Effect of synthetic tachykinin analogues on airway microvascular leakage in rats and guinea-pigs: evidence for the involvement of NK-1 receptors.
1. The NK-1 selective agonists [beta-Ala4, Sar9]SP-(4-11) sulphone and [pGlu6, Pro9]SP-(6-11) dose-dependently increased vascular permeability in various segments of rat and guinea-pig tracheo-bronchial region, while the NK-2 ([Nle10]NKA-(4-10) and [beta-Ala8]NKA-(4-10)) or NK-3 ([MePhe7]NKB and [MePhe7]NKB-(4-10)) selective agonists were inactive. These findings provide evidence that the inflammatory response of the airway to intravenous tachykinins is exclusively mediated by the NK-1 receptor subtype. 2. Plasma protein extravasation induced by capsaicin was more intense in the caudal segments of the rat airways and paralleled the tissue concentration of substance P-like and calcitonin gene-related peptide-like immunoreactivity. The response to capsaicin was greatly reduced in rats pretreated with high dose of the toxin (655 mumol kg-1 s.c., 3 weeks before) and was smallest in the airway regions where the depletion of neuropeptides had been more severe. 3. The depletion of transmitters from capsaicin-sensitive nerves did not affect the inflammatory response of the airway to serotonin (500 nmol kg-1 i.v.), while increased responsiveness to a threshold dose (0.37 nmol kg-1 i.v.) of [beta-Ala4, Sar9]SP-(4-11) sulphone was observed. This finding gives preliminary evidence that, after depletion of transmitters from capsaicin-sensitive nerves, upregulation of NK-1 receptors may develop in rat trachea.
Pharmacology Department, Menarini Richerche Sud, Pomexia, Roma, Italy.
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Abelli
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Maggi
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Del Bianco
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Drapeau
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Giachetti
D000818:Animals; D001798:Blood Proteins / Q000378:metabolism; D015740:Calcitonin Gene-Related Peptide / Q000378:metabolism / Q000494:pharmacology; D002199:Capillary Permeability / Q000187:drug effects; D002211:Capsaicin / Q000494:pharmacology; D006168:Guinea Pigs; D007249:Inflammation / Q000378:metabolism; D008297:Male; D008833:Microcirculation / Q000378:metabolism*; D009479:Neuropeptides / Q000378:metabolism; D018377:Neurotransmitter Agents / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D018041:Receptors, Neurokinin-2; D017981:Receptors, Neurotransmitter / Q000378:metabolism*; D012137:Respiratory System / Q000098:blood supply / Q000378:metabolism*; D012701:Serotonin / Q000494:pharmacology; D015320:Tachykinins / Q000494:pharmacology*
D001798:Blood Proteins; D009479:Neuropeptides; D018377:Neurotransmitter Agents; D018041:Receptors, Neurokinin-2; D017981:Receptors, Neurotransmitter; D015320:Tachykinins; D012701:Serotonin; D015740:Calcitonin Gene-Related Peptide; D002211:Capsaicin