Preventive roles of renal Kallikrein-kinin system for hypertension

肾激肽释放酶-激肽系统对高血压的预防作用

基本信息

批准号：
07672472
负责人：
MAJIMA Masataka
金额：
$ 1.6万
依托单位：
KITASATO UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
1995
资助国家：
日本
起止时间：
1995 至 1997
项目状态：
已结题

项目摘要

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

激肽被大鼠尿液中的中性内肽酶和羧肽酶 Y 样激肽酶 (CPY) 降解，但主要被大鼠血浆中的激肽酶 II (血管紧张素转换酶，ACE) 灭活，Ebelactone B (EB) 是从放线菌中分离出来的。抑制大鼠尿液中的 CPY，而不抑制血浆中的激肽酶，ACE 抑制剂卡托普利显着抑制 CPY 的降解。与同一品系的正常大鼠（BN Kitasato (BN-Ki) 大鼠）相比，缺乏激肽原的 Brown Turkey Katholiek (BN-Ka) 大鼠在尿液中排出的激肽含量可忽略不计。两种大鼠品系的全身血压（SBP）均升高，但 BN-Ka 缺陷大鼠的高血压进展速度比正常 BN-Ki 大鼠每日皮下注射 EB 快得多。 (5mg/kg/天) 3 天，BN-Ki 大鼠的平均 SBP 从 117(]SY.+-.[)3（n=5，媒介物）显着降低至 104(]SY.+-.[) 3 mmHg (n=5, EB) (p<0.05)，但在 BN-Ka 大鼠中则不然，这种治疗显着增加了尿钠排泄。 BN-Ki 大鼠，但 BN-Ka 大鼠，ACE 抑制剂赖诺普利（5mg/kg/天，皮下注射）不会降低任一类型大鼠的收缩压。 DOCA-盐处理为-2.2(]SY.+-。 []0.2pg/ml，但用卡托普利（10mg/kg，s.c.）显着增加至 4.6(]SY.+-.[)0.4pg/ml 然而，输注 BK 时引起低血压的动脉激肽水平。 1000ng/kg/min，静脉注射）是用卡托丙醇达到的内源性动脉激肽水平的 110 倍。表明抑制肾小管管腔一侧的激肽降解可以有效预防高血压。我们之前报道过，垂体激素之一催产素（OT）能够增加血压正常的男性斯普拉格道利尿中活性激肽释放酶的排泄量大鼠静脉输注钾（0.4 mEq/kg/小时）也增加了活性激肽释放酶的尿排泄。断奶后（4-6 周龄）自发性高血压大鼠 (SHR) 的尿激肽释放酶显着低于 Wistar京都大鼠 (WKY)。 4 周龄，雄性）SHR 和 WKY.OT 输注（30 nmol/kg/30 分钟）显着增加了这种排泄WKY，来自基础水平 (25.4(]SY.+-. [)5.6 AU/15 分钟，n=5) 至 37.3(]SY.+-.[)5.0 AU/15 分钟 (p<0.05，n=5) 和 50.7(]SY.+-.[)17.1 AU /15 分钟（p<0.05，n=5）分别在输注开始后 15 分钟和 30 分钟，但在 SHR 中没有。经测定，OT输注并没有改变WKY大鼠的SHR、尿量和钠排泄量，也没有改变其肾脏中活性激肽释放酶的组织浓度。特异性夹心 ELISA，但 SHR 略有增加。OT 输注后，SHR 肾脏中活性激肽释放酶的浓度(770(]SY.+-.[)30 ng/g/湿组织，n=8) 超过 WKY 肾脏中的水平 (560(]SY.+-.[)50 ng/g 湿组织，n=8)在免疫组织化学研究中，在 SHR 的远端肾小管远端观察到强烈的激肽释放酶阳性染色。这些结果表明，SHR 中尿激肽释放酶的排泄较低OT输注期间可能是由于肾小管分泌激肽释放酶的敏感性降低所致。