT1 Receptor Antagonist TCV-116 with Angiotensin Converting Enzyme Inhibitor Delapril.

In the present study, we evaluated the hemodynamic and metabolic profiles derived from oral administration of the angiotensin converting enzyme inhibitor, delapril 50mg/kg/day, and the non-peptide angiotensin II type I (AT1) receptor antagonist, TCV-116 1mg/kg/day, for five days, to try to discriminate AT1 receptor-related responses from the depressor properties of chronic treatment with delapril in spontaneously hypertensive rats (SHRs). Both TCV-116 and delapril oral administrations significantly decreased blood pressure without any changes in heart rate. Delapril induced dipsogenic response and natriuresis associated with augmentation of urinary catecholamine excretion, while TCV-116 did not cause any changes in these variables. Neither delapril nor TCV-116 changed urinary excretion of prostaglandin (PG) E2 and 6-keto PG F1α. We also examined the effects of centrally administered angiotensin converting enzyme inhibitor and AT1 receptor antagonist to determine the central role of these drugs.Either the active metabolite of delapril, delapril-M1 1 mg/kg/day, or the active form of TCV-116, CV-11974 0.1mg/kg/day, were administered intracerebroventricularly for five days. Both treatments significantly decreased the blood pressure, in association with augmentation of the baroreceptor reflex control of heart rate, in response to phenylephrine injection. These findings suggest that the depressor properties of orally administered delapril are more complex than those of TCV-116, while central blockade by both angiotensin converting enzyme and AT1 receptor decreases blood pressure in part through baroreceptor sensitization. (Hypertens Res;1993 16: 239-246)

Unchanged noradrenaline reactivity and blood pressure after corrective surgery in primary hyperparathyroidism.

In order to evaluate the role of the hyperparathyroid state for blood pressure and volume homeostasis, eight patients with primary hyperparathyroidism were studied before and after corrective surgery. Neither noradrenaline induced blood pressure changes nor basal blood pressure were affected by the operation, and the values were the same as in an age- and sex-matched control group. Noradrenaline infusion induced an increase in PTH(1-84) values before (72-86 ng l-1, medians, p < 0.02), in contrast to a decrease after (28 to 19 ng l-1, p < 0.05) operation for primary hyperparathyroidism. Basal plasma atrial natriuretic peptide was lower before than after removal of adenomata (3.2 vs. 4.8 pmol l-1, medians, p < 0.02). Cyclic 3'-5'-guanosine monophosphate was not significantly changed (4.7 vs. 5.5 nmol l-1). Aldosterone was higher before than after surgery (139 vs. 71 pmol l-1, p < 0.02), whereas angiotensin II was unaltered (20 vs. 9 pmol l-1). Arginine vasopressin was higher before than after the operation (0.9 vs. 0.7 pmol l-1, p < 0.05), but urinary excretion of prostaglandin E2 was unchanged. In conclusion primary hyperparathyroidism was not associated with changes in noradrenaline reactivity or basal blood pressure despite derangements of hormones adjusting sodium and water homeostasis. It is suggested that the hormonal changes may be secondary to a relative volume depletion.

Renal effects of nimesulide in furosemide-treated subjects.

In clinical settings where effective plasma volume is decreased, nonsteroidal anti-inflammatory drugs (NSAIDs) may induce acute renal failure. We have evaluated the effects of single and repeated doses of nimesulide on renal haemodynamics and electrolyte excretion in 8 healthy volunteers during a prolonged course of furosemide (frusemide). Under these study conditions, renal prostaglandin synthesis is expected to be elevated, with renal function being dependent upon increased levels of prostaglandins. Nimesulide induced an acute but transient decrease in indices of renal haemodynamics. Furosemide-induced increases in plasma renin activity and aldosterone levels were blunted, and urinary excretion of prostaglandin E2 was markedly reduced by nimesulide. The magnitude and time course of the natriuretic, kaliuretic and diuretic effects of furosemide were attenuated by nimesulide. Although the transient nature of the observed renal haemodynamic changes suggests that the risk of developing acute renal failure is small, the rise should be taken into account in patients with renal dysfunction. Sodium and potassium retention, and the blunting of the diuretic-induced electrolyte excretion, could be of clinical relevance. Nimesulide appears, therefore, to share the prostaglandin-dependent renal effects of other NSAIDs.

Amelioration of ischemic acute renal failure by dietary fish oil administration in conscious dogs.

