Adenosine and 5-HT inhibit substance P release from nerve endings in myenteric ganglia by distinct mechanisms.
Release of substance P-like immunoreactivity (SP-LI) from dissociated enteric ganglia and the receptor-mediated prejunctional inhibition of this release were investigated with the use of a perifusion technique. SP-LI release was evoked by elevated extracellular K+ concentration and was inhibited, in a graded manner, by N6-cyclopentyl adenosine (CPA), an adenosine analogue with selectivity for adenosine A1 receptors. Similar inhibition of SP-LI release was obtained with 5-hydroxytryptamine (5-HT); incrementing concentrations, however, yielded a biphasic concentration-response relationship. The selective adenosine A1 receptor antagonist 1,3-dipropyl-8-cyclopentyl-xanthine abolished the inhibition due to CPA, whereas the inhibitory action of 5-HT was sensitive to the 5-HT1A-selective antagonist 1-(2-methoxyphenyl)-4-[4-(2-phthalimido)butyl]-piperazine hydrobromide. Inhibition due to both agonists was insensitive to blockade by tetrodotoxin, suggesting a prejunctional locus for both adenosine and 5-HT1A receptors on the tachykininergic nerve endings. Pretreatment of ganglia with pertussis toxin had no effect on CPA-mediated inhibition of SP-LI release, whereas 5-HT-mediated inhibition was abolished. The findings demonstrate that adenosine and 5-HT receptors on enteric nerve endings are coupled to inhibition of tachykinin release through distinct mechanisms, putatively distinct G proteins.
Broad
R M
RM
Department of Pharmacology and Toxicology, University of Western Ontario, London, Canada.
McDonald
T J
TJ
Cook
M A
MA
D000241:Adenosine / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D005260:Female; D005724:Ganglia / Q000378:metabolism* / Q000502:physiology; D006168:Guinea Pigs; D008297:Male; D009197:Myenteric Plexus / Q000502:physiology*; D009411:Nerve Endings / Q000378:metabolism* / Q000502:physiology; D010477:Perfusion; D037342:Pertussis Toxin; D011863:Radioimmunoassay; D011983:Receptors, Purinergic / Q000378:metabolism / Q000502:physiology; D011985:Receptors, Serotonin / Q000378:metabolism / Q000502:physiology; D012701:Serotonin / Q000378:metabolism / Q000494:pharmacology*; D013373:Substance P / Q000378:metabolism*; D010566:Virulence Factors, Bordetella / Q000494:pharmacology
D011983:Receptors, Purinergic; D011985:Receptors, Serotonin; D010566:Virulence Factors, Bordetella; D012701:Serotonin; D013373:Substance P; C048599:N(6)-cyclopentyladenosine; D037342:Pertussis Toxin; D000241:Adenosine