A further analysis of the contraction induced by activation of cholecystokinin A receptors in guinea pig isolated ileum longitudinal muscle-myenteric plexus.
The activity of a selective cholecystokinin (CCK)-A receptor agonist, N-acetyl derivative of A71623 (Ac-Trp-Lys(epsilon-N-[2-methylphenylamino-carbonyl]) -Asp-(NMe)Phe-NH2) was investigated in the guinea pig isolated ileum longitudinal muscle myenteric plexus. NAA caused both a phasic and tonic contraction at all concentrations tested (1-1000 nM). The selective CCK-A antagonist L-364,718 (Devazepide) antagonized both types of contraction with a pKB of 10.10 and 9.95, respectively. The CCK-B selective antagonist L-365,260 ((3R(+)-2,3-dihydro-1-methyl-2-oxo-5-phenyl-1H-1, 4-benzodiazepine-3yl)-N-(3-methylphenyl)-urea) was inactive up to a concentration of 30 nM. Atropine at 300 nM and 1000 nM reduced the maximal response of NAA by only 17% and 50%, respectively. The selective neurokinin (NK)-1 antagonists GR 82334 ([D-pro9[Spiro-gamma-Lactam] Leu10, Trp11]-Phys (1-11)9) at 300 and 1000 nM and (+-) CP-96,345 [(2S, 3S)-cis- 2-(diphenylmethyl)-N- [(2-methoxyphenyl)-methyl] -1-azabici-clo [2.2.2]octan-3-amine] at 10 nM were inactive or partially active. When atropine and GR 82334 or (+/-) CP-96,345 were combined, they produced a dose-dependent synergistic inhibition of both phasic and tonic contractions induced by NAA. The selective NK-3 receptor agonist senktide induced both phasic and tonic contractions that were blocked by tetrodotoxin. In the presence of atropine and GR 82334, both 300 nM, a synergistic depression of the response to senktide similar to that observed for the agonist NAA was disclosed.(ABSTRACT TRUNCATED AT 250 WORDS)
Corsi
M
M
Glaxo Research Laboratories, Verona, Italy.
Palea
S
S
Pietra
C
C
Oliosi
B
B
Gaviraghi
G
G
Sugg
E
E
Van Amsterdam
F T
FT
Trist
D G
DG
D000818:Animals; D001285:Atropine / Q000494:pharmacology; D001713:Biphenyl Compounds / Q000494:pharmacology; D004347:Drug Interactions; D006168:Guinea Pigs; D007082:Ileum / Q000502:physiology*; D066298:In Vitro Techniques; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects* / Q000502:physiology; D009197:Myenteric Plexus / Q000502:physiology*; D009469:Neuromuscular Junction / Q000187:drug effects; D010446:Peptide Fragments / Q000494:pharmacology; D010456:Peptides, Cyclic / Q000494:pharmacology; D010803:Physalaemin / Q000031:analogs & derivatives / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D043886:Receptor, Cholecystokinin A; D011949:Receptors, Cholecystokinin / Q000187:drug effects* / Q000502:physiology; D013373:Substance P / Q000031:analogs & derivatives / Q000494:pharmacology; D013758:Tetragastrin / Q000031:analogs & derivatives* / Q000494:pharmacology; D013779:Tetrodotoxin / Q000494:pharmacology
D001713:Biphenyl Compounds; D010446:Peptide Fragments; D010456:Peptides, Cyclic; D043886:Receptor, Cholecystokinin A; D011949:Receptors, Cholecystokinin; D013758:Tetragastrin; C054724:senktide; C073362:L 659837; C079014:GR 82334; C089128:N-acetyltryptophyl-(epsilon-N-(2-methylphenylaminocarbonyl))lysyl-aspartyl-(N-methyl)phenylalaninamide; D010803:Physalaemin; D013373:Substance P; D013779:Tetrodotoxin; D001285:Atropine; C066892:CP 96345