The hypothesis that dietary fish oil would protect dogs from ischemic acute renal failure was tested. Fish oil (eicosapentaenoic acid, 55 mg/kg per day, and docosahexaenoic acid, 40 mg/kg per day was given to eight instrumented, female, beagle dogs for 6 wk, while seven control dogs received vehicle. After 3 wk, unilateral nephrectomy was performed and a pneumatic cuff with flow probe was placed around the remaining renal artery of each dog. Three weeks thereafter, the cuff was inflated for 120 min. Renal function, RBF, and prostanoid excretion were measured 24 and 72 h after ischemia. In dogs receiving fish oil, blood pressure, GFR, RBF, renal vascular resistance (RVR), cholesterol, triglycerides, and prostanoid excretion were measured weekly for 6 wk. Further, cytosolic calcium was measured before and five times after fish oil. Blood pressure decreased, serum cholesterol and triglycerides decreased, and the cytosolic calcium within platelets decreased. The urinary excretion (expressed as picograms per milligram of creatinine) of the thromboxane (TX) metabolite TXB2 and the excretion of prostaglandin (PG)E2, as well as the excretion of the PGI2 metabolite 6-keto PGF1 alpha were decreased. GFR, RBF (Cl inulin and Cl para-aminohippuric acid), and RVR were not influenced by fish oil. Unilateral nephrectomy decreased GFR and RBF and increased RVR as expected, whereas it further decreased prostanoid excretion. Acute renal ischemia caused a significant, reversible decrease in GFR and urine volume in vehicle-treated animals, whereas no significant effect on renal function or urine volume was observed in animals pretreated with fish oil.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of high-protein diet on renal concentration capacity in rabbits

In the present studies, we have found that New Zealand White rabbits kept on normal rabbit chow (16% protein, LP) are unable to raise fractional free water reabsorption [TCH2O divided by glomerular filtration rate (GFR)] as the fractional osmotic load (Cosm/GFR) is increased. Acute administration of urea (400 mosmol/l) or indomethacin (10 mg/kg iv bolus, followed by 0.25 mg/min infusion) corrects the defect. Moreover, rabbits kept for 2 wk on a 40% protein diet (HP) showed marked improvement in their renal concentration capacity. Balance studies showed that, in rabbits on HP, urine prostaglandin E2 (PGE2) excretion was lower while GFR, urine urea, and osmolar excretion were significantly higher than in rabbits in the LP group. Medullary tissue electrolytes in the HP vs. LP group were as follows: urea, 1,035 +/- 90 vs. 790 +/- 60 mmol.l-1 x g wet tissue wt-1; tissue Na+, 548 +/- 96 vs. 298 +/- 37 meq.l-1 x g wet wt-1; and K+, 201 +/- 43 vs. 99 +/- 16 meq.l-1 x g wet wt-1. Also, medullary slices from animals on HP had a lower PGE2 synthesis than those on LP when stimulated with angiotensin II (ANG II). Papillary plasma flow (PPF) measured by the accumulation of 125I-labeled albumin, after infusion of vasopressin, was 13.7 +/- 2.0 in the HP group and 22.7 +/- 3.4 ml.min-1 x 100 g-1 in the LP group. These findings suggest that lower PPF and higher urea and electrolyte content in the medullary interstitium of HP intake results from inability to produce medullary PGE2 even during ANG II or antidiuretic hormone (ADH) stimulation.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of somatostatin on renal function in cirrhosis

To investigate the renal effects of somatostatin in cirrhosis, renal function and plasma and urinary levels of endogenous neurohumoral vasoactive substances were measured in conditions of intravenous water overload (20 mL/kg body wt with 5% glucose) before and during the intravenous infusion of somatostatin (250–500 μg/h) in 6 cirrhotic patients without ascites and 17 nonazotemic cirrhotic patients with ascites. Somatostatin induced a significant reduction of renal plasma flow, glomerular filtration rate, and free water clearance in both groups of patients. In patients with ascites, somatostatin also reduced urinary sodium excretion. Changes in renal function were significantly more marked in patients with ascites than in those without ascites and occurred in the absence of changes in mean arterial pressure and plasma levels of renin, aldosterone, norepinephrine, antidiuretic hormone, and atrial natriuretic peptide. Somatostatin induced a significant reduction in the plasma concentration of glucagon and urinary excretion of prostaglandin E2 that was not related to changes in renal function. These findings indicate that somatostatin administration induces renal vasoconstriction and impairs glomerular filtration rate, free water clearance, and sodium excretion in cirrhosis by a mechanism unrelated to systemic hemodynamics and endogenous neurohumoral vasoactive systems.

Short-term indomethacin administration does not impair excretion of acute potassium load in humans.

