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.