Functional selectivity of nociceptin/orphanin FQ peptide receptor partial agonists on cardiovascular and renal function.
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)-NH(2), Ac-RYYRIK-NH(2), and Ac-RYYRWK-NH(2)) 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.
Kapusta
Daniel R
DR
Department of Pharmacology and Experimental Therapeutics, Louisiana State University Health Sciences Center, 1901 Perdido St., New Orleans, LA 70112, USA. dkapus@lsuhsc.edu
Burmeister
Melissa A
MA
Calo'
Girolamo
G
Guerrini
Remo
R
Gottlieb
Helmut B
HB
Kenigs
Velga A
VA
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D006439:Hemodynamics / Q000187:drug effects*; D007275:Injections, Intravenous; D007276:Injections, Intraventricular; D007668:Kidney / Q000187:drug effects*; D007677:Kidney Function Tests; D008297:Male; D009842:Oligopeptides / Q000494:pharmacology; D018847:Opioid Peptides / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011957:Receptors, Opioid / Q000819:agonists*; D012079:Renal Circulation / Q000187:drug effects; D013238:Stereotaxic Techniques; D014665:Vasodilator Agents / Q000494:pharmacology; D000094942:Nociceptin Receptor; D000097629:Nociceptin
D009842:Oligopeptides; D018847:Opioid Peptides; D011957:Receptors, Opioid; D014665:Vasodilator Agents; D000094942:Nociceptin Receptor; D000097629:Nociceptin; C404152:CAM 6369; C118945:acetyl-RYYRIK-NH2; C000722285:Oprl1 protein, rat