Neutral endopeptidase inhibition potentiates the natriuretic actions of adrenomedullin

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 (U(Na)V) increased from baseline. Proximal and distal fractional reabsorption of sodium decreased in the ADM-infused kidney. In response to systemic NEP inhibition, U(Na)V and UV increased further in the ADM kidney. Indeed, ΔU(Na)V 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.