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Inhaled FMLP increases microvascular permeability in the rabbit trachea
S C Bell1, A C Rynell, M J Matheson
1Department of Thoracic Medicine, Royal North Shore Hospital, Sydney, New South Wales, Australia.
Abstract:
This study was designed to determine the effect of inhaled N-formyl-methionyl-leucyl-phenylalanine (FMLP) on microvascular permeability in the rabbit trachea and to determine if the effect could be modified by cholinergic antagonism, neutral endopeptidase (NEP) inhibition, opioid receptor antagonism, or an opioid agonist. New Zealand White rabbits were anesthetized and pretreated intravenously with one of the following: saline, dimethyl sulfoxide (DMSO) (both controls), thiorphan, phosphoramidon (both NEP inhibitors), thiorphan and naloxone, morphine, or atropine. All rabbits were then given intravenous Evans blue before inhalation of nebulized DMSO (control) or FMLP. Extravascular tracheal Evans blue concentration was subsequently determined spectrophotometrically. FMLP caused a highly significant increase in microvascular permeability (92.6 +/- 7.1 micrograms/g of trachea, control 20.4' +/- 3.4). The effect of FMLP was significantly modified by cholinergic blockade (61.1 +/- 6.9) and by NEP inhibition (thiorphan 38.8 +/- 5.6, phosphoramidon 52.6 +/- 4.2). This effect of NEP inhibition could be reversed by concurrent treatment with the opioid receptor antagonist naloxone (95.9 +/- 34.6). Morphine had no significant effect. We concluded that FMLP increases microvascular permeability, which may in part explain the effect of FMLP on airway resistance in the rabbit. Inhibiting NEP decreases the response possibly through an effect on endogenous opioids. The response appears to be partially vagally mediated.
Insights
Inhaled N-formyl-methionyl-leucyl-phenylalanine (FMLP) significantly increases microvascular permeability in rabbit trachea. This effect is modulated by cholinergic blockade and neutral endopeptidase (NEP) inhibition, suggesting a role for endogenous opioids.
Area of Science:
- Pulmonary Pharmacology
- Vascular Biology
- Immunopharmacology
Background:
- N-formyl-methionyl-leucyl-phenylalanine (FMLP) is a potent chemoattractant peptide.
- FMLP's role in modulating airway microvascular permeability is not fully understood.
- Understanding FMLP's effects is crucial for respiratory disease research.
Purpose of the Study:
- To investigate the impact of inhaled FMLP on rabbit tracheal microvascular permeability.
- To explore the modulatory effects of cholinergic antagonism, neutral endopeptidase (NEP) inhibition, and opioid receptor modulation on FMLP-induced permeability.
- To elucidate the mechanisms underlying FMLP's effects on airway vasculature.
Main Methods:
- New Zealand White rabbits were used, with intravenous administration of control solutions or specific inhibitors/antagonists.
- Evans blue dye was administered intravenously, followed by nebulized FMLP or control.
- Tracheal microvascular permeability was quantified by measuring extravascular Evans blue concentration spectrophotometrically.
Main Results:
- FMLP significantly increased tracheal microvascular permeability compared to controls.
- Cholinergic blockade and NEP inhibition (thiorphan, phosphoramidon) significantly reduced the FMLP-induced increase in permeability.
- The inhibitory effect of NEP inhibition was reversed by the opioid antagonist naloxone, while morphine had no significant effect.
Conclusions:
- Inhaled FMLP increases microvascular permeability in the rabbit trachea, potentially contributing to airway resistance changes.
- NEP inhibition attenuates FMLP's effect, possibly via modulation of endogenous opioid pathways.
- The FMLP-induced increase in microvascular permeability is partially mediated by vagal pathways.