Maintenance treatment with prostaglandin synthesis inhibitors often causes some degree of hyperkalemia, indicating impaired potassium (K) excretion. Hypoaldosteronism probably is a mediating factor, but it is unknown whether these drugs also impair renal K excretion directly. Indomethacin, for example, stimulates NaCl reabsorption in Henle's loop, and thus may impair K excretion by decreasing distal NaCl delivery. We therefore studied the effect of 1 day administration of indomethacin (50 mg tid) on the excretion of a single oral KCl (1 mmol kg-1 body weight) in six healthy volunteers taking a 40 mmol sodium diet. To allow analysis of renal sodium handling, clearance studies were performed during water loading. In this acute setting, indomethacin had no effect on plasma K, and did not decrease plasma aldosterone. However, indomethacin clearly reduced NaCl excretion. Nonetheless, the excretion of the K load was entirely normal. Excretion of the K load was accompanied by increased clearance of phosphate and uric acid, and natriuresis. Data derived from the maximal free water clearance were compatible with increased delivery to and decreased reabsorption from the diluting segment. Occurrence of these effects was not prevented by indomethacin, although overall NaCl excretion remained less than observed without indomethacin. Indomethacin reduced prostaglandin E2 excretion substantially. Apparently, in normal man indomethacin does not impair K excretion directly, even though it greatly reduces NaCl excretion. Moreover, the effects of K on renal NaCl handling, probably contributing to the excretion of a K load, are not dependent on renal prostaglandins.

Protective effect of cicletanine on hypertension-induced decreases in the renal kallikrein-kinin and prostaglandin systems in stroke-prone spontaneously hypertensive rats.

We investigated the effect of two oral (p.o.) doses of cicletanine (5 and 30 mg/kg/day) for 4 weeks on urinary excretion (UKE), renal concentration (RKC) of kallikrein, and prostaglandin E2 (PGE2) and 6-keto-PGF1 alpha urinary excretion of stroke-prone (SP) spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY) rats submitted to a high sodium intake (1%). Both doses of cicletanine induced a significant antihypertensive effect in treated SHR as compared with hypertensive untreated controls (HC). After 4-week treatment, a significant difference in mortality was observed between normotensive controls (NC) (0%) and HC (84%). Both doses of cicletanine reduced the mortality of hypertensive animals (8% SHR with 5 mg and 24% SHR with 30 mg vs. 84% in HC). Whereas UKE and RKC were decreased in HC during the progression of untreated hypertension from week 1 to week 4, both doses of cicletanine administration significantly prevented this decrease. Consistently with maintenance of UKE during the course of hypertension, the level of tissue kallikrein was higher in hypertensive cicletanine-treated than in untreated SHR. This increased RKC was associated with a significantly higher rate of kallikrein biosynthesis. The increased level of the urinary excretion and tissue concentration of PGE2 and 6-keto-PGF1 alpha in cicletanine-treated SHR as compared with untreated animals was also of interest. This protective effect on PG excretion correlated with that on kallikrein excretion. The results confirm the efficiency of cicletatine as an antihypertensive treatment. The antihypertensive action includes protective effects on potential vasodepressor kallikrein-kinin and prostaglandin systems.(ABSTRACT TRUNCATED AT 250 WORDS)

Renal excretion of kallikrein and eicosanoids in patients with type 1 (insulin-dependent) diabetes mellitus. Relationship to glomerular and tubular function.

Glomerular filtration rate, renal plasma flow, renal tubular sodium reabsorption (derived from lithium clearance) and renal excretion rates of kallikrein, prostaglandin E2 and systemic and renally-derived metabolites of prostacyclin and thromboxane A2 were measured in patients with Type 1 (insulin-dependent) diabetes mellitus and in normal subjects. Diabetic patients with glomerular hyperfiltration had greater active kallikrein and prostaglandin E2 excretion than patients with normal glomerular filtration rate or than normal control subjects. Both active kallikrein and prostaglandin E2 excretion correlated directly with glomerular filtration rate. Active kallikrein excretion correlated directly with the reabsorption of sodium in the distal tubule. The excretion rates of 6-keto prostaglandin F1 alpha, 2,3 dinor 6-keto prostaglandin F1 alpha, thromboxane B2, 2,3 dinor thromboxane B2 and 11-dehydro thromboxane B2 excretion were not different between the groups. This study confirms in man our previous finding of increased renal kallikrein production in the hyperfiltering streptozotocin-diabetic rat model. Given that kinins generated by kallikrein are extremely potent vasodilators and stimulate the renal production of eicosanoids that also regulate glomerular function, our findings suggest that increased kallikrein activity and prostaglandin E2 production may contribute to renal vasodilatation and hyperfiltration in human diabetes. The localization of kallikrein in the distal connecting tubule makes it plausible that altered sodium transport in the distal tubule may be a signal to increase generation of kallikrein.