Adenosine A1 receptors mediate inhibition of tachykinin release from perifused enteric nerve endings.
A perifused preparation of guinea pig myenteric nerve varicosities (synaptosomes) was used to determine the characteristics of evoked tachykinin release and the inhibition of such release by adenosine analogues. Release of substance P-like immunoreactivity (SP-LI) and neurokinin A-like immunoreactivity (NKA-LI) was evoked by elevated extracellular [K+] in a reversible and repeatable manner. This release was completely abolished in the absence of extracellular Ca2+. Perifusion in the presence of 5'-N-ethylcarboxamidoadenosine (NECA), a nonselective A1/A2 adenosine receptor agonist, decreased K(+)-evoked release of SP-LI and NKA-LI compared with that in the absence of the nucleoside. Similar decrements in peptide release were obtained with N6-cyclopentyl adenosine (CPA), a selective A1 agonist, and 2-[p-(2-carboxyethyl)]phenethylamino-5'-N-ethyl-carboxamidoadenosi ne (CGS 21680), a selective A2 agonist. Response to all nucleosides was graded. Potency order of adenosine analogues was CPA greater than NECA much greater than CGS 21680. Inhibition due to the nucleosides was diminished in the presence of the highly selective A1-receptor antagonist 1,3-dipropyl-8-cyclopentylxanthine (DPCPX) while perifusion in the presence of DPCPX alone did not alter evoked release of either peptide. These findings provide direct measurements of inhibitory effects of adenine nucleosides on the release, from enteric nerve endings, of endogenous neuromediators SP and NKA. The findings also directly demonstrate the presence of functional adenosine receptors of the A1 subtype on enteric nerve endings coupled negatively to release of tachykinins. The presence of A2 receptors on enteric nerve endings is neither supported nor excluded.
Department of Pharmacology, University of Western Ontario, London, Canada.
R M
RM
Broad
T J
TJ
McDonald
E
E
Brodin
M A
MA
Cook
D000241:Adenosine / Q000031:analogs & derivatives / Q000494:pharmacology; D019830:Adenosine-5'-(N-ethylcarboxamide); D000818:Animals; D004246:Dimethylphenylpiperazinium Iodide / Q000494:pharmacology; D005260:Female; D006168:Guinea Pigs; D066298:In Vitro Techniques; D007421:Intestine, Small / Q000294:innervation; D008297:Male; D009130:Muscle, Smooth / Q000294:innervation; D009197:Myenteric Plexus / Q000187:drug effects / Q000378:metabolism*; D015288:Neurokinin A / Q000378:metabolism*; D010627:Phenethylamines / Q000494:pharmacology; D011188:Potassium / Q000494:pharmacology; D011983:Receptors, Purinergic / Q000187:drug effects / Q000378:metabolism*; D013329:Structure-Activity Relationship; D013373:Substance P / Q000378:metabolism*; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism*; D014701:Veratridine / Q000494:pharmacology
D010627:Phenethylamines; D011983:Receptors, Purinergic; C061282:2-(4-(2-carboxyethyl)phenethylamino)-5'-N-ethylcarboxamidoadenosine; D013373:Substance P; D019830:Adenosine-5'-(N-ethylcarboxamide); C048599:N(6)-cyclopentyladenosine; D004246:Dimethylphenylpiperazinium Iodide; D014701:Veratridine; D015288:Neurokinin A; D000241:Adenosine; D011188:Potassium