NK1 and NK2 receptors mediate tachykinin and resiniferatoxin-induced bronchospasm in guinea pigs.
The present study characterized neurokinin receptor-mediated bronchoconstrictor responses in anesthetized guinea pigs. Thus, we have compared the actions of the selective neurokinin 1 (NK1) (CP-99,994) and neurokinin 2 (NK2) (SR-48,968) receptor antagonists against dose-response curves (DRC) induced by intravenously administered substance P (SP), neurokinin A (NKA), neurokinin B (NKB), beta Ala8-NKA (4-10),Sar9-Met(O2)11SP, and single dose (intravenous) challenge with resiniferatoxin (RTX), a capsaicin-like sensory neurotoxin, leukotriene D4 (LTD4) and antigen. The rank order of potency of the neurokinins for inducing bronchoconstriction was beta Ala8-NKA(4-10) > NKA > Sar9-Met(O2)11Sp > SP >> NKB. The DRC to the selective NK1 agonist Sar9-Met(O2)11SP was shifted to the right 10-fold by the selective NK1 antagonist, CP-99,994 (1 mg/kg, intravenously), but was not shifted by SR-48,968 (3 mg/kg, intravenously). The DRC to the selective NK2 agonist beta-Ala8-NKA(4-10) was shifted to the right 82-fold by the NK2 antagonist, SR-48,968 (1 mg/kg), but was not shifted by CP-99,994 (3 mg/kg, intravenously). SR-48,968 (1 mg/kg) also blocked NKA (3-fold shift) but did not block SP. CP-99,994 failed to produce a significant rightward shift of the DRC to either SP or NKA. However, the combination of 1 mg/kg CP-99,994 and 1 mg/kg SR-48,968 produced significant shifts of the DRCs to SP (> 5-fold) and NKA (> 300-fold). Hypotension induced by NKA and SP was also blocked by this combination.(ABSTRACT TRUNCATED AT 250 WORDS)
Foulon
D M
DM
Merck Frosst Centre for Therapeutic Research, Pointe Claire-Dorval, Québec, Canada.
Champion
E
E
Masson
P
P
Rodger
I W
IW
Jones
T R
TR
D000818:Animals; D001549:Benzamides / Q000494:pharmacology; D001986:Bronchial Spasm / Q000139:chemically induced* / Q000503:physiopathology; D016084:Bronchoconstriction / Q000187:drug effects / Q000502:physiology; D004224:Diterpenes / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D006168:Guinea Pigs; 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; D015320:Tachykinins / Q000494:pharmacology*
D001549:Benzamides; D004224:Diterpenes; D010446:Peptide Fragments; D010880:Piperidines; D018040:Receptors, Neurokinin-1; D018041:Receptors, Neurokinin-2; D015320:Tachykinins; C062618:substance P, Sar(9)-Met(O2)(11)-; C080755:3-(2-methoxybenzylamino)-2-phenylpiperidine; D013373:Substance P; C073839:SR 48968; D015288:Neurokinin A; C056408:neurokinin A(4-10); C024353:resiniferatoxin