Evidence that the presynaptic A2a-adenosine receptor of the rat motor nerve endings is positively coupled to adenylate cyclase.
The action of the A2a-adenosine analogue, CGS 21680C, on electrically evoked [3H]acetylcholine ([3H]-ACh) release, and its interaction with forskolin (an activator of adenylate cyclase), MDL 12,330A (an irreversible inhibitor of adenylate cyclase), rolipram (an inhibitor of cyclic AMP specific phosphodiesterase), dibutyryl- (db-cAMP) and 8-bromo- (8-Br-cAMP) cyclic AMP analogues (substances that mimic intracellular actions of cyclic AMP), were investigated using rat phrenic nerve-hemidiaphragm preparations. CGS 21680C facilitated [3H]-ACh release. Forskolin (but not 1,9-dideoxy forskolin), rolipram, db-cAMP and 8-Br-cAMP also increased evoked neurotransmitter release in a concentration-dependent manner. When the evoked [3H]-ACh release that is dependent on stimulation of the adenylate cyclase/cyclic AMP transduction system was supramaximally stimulated by these compounds, CGS 21680C (3 nmol/l) could not further increase [3H]-ACh release. Phosphodiesterase inhibition with low concentrations (< or = 30 mumol/l) of rolipram significantly potentiated the augmenting effect of CGS 21680C (1 nmol/l) on evoked [3H]-ACh release. MDL 12,330A (an irreversible inhibitor of adenylate cyclase) decreased evoked [3H]-ACh release. The irreversible blocking action of MDL 12,330A on [3H]-ACh release was overcome by by-passing cyclase activation with db-cAMP and 8-Br-cAMP, but could not be overcome with FSK or CGS 21680C. The inhibitory effect of MDL 12,330A on evoked [3H]-ACh release was not mimicked by nifedipine. It is concluded that the increase in [3H]-ACh release caused by CGS 21680C results from activation of an A2a-adenosine receptor positively linked to the adenylate cyclase/cyclic AMP system.
Correia-de-Sá
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P
Laboratory of Pharmacology, ICBAS, University of Oporto, Portugal.
Ribeiro
J A
JA
D000109:Acetylcholine / Q000378:metabolism*; D000241:Adenosine / Q000031:analogs & derivatives / Q000494:pharmacology; D000067956:Adenylyl Cyclase Inhibitors; D000262:Adenylyl Cyclases / Q000378:metabolism*; D000818:Animals; D005576:Colforsin / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004558:Electric Stimulation; D005260:Female; D007097:Imines / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D010627:Phenethylamines / Q000494:pharmacology; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D010791:Phrenic Nerve / Q000378:metabolism; D058906:Purinergic P1 Receptor Agonists; D011760:Pyrrolidinones / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D018047:Receptors, Purinergic P1 / Q000378:metabolism*; D020889:Rolipram
D000067956:Adenylyl Cyclase Inhibitors; D007097:Imines; D010627:Phenethylamines; D010726:Phosphodiesterase Inhibitors; D058906:Purinergic P1 Receptor Agonists; D011760:Pyrrolidinones; D018047:Receptors, Purinergic P1; C061282:2-(4-(2-carboxyethyl)phenethylamino)-5'-N-ethylcarboxamidoadenosine; D005576:Colforsin; C014925:RMI 12330A; D000262:Adenylyl Cyclases; D020889:Rolipram; D000241:Adenosine; D000109:Acetylcholine