A B S T R A C T The kallikrein-kinin system was characterized in seven patients with Bartter's syndrome on constant metabolic regimens before, during, and after treatment with prostaglandin synthetase inhibitors. Patients with Bartter's 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 bradykinini (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 ,ug/day to 8.5±2.5 ,ug/day. Plasma prekallikrein remained unchanged at 1.4 TU/ml. Thus, with prostaglandin synthetase inhibition, values for uriniary kallikrein and kinin and plasma bradykinin returned to normal pari passu with changes in PRA, in aldosterone, and in prostaglandin E. The

Sodium-retaining steroids increase urinary kallikrein but their effects on urinary kinins and plasma bradykinin are not known. Thirty-six normal subjects were studied during several different manipulations of dietary sodium and potassium or the administration of fludrocortisone or adrenocorticotropic hormone (ACTH). Urinary kallikrein and aldosterone excretion changed pari passu over a 30-fold range for kallikrein and an 80-fold range for aldosterone. Urinary kinin excretion was invariant. Plasma, bradykinin, on the other hand, responded to the same stimuli as plasma renin activity and not primarily to the level of sodium-retaining steroid. These studies show that: (1) urinary kallikrein is dependent on the level of aldosterone over a wide range of excretion values; (2) urinary kallikrein determines neither the level of urinary kinins nor the level of plasma kinins; (3) urinary kinins are independent of the level of sodium-retaining steroid; and (4) there is a strong correlation between plasma bradykinin and renin activity but not between plasma bradykinin and sodium-retaining steroid activty. We suggest that: (1) urinary kallikrein is an index of sodium-retaining steroid activity and may participate in the antinatriuretic and kaliuretic effects of these hormones; (2) plasma bradykinin is highly correlated with plasma renin activity because both responded to changes in extracellular fluid volume and not because angiotensin-converting enzyme controls both systems in an interrelated fashion; and (3) plasma bradykinin may act physiologically to antagonize angiotensin II and may contribute to maintenance of normal blood pressure in hyperreninemic states. Ore Res 44: [228][229][230][231][232][233][234][235][236][237]1979

SUMMARYThe relationship between levels of angiotensin II, kinins, and prostaglandin E and the depressor response to 1 or 3 mg/kg of the conrerting enzyme inhibitor SQ20.88I was studied in recumbent hypertensive subjects during 109 mEq and 9 mEq/day sodium intake. In 13 sodium-replete patients, SQ20,881 decreased angiotensin II from 46.7 ± 9.2 (mean ± SEM) to 31.7 ± 5.1 pg/ml and plasma aldosterone from 6.8 ± 0.9 to 2.9 ± 0.6 ng/dl (p < 0.003) without compensatory elevations of plasma renin activity and angiotensin I. Administration of SQ20.881 had no effect on plasma bradyklnin but it increased mean immunoreactive prostaglandin E from 143 ± 17 to 302 ± 75 pg/ml (p < 0.02) and in some patients it increased urinary kinin excretion. The distribution of the mean 2-hour depressor response was bimodal as four patients had a fall in diastollc pressure of at least 11 torr (mean 14 ± 1 torr) and nine had a minimal depressor response £ 4 torr, (-1 ± 1 torr); patients with a greater decrease in blood pressure showed an increase in urinary kinin excretion rate, whereas the other patients showed a fall (471 ± 121 vs -99 ± 106 ng/hr; p < 0.005); both had similar control levels and responses of plasma angiotensin II, aldosterone, immunoreactive prostaglandin E, and brad} kinin. In nine sodium-depleted patients, SQ20.881 slightly decreased mean angiotensin II from 30.5 ± 4.5 to 22.4 ± 4.3 pg/ml early after drug administration, but because this was accompanied by rapid compensatory elevations of angiotensin I (which increased from < 14 pg/ml to levels as high as 513 pg/ml) and mean plasma renin activity from 43 ± 1.6 to 13.9 ± 43 ng/ml/hr, levels of angiotensin II returned toward control soon after drug administration. We found that SQ20381 had no effect on plasma bradykinin but increased urinary kinin excretion by 203 ± 63 ng/hr (p <0.02) and in some patients increased plasma prostaglandin E. The distribution of the mean 2-hour depressor response in these nine sodium-depleted patients was also bimodal as flve sodium-depleted patients had a depressor response to drug of at least 7 torr (10 ± 1 torr) while four sodium-depleted patients had a minimal response (-1 ± 1 torr). The patients with a greater decrease in blood pressure showed a greater (p < 0.05) increase in both immunoreactive prostaglandin E (248 ± 99 vs 20 ± 12 pg/ml) and urinary kinin excretion (270 ± 69 vs 83 ± 75 ng/hr) whereas decrements in plasma angiotensin II and aldosterone were similar. Thus, the depressor response to SQ20,881 correlated better with alterations in urinary kinins and plasma prostaglandin E than with changes in plasma levels of angiotensin II.

The effect of prostaglandin synthesis inhibition on basal and ACTH-stimulated adrenal and renal function was investigated in normal volunteers. Data were collected during control and experimental study periods (13 days each). Adrenocorticotrophic hormone (Cosyntropin, 80 U/day) was administered i.v. on days 8 and 9 of each period. Indomethacin (150 mg/day) was given on days 5 through 13 of the experimental period. The subjects ate a constant diet containing 9 mEq of sodium, 100 mEq of potassium, and 2,500 ml of fluid daily. Indomethacin markedly inhibited urinary PGE excretion and plasma PGE concentration. The effect of ACTH alone as compared to the effect of ACTH and indomethacin showed: plasma sodium concentration, 139 +/- 1 vs. 131 +/ 3 mEg/liter (P less than 0.01, mean +/- SEM); plasma osmolality, 287 +/- 3 vs. 270 +/- 3 mOsm/liter (P less than 0.01); free water clearance, 97 +/- 66 vs. -1100 +/- 380 ml/24hr (P less than 0.01); urine volume, 2,000 +/- 60 vs. 950 +/- 200 ml/day (P less than 0.01); and urine osmolality 282 +/- 12 vs. 720 +/- 144 mOsm/liter (P less than 0.01). We conclude that the effects of ACTH and prostaglandin synthesis inhibition interact to result in inappropriate antidiuresis.