The Role of Kinins and Atrial Natriuretic Peptide on the Renal Effects of Neutral Endopeptidase Inhibitor in Rats

Abstract

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.

A Modern Understanding of the Traditional and Nontraditional Biological Functions of Angiotensin-Converting Enzyme

“…Bradykinin has a short half-life of approximately 15 seconds in plasma due to the action of multiple metalloproteases (Nussberger et al, 1999;Moreau et al, 2005). Neutral endopeptidase and ACE are the two major bradykinindegrading enzymes (Ura et al, 1994;Duncan et al, 2000). Pharmacologic inhibition of ACE increases plasma bradykinin levels in patients, but has very little or no effect on the concentration of kallidin.…”

Acute Natriuretic Effect of Fasidotrilat, a Mixed Inhibitor of Neutral Endopeptidase and Angiotensin I-Converting Enzyme, in Rats with Heart Failure

“…The natriuretic effect was associated with an enhanced urinary excretion of ANF and bradykinin, which is a substrate for both NEP and ACE. There is evidence that bradykinin can contribute to the effects of ACE inhibition alone [21][22][23] and NEP inhibition alone [24,25].…”

Role of bradykinin receptors in the renal effects of inhibition of angiotensin converting enzyme and endopeptidases 24.11 and 24.15 in conscious rabbits

“…There is also evidence from studies with bradykinin antagonists suggesting that bradykinin can contribute to the renal effects of ACE inhibition alone (Kon et al, 1993;Bouaziz et al, 1994) and EP 24.11 inhibition alone (Ura et al, 1994). We tested the effects of the bradykinin B2-receptor antagonist Hoe 140 on the systemic haemodynamic and renal effects of combined inhibition of ACE and EP 24.11.…”