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

大鼠尿液中的中性内肽酶和羧肽酶Y样激酶（CPY）降解，但主要由大鼠血浆中的酶II（血管紧张素转化酶，ACE）灭活。从放线菌分离的ebelactone B（EB）抑制了大鼠尿液中的CPY，而不抑制血浆中的激酶。 ACE抑制剂卡托普利明显抑制了血浆中基因蛋白的降解。与来自相同菌株（BN Kitasato（BN-KI）大鼠）的正常大鼠相比，缺乏动力学的棕色挪威挪威Katholiek（BN-KA）大鼠尿液中的kinin量忽略不计。 DOCA盐处理增加了两种大鼠菌株中的全身血压（SBP），但高血压在不足的BN-KA大鼠中的发展速度要比正常的BN-KI大鼠快得多。每天在BN-KI大鼠中，每天使用EB（5mg/kg/day）持续3天，将BN-KI大鼠的平均SBP显着降低，从117（]SY。+ - 。[）3（n = 5，载体）增加到104（n = 5，载体）至SY。+ - 。[）3 mmHg（n = 5，eb）（n = 5，eb）（p <0.05）（p <0.05），但bn-bn-ka rats rats rats rats。这种治疗方法……更详细地增加了BN-KI大鼠的泌尿钠排泄，而不是BN-KA大鼠的尿钠排泄。 ACE抑制剂Lisinopril（5mg/kg/day，S.C。）均未减少任何一种大鼠的SBP。接受DOCA-SALT治疗的BN-KI大鼠中的动脉KININ水平为2.2（]SY。+ - 。[）0.2pg/ml，但与Captopril（10mg/kg，s.c.）明显至4.6（] SY.+ - 。[）0.4pg/ml。然而，在输注BK（1000ng/kg/min，i.v.）中诱导低血压的动脉运动水平是内源性动脉基因素水平的110倍。这些结果表明，在肾小管腔侧抑制基因蛋白降解可能有效预防高血压。我们先前报告说，氧气（OT）的一种垂体恐怖症（OT）具有增加正常加速的男性Sprague-Dawley大鼠的尿尿液极高排泄的能力。静脉输注钾（0.4 mEq/kg/小时）也增加了活性kallikrein的尿极端排泄。断奶（4-6周）大鼠后，卡利克林自发性高血压大鼠（SHR）中的尿极高排泄明显小于Wistar Kyoto大鼠（WKY）。在催产素（OT）输注过程中活跃的kallikrein的排泄在麻醉的年轻（4周大，男性）SHR和WKY.OT输注（30 nmol/kg/30 min）中显着增加了WKY的这一排泄，从基本水平中提高了WKY（25.4（25.4）（25.4（]sy。+ - 。+ - 。 AU/15分钟（p <0.05，n = 5）和50.7（]SY。+ - 。[）17.1 AU/15分钟（p <0.05，n = 5）15和30分钟，在输注开始后，相对，但不在Shr.in SHR，尿液体积和钠的极端排泄物下降。 OT输注并未改变大鼠TYPR中的全身性血压或尿肌氨酸的极端排泄。 It also failed to alter the tissue Concentration of active kallikrein in the kids 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湿组织，n = 8）。在免疫组织化学研究中，SHR远端管的远端观察到了强烈的Kallikrein阳性染色。这些结果表明，在OT输注过程中，SHR尿中尿中的Kallikrein较低的排泄可能归因于肾脏中Kallikrein sercition的敏感性降低。较少的

项目成果

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.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。”

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 他10名: "Defermination of bradykinin-(1-5) in inflammntory e rdete by a new ELISA as a reliable imdic tor of bradylcinin gene ation." Inflamm.Res.45. 416-423 (1996)

M.Majima 和其他 10 人：“通过新的 ELISA 确定炎症反应中的缓激肽-(1-5)，作为缓激肽基因的可靠指标。Res.45 (1996)”。