Differential blockade by tachykinin NK1 and NK2 receptor antagonists of bronchoconstriction induced by direct-acting agonists and the indirect-acting mimetics capsaicin, serotonin and 2-methyl-serotonin in the anesthetized guinea pig.
This study has examined the abilities of (+/-)-CP96345 and (+/-)-SR48968, nonpeptide antagonists selective for the tachykinin NK1 and NK2 receptors, respectively, to block bronchoconstriction caused by intravenous administration of direct-acting receptor agonists and the indirect-acting mimetics capsaicin, serotonin and 2-methyl-serotonin in the anesthetized guinea pig. The NK1 antagonist (+/-)-CP96345 was found to cause, at a maximally tolerated dose of 9 mumol/kg, an approximate 10-fold rightward shift of the dose-response curves for selective NK1 agonists substance P (SP), [Sar9,Met(O2)11]SP and Ac-[Arg6,Sar9,Met(O2)11]SP6-11 without altering responses to selective NK2 agonists neurokinin A (NKA), [Nle10]NKA4-10 or [beta-Ala8]NKA4-10. The NK2 antagonist (+/-)-SR48968 caused dose-dependent rightward shifts of the dose-response curves for the NK2 but not the NK1 agonists. Results using combinations of the receptor antagonists indicate that the NK2 agonists could cause bronchoconstriction by acting on the NK1 receptors at large doses relative to those used without antagonists. Of the agonists used here, [beta-Ala8]NKA4-10 appeared to be the most selective for the NK2 receptors. When used alone, only (+/-)-SR48968 was found to block bronchoconstriction caused by capsaicin, serotonin (after blockade of 5-HT2 receptors by LY53857) and 2-methyl-serotonin. When (+/-)-CP96345 was also given, larger additional blockade was seen with capsaicin than with serotonin or 2-methyl-serotonin as mimetic substance. Atropine caused small and variable degrees of blockade of serotonin and 2-methyl-serotonin but not of capsaicin after combinations of the two antagonists.(ABSTRACT TRUNCATED AT 250 WORDS)
Buckner
C K
CK
Department of Pharmacology, ZENECA Pharmaceuticals Group, ZENECA Inc., Wilmington, Delaware.
Liberati
N
N
Dea
D
D
Lengel
D
D
Stinson-Fisher
C
C
Campbell
J
J
Miller
S
S
Shenvi
A
A
Krell
R D
RD
D000595:Amino Acid Sequence; D000758:Anesthesia; D000818:Animals; D001549:Benzamides / Q000494:pharmacology; D001713:Biphenyl Compounds / Q000494:pharmacology; D001986:Bronchial Spasm / Q000188:drug therapy* / Q000503:physiopathology; D016084:Bronchoconstriction / Q000187:drug effects* / Q000502:physiology; D002211:Capsaicin / Q000494:pharmacology*; D006168:Guinea Pigs; D006993:Hypnotics and Sedatives / Q000494:pharmacology; D007275:Injections, Intravenous; D008297:Male; D008969:Molecular Sequence Data; D015288:Neurokinin A / Q000037:antagonists & inhibitors; D010880:Piperidines / Q000494:pharmacology; D018039:Receptors, Tachykinin / Q000037:antagonists & inhibitors* / Q000502:physiology; D012701:Serotonin / Q000031:analogs & derivatives* / Q000494:pharmacology*
D001549:Benzamides; D001713:Biphenyl Compounds; D006993:Hypnotics and Sedatives; D010880:Piperidines; D018039:Receptors, Tachykinin; D012701:Serotonin; C073839:SR 48968; C045918:2-methyl-5-HT; D015288:Neurokinin A; D002211:Capsaicin; C066892:CP 96345