TY - JOUR

T1 - Nociceptin/orphanin FQ peptide receptor agonist Ac-RYYRWKKKKKKK-NH2 (ZP120) induces antinatriuresis in rats by stimulation of amiloride-sensitive sodium reabsorption

AU - van Deurs, Ulla S K

AU - Hadrup, Niels

AU - Petersen, Jørgen Søberg

AU - Christensen, Sten

AU - Jonassen, Thomas

N1 - Keywords: Absorption; Amiloride; Animals; Drug Interactions; Immunohistochemistry; Natriuresis; Oligopeptides; Opioid Peptides; Rats; Rats, Wistar; Receptors, Opioid; Sodium

PY - 2008

Y1 - 2008

N2 - 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 Ac-RYYRWKKKKKKK-NH(2) (ZP120). Using immunohistochemistry, we showed that in the cortex NOP receptors are expressed in the distal convoluted tubules, the connecting tubules, and the collecting ducts. Using clearance techniques, we evaluated renal excretory function during acute administration of ZP120 (1 nmol/kg/min) in chronically catheterized, 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 coadministration of an inhibitor of the NaCl cotransporter, bendroflumethiazide, or a blocker of the epithelial sodium channel, amiloride, respectively. ZP120 produced a marked antinatriuresis [fractional excretion of sodium (FE(Na)): ZP120, 0.3 +/- 0.1% versus control, 0.9 +/- 0.1%; p < 0.05] in sodium-replete rats. The natriuretic response to amiloride was significantly increased in ZP120-treated rats compared with controls (DeltaFE(Na): ZP120, 1.1 +/- 0.2% versus control, 0.5 +/- 0.2%; p < 0.01), whereas 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.

AB - 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 Ac-RYYRWKKKKKKK-NH(2) (ZP120). Using immunohistochemistry, we showed that in the cortex NOP receptors are expressed in the distal convoluted tubules, the connecting tubules, and the collecting ducts. Using clearance techniques, we evaluated renal excretory function during acute administration of ZP120 (1 nmol/kg/min) in chronically catheterized, 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 coadministration of an inhibitor of the NaCl cotransporter, bendroflumethiazide, or a blocker of the epithelial sodium channel, amiloride, respectively. ZP120 produced a marked antinatriuresis [fractional excretion of sodium (FE(Na)): ZP120, 0.3 +/- 0.1% versus control, 0.9 +/- 0.1%; p < 0.05] in sodium-replete rats. The natriuretic response to amiloride was significantly increased in ZP120-treated rats compared with controls (DeltaFE(Na): ZP120, 1.1 +/- 0.2% versus control, 0.5 +/- 0.2%; p < 0.01), whereas 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.

U2 - 10.1124/jpet.108.144774

DO - 10.1124/jpet.108.144774

M3 - Journal article

C2 - 19028991

VL - 328

SP - 533

EP - 539

JO - Journal of Pharmacology and Experimental Therapeutics

JF - Journal of Pharmacology and Experimental Therapeutics

SN - 0022-3565

IS - 2

ER -