Prevention of reflex natriuresis after acute unilateral nephrectomy by melanocortin receptor antagonists.
Prevention of reflex natriuresis after acute unilateral nephrectomy by melanocortin receptor antagonists.
复制标题
黑皮质素受体拮抗剂预防急性单侧肾切除术后反射性尿钠。
DOI：
10.1152/ajpregu.1998.274.4.r931
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发表时间：
1998
期刊：
影响因子：
--
通讯作者：
Humphreys,MH
中科院分区：
文献类型：
--
作者：
Ni,XP;Kesterson,RA;Sharma,SD;Hruby,VJ;Cone,RD;Wiedemann,E;Humphreys,MH
γ-促黑素细胞激素（γ-MSH）、心房利钠肽（ANP）和催产素已被确定为急性单侧肾切除术（AUN）后反射性尿钠排泄的候选激素介质。第三黑皮质素受体（MC 3-R）的药理学特征表明，它独特地响应于生理浓度的γ-MSH。我们通过在持续肾内输注其同源受体的特异性拮抗剂期间进行AUN来检测γ-MSH、ANP和催产素在肾切除术后尿钠排泄中的作用。在麻醉的Sprague-Dawley大鼠中，AUN后90 min尿钠排泄量（UNaV）从0.34 ± 0.04 μeq/min增加到1.12 ± 0.11 μeq/min（P< 0.001）。在接受假AUN手术的大鼠中，UNaV没有变化。血浆γ-MSH免疫反应性浓度在假手术后为53 ± 8 fmol/ml，而在手术后为112 ± 17 fmol/ml（P< 0.01）。SHU-9119和SHU-9005是α-MSH的取代衍生物，在体外对MC 3-R具有强效拮抗作用。以5 pmol/min的速率输注这些化合物完全阻断了对AUN的利钠反应，尽管血浆γ-MSH也有类似的升高（111 ± 12 fmol/ml对假手术大鼠的49 ± 8 fmol/ml，P< 0.01）。肾内注射ANP受体拮抗剂A-71915（5 pmol/min）或催产素受体拮抗剂[d（CH 2）51，Tyr（Me）2，Orn 8] vasotocin（10 pmol/min）可分别有效地抑制静脉注射ANP或催产素（各1 pmol/min）引起的尿钠排泄，但不能阻断AUN后的尿钠排泄。这些肽的血浆免疫反应性在AUN后没有增加。这些结果表明，AON后的反射性钠尿排泄伴随着血浆γ-MSH而不是ANP或催产素浓度的增加，并且可通过肾内输注对MC 3-R具有选择性的受体拮抗剂来防止。这些数据表明，γ-MSH或一种密切相关的肽介导肾切除术后尿钠排泄，并进一步支持γ-MSH可能在钠稳态中发挥更广泛作用的可能性。
γ-Melanocyte-stimulating hormone (γ-MSH), atrial natriuretic peptide (ANP), and oxytocin have been identified as candidate hormonal mediators of the reflex natriuresis that follows acute unilateral nephrectomy (AUN). Pharmacological characterization of the third melanocortin receptor (MC3-R) indicates that it uniquely responds to physiological concentrations of γ-MSH. We tested the roles of γ-MSH, ANP, and oxytocin in the postnephrectomy natriuresis by carrying out AUN during continuous intrarenal infusion of specific antagonists for their cognate receptors. In anesthetized Sprague-Dawley rats, urinary sodium excretion (UNaV) increased from 0.34 ± 0.04 to 1.12 ± 0.11 μeq/min 90 min after AUN (P< 0.001). No change in UNaV occurred in rats undergoing a sham AUN procedure. Plasma immunoreactive γ-MSH concentration was 53 ± 8 fmol/ml after sham AUN but 112 ± 17 fmol/ml after AUN (P< 0.01). SHU-9119 and SHU-9005 are substituted derivatives of α-MSH with potent antagonism at the MC3-R in vitro. Infusion of these compounds at 5 pmol/min completely blocked the natriuretic response to AUN despite a similar elevation in plasma γ-MSH (111 ± 12 vs. 49 ± 8 fmol/ml in sham rats,P< 0.01). Intrarenal infusion of the ANP receptor antagonist A-71915 (5 pmol/min) or the oxytocin receptor antagonist [d(CH2)51, Tyr(Me)2,Orn8] vasotocin (10 pmol/min) effectively inhibited the natriuresis induced by intravenous infusion of ANP or oxytocin (each at 1 pmol/min), respectively, but did not block the natriuresis after AUN. Plasma immunoreactivity of these peptides was not increased after AUN. These results indicate that reflex natriuresis after AUN is accompanied by an increase in plasma γ-MSH but not ANP or oxytocin concentration and is prevented by intrarenal infusion of receptor antagonists with selectivity for MC3-R. The data indicate that γ-MSH or a closely related peptide mediates postnephrectomy natriuresis and provide further support for the possibility that γ-MSH may play a wider role in sodium homeostasis.