Preventive roles of renal Kallikrein-kinin system for hypertension

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Kinins were degraded by neutral endopeptidase and carboxypeptidase Y-like kininase (CPY) in rat urine, but were inactivated mainly by kininase II (angiotensin-converting enzyme, ACE) in rat plasma. Ebelactone B (EB), which was isolated from Actinomycetes, inhibited CPY in rat urine without inhibiting kininases in plasma. The ACE inhibitor captopril significantly inhibited the degradation of kinin in plasma. Kininogen-deficient Brown Norway Katholiek (BN-Ka) rats excreted a negligible amount of kinin in the urine, compared with normal rats from the same strain (BN Kitasato (BN-Ki) rats). DOCA-salt treatment increased systemic blood pressure (SBP) in both rat strains, but hypertension developed much faster in deficient BN-Ka rats than in normal BN-Ki rats. Daily subcutaneous administration of EB (5mg/kg/day) for 3 days significantly reduced mean SBP in the BN-Ki rats from 117(]SY.+-。[)3 (n=5, vehicle) to 104(]SY.+-。[)3 mmHg (n=5, EB) (p<0.05), but not in the BN-Ka rats. This treatment si … More gnificantly increased the urinary sodium excretion of the BN-Ki rats, but not of the BN-Ka rats. An ACE inhibitor, lisinopril (5mg/kg/day, s.c.), did not reduce the SBP in either type of rats. The arterial kinin levels in BN-Ki rats undergoing DOCA-salt treatment were-2.2(]SY.+-。[)0.2pg/ml, but were increased significantly to 4.6(]SY.+-。[)0.4pg/ml with captopril (10mg/kg, s.c.). However, the arterial kinin levels that induced hypotension on infusion of BK (1000ng/kg/min, i.v.) were 110 times the endogenous arterial kinin levels attained with captoprol. These results suggested that inhibition of kinin degradation on the luminal side of the renal tubules may effectively prevent hypertension.We have previously reported that one of the pituitary hormones, oxytocin (OT) has a capacity to increasee urinary excretion of active kallikrein in normotensive male Sprague-Dawley rats. Intravenous infusion of potassium (0.4 mEq/kg/hour) also increased the urinary excretion of active kallikrein. Urinary excretion of kallikrein in spontaneously hypertensive rats (SHR) was significantly less than that in Wistar Kyoto rats (WKY) immediately after weaning (4-6 weeks old). Excretion of active kallikrein during oxytocin (OT) infusion was studied in anesthetized young (4 weeks old, male) SHR and WKY.OT infusion (30 nmol/kg/30 min) significantly increased this excretion in WKY,from the basal levels (25.4(]SY.+-。[)5.6 AU/15 min, n=5) to 37.3(]SY.+-。[)5.0 AU/15 min (p<0.05, n=5) and 50.7(]SY.+-。[)17.1 AU/15 min (p<0.05, n=5) 15 and 30 min after the start of infusion, respectivey, but not in SHR.In SHR,urine volume and sodium excretion fell. The OT infusion did not change the systemic blood pressure or the urinary creatinine excretion in either typr of rats. It also failed to alter the tissue concentration of active kallikrein in the kidneys of WKY,as determined by a specific sandwich ELISA,but slightly increased those of SHR.After OT infusion, the concentrations of active kallikrein in SHR kidneys (770(]SY.+-。[)30 ng/g/ wet tissue, n=8) exceeded those in WKY kidneys (560(]SY.+-。[)50 ng/g wet tissue, n=8). In immunohistochemical studies, an intense kallikrein-positive stain was observed in the distal in the distal tubules in SHR.These results suggested that the lower excretion of urinary kallikrein in SHR during OT infusion may be attributable to diminished sensitivity in secretion of kallikrein from the renal tubules. Less