A new NK1 receptor antagonist (CP-99,994) prevents the increase in tracheal vascular permeability produced by hypertonic saline.
The increase in tracheal vascular permeability evoked by hypertonic saline depends on capsaicin-sensitive sensory nerves, which contain substance P and other neuropeptides. The present study was performed to determine whether a novel, nonpeptide, selective antagonist of the NK1 tachykinin receptor CP-99,994, [(+)-(2S-3S)-3-(2-methoxybenzylamino)-2-phenylpiperidine], can prevent the effect of substance P, capsaicin and hypertonic saline on tracheal vascular permeability. CP-99,994 was also tested against a nonpeptide inflammatory mediator, platelet-activating factor (PAF), to assess the selectivity of its action. Anesthetized F-344 rats were injected with either substance P (5 micrograms/kg i.v.), capsaicin (100 micrograms/kg i.v.) or PAF (10 micrograms/kg i.v.), or were exposed to ultrasonically nebulized 3.6% NaCl. In each group, some of the rats were pretreated with CP-99,994 (1 to 4 mg/kg i.v.), and some with its vehicle (0.9% NaCl). Groups of rats injected with substance P or exposed to hypertonic saline were pretreated with the (2R, 3R)-enantiomer CP-100,263, [(-)-(2R-3R)-3-(2-methoxybenzylamino)-2-phenylpiperidine] (2 or 4 mg/kg i.v.). The magnitude of the increase in tracheal vascular permeability was measured by quantifying the extravasation of Evans blue dye. CP-99,994 prevented the increase in tracheal vascular permeability produced by inhalation of hypertonic saline, by substance P and by capsaicin, but did not prevent the effect of PAF. CP-100,263 did not affect substance P- and hypertonic saline-induced increase in vascular permeability. These results indicate that the NK1 receptor antagonist CP-99,994 produces stereoselective inhibition of neurogenic plasma extravasation evoked by inhalation of hypertonic saline.
Piedimonte
G
G
Cardiovascular Research Institute, University of California, San Francisco.
Bertrand
C
C
Geppetti
P
P
Snider
R M
RM
Desai
M C
MC
Nadel
J A
JA
D000818:Animals; D002199:Capillary Permeability / Q000187:drug effects*; D002211:Capsaicin / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004487:Edema / Q000517:prevention & control*; D005070:Evans Blue / Q000493:pharmacokinetics; D005119:Extravasation of Diagnostic and Therapeutic Materials; D006982:Hypertonic Solutions; D015288:Neurokinin A / Q000037:antagonists & inhibitors; D009475:Neurons, Afferent / Q000187:drug effects / Q000502:physiology; D010880:Piperidines / Q000494:pharmacology*; D010972:Platelet Activating Factor / Q000494:pharmacology; D051381:Rats; D011916:Rats, Inbred F344; D017981:Receptors, Neurotransmitter / Q000037:antagonists & inhibitors* / Q000502:physiology; D018039:Receptors, Tachykinin; D012965:Sodium Chloride / Q000494:pharmacology*; D013268:Stimulation, Chemical; D013373:Substance P / Q000494:pharmacology; D014132:Trachea / Q000098:blood supply* / Q000187:drug effects / Q000294:innervation; D014133:Tracheal Diseases / Q000517:prevention & control*
D006982:Hypertonic Solutions; D010880:Piperidines; D010972:Platelet Activating Factor; D017981:Receptors, Neurotransmitter; D018039:Receptors, Tachykinin; C080755:3-(2-methoxybenzylamino)-2-phenylpiperidine; D013373:Substance P; D012965:Sodium Chloride; D005070:Evans Blue; D015288:Neurokinin A; D002211:Capsaicin