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Cardiorenal Research Laboratory, Division of Cardiovascular Diseases, Department of Physiology, Mayo Clinic and Foundation, Rochester, Minnesota 55905
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 · min1)
while the contralateral kidney served as control before and during the
systemic infusion of a NEP inhibitor (Candoxatrilat, 8 µg · kg1 · min1;
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, 
UNaV
and UV 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.
metalloprotease inhibitor; sodium excretion; kidney; natriuretic peptide
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