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

• 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
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-07672472/
• 关键词: Kinin; Kallikrein; Kidney; Kininase; Hypertension; Natriuresis; Potassium; Ion Channel; kininase; kinin; kidney; hypertensiun; Ion channel; ATP sensitive potassium channel; ラット; 尿; キンナーゼ; ナトリウム; 高血圧; DOCA; 食塩; キニン; キニナーゼ; キニノゲン; カル

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

激肽在大鼠尿液中被中性肽链内切酶和羧肽酶Y样激肽酶（CPY）降解，但在大鼠血浆中主要被激肽酶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，可抑制大鼠尿液中的 CPY，而不抑制血浆中的激肽酶。 ACE抑制剂卡托普利显着抑制血浆中激肽的降解。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挪威 Katholiek (BN-Ka) 大鼠在尿液中排出的激肽含量可以忽略不计。 DOCA-盐治疗会增加两种大鼠品系的全身血压 (SBP)，但 BN-Ka 缺陷大鼠的高血压进展速度比正常 BN-Ki 大鼠快得多。每日皮下注射 EB（5mg/kg/天）连续 3 天，可显着降低 BN-Ki 大鼠的平均收缩压，从 117(]SY.+-。[)3 (n=5，媒介物) 降至 104(]SY.+-。[)3 mmHg (n=5，EB)（p<0.05），但 BN-Ka 大鼠则不然。这种治疗显着增加了 BN-Ki 大鼠的尿钠排泄量，但没有增加 BN-Ka 大鼠的尿钠排泄量。 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。接受 DOCA-盐治疗的 BN-Ki 大鼠的动脉激肽水平为-2.2(]SY.+-。[)0.2pg/ml，但使用卡托普利 (10mg/kg, s.c.) 后显着增加至 4.6(]SY.+-。[)0.4pg/ml。然而，输注 BK（1000ng/kg/min，静脉注射）时引起低血压的动脉激肽水平是用卡托丙醇达到的内源性动脉激肽水平的 110 倍。这些结果表明，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雄性斯普拉格道利大鼠尿中活性激肽释放酶的排泄。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）尿激肽释放酶的排泄量显着低于Wistar京都大鼠（WKY）。在麻醉的幼年（4周大，雄性）SHR和WKY中研究了催产素（OT）输注期间活性激肽释放酶的排泄。OT输注（30 nmol/kg/30分钟）显着增加了WKY中的这种排泄，从基础水平（25.4（]SY.+-。[）5.6 AU/15分钟，n=5）到 37.3(]SY.+-。[)5.0 AU/15 min (p<0.05, n=5) 和 50.7(]SY.+-。[)17.1 AU/15 min (p<0.05, n=5) 分别在输注开始后 15 和 30 分钟，但在 SHR 中没有。在 SHR 中，尿量和钠排泄下降。 OT输注不会改变任一类型大鼠的全身血压或尿肌酐排泄量。通过特异性夹心 ELISA 测定，它也未能改变 WKY 肾脏中活性激肽释放酶的组织浓度，但略微增加了 SHR 的组织浓度。 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 肾脏中的活性激肽释放酶浓度 (560(]SY.+-。[)50 ng/g湿纸巾，n=8)。在免疫组织化学研究中，在 SHR 远端肾小管的远端观察到强烈的激肽释放酶阳性染色。这些结果表明，OT 输注期间 SHR 中尿激肽释放酶的排泄量较低可能归因于肾小管分泌激肽释放酶的敏感性降低。较少的

项目成果

M.Saito他7名: "Degradation of bradylcinin in human urine by cnrboxyjeptidase Y-like sopeptidase and NEUTRAL ENDOPEOT-IDASE tidrse and thweir inbibition by EBELACTONE- B and ths PHOSPHORAMIDON." Int.J.tiss.Reac. XVII. 181-190 (1995)

M. Saito 和其他 7 人：“羧肽酶 Y 样肽酶和中性内皮酶 tidrse 降解人尿中的缓激肽，以及 EBELACTONE-B 和 PHOSPHORAMIDON 的抑制作用”，Int.J.tiss.Reac 181-。 190 (1995)

M.Majima et al.: "Ebelactone B,an inhibitor of cerinary carboxypeptidase Y-like kininase,preverts the development of deorycortico sterone acetate-galt hypertension in rats." Eur. J. of Pharmacology. 284. 1-11 (1996)

M.Majima 等人：“Ebelactone B 是一种 cerinary 羧肽酶 Y 样激酶抑制剂，可预防大鼠醋酸去皮质甾酮半乳糖高血压的发生。”

S Nakajima, M Majima, H Ito, I Hayashi, Y Yajima, M Katori: "Effects of a ncutral cndopeptidase inhibitor, BP102, on the development of deoxycorticosterone acetate-salt hypertension in kininogen deficient Brown Norway Katholiek rats." Int.J.Tissue React.(

S Nakajima、M Majima、H Ito、I Hayashi、Y Yajima、M Katori：“中性肽酶抑制剂 BP102 对激肽原缺乏的 Brown挪威 Katholiek 大鼠发生醋酸脱氧皮质酮盐高血压的影响。”

M Katori, M Majima: "Role of the renal kallikrein-kinin system in the development of hypertension." Immunopharmacology. 36. 237-242 (1997)

M Katori、M Majima：“肾激肽释放酶-激肽系统在高血压发展中的作用。”

M Majima, M Katori, M Ogino, M Saito, K Sugimoto, K Adachi, T Ohno, N Sunahara, K Kato, N Tatemichi, Y Takei: "Lack of contribution of circulatory kinin elevated by captopril to induce hypotension in normotensive and hypertensive rats." Immunopharmacology

M Majima、M Katori、M Ogino、M Saito、K Sugimoto、K Adachi、T Ohno、N Sunahara、K Kato、N Tatemichi、Y Takei：“缺乏卡托普利升高的循环激肽来诱导正常血压和高血压患者的低血压