Prostaglandins: modulators of renal function and pressor resistance in chronic liver disease.

Prostaglandins may modulate renal function and play a role in the hyperreninism and angiotensin pressor resistance of chronic liver disease. To study this possibility, we evaluated 12 patients with alcoholic cirrhosis and ascites. Urine immunoassayable prostaglandin E in 5 female patients was 3.3 +/- 0.5 micrograms/day [normal, 0.3 +/- 0.1 (SE)], renin was 14.6 +/- 3.7 ng/ml.h, and aldosterone was 76 +/- 19 ng/dl. After either indomethacin (200 mg) or ibuprofen (2000 mg) for 1 day, urine immunoassayable prostaglandin E fell to 0.8 +/- 0.4 micrograms/day, renin to 8.0 +/- 2.4 ng/mol.h, and aldosterone to 54 +/- 14 ng/dl (all P less than 0.01). Pressor sensitivity increased dramatically, and creatinine clearance transiently fell from 73 +/- 10 to 32 +/- 7 cc/min (P less than 0.01). Because a primary effect on renin might explain the renal impairment, an additional study used propranolol to lower renin activity. Renal function was unaltered by propranolol. We conclude that prostaglandins play a supportive role in maintaining renal function and are involved in the hyperreninism and pressor resistance of patients with liver disease.

Release of immunoassayable prostaglandin E by the human ischemic kidney.

Immunoassayable prostaglandin E concentration in renal venous plasma was measured in eight patients with renovascular hypertension. Two subjects with bilateral renal artery stenosis had similar concentrations from both renal veins. The six subjects with unilateral artery stenosis had greater concentration on the stenotic side in each case, suggesting that the human ischemic kidney produces increased amounts of prostaglandins.

The measurement of urinary prostaglandin E in normal subjects and in high-renin states.

Antisera generated toward PGE was obtained from rabbits immunized with PGE2 conjugated to bovine thyroglobulin by the carbodiimide reaction. The specificity of the antibody is such that only PGE1 and PGE2 has significant cross-reactions. 13, 14-Dihydro and 15-keto PG's did not react. An RIA capable of measuring 6 pg of PGE2 was developed to measure PGE in human urine. Urine samples adjusted with buffer to pH-5 are extracted with 5% MeOH in CH2CI2 and chromatographed through Sephadex LH-20 columns. The second-antibody technique is used to separate bound from free. This urine method yields blank values of 2 +/- 2 pg per sample, with a between-assay precision determined by duplicate analysis of 14% and intra-assay precision of 8%. The mean urinary excretion rate is 500 +/- 74 (S.E.), +/- 209 (S.D.) ng/day (n = 8) in men and 300 +/- 70, +/- 242 (n = 12) in women. These values are in agreement with those reported by others using gas chromatography-mass spectrometry of receptor assay with hepatic plasma membranes. Patients in a high-renin state, whether normotensive or hypertensive, have elevated PGE in urine. These studies suggest a relationship between the renin-angiotensin system and renal PG's in man.

The effect of sodium restriction and prostaglandin inhibition on the renin-angiotensin system in man.

To investigate the possible interrelationship between the renin-angiotensin and prostaglandin systems, two groups of normal men were evaluated under conditions of varied sodium intake and after indomethacin, an inhibitor of prostaglandin synthesis. Eight subjects were placed on a 200 mEq Na diet and given 45 min infusions of prostaglandin A1 (PGA1) at 0.075 microng/kg/min and angiotensin II at 10 ng/kg/min on separate mornings. PGA1 produced a significant rise in both plasma renin activity (PRA) and aldosterone. Angiotensin II caused a similar rise in aldosterone. The patients were then placed on a 10-20 mEq Na diet and the infusions repeated. PGA1 again induced a further increase in both PRA and aldosterone. Angiotensin II produced the expected increase in aldosterone while PRA decreased. Body weight and 24 h sodium excretion were not different from control days on either diet. When indomethacin was administered to patients on the low sodium diet, PRA fell significantly and there was an increased pressor responsiveness to angiotensin. In a separate group of 4 patients on a low salt intake, basal PRA fell significantly during a 4 day period of indomethacin administration and returned to control values within 48 h after discontinuing the drug. These studies suggest that PGA1 infusions stimulate renin release independently of sodium balance. Inhibition of prostaglandin synthesis lowers PRA and increases pressor responsiveness to angiotensin. The data provide further evidence that vasodepressor prostaglandins may play a role in renin release and blood pressure homeostasis.

The effect of ACTH and cortisol on aldosterone and cortisol clearance and distribution in plasma and whole blood.

