NK1 receptors mediate neurogenic inflammatory increase in blood flow in rat airways.
We studied the effect of neurogenic inflammation on airway blood flow in anesthetized F-344 rats. Three successive determinations of blood flow were made by injecting radionuclide-labeled microspheres suspended in 70% dextrose into the left ventricle. A selective agonist of the tachykinin receptor neurokinin 1 (NK1) increased airway blood flow, but NK2- and NK3-selective agonists were without effect. The natural agonist of NK1 receptors, substance P (1 micrograms/kg), increased airway blood flow, an effect that was abolished by the selective NK1 receptor antagonist CP-99,994 [(+)-(2S,3S)-3-(2-methoxybenzylamino)-2-phenylpiperidine] but not by the (2R,3R)-enantiomer CP-100,263. Capsaicin (25 micrograms/kg), a drug that releases tachykinins and calcitonin gene-related peptide from sensory nerves, increased airway blood flow, and again this effect was abolished by CP-99,994. We also studied the effect of a selective inhibitor (captopril, 2.5 mg/kg) of the tachykinin-degrading enzyme kininase II [or angiotensin-converting enzyme (ACE)] on substance P-induced airway vasodilation. Captopril potentiated and prolonged the vasodilator effect of substance P. We conclude that neurogenic vasodilation in rat airways is due to the release of substance P, acts via NK1 receptors, and may be modulated by ACE.
Piedimonte
G
G
Cardiovascular Research Institute, University of California, San Francisco 94143.
Hoffman
J I
JI
Husseini
W K
WK
Snider
R M
RM
Desai
M C
MC
Nadel
J A
JA
D000818:Animals; D002211:Capsaicin / Q000494:pharmacology; D007249:Inflammation / Q000503:physiopathology*; D008297:Male; D008863:Microspheres; D009475:Neurons, Afferent / Q000187:drug effects / Q000378:metabolism; D007703:Peptidyl-Dipeptidase A / Q000378:metabolism; D010880:Piperidines / Q000494:pharmacology; D051381:Rats; D011916:Rats, Inbred F344; D018041:Receptors, Neurokinin-2; D017981:Receptors, Neurotransmitter / Q000037:antagonists & inhibitors / Q000502:physiology*; D012039:Regional Blood Flow / Q000502:physiology; D012137:Respiratory System / Q000098:blood supply*; D012140:Respiratory Tract Diseases / Q000503:physiopathology*; D013373:Substance P / Q000378:metabolism / Q000494:pharmacology; D015320:Tachykinins / Q000378:metabolism / Q000494:pharmacology; D014664:Vasodilation / Q000187:drug effects
D010880:Piperidines; D018041:Receptors, Neurokinin-2; D017981:Receptors, Neurotransmitter; D015320:Tachykinins; C080755:3-(2-methoxybenzylamino)-2-phenylpiperidine; D013373:Substance P; D007703:Peptidyl-Dipeptidase A; D002211:Capsaicin