Robert E. Bowden

Bartter's syndrome: A disorder characterized by high urinary prostaglandins and a dependence of hyperreninemia on prostaglandin synthesis

Urinary prostaglandins E2 and F2alpha were measured by gas chromatography-mass spectrometry in three adult women and an adolescent girl with Bartters syndrome. On a constant metabolic diet prostaglandin E2 ranged from 293 to 1,221 ng/day (mean, 640 ng/day) and exceeded the normal range for adults of 76 to 281 ng/day in all patients. Prostaglandins F2alpha ranged from 291 to 1,061 ng/day (mean, 747 ng/day) in the adult women. Only in a young girl did prostaglandins F2alpha (1,677 ng/day) clearly exceed the normal range for adults of 422 to 871 ng/day. Treatment with indomethacin, which decreased urinary prostaglandin E-like material by 69 per cent or more, did not affect blood pressure. Plasma renin activity, which ranged from 5.2 to 22.2 ng/ml/hour (patients supine) and from 23.3 to 30.4 ng/ml/hour (patients upright), and urinary aldosterone, which ranged from 14.0 to 45.6 ng/day, decreased by 79, 65 and 52 per cent, respectively. The clearance of creatinine was lower for the eight or nine days of treatment, the balances of sodium and potassium were positive, and serum potassium was higher than in control. Ibuprofen, an inhibitor of prostaglandin synthetase which differs in structure from indomethacin, produced metabolic effects which were qualitatively similar to those of indomethacin. The results indicate that the renal synthesis of prostaglandins is increased in Bartters syndrome and that prostaglandins mediate the hyperreninemia and hyperaldosteronism which characterize the disorder. The over-production of prostaglandins by the kidney could be proximal cause of the syndrome, or secondary to intrarenal changes of an unknown nature. This study provides additional evidence for an important role for prostaglandins in the release of renin.

Reduction of renal function by newer nonsteroidal anti-inflammatory drugs

Because aspirin and indomethacin, two structurally dissimilar anti-inflammatory agents which reduce prostaglandin synthesis, both alter renal function, we studied the effect on renal function of three new nonsteroidal anti-inflammatory drugs which also reduce prostaglandin synthesis. We have shown that ibuprofen, naproxen, and fenoprofen are able to reduce renal function in patients with systemic lupus erythematosus and that such changes are associated with reduced excretion of urinary prostaglandin E (PGE)-like compounds. The changes may attenuate despite continued drug administration. These findings emphasize that renal function must be assessed with caution in patients taking these and perhaps other drugs which inhibit prostaglandin synthesis.

Elevated Urinary Prostaglandins and the Effects of Aspirin on Renal Function in Lupus Erythematosus

We studied the urinary excretion of immunoreactive prostaglandin E-like material (iPGE) and renal function in seven women with systemic lupus erythematosus to evaluate the relation between urinary iPGE and the increase in serum creatinine in patients taking aspirin. The mean pretreatment excretion of urinary iPGE in patients with lupus erythematosus, 42.7 +/- 6.4 ng/h, was significantly higher than the value of 29.0 +/- 1.9 ng/h for normal subjects (P less than 0.02). With aspirin, the urinary iPGE decreased an average of 45% (P less than 0.001). Increases in serum creatinine and blood urea nitrogen confirmed our previous clinical observations. The concomitant mean fall in creatinine clearance of 18% (P less than 0.001) was accompanied by a 14% decrease in inulin clearance (P less than 0.005); p-aminohippurate clearance fell 29% (P less than 0.005). The decline in urinary iPGE preceded the fall in creatinine clearance but was significantly correlated with it (r = 0.78; P less than 0.001). The observed changes reversed rapidly when aspirin was stopped. These data show that, in these patients with high urinary iPGE excretion, aspirin causes significant changes in renal function that may be mediated by the inhibition of prostaglandin synthesis.

The Kallikrein-Kinin System in Bartter's Syndrome and Its Response to Prostaglandin Synthetase Inhibition

The kallikrein-kinin system was characterized in seven patients with Bartters syndrome on constant metabolic regimens before, during, and after treatment with prostaglandin synthetase inhibitors. Patients with Bartters syndrome had high values for plasma bradykinin, plasma renin activity (PRA), urinary kallikrein, urinary immunoreactive prostaglandin E excretion, and urinary aldosterone; urinary kinins were subnormal and plasma prekallikrein was normal. Treatment with indomethacin or ibuprofen which decreased urinary immunoreactive prostaglandin E excretion by 67%, decreased mean PRA (patients recumbent) from 17.3+/-5.3 (S.E.M.) ng/ml per h to 3.3+/-1.1 ng/ml per h, mean plasma bradykinin (patients recumbent) from 15.4+/-4.4 ng/ml to 3.9+/-0.9 ng/ml, mean urinary kallikrein excretion from 24.8+/-3.2 tosyl-arginine-methyl ester units (TU)/day to 12.4+/-2.0 TU/day, but increased mean urinary kinin excretion from 3.8+/-1.3 mug/day to 8.5+/-2.5 mug/day. Plasma prekallikrein remained unchanged at 1.4 TU/ml. Thus, with prostaglandin synthetase inhibition, values for urinary kallikrein and kinin and plasma bradykinin returned to normal pari passu with changes in PRA, in aldosterone, and in prostaglandin E. The results suggest that, in Bartters syndrome, prostaglandins mediate the low urinary kinins and the high plasma bradykinin, and that urinary kallikrein, which is aldosterone dependent, does not control kinin excretion. The high plasma bradykinin may be a cause of the pressor hyporesponsiveness to angiotensin II which characterizes the syndrome.

