Pivotal role of renal kallikrein-kinin system in the development of hypertension and approaches to new drugs based on this relationship.
Renal kallikrein is one of the tissue kallikreins, and the distal nephron is fully equipped as an element of the kallikrein-kinin system. Although a low excretion of urinary kallikrein has been reported in essential hypertension, the results from studies on patients with hypertension are not consistent. Congenitally hypertensive animals also excrete lowered levels of urinary kallikrein, but the effects of this are yet unknown. Extensive genetic and environmental studies on large Utah pedigrees suggest that the causes of hypertension are closely related to the combination of low kallikrein excretion and the potassium intake. Mutant kininogen-deficient Brown Norway-Katholiek rats, which cannot generate kinin in the urine, are very sensitive to salt loading and to sodium retention by aldosterone released by a non-pressor dose of angiotensin II, which results in hypertension. The major function of renal kallikrein-kinin system is to excrete sodium and water when excess sodium is present in the body. Failure of this function causes accumulation of sodium in the cerebrospinal fluid and erythrocytes, and probably in the vascular smooth muscle, which become sensitive to vasoconstrictors. We hypothesize that impaired function of the renal kallikrein-kinin system may play a pivotal role in the early development of hypertension. Inhibitors of kinin degradation in renal tubules and agents, which accelerate the secretion of urinary kallikrein from the connecting tubules and increase the generation of urinary kinin, may be novel drugs against hypertension.
Katori
M
M
Department of Pharmacology, Kitasato University School of Medicine, Kanagawa, Japan.
Majima
M
M
D000818:Animals; D006973:Hypertension / Q000378:metabolism*; D007610:Kallikreins / Q000378:metabolism*; D007668:Kidney / Q000378:metabolism*; D007704:Kininogens / Q000378:metabolism*; D012964:Sodium / Q000378:metabolism
D007704:Kininogens; D012964:Sodium; D007610:Kallikreins