Crucial suppressive role of renal kallikrein-kinin system in development of salt-sensitive hypertension.
Tissue kallikrein and low molecular weight kininogen are localized in the particular cells of the connecting tubules, indicating that kinin is immediately generated in the lumina of the lower nephrons. The role of the renal kallikreinkinin system was studied using mutant kininogen-deficient Brown NorwayKatholiek (BN-Ka) rats, and compared with that in normal BN-Kitasato rats of the same strain. Mutant BN-Ka rats showed no visible changes, but they were very sensitive to excess sodium ingestion and to the tendency of sodium to accumulate in the body by aldosterone released by angiotensin II, so that sodium was accumulated in erythrocytes and cerebrospinal fluid in BN-Ka rats and hypertension was induced. After four days infusion of 0.3 M NaCl solution to conscious and unrestrained mutant BN-Ka rats, the sensitivity of the vascular smooth muscle to norepinephrine and angiotensin II increased 30-fold and 10-fold, respectively. Bradykinin was degraded by neutral endopeptidase (NEP) and carboxypeptidase Y-like exopeptidase (CPY) in rat and human urine. Daily oral administration of a selective inhibitor of CPY, ebelactone B, or that of NEP, BP1O2, prevented development of deoxycorticosterone acetate-salt hypertension in Sprague-Dawley rats. These results indicate that: 1) the renal kallikrein-kinin system allows excretion of excess sodium in the body, 2) decreased sodium excretion due to reduced excretion of urinary kallikrein in patients with essential hypertension or in genetically hypertensive rats may cause hypertension, and 3) urine kininase inhibitors such as ebelactone B may emerge as a new antihypertensive drug.
Katori
M
M
Department of Pharmacology, Kitasato University School of Medicine, Kanagawa, Japan. hy3m-ktr@ashi-net.or.jp
Majima
M
M
Hayashi
I
I
D000818:Animals; D000959:Antihypertensive Agents; D015853:Cysteine Proteinase Inhibitors / Q000172:deficiency; D003900:Desoxycorticosterone; D006973:Hypertension / Q000378:metabolism*; D016234:Kallikrein-Kinin System / Q000502:physiology*; D007668:Kidney / Q000378:metabolism*; D007704:Kininogens / Q000172:deficiency; D007783:Lactones; D051381:Rats; D011914:Rats, Inbred BN; D011922:Rats, Mutant Strains; D017207:Rats, Sprague-Dawley; D012964:Sodium / Q000652:urine
D000959:Antihypertensive Agents; D015853:Cysteine Proteinase Inhibitors; D007704:Kininogens; D007783:Lactones; D003900:Desoxycorticosterone; C030795:ebelactone B; D012964:Sodium