Nociceptin/Orphanin FQ (N/OFQ)-Evoked Bradycardia, Hypotension, and Diuresis Are Absent in N/OFQ Peptide (NOP) Receptor Knockout Mice

Burmeister, Melissa A.; Ansonoff, Michael; Pintar, John E.; Kapusta, Daniel R.

doi:10.1124/jpet.107.135905

Cited by 17 publications

(8 citation statements)

References 33 publications

(46 reference statements)

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“…to mice [36]. Further studies likewise reported no differences in MAP between NOP -/- and wild-type mice [8]. However, our findings of tachycardia are in contrast to Burmeister & Kapusta [36].…”

Section: Discussioncontrasting

confidence: 45%

“…N/OFQ also increased aortic blood flow and induced dilation of large blood vessels >200 µm [4,7]. The cardiovascular effects of N/OFQ are absent in mouse knockouts for NOP (NOP -/- ) [8]. Within smaller blood vessels (15 to 40 µm) N/OFQ also induces dilation, along with inflammatory responses such as increased permeability and leukocyte-endothelial interactions within postcapillary venules [9].…”

Section: Introductionmentioning

confidence: 99%

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The Nociceptin/Orphanin FQ Receptor Antagonist UFP-101 Reduces Microvascular Inflammation to Lipopolysaccharide In Vivo

et al. 2013

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Microvascular inflammation occurs during sepsis and the endogenous opioid-like peptide nociceptin/orphanin FQ (N/OFQ) is known to regulate inflammation. This study aimed to determine the inflammatory role of N/OFQ and its receptor NOP (ORL1) within the microcirculation, along with anti-inflammatory effects of the NOP antagonist UFP-101 (University of Ferrara Peptide-101) in an animal model of sepsis (endotoxemia).Male Wistar rats (220 to 300 g) were administered lipopolysaccharide (LPS) for 24 h (-24 h, 1 mg kg-1; -2 h, 1 mg kg-1 i.v., tail vein). They were then either anesthetised for observation of the mesenteric microcirculation using fluorescent in vivo microscopy, or isolated arterioles (~200 µm) were studied in vitro with pressure myography.200 nM kg-1 fluorescently labelled N/OFQ (FITC-N/OFQ, i.a., mesenteric artery) bound to specific sites on the microvascular endothelium in vivo, indicating sparse distribution of NOP receptors. In vitro, arterioles (~200 µm) dilated to intraluminal N/OFQ (10-5M) (32.6 + 8.4%) and this response was exaggerated with LPS (62.0 +7.9%, p=0.031). In vivo, LPS induced macromolecular leak of FITC-BSA (0.02 g kg-1 i.v.) (LPS: 95.3 (86.7 to 97.9)%, p=0.043) from post-capillary venules (<40 µm) and increased leukocyte rolling as endotoxemia progressed (p=0.027), both being reduced by 150 nmol kg-1 UFP-101 (i.v., jugular vein).Firstly, the rat mesenteric microcirculation expresses NOP receptors and secondly, NOP function (ability to induce dilation) is enhanced with LPS. UFP-101 also reduced microvascular inflammation to endotoxemia in vivo. Hence inhibition of the microvascular N/OFQ-NOP pathway may have therapeutic potential during sepsis and warrants further investigation.

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Section: Discussioncontrasting

confidence: 45%

Section: Introductionmentioning

confidence: 99%

The Nociceptin/Orphanin FQ Receptor Antagonist UFP-101 Reduces Microvascular Inflammation to Lipopolysaccharide In Vivo

et al. 2013

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“…However, the peripheral actions of PNOC have not been fully described. Outside the brain, OPRL1 has been detected in the rat peripheral ganglia, airways, and intestines; the mice heart, vas deferens, and colon; the guinea pig retina; and in the human airways and mononuclear cells [6][7][8][9][10][11]. As regards the visceral smooth muscles, PNOC has been found to inhibit nonadrenergic-noncholinergic bronchoconstriction in the guinea pig airways via the prejunctional modulation of tachykinin release [12] and to inhibit distal colon motility in the rat [13].…”

Section: Introductionmentioning

confidence: 96%

Nociceptin Inhibits Uterine Contractions in Term-Pregnant Rats by Signaling Through Multiple Pathways1

