Abstract
<jats:p> 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<jats:sup>−1</jats:sup>·h<jats:sup>−1</jats:sup> 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 [Nphe<jats:sup>1</jats:sup>,Arg<jats:sup>14</jats:sup>,Lys<jats:sup>15</jats:sup>]N/OFQ-NH<jats:sub>2</jats:sub> (UFP-101; 60 and 150 nmol/kg iv), H<jats:sub>1</jats:sub> and H<jats:sub>2</jats:sub>antagonists pyrilamine (mepyramine, 1 mg/kg iv) and ranitidine (1 mg/kg iv), and mast cell stabilizer cromolyn (1 mg·kg<jats:sup>−1</jats:sup>·min<jats:sup>−1</jats:sup>) 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<jats:sup>−5</jats:sup> 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. </jats:p>
Original language | English |
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Pages (from-to) | H2977-H2985 |
Number of pages | 0 |
Journal | American Journal of Physiology-Heart and Circulatory Physiology |
Volume | 293 |
Issue number | 5 |
DOIs | |
Publication status | Published - Nov 2007 |