Characterization of tachykinin receptors mediating bronchomotor and vasodepressor responses to neuropeptide gamma and substance P in the anaesthetized rabbit.
The effects of i.v. injections of two endogenous tachykinins, substance P (SP) and neuropeptide gamma and the highly selective tachykinin agonists [Sar9,Met(O2)11]-SP, [Lys5,MeLeu9, Nle10]-NKA(4-10) and senktide, on total lung resistance (RL), dynamic lung compliance (Cdyn) and systemic blood pressure, were compared in the anaesthetized rabbit. Senktide, the NK-3 receptor selective agonist, had no effect on RL, Cdyn or blood pressure. The other four agonists caused dose-dependent increases in RL and Cdyn, with [Sar9,Met(O2)11]-SP being the most potent agonist in producing changes in the absence of phosphoramidon. This suggested that NK-1 receptors play an important role in these responses. [Sar9, Met(O2)11]-SP, SP and neuropeptide gamma also decreased blood pressure. Phosphoramidon (1 mg/kg) potentiated the changes in RL and Cdyn evoked by [Sar9,Met(O2)11]-SP and SP, with very marked enhancement of responses to neuropeptide gamma. Responses to [Lys5, MeLeu9,Nle10]-NKA(4-10) were unaffected, suggesting that this NK-2 selective agonist may not be catabolized by neutral endopeptidase (NEP). In the presence of phosphoramidon, the non-peptide tachykinin NK-1 receptor selective antagonist CP 96345 (80 nmol/kg) reduced all responses to [Sar9,Met(O2)11]-SP and SP, whereas the NK-2 selective antagonist SR 48968 (40 nmol/kg) inhibited the bronchomotor but not the vasodepressor responses to neuropeptide gamma and [Lys5,MeLeu9, Nle10]-NKA(4-10). The fall in blood pressure induced by neuropeptide gamma was diminished by CP 96345, whereas bronchoconstriction was unaffected, indicating possible differences in NK-1 receptors in the vasculature and airways. Electrical stimulation of the distal ends of vagus nerves caused increases in RL which were abolished by atropine (1 mg/kg).
Yuan
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School of Physiology and Pharmacology, University of New South Wales, Sydney, NSW 2052, Australia.
Burcher
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Nail
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D000758:Anesthesia; D000818:Animals; D001549:Benzamides / Q000494:pharmacology; D001713:Biphenyl Compounds / Q000494:pharmacology; D016084:Bronchoconstriction / Q000187:drug effects; D004347:Drug Interactions; D006020:Glycopeptides / Q000494:pharmacology*; D015260:Neprilysin / Q000037:antagonists & inhibitors; D064729:Neurokinin-1 Receptor Antagonists; D010446:Peptide Fragments / Q000494:pharmacology / Q000502:physiology*; D010880:Piperidines / Q000494:pharmacology; D011480:Protease Inhibitors / Q000494:pharmacology*; D011817:Rabbits; D018040:Receptors, Neurokinin-1 / Q000819:agonists*; D018041:Receptors, Neurokinin-2 / Q000819:agonists* / Q000037:antagonists & inhibitors; D013373:Substance P / Q000494:pharmacology / Q000502:physiology*; D015320:Tachykinins / Q000494:pharmacology / Q000502:physiology*; D014630:Vagus Nerve / Q000187:drug effects / Q000502:physiology; D014661:Vasoconstriction / Q000187:drug effects
D001549:Benzamides; D001713:Biphenyl Compounds; D006020:Glycopeptides; D064729:Neurokinin-1 Receptor Antagonists; D010446:Peptide Fragments; D010880:Piperidines; D011480:Protease Inhibitors; D018040:Receptors, Neurokinin-1; D018041:Receptors, Neurokinin-2; D015320:Tachykinins; C059905:tachykinin neuropeptide gamma; D013373:Substance P; C073839:SR 48968; D015260:Neprilysin; C008890:phosphoramidon; C066892:CP 96345