The mechanisms of increased aldosterone and cortisol metabolic clearance rates (MCR) following ACTH or cortisol administration were studied in 13 subjects undergoing cardiac catheterization and in 9 healthy controls. In control subjects, the MCR (plasma) of both steroids increased by 29% (aldosterone: from 936 +/- 57 to 1204 +/- 55 l/day/m2, cortisol: from 205 +/- 12 to 264 +/- 17 l/day/m2 +/- SE) after ACTH (12 units/h) for 1 to 4 h, and by 20 and 32%, respectively, after cortisol (12 mg/h) for 1 to 2 h. In contrast, aldosterone MCR (whole blood) did not change with ACTH or cortisol administration (from 1276 +/- 57 to 1330 +/- 59 l/day/m2), indicating that the plasma MCR increase results from a redistribution of aldosterone from plasma to red cells. Aldosterone splanchnic extraction was 92 +/- 1% (n = 12) with normal morning cortisol levels, and extraction was unchanged after ACTH administration. For cortisol, however, the splanchnic extraction increased from 8 +/- 0.8% to 17.8 +/- 5.0%, and the MCR (whole blood) likewise increased by 15 to 31% (from 295 +/- 23 to 357 +/- 30 l/day/m2), after ACTH or cortisol administration. In vivo and in vitro measurements (at 37 C) of tracer aldosterone concentration in plasma and in red cells showed an increase in distribution to red cells with increasing cortisol concentrations. The results suggest that a fraction of aldosterone is bound in plasma and displaced by cortisol into red cells. There is an increased aldosterone plasma MCR, but unaltered whole blood MCR, since the liver extracts aldosterone almost completely from both plasma and red cells. The increase in cortisol MCR (plasma) results from both an increased splanchnic extraction as plasma binding sites approach saturation and a redistribution into red cells.

The effect of prostaglandin A1 on renin and aldosterone in man.

Blood pressure, pulse rate, plasma aldosterone (PA), renin, and cortisol were monitored during graded intravenous infusions of prostaglandin At (PGA)1), 0.075-0.6 mug/kg min-1, alone and superimposed on angiotensin II (A II) administration in five normal men. The infusions of PGA1 did not affect blood pressure, but did progressively increase the pulse rate up to 15.2 +/- 2.0 (SEM- beats/min at the highest prostaglandin dose (0.6 mug/kg min-1). Both PA and plasma renin activity (PRA) increased in a dose-related fashion in response to the prostaglandin infusions. Aldosterone increased from a control of 4.8 +/- 0.4 to 20.7 +/- 1.2 ng and PRA increased from 0.9 +/- 0.1 to 5.4 +/- 0.4 ng/ml hr-1 at the dose of 0.6 mug/kg min-1. The correlation between the aldosterone and renin values was r = 0.85 P less than 0.001. In separate experiments, acute volume expansion with 2 liters of saline did not affect the increase in renin activity induced by exogenous prostaglandin. A II (5 ng/kg min-1) increased aldosterone and blood pressure and decreased the pulse rate. The hemodynamic effects were progressively reversed by the superimposed prostaglandin infusions, but the observed changes in renin and aldosterone concentrations were not further altered. The PA response to A II infusions was not influenced by indomethacin pretreatment. Prostaglandin A (infusion) appears to have a direct effect on renin release in man.

Role of prostaglandins in the pathogenesis of Bartter's syndrome.

Increased renal prostaglandins activated by beta-catecholamines could produce renal tubular sodium wasting and angiotensin pressor resistance observed in Bartter's syndrome. We therefore measured plasma renin activity (PRA), aldosterone and prostaglandin A (PGA) by radioimmunoassay, and body composition by isotope dilution prior to and following beta-adrenergic blockade with propranolol (200 mg/day for 4 days) and prostaglandin synthesis inhibition by indomethacin (200 mg/day for 4 days) in a patient with Bartter's syndrome on a 250 meq sodium diet. After the administration of propranolol, body weight increased 3 kg, daily urine sodium decreased within 24 hours from 230 to 64 meq, and urine potassium from 102 to 45 meq, but PRA and the aldosterone level remained elevated. With the administration of indomethacin, body weight increased 5 kg, daily urinary sodium decreased within 24 hours to 11meq and urine potassium to 16 meq, PRA (normal less than 3 ng/100 ml/hour) decreased from 55 to 4.3 ng/ml/hour, plasma aldosterone (normal less than 8 ng/100 ml) from 74.1 to 3.6 ng/100 ml, and whole blood PGA (normal 546 +/- 307 pg/ml) decreased from 1,390 and 945 to 86 pg/ml. After the administration of propranolol or indomethacin, exchangeable sodium, total body water, extracellular volume and plasma volume all increased from less than to greater than predicted, and pressor resistance to angiotensin was normalized. These results suggest that Bartter's syndrome results from beta adrenergic and prostaglandin-mediated proximal tubular rejection of sodium leading to increased distal sodium-potassium exchange.

The effect of angiotensin II and indomethacin on immunoreactive prostaglandin "A" levels in man.

The effect of angiotensin II on peripheral levels of immunoreactive prostaglandin A2 (IR-PGA) was determined in 17 normal male volunteers. IR-PGA rose from 338 +/-65 (SE) pg/ml to 635+/-142 in response to pressor infusions of angiotensin II (p less than 0.05 on paired analysis). This increase was not observed when indomethacin, 75 mg p.o., was given to 8 patients two hours prior to a repeat infusion. Five patients of the original group were placed on a low sodium diet (10-20 mEg). The response to angiotensin was now exaggerated (278+/-52 pg/ml to 916+/-284). These five patients were kept on a low sodium intake and given indomethacin 50 mg p.o. g 6 hourly for 4 days. There was no significant rise with angiotensin infusion (106+/-31 pg/ml to 120+/-70). Pressor infusions of angiotensin II raise peripheral levels of IR-PGA, and this response is exaggerated by a low sodium diet and blocked by either acute or chronic indomethacin administration. This data supports the concept that vasodilatory prostaglandins may be released by endogenous angiotensin and thus provide a dynamic antagonism to the renin angiotensin system in man.