The mechanisms of the renal effects of neutral endopeptidase 24.11 inhibitor in DOCA-salt hypertensive rats

Neutral endopeptidase 24.11 （NEP） degrades both kinin and atrial natriuretic peptide （ANP） in vitro. We have reported that the administration of the NEP inhibitor UK73967 （UK） increases urinary kinin, urine volume （UV） and urinary sodium excretion （UNaV）, but does not affect plasma ANP level in normotensive rats. In addition, the kinin receptor antagonist Hoe140 （Hoe） clearly canceled the increases of UV and UNaV produced by UK. Therefore, we thought that the renal effects of NEP inhibitor could mainly depend on the suppression of kinin metabolism in normotensive rats. Some reports have suggested, however, that the renal effects of NEP inhibitor might act through inhibition of the ANP metabolism. In this study, we employed UK with or without Hoe and evaluated the renal kallikrein-kinin system and plasma ANP in deoxycorticosterone acetate-salt （DOCA-salt） hypertensive rats in an attempt to further elucidate the mechanisms of the diuretic and natriuretic effects of NEP inhibition. Twenty-nine DOCA-salt hypertensive rats were employed. All rats were anesthetized with sodium pentobarbital, and polyethylene tubes were cannulated into the trachea, bladder, femoral artery and femoral vein. After the control period, the rats were divided into the control group （n=9）, UK group （UK 10 mg/kg, i. v., n=10） and UK+Hoe group （Hoe 20 nmol/kg, s. c., n=10）. Urinary total kininase, NEP, cGMP, UV and UNaV were determined before and after injection of each reagent, and plasma ANP was measured at the end of the protocol in each group. UK injection decreased total kininase and NEP activities, while vehicle injection did not change any of the parameters. Plasma ANP was significantly higher in the UK group than in the control group. With injection of UK, UV, UNaV and urinary cGMP increased significantly. There were significant positive correlations between plasma ANP level and the change in urinary cGMP, and between the change in urinary cGMP and the change in UV or UNaV in the control and UK groups. Simultaneous administration of Hoe showed no effect on the increases of UV and UNaV induced by UK. In conclusion, it was suggested that diuretic and natriuretic effects of NEP inhibitor are mainly due to the suppression of ANP metabolism in DOCA-salt hypertensive rats, while previous results from our laboratory have shown those effects are mainly due to the suppression of kinin metabolism in normotensive rats. Thus, the main mechanism of renal effects of NEP inhibition should be considered to be different between normotensive rats and DOCA-salt hypertensive rats.departmental bulletin pape