icatibant and candoxatrilat

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.

Topics: Adrenergic beta-Antagonists; Animals; Arginine; Atrial Natriuretic Factor; Bradykinin; Cyclic GMP; Cyclohexanecarboxylic Acids; Kidney; Kinins; Male; Neprilysin; Nitric Oxide; omega-N-Methylarginine; Protease Inhibitors; Rats; Rats, Sprague-Dawley

To further elucidate the renal effects of NEP inhibition, we employed NEP inhibitor UK 73967 (UK), with or without a kinin receptor antagonist Hoe 140 (Hoe), in Sprague-Dawley normotensive rats and DOCA-salt hypertensive rats. In Sprague-Dawley rats: 1) injected UK significantly decreased NEP, and increased kinins, urine volume (UV) and urinary sodium excretion (UNaV), while none of the variables changed with vehicle treatment; 2) no difference was found in plasma ANP between the vehicle and UK groups; and 3) Hoe canceled the increases of UV and UNaV caused by UK. In DOCA-salt rats: 1) infused UK significantly decreased NEP, and increased UV and UNaV, while UV and UNaV were slightly decreased, and NEP did not change with vehicle treatment; 2) plasma ANP was significantly higher in UK group than in the vehicle group; and 3) Hoe could not abolish the increase of UV and UNaV induced by UK. These data indicate that the contributions of renal kinins and plasma ANP to the diuretic and natriuretic mechanisms of NEP inhibition may differ between Sprague-Dawley normotensive rats and DOCA-salt hypertensive rats.

Topics: Adrenergic beta-Antagonists; Animals; Atrial Natriuretic Factor; Bradykinin; Cyclohexanecarboxylic Acids; Desoxycorticosterone; Hypertension; Kidney; Kinins; Male; Neprilysin; Protease Inhibitors; Rats; Rats, Sprague-Dawley

The activity of the renal kallikrein-kinin system is controlled by the concentration of intrarenal kinins. Neutral endopeptidase 24.11 (NEP) cleaves kinins as effectively as kininase I and kininase II. It is also well known that NEP metabolizes atrial natriuretic peptide (ANP). The present study evaluated the effects of NEP inhibitor on renal action by kinins, ANP and nitric oxide in Sprague-Dawley normotensive rats and DOCA-salt hypertensive rats. In normotensive rats, we demonstrated that 1) inhibition of NEP potentiates the contribution of kinins to the renal water-sodium metabolism and overcomes the contribution of ANP to that metabolism, 2) nitric oxide participates in the action of kinins, and 3) changes in urinary cGMP excretion do not reflect the changes in plasma ANP, but the changes in nitric oxide, under these conditions. On the other hand, it was also suggested that augmented ANP may contribute mainly to renal water-sodium handling by NEP inhibitor in DOCA-salt rats. Therefore, the contributions of the two systems to the diuretic and natriuretic mechanisms of NEP inhibition may differ between Sprague-Dawley normotensive rats and DOCA-salt hypertensive rats.

Topics: Animals; Atrial Natriuretic Factor; Bradykinin; Cyclic GMP; Cyclohexanecarboxylic Acids; Diuresis; Kallikrein-Kinin System; Kidney; Kinins; Natriuresis; Neprilysin; Rats; Rats, Sprague-Dawley; Sodium

To further elucidate the natriuretic mechanisms of neutral endopeptidase 24.11 (NEP) inhibition, we employed a new specific NEP inhibitor, UK 73967 (UK), with or without a specific kinin receptor antagonist, Hoe 140 (Hoe), in Sprague-Dawley rats, and evaluated the renal NEP, kinins and plasma ANP simultaneously. There were no significant changes in urinary NEP, kinins, urine volume (UV) or urinary sodium excretion (UNaV) with vehicle treatment in anesthetized normotensive rats. Infused UK (10 mg/kg) significantly decreased NEP, and increased kinins, UV and UNaV. There was not a significant difference in plasma ANP between the vehicle and UK groups. Simultaneous administration of Hoe (20 nmol/kg) canceled the increases of UV and UNaV caused by UK. From these results, we conclude that inhibition of NEP may exaggerate the contribution of renal kinins to the renal water-sodium metabolism and overcome the contribution of ANP on that metabolism at least in normotensive rats.

Topics: Animals; Atrial Natriuretic Factor; Bradykinin; Cyclohexanecarboxylic Acids; Diuresis; Kidney; Kinins; Male; Natriuresis; Neprilysin; Rats; Rats, Sprague-Dawley