Neutral endopeptidase inhibition potentiates the natriuretic actions of adrenomedullin

Abstract

Adrenomedullin (ADM) is a potent renal vasodilating and natriuretic peptide possessing a six amino acid disulfide ring. Neutral endopeptidase 24.11 (NEP) is localized in greatest abundance in the kidney and cleaves endogenous peptides like atrial natriuretic peptide, which also possesses a disulfide ring. We hypothesized that NEP inhibition potentiates the natriuretic actions of exogenous ADM in anesthetized dogs ( n = 6). We therefore investigated renal function in which one kidney received intrarenal infusion of ADM (1 ng ⋅ kg−1 ⋅ min−1) while the contralateral kidney served as control before and during the systemic infusion of a NEP inhibitor (Candoxatrilat, 8 μg ⋅ kg−1 ⋅ min−1; Pfizer). In response to ADM, glomerular filtration rate (GFR) in the ADM kidney did not change, whereas renal blood flow, urine flow (UV), and urinary sodium excretion (UNaV) increased from baseline. Proximal and distal fractional reabsorption of sodium decreased in the ADM-infused kidney. In response to systemic NEP inhibition, UNaV and UV increased further in the ADM kidney. Indeed, ΔUNaV and ΔUV were markedly greater in the ADM kidney compared with the control kidney. Plasma ADM was unchanged during ADM infusion but increased during NEP inhibition. In conclusion, the present investigation is the first to demonstrate that NEP inhibition potentiates the natriuretic and diuretic responses to intrarenal ADM. This potentiation occurs secondary to a decrease in tubular sodium reabsorption. Lastly, the increase in plasma ADM during systemic NEP inhibition supports the conclusion that ADM is a substrate for NEP.

Role of the natriuretic peptides in the cardiorenal and humoral actions of omapatrilat: Insights from experimental heart failure

“…These results strongly support the conclusion that the renal effects of short-term VP inhibition with omapatrilat in this model of congestive heart failure are partly mediated via the potentiation of the endogenous natriuretic peptides. Because NEP and ACE may degrade other vasoactive and natriuretic peptides, such as adrenomedullin and bradykinin, dual NEP/ACE inhibition may result in the potentiation of several biologically active peptides that will require further investigation [16,17]. Finally, the increase in plasma ANP with omapatrilat despite reductions in cardiac filling pressures (and thus atrial stretch) underscores the importance of NEP inhibition in augmenting the natriuretic peptides.…”

Effects of omapatrilat on pharmacodynamic biomarkers of neutral endopeptidase and angiotensin-converting enzyme activity in humans

“…Plasma concentrations of ADM are elevated in congestive heart failure [32]. Although the pathway for ADM clearance is not well defined, inhibition of NEP potentiates the natriuretic actions of infused ADM [33]. In patients with salt-sensitive hypertension, omapatrilat increased plasma concentrations of ADM by 50% at 4 hours after dose (Fig.…”

Neprilysin Inhibition as a PARADIGM Shift in Heart Failure Therapy

“…Neprilysin also inactivates systemic vasoconstrictors such as endothelin I and angiotensin II. In addition, it can convert angiotensin I to angiotensin (1-7), a peptide that can offset many effects of angiotensin II leading to direct vasodilatory, natriuretic, and anti-proliferative effects [21]. Thus, neprilysin inhibition alone would have mixed effects based on its ability to increase both peptides that have vasodilatory and other favorable effects and peptides such as angiotensin II that have unwanted cardiovascular effects [2].…”