The mechanisms of the renal effects of neutral endopeptidase inhibitor in rats.
To further investigate the mechanisms of renal effects of neutral endopeptidase 24.11 (NEP) inhibition, we employed a specific NEP inhibitor, UK 73967 (UK), with or without a specific kinin receptor antagonist, Hoe 140 (Hoe), or nitric oxide (NO) synthase inhibitor, N-monomethyl-L-arginine (L-NMMA), in Sprague-Dawley rats, and evaluated the urinary NEP, kinins, cGMP and plasma atrial natriuretic peptide (ANP). None of the variables changed with vehicle injection. After injection of UK, NEP decreased significantly and urinary kinins, cGMP, urine volume (UV) and urinary sodium excretion (UNaV) increased significantly. Injected Hoe canceled the increase in UV and UNaV induced by UK. Plasma ANP did not show any difference between vehicle and UK groups. With a pretreatment of L-NMMA, injected UK decreased NEP and increased kinins, while urinary cGMP, UV and UNaV did not increase. In conclusion, augmented kinins may play an important role in the renal water-sodium metabolism by NEP inhibition, and NO may contribute to the kinins' action on this mechanism, while ANP may not contribute to it, at least in normotensive rats. Moreover, changes in urinary cGMP do not reflect the changes in plasma ANP, but rather, those in NO under this condition.
Ura
N
N
Second Department of Internal Medicine, Sapporo Medical University School of Medicine, Japan.
Shimamoto
K
K
Nomura
N
N
Aoyama
T
T
Iwata
M
M
Takagawa
Y
Y
Iimura
O
O
D000319:Adrenergic beta-Antagonists / Q000494:pharmacology; D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives / Q000494:pharmacology; D009320:Atrial Natriuretic Factor / Q000097:blood*; D001920:Bradykinin / Q000031:analogs & derivatives / Q000494:pharmacology; D006152:Cyclic GMP / Q000097:blood; D003509:Cyclohexanecarboxylic Acids / Q000494:pharmacology*; D007668:Kidney / Q000378:metabolism*; D007705:Kinins / Q000652:urine*; D008297:Male; D015260:Neprilysin / Q000037:antagonists & inhibitors* / Q000652:urine; D009569:Nitric Oxide / Q000097:blood; D011480:Protease Inhibitors / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D019323:omega-N-Methylarginine
D000319:Adrenergic beta-Antagonists; D003509:Cyclohexanecarboxylic Acids; D007705:Kinins; D011480:Protease Inhibitors; D019323:omega-N-Methylarginine; D009569:Nitric Oxide; C065679:icatibant; C060942:candoxatrilat; D009320:Atrial Natriuretic Factor; D001120:Arginine; D015260:Neprilysin; D006152:Cyclic GMP; D001920:Bradykinin