Priscilla K. Zia

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 Bartters 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 Bartters 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 Bartters syndrome results from beta adrenergic and prostaglandin-mediated proximal tubular rejection of sodium leading to increased distal sodium-potassium exchange.

Regulation of urinary prostaglandins in Bartter's syndrome

Abstract Enhanced prostaglandin production, possibly stimulated by hypokalemia, may mediate the manifestations of Bartters syndrome. To investigate the cause of increased urinary prostaglandin excretion, we measured urinary immunoreactive prostaglandin E (iPGE) during the oral administration of potassium and the parenteral administration of magnesium, and during water restriction and oral water loading in two subjects with Bartters syndrome. In one patient (Case 1), iPGE was 0.91 μg/day (normal 0.50 ± 0.20 μg/day, SD). Following the administration of indomethacin, 200 mg/day, iPGE, plasma renin activity (PRA), plasma aldosterone and angiotensin pressor sensitivity returned to normal but serum potassium did not. The oral administration of potassium citrate, acetate, bicarbonate, (Potassium Triplex), 240 meq/day for four days, increased iPGE to 2:3 μg/day and PRA from 47 to 73 ng/ml/hour (normal 1 to 3 ng/ml/hour). In the second patient (Case 2), iPGE was 1.4 μg/day. Therapy with ibuprofen, 1,600 mg/day, and indomethacin, 200 mg/day, again resulted in the return of iPGE, PRA, plasma aldosterone and angiotensin pressor sensitivity to normal, but serum potassium increased only transiently from 2.1 to 3.1 meq/liter. The oral administration of potassium chloride, 240 meq/day for four days, increased potassium to 3.0 meq/liter and increased iPGE to 8.0 μg/day. The administration of potassium triplex, 240 meq/day for four more days, further increased potassium to 3.4 meq/liter and iPGE to 9.3 μg/day, and PRA increased from 7.1 to 13.8 ng/ml/hour. This patient (Case 2) was hypomagnesemic (1.0 meq/liter, normal 1.5 to 2.4 meq/liter), and the intravenous administration of magnesium transiently increased iPGE by 15-fold. Following water restriction iPGE returned to normal (0.35 μg/day), and water loading increased iPGE to 3.0 μg/day, but neither maneuver altered PRA, aldosterone or serum electrolytes. The findings that potassium administration failed to reduce iPGE excretion and that water restriction renormalized iPGE excretion suggest that hypokalemia is not the primary stimulus to prostaglandin excretion.

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 A, (PGA,), 0.075–0.6 μg/kg min−1, alone and superimposed on angiotensin II (A II) administration in fire normal men. The infusions of PGA, did not affect Mood pressure, but did progressively increase tbe pulse rate up to 15.2 ± 2.0 (SEM) beats/min at the highest prostaglandin dose (0.6 μg/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/dl and PRA increased from 0.9 ± 0.1 to 5.4 ± 0.4 ng/ml hr−1 at the dose of 0.6 μg/kg.

Renal prostaglandins and sodium balance in normal man

We investigated the relationship between urinary prostaglandin E (PGE) excretion and sodium and water balance. PGE excretion was measured in thirteen healthy male volunteers on the metabolic ward during conditions of high sodium (200 mmols/day) and low sodium diets (40 mmols/day) and during intravenous administration of saline and of dextrose and water, using each subject as his own control. PGE excretion was higher on the high sodium than on the low sodium diet (191 +/- 37 SE versus 98 +/- 41 ng/6h, p less than 0.01). Saline and dextrose and water infusions significantly increased PGE excretion while subjects were on low sodium diets (to 314 +/- 74 and 443 +/- 152 ng/6h, respectively, p less than 0.01). While on high sodium diets the increase in PGE excretion during infusions was not significant. To further evaluate the role of prostaglandin in sodium excretion the study was repeated with simultaneous administration of indomethacin or ibuprofen to inhibit prostaglandin synthesis. Sodium excretion from saline and dextrose and water infusions were unaltered. The data suggest that dietary content of sodium may alter PGE excretion, but that acute changes in PGE excretion during saline administration reflect water balance rather than sodium load.

