Capsaicin increases airflow resistance in guinea pigs in vivo by activating both NK2 and NK1 tachykinin receptors.
The role of NK1 tachykinin receptors in the increase in total pulmonary resistance (RL) produced by release of endogenous tachykinins was investigated in anesthetized guinea pigs pretreated intravenously with atropine (1 mumol/kg) by using the novel nonpeptide antagonists of NK1 (CP-96,345) and NK2 (SR 48968) tachykinin receptors. SR 48968 (0.3 mumol/kg) and CP-96,345 (2 mumol/kg) given intravenously completely blocked the response to the selective NK2 receptor agonist [beta Ala8]neurokinin A(4-10) and NK1 receptor agonist [Sar9,Met(O2)11]substance P, respectively. The response to neurokinin A was reduced dose-dependently, but not abolished, by SR 48968, and it was completely prevented by a combination of SR 48968 and CP-96,345. The response to capsaicin was reduced, but not blocked, by SR 48968, and it was completely abolished by the combination of the two antagonists. The combination of SR 48968 and CP-96,345 did not affect the increase in RL evoked by histamine. Thus, NK1, as well as NK2, receptor activation contributes to the noncholinergic increase in RL evoked by capsaicin and ascribed to release of endogenous tachykinins from sensory nerves.
Bertrand
C
C
Cardiovascular Research Institute, University of California at San Francisco 94143-0130.
Nadel
J A
JA
Graf
P D
PD
Geppetti
P
P
D000403:Airway Resistance / Q000187:drug effects* / Q000502:physiology; D000818:Animals; D001285:Atropine / Q000494:pharmacology; D001549:Benzamides / Q000494:pharmacology; D001713:Biphenyl Compounds / Q000494:pharmacology; D002211:Capsaicin / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D006168:Guinea Pigs; D006632:Histamine / Q000494:pharmacology; D008297:Male; D015288:Neurokinin A / Q000037:antagonists & inhibitors / Q000494:pharmacology; D010446:Peptide Fragments / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D018040:Receptors, Neurokinin-1 / Q000187:drug effects* / Q000502:physiology; D018041:Receptors, Neurokinin-2 / Q000187:drug effects* / Q000502:physiology; D013373:Substance P / Q000031:analogs & derivatives / Q000494:pharmacology
D001549:Benzamides; D001713:Biphenyl Compounds; D010446:Peptide Fragments; D010880:Piperidines; D018040:Receptors, Neurokinin-1; D018041:Receptors, Neurokinin-2; C062618:substance P, Sar(9)-Met(O2)(11)-; D013373:Substance P; C073839:SR 48968; D001285:Atropine; D006632:Histamine; D015288:Neurokinin A; C056408:neurokinin A(4-10); D002211:Capsaicin; C066892:CP 96345