ZP120 causes relaxation by pre-junctional inhibition of noradrenergic neurotransmission in rat mesenteric resistance arteries.
OBJECTIVE
ZP120 (Ac-RYYRWKKKKKKK-NH(2)), 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.


METHODS
Arterial segments (internal diameters 206+/-4 microm, n=224) were mounted in microvascular myographs for isometric tension recordings and electrical field stimulation (EFS).


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 alpha(1)-adrenoceptor antagonist prazosin. N/OFQ inhibited, concentration-dependently, EFS-evoked contractions with a maximal effect of 52+/-3% (n=8) at 1 microM. The maximal effect of 1 microM 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 alpha(2)-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 microM), 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
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.
Simonsen
U
U
Department of Pharmacology, Faculty of Health Sciences, University of Aarhus, Aarhus, Denmark. us@farm.au.dk
Laursen
B E
BE
Petersen
J S
JS
D000255:Adenosine Triphosphate / Q000494:pharmacology; D000818:Animals; D004558:Electric Stimulation; D066298:In Vitro Techniques; D007537:Isometric Contraction; D008297:Male; D008638:Mesenteric Arteries / Q000187:drug effects* / Q000378:metabolism; D009638:Norepinephrine / Q000494:pharmacology; D009842:Oligopeptides / Q000008:administration & dosage / Q000494:pharmacology*; D018847:Opioid Peptides / Q000008:administration & dosage / Q000494:pharmacology; D010446:Peptide Fragments / Q000008:administration & dosage / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D011957:Receptors, Opioid / Q000819:agonists*; D013564:Sympathetic Nervous System / Q000187:drug effects / Q000378:metabolism; D014661:Vasoconstriction / Q000187:drug effects; D014664:Vasodilation / Q000187:drug effects*; D000094942:Nociceptin Receptor
D000255:Adenosine Triphosphate; D009638:Norepinephrine; D009842:Oligopeptides; D018847:Opioid Peptides; D010446:Peptide Fragments; D011957:Receptors, Opioid; D000094942:Nociceptin Receptor; C466980:nociceptin orphanin FQ(1-17)OH; C473470:ZP120; C000722285:Oprl1 protein, rat