Facilitation of renal kallikrein-kinin system prevents the development of hypertension by inhibition of sodium retention.
We have previously reported that the renal kallikrein-kinin system suppressed the development of hypertension, using kininogen deficient Brown Norway Katholiek rats. Kinins were degraded in urine mainly by carboxypeptidase Y-like kininase (CPY). Blockade of renal kinin degradation may prevent the experimental hypertension through the facilitation of the renal kallikrein-kinin system. Daily administration of ebelactone B (EB), which is isolated from Actinomycetes and strongly inhibits CPY, from the first day of deoxycorticosterone acetate (DOCA)-salt treatment for 4 weeks completely blocked hypertension in Sprague-Dawley rats. This treatment reduced sodium levels in erythrocytes and cerebrospinal fluids (CSF) significantly. By contrast, an ACE inhibitor, lisinopril did not prevent hypertension. The development of hypertension in young spontaneously hypertensive rats was also blunted by EB with reductions in sodium levels in erythrocytes and in CSF. The arterial kinin levels in rats undergoing DOCA-salt treatment were 2.2 +/- 0.2 pg/ml, which were increased significantly to 4.6 +/- 0.4 pg/ml with captopril (10 mg/kg, s.c.). The increased kinin levels were less than those to show hypotension. EB did not increase the arterial kinin levels, with significant increase in urinary kinin secretion. These results suggested that facilitation of the renal kallikrein-kinin system by inhibition of kinin degradation on the luminal side of the renal tubules may effectively prevent hypertension.
Majima
M
M
Department of Pharmacology, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan.
Hayashi
I
I
Fujita
T
T
Ito
H
H
Nakajima
S
S
Katori
M
M
D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D006955:Hypernatremia / Q000201:enzymology / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control; D006973:Hypertension / Q000201:enzymology / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*; D016234:Kallikrein-Kinin System / Q000187:drug effects; D007668:Kidney / Q000187:drug effects / Q000503:physiopathology*; D008297:Male; D007703:Peptidyl-Dipeptidase A / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012964:Sodium / Q000378:metabolism*
D000806:Angiotensin-Converting Enzyme Inhibitors; D012964:Sodium; D007703:Peptidyl-Dipeptidase A