Lisy O, Jougasaki M, Schirger J A, Chen H H, Barclay P T, Burnett J C
Cardiorenal Research Laboratory, Division of Cardiovascular Diseases, Department of Physiology, Mayo Clinic and Foundation, Rochester, Minnesota 55905, USA.
Am J Physiol. 1998 Sep;275(3):F410-4. doi: 10.1152/ajprenal.1998.275.3.F410.
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 microg . 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, DeltaUNaV and DeltaUV 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.
肾上腺髓质素（ADM）是一种具有六氨基酸二硫环的强效肾血管舒张和利钠肽。中性内肽酶24.11（NEP）在肾脏中分布最为丰富，可裂解内源性肽，如同样具有二硫环的心房利钠肽。我们假设NEP抑制可增强外源性ADM对麻醉犬（n = 6）的利钠作用。因此，我们研究了肾功能，其中一侧肾脏接受肾内输注ADM（1 ng·kg-1·min-1），而对侧肾脏在全身输注NEP抑制剂（坎多沙坦酯，8 μg·kg-1·min-1；辉瑞公司）之前和期间作为对照。对ADM的反应中，ADM肾脏的肾小球滤过率（GFR）未改变，而肾血流量、尿流量（UV）和尿钠排泄（UNaV）较基线增加。输注ADM的肾脏中钠的近端和远端分数重吸收减少。对全身NEP抑制的反应中，ADM肾脏的UNaV和UV进一步增加。实际上，与对照肾脏相比，ADM肾脏的ΔUNaV和ΔUV明显更大。ADM输注期间血浆ADM未改变，但NEP抑制期间增加。总之，本研究首次证明NEP抑制可增强对肾内ADM的利钠和利尿反应。这种增强是由于肾小管钠重吸收减少所致。最后，全身NEP抑制期间血浆ADM的增加支持了ADM是NEP底物的结论。
