Harry S. Margolius

Urinary Kallikrein Excretion in Normal Man: Relationships to Sodium Intake and Sodium-Retaining Steroids

The urinary excretion of kallikrein, a renal enzyme that cleaves the potent vasodilator kinin, kallidin, from kininogen, was measured in normal volunteers by three different assays, one of which was a bioassay. When sodium intake was changed from ad libitum or 109 mEq/day to 9 mEq/day, daily kallikrein excretion increased progressively in every subject to a mean maximal value that was 271% of control by day 7; an increase in sodium intake to 259 mEq/day resulted in the return of kallikrein excretion to control values. Urinary excretion of amylase, a protein with a molecular weight similar to that of kallikrein, did not change when sodium intake was changed, but plasma renin activity and aldosterone excretion changed appropriately. In subjects on a constant-sodium (109 mEq/day), constant-potassium (100 mEq/day) diet, fludrocortisone, 0.5 mg/day for 10 days, increased kallikrein excretion to a mean maximal value that was 203% of control. In subjects on a diet containing 9 mEq sodium/day, elevated kallikrein excretion decreased during treatment with spironolactone, 400 mg/day. Rapid administration of water (1 or 2 liters in 30 minutes, orally) or rapid infusion of 2.4 liters of normal saline did not significantly alter urinary kallikrein excretion despite large changes in urine volume or sodium excretion. Thus, kallikrein excretion appears to be directly related to the effective level of circulating sodium-retaining steroid. The findings are consistent with a role for the kallikrein-kinin system in the renal response to sodium-retaining hormones.

Urinary Kallikrein Excretion in Hypertensive Man: Relationships to Sodium intake and Sodium-Retaining Steroids

Urinary kallikrein excretion was measured by a radiochemical esterolytic assay in patients with essential hypertension or primary aldosteronism. Patients with essential hypertension excreted significantly less (P < 0.001) kallikrein than did normal subjects when they were allowed an ad libitum sodium intake or given 259 mEq sodium/day. When sodium intake was changed from ad libitum to 9 mEq/day, kallikrein excretion increased in the majority of patients with essential hypertension, but it remained significantly less (P < 0.001) than that in normal subjects; however, aldosterone excretion was similar in both groups. Fludrocortisone, 0.5 mg/day for 10 days, increased kallikrein excretion in three patients with essential hypertension. In patients with primary aldosteronism, mean kallikrein excretion was sevenfold higher (P < 0.001) than that in patients with essential hypertension; kallikrein excretion remained unchanged when dietary sodium was altered, but it was decreased by treatment with spironolactone. Mean kallikrein excretion in patients with primary aldosteronism was also significantly higher (P < 0.001) than that in a normotensive control population. The results show that kallikrein excretion reflects the effective level of circulating sodium-retaining steroid in patients with primary aldosteronism but suggest that it is relatively unresponsive to endogenous sodium-retaining steroid in patients with essential hypertension. The data raise the possibility that the kallikrein-kinin system is of pathogenetic significance in human hypertensive disease.

Stability of blood pressure rank and urinary kallikrein concentration in childhood: an eight-year follow-up.

SUMMARY Previous studies in a population of 721 children aged 2-14 years demonstrated the familial aggregation of blood pressure in children, and a significant regression coefficient (b = 0.25) of follow-up on initial blood pressures over a four-year period. Urinary kallikrein concentration (UKal) also aggregated in families, was lower in black than in white children and was inversely related to blood pressure.Further studies in the same cohort have been conducted. These variables were again measured in 484 children in 129 families seven to eight years after the initial blood pressure and three to four years after the original UKal measurements were made.Familial aggregation again was found for blood pressure and urinary kallikrein. Blood pressure tracking was demonstrated by the finding that blood pressure scores at the third survey were related significantly to those at both previous surveys.Kallikrein concentrations in casual urines at Survey 3 were related to those obtained at Survey 2 (r = 0.499), and were again significantly lower in black than in white children (log = 3.84 ± 0.8 vs 4.37 ± 0.7; P < 0.001). There were significant inverse relations between UKal/creatinine concentration and blood pressure in both white and black children.Thus, familial aggregation of blood pressure, blood pressure rank and concentration of kallikrein in casual urine specimens are relatively stable in children over an eight-year period of observation. This study demonstrates in a free living population of normal children, a stable relation between blood pressure and an enzyme which is involved in the production of potent vasodilator peptides and is related to hypertension in adults.

Altered Urinary Kallikrein Excretion in Rats with Hypertension

The urinary excretion of kallikrein, an enzyme which cleaves a vasodilator kinin from kininogen substrate, was examined in three types of hypertensive rats. Enzyme activity was measured by both esterase activity (isotopic assay) and bioassay with purified rat urinary kallikrein as a standard. Excretion of kallikrein was found to increase with age in spontaneously hypertensive rats, but levels were lower and stable in normotensive Wistar control animals. Rats with desoxycorticosterone-salt hypertension excreted markedly more, whereas rats with renal hypertension excreted significantly less kallikrein than did control animals. The alterations in kallikrein excretion were unrelated to changes in urine volume and protein excretion. The findings indicate that the kallikrein-kinin system may be involved in different forms of hypertension in the rat.

Effects of Mineralocorticoids, Altered Sodium Intake, and Adrenalectomy on Urinary Kallikrein in Rats

The urinary excretion of kallikrein was examined in rats whose mineralocorticoid level was increased by the administration of deoxycorticosterone or a low-sodium diet and decreased by adrenalectomy. Administration of deoxycorticosterone by injection or by subcutaneous implantation of pellets resulted in a threefold increase in kallikrein excretion after 10–30 days (P < 0.01). Low-sodium intake produced a twofold increase in kallikrein excretion after 2 and 4 weeks (P < 0.01). Urine volume and blood pressure were normal and unchanged throughout the study. Sodium excretion was unaltered by deoxycorticosterone but was essentially zero during low-sodium intake. Adrenalectomized rats excreted less than half the kallikrein of shamoperated control rats (P < 0.01). These data show a direct relationship between mineralocorticoids and kallikrein excretion and suggest that mineralocorticoids are a primary factor regulating the urinary excretion of kallikrein in rats.

Urinary kallikrein excretion in spontaneously hypertensive rats.

Urinary kallikrein was similar in 16-week-old Wistar/Kyoto (VV/Ky) and spontaneously hypertensive (SH) rats, but at 23 weeks the SH rats excreted significantly less kallikrein. When dietary sodium was restricted, kallikrein excretion increased in the W/Ky but not in the SH rats. On high dietary sodium the opposite occurred: kallikrein excretion increased in the SH but not in the W/Ky rats. The pattern of urinary kallikrein excretion has some similarity to that seen in human hypertensive disease, i.e., the SH rat excretes less kallikrein than the normotensive control at 23 weeks of age and does not show an increased excretion when fed a low sodium diet. However, the rise in kallikrein shown by the SH rat on a high sodium diet is unique for this hypertensive model.