Effect of prolonged administration of a urinary kinase inhibitor, ebelactone B on the development of deoxycorticosterone acetate-salt hypertension in rats.
The effect of prolonged administration of a carboxypeptidase Y-like kininase inhibitor, ebelactone B (EB) (2-ethyl-3, 11-dihydroxy-4, 6, 8, 10, 12-pentamethyl-9-oxo-6-tetradecenoic 1, 3-lactone), on the development of deoxycorticosterone acetate (DOCA)-salt hypertension was tested. The systolic blood pressure (SBP) of non-treated 6-week-old Sprague-Dawley strain rats was gradually increased by DOCA-salt treatment from 137+/-2 mmHg (n=11) to 195+/-7 mmHg at 10 weeks of age. With daily oral administration of lisinopril (5 mg kg(-1), twice a day), which is an inhibitor of angiotensin converting enzyme, a major kininase in plasma, the development of hypertension was not suppressed. By contrast, administration of EB (5 mg kg(-1), twice a day), completely inhibited the development of hypertension (SBP: 146+/-1 mmHg, n=5, 10 weeks old). The reduced SBP at 10 weeks of age was equal to the SBP before any treatment (142+/-1 mmHg, n=5). Direct determination of mean blood pressure (MBP) in conscious, unrestrained rats confirmed that MBP elevation was completely inhibited by EB. Continuous subcutaneous infusion (5 mg kg(-1) day(-1)) of HOE140, a bradykinin B2 receptor antagonist, restored the elevation of SBP, which was suppressed by EB. The weights of left ventricle of DOCA-salt treated rats 10-weeks-old (0.36+/-0.02 g 100 g body weight(-1), n=11) was significantly reduced by EB (0.27+/-0.01, n=5), as were the sodium levels in serum, cerebrospinal fluid and erythrocyte. These findings suggested that EB is effective in preventing salt-related hypertension presumably by eliminating sodium retention.
Ito
H
H
Department of Pharmacology, Kitasato University School of Medicine, Kanagawa, Japan.
Majima
M
M
Nakajima
S
S
Hayashi
I
I
Katori
M
M
Izumi
T
T
D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001794:Blood Pressure / Q000187:drug effects; D001920:Bradykinin / Q000031:analogs & derivatives / Q000494:pharmacology; D065168:Bradykinin Receptor Antagonists; D002268:Carboxypeptidases / Q000037:antagonists & inhibitors* / Q000652:urine; D043402:Cathepsin A; D003900:Desoxycorticosterone; D004326:Drinking / Q000187:drug effects; D006321:Heart / Q000187:drug effects / Q000254:growth & development; D006352:Heart Ventricles / Q000187:drug effects / Q000254:growth & development; D006973:Hypertension / Q000139:chemically induced / Q000517:prevention & control*; D007610:Kallikreins / Q000652:urine; D007668:Kidney / Q000187:drug effects / Q000254:growth & development; D007705:Kinins / Q000652:urine; D007783:Lactones / Q000494:pharmacology / Q000627:therapeutic use; D017706:Lisinopril / Q000494:pharmacology; D008297:Male; D009929:Organ Size / Q000187:drug effects; D011480:Protease Inhibitors / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013047:Specific Pathogen-Free Organisms; D015244:Thiorphan / Q000031:analogs & derivatives / Q000494:pharmacology; D013997:Time Factors; D014554:Urination / Q000187:drug effects; D014882:Water-Electrolyte Balance / Q000187:drug effects
D000806:Angiotensin-Converting Enzyme Inhibitors; D000959:Antihypertensive Agents; D065168:Bradykinin Receptor Antagonists; D007705:Kinins; D007783:Lactones; D011480:Protease Inhibitors; D003900:Desoxycorticosterone; C030795:ebelactone B; C049331:racecadotril; C065679:icatibant; D015244:Thiorphan; D017706:Lisinopril; D002268:Carboxypeptidases; D043402:Cathepsin A; D007610:Kallikreins; D001920:Bradykinin