Neutralb endopeptidase 24.11阻害剤の腎作用におけるkinin,atrial natritiretic peptide, nitric oxideの役割

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Neutral endopeptidase 24.11 (NEP) catabolizes both kinin and atrial natriuretic peptide (ANP) in vitro. We reported previously that the administration of the NEP inhibitor phosphoramidon decreases urinary NEP activity and increases urinary kinin excretion, urine volume (UV) and urinary sodium excretion (U Na V) in rats. On the other hand, some investigators have reported that this renal diuretic and natriuretic effects of NEP inhibition might result from suppression of the ANP metabolism. It is reported that nitric oxide (NO) contributes to the vasodilative effects of kinin in vessels, while there is no report concerning the participation of NO in the renal effects of kinin. To further investigate the mechanisms of renal effects of NEP inhibition, we applied the specific NEP inhibitor UK73967 (UK), with or without the specific kinin receptor antagonist Hoe140 (Hoe), or the NO synthase inhibitor N-monomethyl-L-arginine (L-NMMA) to Sprague-Dawley normotensive rats, and evaluated the urinary kinin, cGMP and plasma ANP. Fifty one Sprague-Dawley normotensive rats (240～330 g) were employed in this study. 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 infused with physiological saline (control group, n=8), UK (UK group, 10 mg/kg, i. v., n=9), or UK+Hoe (UK+Hoe group, Hoe 20 nmol/kg, s. c., n=10). In another series of these groups (n=8 each), the continuous infusion of L-NMMA at a dose of 200 μg/kg/min was started at 60 minutes prior to the control period. Mean blood pressure (MBP), heart rate (HR), UV, U Na V, urinary total kininase, NEP, kinin, and cGMP were determined before and after infusion of each reagent, and plasma ANP was measured at the end of the protocol in each group. Without a pretreatment of L-NMMA, UK infusion decreased total kininase and NEP activities, and increased kinin, cGMP, UV and U Na V; vehicle infusion did not change these parameters, except for decreasing cGMP. As a result, the UK group showed significantly lower total kininase and NEP activities and significantly higher urinary kinin, urinary cGMP, UV and U Na V than those in the control group. There were significant positive correlations between the changes in kinin and those in UV (r=0.497, p<0.05) and U Na V (r=0.576, p<0.05), and between the changes in cGMP and those in U Na V (r=0.501, p<0.05). Simultaneous administration of Hoe clearly canceled the increase of UV and U Na V induced by UK. With a pretreatment of L-NMMA, UK infusion decreased total kininase and NEP activities and increased kinin, while it did not increase UV, U Na ?or cGMP. None of the variables changed in the control group even with a pretreatment of L-NMMA. There were no differences in UV, UNaV and cGMP between the UK and control groups. With a pretreatment of L-NMMA, no correlation was found between the changes in kinin and those in UV and UNaV, and between the changes in cGMP and those in UNaV. There was no significant difference in plasma ANP between the UK and control groups with or without pretreatment of L-NMMA. MBP and HR did not change significantly in all 6 groups. In conclusion, the diuretic and natriuretic actions of NEP inhibitor may be mainly caused by augmentation of kinin, but not by suppression of ANP catabolization, and NO may contribute to renal effect of kinin, at least in normotensive rats. Moreover, changes in urinary cGMP does not reflect the changes in plasma ANP, but rather, those in NO under this condition.
札幌医科大学の論文
1996-02-01

Neutralb endopeptidase 24.11阻害剤の腎作用におけるkinin,atrial natritiretic peptide, nitric oxideの役割

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札幌医科大学 | 論文

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