Effect of prolonged administration of a urinary kininase 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 B 2 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.British Journal of Pharmacology (1999) 126 , 613–620; doi: 10.1038/sj.bjp.0702340