Katori Makoto, Majima Masataka
Department of Pharmacology, School of Medicine, Kitasato University, Sagamihara, Kanagawa 228-8555, Japan.
Pharmaceuticals (Basel). 2010 Jan 7;3(1):59-109. doi: 10.3390/ph3010059.
Terrestrial animals must conserve water and NaCl to survive dry environments. The kidney reabsorbs 95% of the sodium filtered from the glomeruli before sodium reaches the distal connecting tubules. Excess sodium intake requires the renal kallikrein-kinin system for additional excretion. Renal kallikrein is secreted from the distal connecting tubule cells of the kidney, and its substrates, low molecular kininogen, from the principal cells of the cortical collecting ducts (CD). Formed kinins inhibit reabsorption of NaCl through bradykinin (BK)-B₂ receptors, localized along the CD. Degradation pathway of BK by kinin-destroying enzymes in urine differs completely from that in plasma, so that ACE inhibitors are ineffective. Urinary BK is destroyed mainly by a carboxypeptidase-Y-like exopeptidase (CPY) and partly by a neutral endopeptidase (NEP). Inhibitors of CPY and NEP, ebelactone B and poststatin, respectively, were found. Renal kallikrein secretion is accelerated by potassium and ATP-sensitive potassium (K) channel blockers, such as PNU-37883A. Ebelactone B prevents DOCA-salt hypertension in rats. Only high salt intake causes hypertension in animals deficient in BK-B receptors, tissue kallikrein, or kininogen. Hypertensive patients, and spontaneously hypertensive rats, excrete less kallikrein than normal subjects, irrespective of races, and become salt-sensitive. Ebelactone B, poststatin, and K channel blockers could become novel antihypertensive drugs by increase in urinary kinin levels. Roles of kinin in cardiovascular diseases were discussed.
陆生动物必须保存水分和氯化钠以在干燥环境中生存。在钠到达远曲小管之前，肾脏会重吸收从肾小球滤过的95%的钠。过量的钠摄入需要肾激肽释放酶-激肽系统进行额外排泄。肾激肽释放酶由肾脏的远曲小管细胞分泌，其底物低分子激肽原则来自皮质集合管（CD）的主细胞。生成的激肽通过沿CD分布的缓激肽（BK）-B₂受体抑制氯化钠的重吸收。尿液中激肽破坏酶对BK的降解途径与血浆中的完全不同，因此血管紧张素转换酶抑制剂无效。尿BK主要被一种羧肽酶-Y样外肽酶（CPY）破坏，部分被中性内肽酶（NEP）破坏。分别发现了CPY和NEP的抑制剂依贝内酯B和后他汀。钾和ATP敏感性钾（K）通道阻滞剂，如PNU-37883A，可加速肾激肽释放酶的分泌。依贝内酯B可预防大鼠的去氧皮质酮盐性高血压。只有高盐摄入会导致BK-B受体、组织激肽释放酶或激肽原缺乏的动物患高血压。高血压患者和自发性高血压大鼠，无论种族如何，其激肽释放酶排泄量均低于正常受试者，且对盐敏感。依贝内酯B、后他汀和K通道阻滞剂可通过增加尿激肽水平成为新型抗高血压药物。文中讨论了激肽在心血管疾病中的作用。