A chromatographic technique (sephadex LH-20) for the separation of major prostaglandins

Abstract A chromatographic system for prostaglandins has been developed using a column containing LH-20 sephadex. Different degrees of resolution are possible by altering the fraction of methanol in methylenechloride. A 80 × 1 cm column with 5% methanol:CH 2 Cl 2 separates the major classes A, E, F. 2% methanol:CH 2 Cl 2 separates A 1 from A 2 and B 2 . Experience with LH-20 sephadex suggests its value in terms of reproducibility, recovery, speed, and evidence for low blank readings in a radioimmunoassay.

Metabolism of prostaglandins A1 and A2 by human whole blood

Abstract The effect of human blood on prostaglandin metabolism in vitro was studied at 37°C and 4°C. Labeled prostaglandins were incubated for up to one hour in whole blood or plasma. After extraction, the prostaglandins were purified by LH-20 Sephadex chromatography. Appropriate 14 C labeled compounds, when available, were used to correct for losses. Metabolism was determined by comparison of incubated samples with zero time controls. There was no reduction in isotopic recovery of prostaglandins B 1 , B 2 and E 1 after incubation with whole blood for up to one hour. In contrast, human whole blood, but not plasma, rapidly metabolized prostaglandins A 1 and A 2 at 37°C. The rate of metabolism was temperature dependent, but still continued at 4°C. The products of these reactions were not identified, but they appeared to remain in the aqueous solution after extraction with the neutral organic solvent.

Is urinary flow rate a major regulator of prostaglandin E excretion in man

Urinary PGE2 excretion is enhanced in several polyuric states in man suggesting that PGE2 synthesis could be a mediator of diuresis. To explore the alternate hypothesis that polyuria is the cause of the increased PGE2 excretion, we increased urine flow rate by intravenous administration of dextrose and water with different magnesium, calcium and potassium solutions in four normal males. Urinary PGE excretion rose in parallel with urine volume (r = 0.65 p < 0.01) independently of the electrolyte solution. To determine the effects of chronic alterations in water balance in 5 female subjects, we sequentially regulated oral water intake to induce 1, 2, 4 and 8 liters of urine volume/day. During low (40 mEq) sodium diets, PGE increased from 540 +/- 50 to 4880 +/- 1240 ng/d with increasing urinary volume (r = 0.81, p < 0.01). Similarly, for 200 mEq sodium intake PGE paralleled urinary volume (from 630 +/- 100 to 4740 +/- 800 ng/d, r = 0.61, p < 0.01). In vitro sample dilution studies demonstrated no interference from method blank, and the addition of thin layer chromatography prior to Sephadex chromatography failed to alter assay measurements. We conclude that extreme increases in urinary flow rate may directly enhance PGE excretion in man.

Induction of renin release by exogenous prostaglandins in hyporeninemic hypoaldosteronism.

A deficiency in renal prostaglandin synthesis has been proposed as the cause of the syndrome of hyporeninemic hypoaldosteronism. To determine if renin release could be stimulated by pharmacologic infusions of PGA1, we infused PGA1 0.075 to 0.60 microgram/kg/min to nine patients with the syndrome. Total renal PGE production as measured by urinary PGE excretion was normal (650 +/- 169 vs 400 +/- 55 ng/24hr in normal subjects). Renin (PRA) was markedly depressed in all patients despite stimulation with upright posture and furosemide (1.0 +/- 0.4 vs 9.3 +/- 0.7 ng/ml/hr, p < 0.001). But in two patients PGA1, induced an increase in renin similar to that of normal subjects. PRA increased to a lesser degree in two other patients and plasma aldosterone slightly increased. Five showed no response. Infusions of nitroprusside in doses and duration that mimicked the hypotensive effects of PGA1 failed to increase PRA or aldosterone. The data suggest that total renal PGE production is normal in patients with the syndrome of hyporeninemic hypoaldosteronism. Although orthostasis, furosemide and nitroprusside do not increase renin, prostaglandin A1 infusion appears to be a potent stimulus to renin release in some of the patients.

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.