Urinary Excretion Of Active Kallikrein Research Articles

Furosemide Compounds Enhance Urinary Excretion of Active Kallikrein Independently of Their Effects on Urinary Electrolyte Excretion

The chemical and diuretic effects of furosemide on the excretion and activation of urinary prokallikrein were investigated in rats by treatment with furosemide compounds with a range of diuretic activity or amiloride hydrochloride or the vehicle. Diuresis occurred with furosemide and benzyl furosemide, but not with isofurosemide, amiloride hydrochloride, or the vehicle. The urinary excretion rate of active kallikrein was significantly elevated above controls throughout the 72 h of treatment with all of the drugs tested, regardless of the level of diuresis or the rate of urinary electrolyte excretion. In contrast, the urinary excretion rate of total kallikrein (prokallikrein + active kallikrein) was unchanged in all groups. These data indicate that furosemide derivatives increase the activation, but not the excretion, of urinary prokallikrein and that these effects are unrelated to the chemical structure or diuretic activity of the compounds or to overall changes in urinary electrolyte excretion rates.

Effects of benidipine, a calcium antagonist, on urinary kallikrein excretion and renal impairment in experimental diabetes

To assess the long-term effects of different antihypertensive agents on urinary protein excretion and kallikrein excretion in diabetic rats with renal impairment. Uninephrectomized streptozotocin diabetic Wistar-Kyoto rats were randomly assigned to receive vehicle, a calcium antagonist (benidipine) or an angiotensin converting enzyme inhibitor (captopril) for up to 12 weeks. Active kallikrein was determined by its kininogenase activity, and generated kinins were measured by radioimmunoassay. Total kallikrein was also determined by measuring kininogenase activity after inactive kallikrein had been activated with trypsin. Urinary protein excretion increased significantly in diabetic rats compared with non-diabetic rats. Urinary active kallikrein excretion was significantly reduced in diabetic rats, whereas urinary total kallikrein excretion was unchanged, resulting in a reduced percentage of active to total kallikrein compared with that in non-diabetic rats. Benidipine and captopril reduced blood pressure and attenuated the development of diabetic renal impairment in a similar manner. However, only benidipine attenuated the decreases in urinary active kallikrein excretion and the ratio of active to total kallikrein in diabetic rats. Although pathophysiological relevance of impaired urinary kallikrein activation to the development of diabetic renal impairment remains to be determined, our result might suggest a new mechanism by which calcium antagonists protect the kidney from diabetic renal impairment.

Failure of the Oxytocin-Induced Increase in Secretion of Urinary Kallikrein in Young Spontaneously Hypertensive Rats

Urinary kallikrein excretion during oxytocin (OT) infusion were studied in anesthetized (sodium pentobarbital, 50 mg/kg, i.p.) young (4-weeks-old) spontaneously hypertensive rats (SHR) and Wistar Kyoto rats (WKY). OT-infusion (30 nmol/kg/30 min) to WKY significantly increased urinary excretion of the active kallikrein from the basal levels (25.4±5.6 10−2 × AU/15 min, n = 5) to 37.3±5.0 10−2 × AU/15 min (P<0.05, n=5) and 50.7±17.1 10−2 × AU/15 min (P<0.05, n=5) 15 and 30 min after the start of OT-infusion, respectively. In SHR, OT-infusion did not increase the urinary excretion of active kallikrein, but did decrease the urine volume and sodium excretion. The concentration of the active kallikrein in the kidney of WKY was not changed by OT-infusion, but that of SHR was slightly increased. The OT-infusion resulted in significantly higher concentrations of the active kallikrein in SHR kidney than in WKY kidney. These results suggest that less excretion of urinary kallikrein in SHR during OT-infusion may be attributable to a lower response in the secretion of kallikrein from the kidney.

