Abstract
The opioid-like peptide nociceptin/orphanin FQ (N/OFQ) produces marked cardiovascular and renal responses after central or peripheral administration in rats. Due to their ability to behave as full/partial agonists or antagonists in different cellular and tissue assays, the present studies were performed to determine how compounds classified as N/OFQ peptide (NOP) receptor partial agonists ([F/G]N/OFQ(1-13)-NH2, Ac-RYYRIK-NH2, and Ac-RYYRWK-NH2) affect cardiovascular and renal function in vivo. In conscious Sprague-Dawley rats, intracerebroventricular (i.c.v.) administration of each of the three NOP receptor ligands produced profound cardiovascular (depressor), renal excretory (water diuresis), and renal sympathetic nerve activity (inhibitory) responses that were similar to those produced by i.c.v. injection of the native ligand N/OFQ. In contrast, in other groups of rats, the intravenous (i.v.) bolus injection of these same NOP receptor ligands produced responses unlike N/OFQ; N/OFQ evoked an immediate and profound bradycardia and hypotension with no change in urine output, whereas all purported NOP receptor partial agonists elicited a subtle slow onset hypotension, no change in heart rate, and a marked water diuresis. In other studies, i.v. bolus pretreatment of rats with NOP receptor partial agonists prevented/attenuated the cardiovascular depressor effects produced by a subsequent i.v. bolus N/OFQ challenge without affecting the cardiovascular responses to i.c.v. N/OFQ. Together, these findings demonstrate that in conscious rats, NOP receptor partial agonists produce functionally selective effects on cardiovascular and renal function ranging from full agonist (i.c.v., cardiovascular depressor; i.c.v. and i.v., water diuresis), partial agonist (i.v., submaximal hypotension) to antagonist (i.v., blockade of N/OFQ-evoked bradycardia and hypotension) behavior.
Footnotes
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This work was supported by National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases Grants DK-43337 and DK-02605; American Heart Association, Southeastern Affiliate 0255314B (to D.R.K.); and National Institutes of Health, Heart, Lung, and Blood Institute Grant HL71212 (to D.R.K. and G.C.). We note that funds made available to D.R.K. from the American Heart Association Grant 0255314B were entirely provided to the American Heart Association by a gracious donation from Herbert H. McElveen (DeRidder, LA).
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doi:10.1124/jpet.104.082768.
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ABBREVIATIONS: N/OFQ, nociceptin/orphanin FQ; NOP, nociceptin/orphanin FQ peptide; [F/G], [Phe1ψ(CH2-NH)Gly2]N/OFQ(1-13)-NH2; HEX 1, Ac-RYYRIK-NH2; HEX 2, Ac-RYYRWK-NH2; PE, polyethylene; HR, heart rate; bmp, beats per minute; MAP, mean arterial pressure; V, urine flow rate; UNaV, urinary sodium excretion; CNS, central nervous system; ZP120, Ac-RYYRWKKKKKKK-NH2; Ro64-6198, (1S,3aS)-8-(2,3,3a,4,5,6-hexahydro-1H-1-phenalen-1-yl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one.
- Received January 10, 2005.
- Accepted April 18, 2005.
- The American Society for Pharmacology and Experimental Therapeutics
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