PREVENTION OF REFLEX NATRIURESIS AFTER ACUTE UNILATERAL NEPHRECTOMY BY MELANOCORTIN RECEPTOR ANTAGONISTS

gamma-Melanocyte-stimulating hormone (gamma-MSH), atrial natriuretic p eptide (ANP), and oxytocin have been identified as candidate hormonal mediators of the reflex natriuresis that follows acute unilateral neph rectomy (AUN). Pharmacological characterization of the third melanocor tin receptor (MC3-R) indicates that it uniquely responds to physiologi cal concentrations of gamma-MSH. We tested the roles of gamma-MSH, ANP , and oxytocin in the postnephrectomy natriuresis by carrying out AUN during continuous intrarenal infusion of specific antagonists for thei r cognate receptors. In anesthetized Sprague-Dawley rats, urinary sodi um excretion (UNaV) increased from 0.34 +/- 0.04 to 1.12 +/- 0.11 mu e q/min 90 min after AUN (P < 0.001). No change in UNaV occurred in rats undergoing a sham AUN procedure. Plasma immunoreactive gamma-MSH conc entration was 53 +/- 8 fmol/ml after sham AUN but 112 +/- 17 fmol/ml a fter AUN (P < 0.01). SHU-9119 and SHU-9005 are substituted derivatives of alpha-MSH with potent antagonism at the MC3-R in vitro. Infusion o f these compounds at 5 pmol/min completely blocked the natriuretic res ponse to AUN despite a similar elevation in plasma gamma-MSH (111 +/- 12 vs. 49 +/- 8 fmol/ml in sham rats, P < 0.01). Intrarenal infusion o f the ANP receptor antagonist A-71915 (5 pmol/min) or the oxytocin rec eptor antagonist [d(CH2)(5)(1), Tyr(Me)(2),Orn(8)] vasotocin (10 pmol/ min) effectively inhibited the natriuresis induced by intravenous infu sion of ANP or oxytocin (each at 1 pmol/min), respectively, but did no t block the natriuresis after AUN. Plasma immunoreactivity of these pe ptides was not increased after AUN. These results indicate that reflex natriuresis after AUN is accompanied by an increase in plasma gamma-M SH but not ANP or oxytocin concentration and is prevented by intrarena l infusion of receptor antagonists with selectivity for MC3-R. The dat a indicate that gamma-MSH or a closely related peptide mediates postne phrectomy natriuresis and provide further support for the possibility that gamma-MSH may play a wider role in sodium homeostasis.