Urinary kallikrein and salt sensitivity in essential hypertensive males

A strong influence of urinary kallikrein excretion on the salt sensitivity of blood pressure has been recently suggested in normotensive patients. To evaluate the relationship between kallikrein and salt sensitivity in essential hypertension, active kallikrein excretion, plasma renin activity, atrial natriuretic peptide and aldosterone levels were evaluated in 37 male hypertensives (mean age 43.3 +/- 4.7 years) after two weeks on a normal NaCl diet (120 mmol NaCl per day). After kallikrein determination, salt sensitivity was assessed in a randomized cross-over double-blind fashion by evaluating the blood pressure response to a high (240 mmol NaCl per day for two weeks) and a low (40 mmol NaCl per day for 2 weeks) NaCl intake. Blood pressure changes were evaluated considering as baseline blood pressure the measurement taken at the end of the 2 weeks under normal NaCl intake. Patients were classified as salt sensitive when a diastolic blood pressure change of 10 mm Hg or more occurred after both periods of low and high NaCl intake. At the end of the assessment of salt sensitivity, 19 hypertensive patients (mean age 43.0 +/- 4.6 years) were resistant. The urinary excretion of active kallikrein was significantly lower (P < 0.0001) in salt sensitive (0.51 +/- 0.36 U/24 hr) than in salt resistant patients (1.28 +/- 0.48 U/24 hr). Also, plasma atrial natriuretic peptide levels were higher in salt sensitive than in salt resistant hypertensives (P < 0.02), and a significant correlation between urinary kallikrein and plasma atrial natriuretic peptide was demonstrated in salt sensitive hypertensives (r = -0.691, P < 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

High sensitivity to salt in kininogen-deficient brown Norway Katholiek rats.

Brown Norway Katholiek rats, which have very low levels of plasma kininogens, excreted a much smaller amount of kinin in the urine than normal rats of the same strain. The systolic blood pressure of 7-week-old kininogen-deficient rats fed low (0.3%) NaCl diets (131 +/- 4 mm Hg, n = 12) was not different from that in normal rats. Two percent NaCl diets given from 7 weeks of age for 4 weeks caused rapid increases in blood pressure (167 +/- 4 mm Hg, n = 12, 9 weeks old) in deficient rats, although the same diets induced no blood pressure increase in normal rats. Urinary excretion of active kallikrein and prokallikrein remained constant in both rat groups throughout NaCl loading. During this period, the deficient rats secreted less urine (9 weeks old, P < .05) and less urinary sodium (11 weeks old, P < .05). Serum levels of sodium in deficient rats were higher (P < .05) than in normal rats at 9 weeks of age. Intracellular concentrations of sodium in the erythrocytes of deficient rats were higher (P < .05) than in normal rats throughout NaCl loading. Subcutaneous infusion of bovine low molecular weight kininogen with an osmotic pump in NaCl-loaded deficient rats induced a reduction (P < .01) in blood pressure and increases (P < .05) in urine volume and urinary sodium and kinin levels. By contrast, subcutaneous infusion of the bradykinin antagonist Hoe 140 or of aprotinin in NaCl-loaded normal rats induced a hypertensive response. This antagonist treatment reduced urine volume and urinary sodium. These results indicate that the lack of kinin generation observed in the kininogen-deficient rats was related through sodium retention to the hypertensive response to NaCl loading.

Urinary active kallikrein excretion and diabetic renal impairments in streptozotocin-treated rats.

To assess possible roles of the renal kallikrein-kinin system in the development of renal impairments in diabetes mellitus, we determined daily excretion of urinary total and active kallikrein in uninephrectomized Wistar-Kyoto rats made diabetic by streptozotocin (45 mg/kg) as a bolus injection. We also evaluated the effect of captopril (50 mg/kg/day) administered orally on the development of diabetic renal impairments in the streptozotocin-treated rats. Active kallikrein was determined by its kininogenase activity, and generated kinins were radioimmunologically measured. Total kallikrein was also determined by measuring kininogenase activity after inactive kallikrein had been activated with trypsin (200 micrograms/ml). Urinary active kallikrein excretion was significantly reduced in streptozotocin-treated rats whereas urinary total kallikrein excretion was unchanged, resulting in the decreased ratio of active to total kallikrein compared to that in the controls. These reductions were preceded by the increased excretion of urine protein measured as an index of renal impairments. The administration of captopril for 12 weeks attenuated the development of diabetic renal impairments evaluated by urine protein excretion in streptozotocin-treated rats, although it did not induce significant changes in urinary total and active kallikrein excretion, and the ratio of active to total kallikrein. Thus the results of this study indicate that the renal kallikrein-kinin system might not play major roles in the development of diabetic renal impairments in the rat, although the pathophysiological relevance of impaired activation of renal kallikrein system to the development of diabetic renal impairments remains to be determined. In addition, they suggest that the renoprotective effects of captopril may be independent of the activation of renal kallikrein system in streptozotocin-treated rats.

