Received for publication August 15, 2008.
Revised November 20, 2008.
Accepted for publication November 20, 2008.

NOP receptor agonist ZP120 induces antinatriuresis in rats by stimulation of amiloride-sensitive sodium reabsorption

Abstract

The aim of the present study was to examine the mechanisms responsible for the antinatriuretic effect of the selective, peripherally acting, nociceptin/orphanin FQ peptide (NOP) receptor partial agonist ZP120. Using immuhistochemistry we showed that in the cortex NOP receptors are expressed in the distal convoluted tubules, the connecting tubules, and in the collecting ducts. Using clearance techniques we evaluated renal excretory function during acute administration of ZP120 (1 nmol/kg/min) in chronically instrumented, conscious rats (n=8/group). To examine the hypothesis that ZP120 induces direct renal effects by modifying the activity of sodium transporters in the distal convoluted tubules or in the collecting ducts, ZP120-induced antinatriuresis was examined during co-administration of an inhibitor of the Na-Cl cotransporter, bendroflumethiazide, or a blocker of the epithelial sodium channel, amiloride, respectively. ZP120 produced a marked antinatriuresis (FE_Na: ZP120: 0.3 ± 0.1% vs. control: 0.9 ± 0.1%; p<0.05) in sodium replete rats. The natriuretic response to amiloride was significantly increased in ZP120-treated rats when compared to controls (FE_Na: ZP120: 1.1% ± 0.2 vs. control: 0.5% ± 0.2; p<0.01), while the effect of BFTZ was equal in ZP120 treated rats and controls. These results suggest that ZP120 exerts a direct renal NOP receptor-mediated stimulatory effect on the epithelial sodium channel in the collecting ducts.

Key words: Amiloride, Antinatriuresis, Clearance study, ENaC, NOP receptor, ZP120