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This Article Full Text Full Text (PDF) All Versions of this Article: 293/5/H2977    most recent 00448.2007v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via ISI Web of Science (1) Citing Articles via Google Scholar Google Scholar Articles by Brookes, Z. L. S. Articles by Lambert, D. G. Search for Related Content PubMed PubMed Citation Articles by Brookes, Z. L. S. Articles by Lambert, D. G.

Proinflammatory and vasodilator effects of nociceptin/orphanin FQ in the rat mesenteric microcirculation are mediated by histamine

¹University of Sheffield, Academic Anaesthesia Unit and Microcirculation Research Group, Royal Hallamshire Hospital, Sheffield; ⁴University of Leicester, Division of Anaesthesia, Critical Care, and Pain Management, Department of Cardiovascular Sciences, Leicester Royal Infirmary, Leicester United Kingdom; ²Department of Pharmaceutical Sciences and Biotechnology Center and ³Department of Experimental and Clinical Medicine, Section of Pharmacology and Neuroscience Center, University of Ferrara, Ferrara, Italy

Submitted 12 April 2007 ; accepted in final form 28 August 2007

Nociceptin/orphanin FQ (N/OFQ) is the endogenous ligand for the N/OFQ peptide receptor (NOP). N/OFQ causes hypotension and vasodilation, and we aimed to determine the role of histamine in inflammatory microvascular responses to N/OFQ. Male Wistar rats (220–300 g, n = 72) were anesthetized with thiopental (30 mg/kg bolus, 40–90 mg·kg^–1·h^–1 iv), and the mesentery was prepared for fluorescent intravital microscopy using fluorescein isothiocyanate-conjugated BSA (FITC-BSA, 0.25 ml/100 g iv) or 1 µm fluorescently labeled microspheres. N/OFQ (0.6–60 nmol/kg iv) caused hypotension (SAP, baseline: 154 ± 11 mmHg, 15 nmol/kg N/OFQ: 112 ± 10 mmHg, P = 0.009), vasodilation (venules: 23.9 ± 1.2 µm, 26.7 ± 1.2 µm, P = 0.006), macromolecular leak (interstitial gray level FITC-BSA: 103.7 ± 3.4, 123.5 ± 11.8, P = 0.009), and leukocyte adhesion (2.0 ± 0.9, 15.2 ± 0.9/100 µm, P = 0.036). Microsphere velocity also decreased (venules: 1,230 ± 370 µm/s, P = 0.037), but there were no significant changes in blood flow. Flow cytometry measured a concurrent increase in neutrophil expression of cd11b with N/OFQ vs. controls (Geo mean fluorescence: 4.19 ± 0.13 vs. 2.06 ± 0.38, P < 0.05). The NOP antagonist [Nphe¹,Arg¹⁴,Lys¹⁵]N/OFQ-NH₂ (UFP-101; 60 and 150 nmol/kg iv), H₁ and H₂antagonists pyrilamine (mepyramine, 1 mg/kg iv) and ranitidine (1 mg/kg iv), and mast cell stabilizer cromolyn (1 mg·kg^–1·min^–1) also abolished vasodilation and macromolecular leak to N/OFQ in vivo (P < 0.05), but did not affect hypotension. Isolated mesenteric arteries (200 µm, n = 25) preconstricted with U-46619 were also mounted on a pressure myograph (60 mmHg), and both intraluminally and extraluminally administered N/OFQ (10^–5 M) caused dilation, inhibited by pyrilamine in the extraluminal but not the intraluminal (control: –6.9 ± 3.8%; N/OFQ: 32.6 ± 8.4%; pyrilamine: 31.5 ± 6.8%, n = 18, P < 0.05) experiments. We conclude that, in vivo, mesenteric microvascular dilation and macromolecular leak occur via N/OFQ-NOP-mediated release of histamine from mast cells. Therefore, N/OFQ-NOP has an important role in microvascular inflammation, and this may be targeted during disease, particularly as we have proven that UFP-101 is an effective antagonist of microvascular responses in vivo.

nociceptin/orphanin FQ; UFP-101; microcirculation; arteriole; nociceptin/orphanin FQ peptide receptor; ORL-1; permeability; vasodilatation; leukocyte