Role of renal kallikrein in the regulation of blood pressure in the rat remnant kidney model of chronic renal failure.

We studied urinary excretion of active and inactive kallikrein every day for 3 weeks in spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY) subjected to 5/6 nephrectomy (5/6), 1/2-nephrectomy (1/2) or sham-operation (Sham). We determined urinary active and inactive kallikrein by measuring kallikrein activity using a kininogenase assay before and after treatment with trypsin (200 micrograms/ml). In the SHR group, blood pressure was significantly elevated in 5/6-animals as compared with 1/2 or sham, whereas in the WKY group blood pressure was not changed after either operation. Urinary active and total kallikrein excretion were decreased in 5/6-SHR to 34% and 59%, respectively, as compared with values of sham-SHR, and in 1/2-SHR to 70% and 70%, respectively. Similarly, they were also decreased in 5/6-WKY to 36% and 55%, respectively, as compared with values of sham-WKY. In 1/2-WKY urinary active kallikrein excretion was decreased to 88% as compared with the value of sham-WKY, but urinary total kallikrein excretion was not different from that of sham-WKY. Thus, the suppressed renal kallikrein activity due to reduced renal mass was not associated with any significant change in blood pressure in WKY, although it induced an elevation of blood pressure in SHR. These results indicate that the decreased production of renal active kallikrein may not play a significant role in the regulation of blood pressure in the rat remnant kidney model of chronic renal failure. In addition, it is suggested that the elevation of blood pressure in this model of SHR may be due to other factors than renal kallikrein.

Role of renal kallikrein in the increased fractional sodium excretion in the rat remnant kidney model of chronic renal failure.

To assess the potential role of renal kallikrein-kinin system in enhancing sodium excretion per nephron in chronic renal failure, we studied urinary excretion of active and inactive kallikrein for 3 weeks in Wistar-Kyoto rats subjected to 5/6 nephrectomy (5/6), 1/2 nephrectomy (1/2) or sham operation (Sham). We determined urinary active and inactive kallikrein by measuring kallikrein activity using a kininogenase assay before and after treatment with trypsin (200 micrograms/ml). Fractional sodium excretion was significantly increased in 5/6-rats as compared with 1/2- or sham-rats. On the contrary, urinary active kallikrein excretion per nephron was not different in the three models whereas a significant rise in urinary inactive kallikrein excretion per nephron was found in 5/6-rats as compared with 1/2- or sham-rats. Urinary total kallikrein excretion per nephron was significantly increased in 5/6-rats as compared with sham-rats. In addition, no correlation was found between fractional sodium excretion and urinary active kallikrein excretion corrected for creatinine clearance (Ccr) in 5/6-rats. These results indicate that decreased excretion of renal active kallikrein may not play a significant role in the increased sodium excretion per nephron in the rat remnant kidney model of chronic renal failure. Furthermore, it is suggested that in this model of rat there might be impaired production of renal active kallikrein although its exact mechanism remains to be determined.

Urinary kallikrein excretion after DDAVP during lithium treatment

AbstractSeveral factors are believed to contribute to impaired responsiveness to arginine vasopressin (AVP) during lithium treatment. The renal kallikrein–kinin system is reported to antagonize the renal effects of AVP in vitro but there are no reports of its activity during lithium treatment. Urinary active kallikrein excretion in 18 lithium‐treated patients was found to be lower than that in eight healthy volunteers. Following intravenous administration of an AVP analogue, des‐amino‐D‐arginine‐vasopressin, to the lithium‐treated patients, the urinary excretion of active kallikrein was unchanged, despite an impaired urine‐concentrating ability. These results suggest that stimulation of renal kallikrein does not contribute to inhibition of the action of AVP, and thus the genesis of nephrogenic diabetes insipidus during lithium treatment.

Abnormal regulation of renal kallikrein in experimental diabetes. Effects of insulin on prokallikrein synthesis and activation.