Hypokalemia, in Bartter's Syndrome and Other Disorders, Produces Resistance to Vasopressors via Prostaglandin Overproduction:

Summary The role of hypokalemia and increased synthesis of prostaglandins in the decreased response of blood pressure to intravenous angiotensin II was studied in patients with Bartters syndrome and in patients with psychogenic vomiting. In patients with Bartters syndrome with high urinary prostaglandin E, treatment with an inhibitor of prostaglandin synthesis corrected the hyperreninemia and restored the pressor response to angiotensin II to normal but only partially corrected the hypokalemia. In patients with psychogenic vomiting with high urinary prostaglandin E, correction of the hypokalemia corrected the hyperreninemia and restored the pressor response to angiotensin II and to norepinephrine to normal. The findings suggest that hypokalemia, by stimulation of the synthesis of prostaglandin E in the kidney, produces hyperreninemia. An increase in synthesis of prostaglandin E in vascular tissue, stimulated by hypokalemia per se or by angiotensin II (produced by the hyperreninemia) or by both, increases the vascular resistance to angiotensin II and to norepinephrine.

Circadian rhythm analysis when output is collected at intervals.

It has long been recognized that many physiological and biochemical parameters show a repeating pattern of variation over 24 hours, i.e., a circadian rhythm. Halberg, Tong and Johnson (1965) used the sinusoidal model with 24-hour cycle to describe this variation. Tong (1976) described the polar coordinate transformation by which the sinusoidal regression problem can be treated as a linear regression problem. When the output of a system following diurnal variation, e.g. the human kidney, is collected at regular intervals and assayed, the expected quantity of substance present corresponds to the integral of the underlying output function. This paper shows that the polar coordinate transformation also linearizes this regression problem. More importantly, the covariance structure of Halberg et al. does not include interindividual variation. An alternative and more general model is proposed here based upon Raos (1959) growth curve analyses. The latter method allows testing for adequacy of the sinusoidal model and leads to inferences about population parameters. An example is given.

Urinary excretion of immunoreactive prostaglandin E: A circadian rhythm and the effect of posture

The excretion of urinary immunoreactive prostaglandin E (iPGE), sodium, potassium, creatinine and volume was studied in 4 hr collections in normal women at normal activity. iPGE exhibited a circadian rhythm with an amplitude of 29% and peak excretion at 4:55 P. M. There were also significant circadian rhythms for sodium, potassium, creatinine, and volume, all peaking in late afternoon. There were no significant changes either in the total excretion or in the circadian rhythms of iPGE, potassium, or creatinine excretion when the subjects remained in bed for an entire day while the circadian rhythms of sodium and volume were significantly modified in amplitude and phase, respectively. Urinary aldosterone excretion decreased significantly when the subjects were at bed rest. iPGE excretion increased 33% when subjects were first recumbent and then erect for consecutive 4 hr period on the same day (but when subjects were erect 1 day for a 4 hr period, iPGE excretion was lower by 32% than for the same 4 hr period the preceding day when they were recumbent). These data indicate that: 1) the sympathetic nervous system and renin-angiotensin-aldosterone system do not affect the circadian rhythms of urinary iPGE, and 2) short-term experiments of prostaglandin E excretion must be designed to avoid misleading results due to the circadian rhythm.

Renal Vasoactive Hormones in Scleroderma (Progressive Systemic Sclerosis)

Plasma renin activity and the urinary excretions of kallikrein, kinin, immunoreactive PGE (iPGE) and aldosterone were determined in 23 patients with progressive systemic sclerosis (PSS) on a fixed sodium and potassium intake who had no clinically apparent renal disease. Urinary excretions of kallikrein and kinin in the PSS patients were not significantly different from those of a group of sex and race-matched normal controls. In the female PSS patients urinary excretion of iPGE was also found to be normal. Upright PRA was appropriate for the urinary sodium excretion in 18 PSS patients (13 normotensive and 5 hypertensives) but was significantly elevated in the remaining 5 (all normotensive). The data suggest that the renal kallikrein-kinin and prostaglandin systems are unaltered in PSS patients without clinical evidence of renal disease.