Role of the renal kallikrein-kinin system in the development of hypertension.
Role of renal kallikrein-kinin system has been studied using mutant Brown-Norway Katholiek (BN-Ka) rats, in which both high- and low-molecular weight kininogens were almost absent in plasma and kinin in urine was mainly not detectable. Mutant BN-Ka rats were very sensitive to increased salt intake, resulting in raised systemic blood pressure that is linked to reduced urinary excretion of sodium, when compared with normal BN-Kitasato (BN-Ki) rats. Consequently, sodium accumulated in erythrocytes and cerebrospinal fluid in mutant BN-Ka rats. Subcutaneous infusion of angiotensin II (20 mg/day/rat) also enhanced the concentration of sodium in erythrocytes and in cerebrospinal fluid and increased the systemic pressure by releasing aldosterone. A 4-day infusion of 0.3 M sodium solution (6 ml/kg/h) to the abdominal aorta of conscious and un-restrained mutant BN-Ka rats increased the pressor responses of the arterioles to norepinephrine and angiotensin II (i.a.) by 30- and 10-fold, respectively. Infusion of ebelactone B, (a selective inhibitor of carboxypeptidase Y-like exopeptidase, a kininase in rat urine), to normal BN-Ki rats during induction of hypertension with DOCA and salt, resulted in the reduction of the raised blood pressure, indicating that a site of action of kinins was at the luminal membrane of the renal tubule cells. Our results support the view that the role of renal kallikrein-kinin system is to excrete 'excess sodium' and a reduction in the generation of renal kinins may be a factor in the development of hypertension as a result of the sodium accumulation in the body.
Katori
M
M
Department of Pharmacology, Kitasato University School of Medicine, Kanagawa, Japan. hy3m-ktr@asahi-net.or.jp
Majima
M
M
D000450:Aldosterone / Q000378:metabolism; D000804:Angiotensin II / Q000008:administration & dosage / Q000633:toxicity; D000818:Animals; D000959:Antihypertensive Agents / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D001160:Arterioles / Q000187:drug effects / Q000378:metabolism; D001794:Blood Pressure / Q000187:drug effects / Q000235:genetics; D001920:Bradykinin / Q000652:urine; D004195:Disease Models, Animal; D006973:Hypertension / Q000235:genetics* / Q000503:physiopathology; D007261:Infusions, Intra-Arterial; D007279:Injections, Subcutaneous; D016234:Kallikrein-Kinin System / Q000235:genetics / Q000502:physiology*; D007684:Kidney Tubules / Q000166:cytology / Q000378:metabolism*; D007704:Kininogens / Q000097:blood / Q000172:deficiency; D007783:Lactones / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D008970:Molecular Weight; D009638:Norepinephrine / Q000633:toxicity; D051381:Rats; D011914:Rats, Inbred BN; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D012964:Sodium / Q000097:blood / Q000134:cerebrospinal fluid / Q000652:urine; D012965:Sodium Chloride / Q000008:administration & dosage / Q000633:toxicity; D012982:Sodium, Dietary / Q000009:adverse effects
D000959:Antihypertensive Agents; D007704:Kininogens; D007783:Lactones; D012982:Sodium, Dietary; D000804:Angiotensin II; D012965:Sodium Chloride; D000450:Aldosterone; C030795:ebelactone B; D012964:Sodium; D001920:Bradykinin; D009638:Norepinephrine