ZP120 causes relaxation by pre‐junctional inhibition of noradrenergic neurotransmission in rat mesenteric resistance arteries

• Published in: British journal of pharmacology Vol. 153; no. 6; pp. 1185 - 1194
• Main Authors: Simonsen, U, Laursen, B E, Petersen, J S
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01-03-2008; Nature Publishing; Nature Publishing Group
• Subjects: Adenosine Triphosphate - pharmacology; Animals; Biological and medical sciences; Electric Stimulation; endothelium; In Vitro Techniques; Isometric Contraction; Male; Medical sciences; Mesenteric Arteries - drug effects; Mesenteric Arteries - metabolism; nociceptin/orphan FQ peptide; noradrenaline; Norepinephrine - pharmacology; Oligopeptides - administration & dosage; Oligopeptides - pharmacology; Opioid Peptides - administration & dosage; Opioid Peptides - pharmacology; Peptide Fragments - administration & dosage; Peptide Fragments - pharmacology; Pharmacology. Drug treatments; Rats; Rats, Wistar; Receptors, Opioid - agonists; Research Papers; Sympathetic Nervous System - drug effects; Sympathetic Nervous System - metabolism; sympathetic neurotransmission; Vasoconstriction - drug effects; Vasodilation - drug effects; ZP120; ZP120; Peptides; Rat; Rodentia; Catecholamine; Sympathetic nervous system; Endothelium; Nociceptin; Resistance; Vertebrata; Mesenteric artery; Mammalia; sympathetic neurotransmission; Autonomic nervous system; Animal; Neurotransmitter; Noradrenergic transmission; Norepinephrine; noradrenaline; Neurotransmission; nociceptin/orphan FQ peptide
• ISSN: 0007-1188; 1476-5381
• DOI: 10.1038/sj.bjp.0707688

Background and purpose:
ZP120 (Ac‐RYYRWKKKKKKK‐NH2), is a new partial nociceptin/orphanin FQ (NOP) receptor agonist with sodium‐potassium sparing aquaretic effects. The mechanisms of vasodilatation of ZP120 were examined in rat mesenteric resistance arteries.
Experimental approach:
Arterial segments (internal diameters 206±4 μm, n=224) were mounted in microvascular myographs for isometric tension recordings and electrical field stimulation (EFS).
Key results:
ZP120 and the endogenous NOP receptor ligand, N/OFQ, did not relax arteries contracted with noradrenaline or adenosine‐triphosphate. EFS‐evoked contractions were inhibited by a purinoceptor antagonist, suramin, and the α1‐adrenoceptor antagonist prazosin. N/OFQ inhibited, concentration‐dependently, EFS‐evoked contractions with a maximal effect of 52±3% (n=8) at 1 μM. The maximal effect of 1 μM ZP120 was lower (27±5%, P<0.05, n=9) than for N/OFQ. Endothelial removal or pretreatment with capsaicin did not influence the vasodilator effects of ZP120 and N/OFQ. ZP120 and N/OFQ responses were preserved in the presence of suramin. The α2‐adrenoceptor antagonist, rauwolscine, antagonized the effect of clonidine and brimonidine, but ZP120 and N/OFQ inhibition of EFS‐evoked contraction was unaltered. The competitive NOP receptor antagonist, UFP‐101 (10 μM), prevented the inhibitory effect of N/OFQ, but not ZP120 suggesting that N/OFQ and ZP120 have distinct modes of interaction with the NOP receptor.
Conclusions and implications:
Our findings suggest that the vasodilator effect of ZP120 and N/OFQ in rat mesenteric resistance arteries is mediated by prejunctional inhibition of adrenergic neurotransmission. These properties, that promote diuresis and attenuate the cardiovascular consequences of increased sympathetic nerve activity, make ZP120 a promising drug candidate.
British Journal of Pharmacology (2008) 153, 1185–1194; doi:10.1038/sj.bjp.0707688; published online 14 January 2008