Klinke

Tekes

Gunduz-Cinar

et al. 2010

Biology of Reproduction

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The actions of the endogenous peptide nociceptin (PNOC; previously abbreviated as N/OFQ) on the myometrium have not been investigated previously. Our aim was to study the presence and functional role of PNOC in the modulation of uterine contractility in pregnant rats at term. The presence of PNOC and its receptors (OPRL1; previously called NOP) in the uterus were detected by radioimmunoassay and radioligand-binding experiments. The PNOC-stimulated G protein activation was assessed by a [(35)S]GTPgammaS-binding technique. The effects of PNOC in uterine rings precontracted with KCl or oxytocin were also tested in vitro. Uterine levels of cAMP were measured by enzyme immunoassay. The K(+) channel blockers tetraethylammonium and paxilline were used to study the role of K(+) channels in mediating the uterine effects of PNOC. Both PNOC and OPRL1 were present in the uterus. PNOC revealed a maximum contraction inhibition of approximately 30%, which was increased to 40% by naloxone. Naloxone and pertussis toxin significantly attenuated the G protein-stimulating effect of PNOC. The uterine cAMP levels were elevated by PNOC and naloxone and after preincubation with pertussis toxin. Tetraethylammonium and paxilline reduced the contraction-inhibiting effect of PNOC and naloxone to approximately 10% and 15%, respectively. We presume that PNOC plays a role in regulating uterine contractility at term. Its effect is mediated partly by stimulatory heterotrimeric G (G(s)) proteins coupled to OPRL1 receptors and elevated cAMP levels, and also by Ca(2+)-dependent K(+) channels. Our results demonstrate a novel action and signaling pathway for PNOC that might be a potential drug target.

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“…(C) The dose-dependent anti-arrhythmic effects of UFP-101 (n = 6 for each dose); (D) the profile of episodes of VEB in the 60 min of CAO in the experimental groups. △difference (P < 0.01 vs. sham); ▲difference (P < 0.01 vs. CAO); *difference (P < 0.01 vs. UFP7); UFP11, UFP-101 at 10 −11 mol·kg Previous reports indicate that the N/OFQ receptor mediates the cardiovascular effects of N/OFQ (Champion et al, 1997;Giuliani et al, 1997;Dumont and Lemaire, 1998;Burmeister et al, 2008) and UFP-101. UFP-101 can reverse central and peripheral actions of N/OFQ (Calo et al, 2005).…”

Section: Figurementioning

confidence: 96%

Antagonism of endogenous nociceptin/orphanin FQ inhibits infarction‐associated ventricular arrhythmias via PKC‐dependent mechanism in rats

Han

Guo

Wang

et al. 2013

British J Pharmacology

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Background and Purpose Evidence indicates nociceptin/orphanin FQ (N/OFQ) may participate in the pathology of cardiac arrhythmias associated with myocardial infarction. But the role of N/OFQ in the arrhythmogenesis in acute myocardial infarction is unclear. The aim of this study was to investigate the effects of endogenous N/OFQ on infarction‐associated arrhythmias. Experimental Approach The expression of N/OFQ, PKC activity and ventricular arrhythmias in presence and absence of UFP‐101, a specific antagonist of N/OFQ receptor, were examined following permanent coronary artery occlusion in anaesthetized rats. The effect of N/OFQ on action potential duration was examined in isolated rat cardiomyocytes. Key Results It was observed that N/OFQ was increased by 41% in the myocardium after coronary artery occlusion (P < 0.01 vs. control). Pretreatment with UFP‐101 (10−7 mol·kg−1, i.v.) reduced the incidence of ventricular ectopic beats by 70% and ventricular tachycardia by 51% respectively (all P < 0.05 vs. control). Meanwhile, PKC activity was elevated in the rats treated with UFP‐101 (by 35%, P < 0.05 vs. control). A selective PKC inhibitor, calphostin C, completely abolished the anti‐arrhythmic effects of UFP‐101 (P < 0.01). N/OFQ (at 10−11, 10−9 and 1 × 10−7 mol·L−1) shortened the action potential duration by 3% (P > 0.05), 10% (P < 0.05) and 22% (P < 0.01), respectively, via N/OFQ receptor. Conclusions and Implications Antagonism of endogenous N/OFQ produces anti‐arrhythmic effects on ventricular arrhythmias in acute myocardial infarction, possibly via modulating PKC activity and action potential of myocytes.

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Nociceptin/Orphanin FQ (N/OFQ)-Evoked Bradycardia, Hypotension, and Diuresis Are Absent in N/OFQ Peptide (NOP) Receptor Knockout Mice

Cited by 17 publications

References 33 publications

The Nociceptin/Orphanin FQ Receptor Antagonist UFP-101 Reduces Microvascular Inflammation to Lipopolysaccharide In Vivo

The Nociceptin/Orphanin FQ Receptor Antagonist UFP-101 Reduces Microvascular Inflammation to Lipopolysaccharide In Vivo

Nociceptin Inhibits Uterine Contractions in Term-Pregnant Rats by Signaling Through Multiple Pathways1

Antagonism of endogenous nociceptin/orphanin FQ inhibits infarction‐associated ventricular arrhythmias via PKC‐dependent mechanism in rats

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