Abstract
The mechanisms coupled to adenosine A1- and histamine H3-receptors have been examined in the presynaptic inhibition of acetylcholine (ACh) release from the guinea pig ileum. Electrically evoked twitch contractions were used as a measure of neuronal ACh release. A1- and H3-receptors were activated by adenosine and R-(α)-methylhistamine (RAMH), respectively. The neuroinhibitory effect of adenosine and RAMH was augmented in the presence of the N-type Ca2+channel blocker, ω-conotoxin GVIA but unaffected by the L-type Ca2+ channel blocker, nifedipine. The irreversible adenylyl cyclase inhibitor, MDL-12330A, potentiated the action of both adenosine and RAMH. Conversely, neither agonist was affected by the cAMP phosphodiesterase III and IV inhibitors, SKF-95654 and Ro-20-1724, respectively, or the cAMP antagonist, (Rp)-adenosine 3′,5′-cyclic monophosphorothioate triethylamine. The neuromodulatory effect of adenosine, only, was potentiated by the cGMP phosphodiesterase V inhibitors, SKF-96231 and 1,3-dimethyl-6-(2-propoxy-5-methanesulfonylamidophenyl)- pyrazolo[3,4-d]pyrimidin-4-(5H)-one but was unmodified by the cGMP analog, 8-bromo-cGMP or the guanylyl cyclase inhibitors, N-methylhydroxylamine and 1H-[1,2,4]oxadiazolo[4,3-a]quinoxaline-1-one (ODQ). N-Methylhydroxylamine reduced, and ODQ potentiated, the inhibitory action of H3-receptor activation, but 8-bromo-cGMP was without effect. The study suggests that presynaptic A1- and H3-receptors inhibit cholinergic neurotransmission in the guinea pig ileum by limiting the availability of intraneuronal Ca2+ via inhibition of N-type Ca2+ channels. The balance of evidence does not support the involvement of the adenylyl cyclase/cAMP or guanylyl cyclase/cGMP systems.
Footnotes
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Send reprint requests to: Prof. M. E. Parsons, Biosciences Division, University of Hertfordshire, College Lane, Hatfield, Hertfordshire AL10 9AB, UK. E-mail:M.E.Parsons{at}herts.ac.uk
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↵1 Current address: Department of Neuroinflammation, Imperial College School of Medicine, Charing Cross Hospital, Fulham Palace Road, London W6 8RF, UK.
- Abbreviations:
- ACh
- acetylcholine
- AC
- adenylyl cyclase
- 8-Br-cGMP
- 8-bromo-cGMP
- 2-CA
- 2-chloroadenosine
- CTX
- ω-conotoxin GVIA
- DMPPO
- 1,3-dimethyl-6-(2-propoxy-5-methanesulfonylamidophenyl)pyrazolo[3,4-d]pyrimidin-4-(5H)-one
- DPCPX
- 1,3-dipropyl-8-cyclopentylxanthine
- GC
- guanylyl cyclase
- NMHA
- N-methylhydroxylamine
- ODQ
- 1H-[1,2,4]oxadiazolo[4,3-a]quinoxaline-1-one
- PDE
- phosphodiesterase
- RAMH
- R-(α)-methylhistamine
- (Rp)-cAMPS
- (Rp)-adenosine 3′,5′-cyclic monophosphorothioate triethylamine
- Received February 2, 2000.
- Accepted July 3, 2000.
- The American Society for Pharmacology and Experimental Therapeutics
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