The effects of streptozotocin (STZ) diabetes and insulin on regulation of renal kallikrein were studied in the rat. 1 and 2 wk after STZ injection, diabetic rats had reduced renal levels and urinary excretion of active kallikrein. Tissue and urinary prokallikrein levels were unchanged, but the rate of renal prokallikrein synthesis relative to total protein synthesis was reduced 30-45% in diabetic rats. Treatment of diabetic rats with insulin prevented or reversed the fall in tissue level and excretion rate of active kallikrein and normalized prokallikrein synthesis rate. To further examine insulin's effects, nondiabetic rats were treated with escalating insulin doses to produce hyperinsulinemia. In these rats, renal active kallikrein increased. Although renal prokallikrein was not increased significantly by hyperinsulinemia, its synthesis was increased. As this was accompanied by proportionally increased total protein synthesis, relative kallikrein synthesis rate was not changed. Excretion of active kallikrein was unchanged, but prokallikrein excretion was markedly reduced. Therefore, increased tissue active kallikrein seen with hyperinsulinemia can be explained not only by increased synthesis but also by retention and increased activation of renal prokallikrein. These studies show that STZ diabetes produces an impairment in renal kallikrein synthesis and suggest that this disease state also impairs renal prokallikrein activation. The findings also suggest that insulin modulates renal kallikrein production, activation, and excretion.

Renal Kallikrein Activity in Spontaneously Hypertensive Rats

To assess possible roles of the renal kallikrein-kinin system in the development of spontaneous hypertension, we determined daily excretion of urinary total and active kallikrein in 6-week-old spontaneously hypertensive rats (SHR) and Wistar-Kyoto (WKY) rats for up to 2 weeks. We also evaluated the effect of aprotinin, a reversible inhibitor of kallikrein and other serine proteases, on the development of hypertension in the 6-week-old SHR on ordinary intakes of sodium or on sodium loading with 1% NaCl for up to 2 weeks. Active kallikrein was determined by its kininogenase activity, and the generated kinins were radio-immunologically measured. Total kallikrein was also determined by measuring kininogenase activity after inactive kallikrein had been activated with trypsin (200 micrograms/ml). Urinary active kallikrein excretion was significantly reduced in 7-week-old SHR (1.5 +/- 0.2 microgram/day compared to 2.8 +/- 0.3 micrograms/day in WKY, P less than 0.05) and in 8-week-old SHR (1.6 +/- 0.2 microgram/day compared to 3.2 +/- 0.4 micrograms/day in WKY, P less than 0.01). Urinary total kallikrein excretion was also reduced in the 7- and 8-week-old SHR whereas the ratio of active to total kallikrein did not change. In addition, renal contents of total and active kallikrein were significantly lower in the 8-week-old SHR than in the controls.(ABSTRACT TRUNCATED AT 250 WORDS)

The Effects of Aprotinin, a Kallikrein Inhibitor, on Renin Release and Urinary Sodium Excretion in Mild Essential Hypertensives

The effects of aprotinin on renin release and renal function were evaluated in 24 male essential hypertensive patients, on unrestricted (n = 17) and on chronic low as well as on high sodium intake. Aprotinin (1 X 10(6) kallikrein inhibitor units) or saline (200 ml) were infused in all patients for 6 h. Blood samples were taken for plasma renin activity (PRA) and 6-h urine collections were obtained for active and inactive kallikrein, sodium and potassium excretion measurement. In patients on unrestricted sodium diet, aprotinin had no effect on blood pressure (BP), glomerular filtration rate, renal plasma flow, urinary sodium and potassium excretion. However, an inverse relationship was found between pretreatment urinary sodium excretion and the per cent reduction of the latter after aprotinin. A significant reduction in urinary sodium excretion was induced by aprotinin in patients on high sodium intake, whereas no change was observed in the same patients when on a low sodium diet. Aprotinin reduced the urinary excretion of active kallikrein by 81% and the active to total kallikrein ratio from 24 to 6%. Infusion of aprotinin induced a significant decline in active renin but did not modify inactive renin levels in patients on unrestricted sodium diet as well as in patients on low or high sodium intake. Our data suggest that the inhibition of kallikrein and/or other serine proteases by aprotinin can interfere with renal release of active renin and also support the hypothesis that the renal kallikrein system exerts a regulatory control on sodium excretion in salt replete hypertensives.