Characterization of the Cardiovascular and Renal Effects of Synthetic Nociceptin/Orphanin FQ Receptor Partial Agonists

Abstract

Following discovery of the endogenous opioid‐like peptide, nociceptin/orphanin FQ (N/OFQ) and the N/OFQ peptide receptor (NOP), numerous peptide and non‐peptide NOP receptor ligands have been developed for potential treatment of disease states including Parkinson's, depression, anxiety, and chronic pain. In addition, our laboratory has demonstrated that NOP receptor peptide ligands produce changes in cardiovascular and renal function. However, we have yet to determine whether non‐peptide NOP receptor ligands have similar cardiovascular and renal effects. Therefore, the aim of the present study was to characterize the cardiovascular and renal profile of the non‐peptide NOP receptor compounds AT‐039, AT‐127, AT‐090, and AT‐403 (Astraea Therapeutics).MethodsMale Sprague‐Dawley rats were surgically implanted with a venous, arterial, and bladder catheter and continuously infused intravenously (i.v.) with isosaline. After stabilization, conscious rats received an i.v. bolus injection of AT‐039, 127, 090, or 403 (30, 100, or 300 nmol/kg) while mean arterial pressure (MAP), heart rate (HR), and urine flow rate (V) were measured for 90 minutes. Urine samples were analyzed for urinary sodium excretion (UNaV) and urinary potassium excretion (UKV).ResultsFollowing i.v. bolus administration all AT compounds produced a dose‐dependent diuresis with a decrease in MAP, HR, MAP, UNaV, and UKV. Each ligand also produced sedation with the exception of AT‐039. Further studies with AT‐039 demonstrated that i.v. infusion of this ligand produced dose‐dependent effects on water and electrolyte excretion and blood pressure, but did not alter HR or produce sedation.ConclusionsThese findings indicate that i.v. injection of all non‐peptide NOP receptor AT compounds produced a significant diuretic and hypotensive effects. However, sedation and bradycardia were absent with AT‐039 i.v. infusion treatment. Further studies are needed to explore the mechanisms by which these compounds produce their cardiorenal responses.Support or Funding InformationFunding for this work was supported by Astraea Therapeutics (NZ), R01DA027811 (NZ), R01014026 (NZ), and NIH P30GM106392 (DRK).This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.