Signaling mechanisms coupled to presynaptic A(1)- and H(3)-receptors in the inhibition of cholinergic contractile responses of the guinea pig ileum.
The mechanisms coupled to adenosine A(1)- and histamine H(3)-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. A(1)- and H(3)-receptors were activated by adenosine and R-(alpha)-methylhistamine (RAMH), respectively. The neuroinhibitory effect of adenosine and RAMH was augmented in the presence of the N-type Ca(2+) channel blocker, omega-conotoxin GVIA but unaffected by the L-type Ca(2+) 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, (R(p))-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 H(3)-receptor activation, but 8-bromo-cGMP was without effect. The study suggests that presynaptic A(1)- and H(3)-receptors inhibit cholinergic neurotransmission in the guinea pig ileum by limiting the availability of intraneuronal Ca(2+) via inhibition of N-type Ca(2+) channels. The balance of evidence does not support the involvement of the adenylyl cyclase/cAMP or guanylyl cyclase/cGMP systems.
Lee
J J
JJ
Biosciences Department, University of Hertfordshire, Hatfield, Hertfordshire, United Kingdom.
Parsons
M E
ME
D000109:Acetylcholine / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000241:Adenosine / Q000494:pharmacology; D000818:Animals; D002121:Calcium Channel Blockers / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism / Q000502:physiology; D006152:Cyclic GMP / Q000378:metabolism / Q000502:physiology; D004558:Electric Stimulation; D005260:Female; D006168:Guinea Pigs; D017442:Histamine Agonists / Q000494:pharmacology; D007082:Ileum / Q000187:drug effects / Q000294:innervation / Q000502:physiology; D008297:Male; D008762:Methylhistidines / Q000494:pharmacology; D009119:Muscle Contraction / Q000187:drug effects / Q000502:physiology*; D009130:Muscle, Smooth / Q000187:drug effects / Q000294:innervation / Q000502:physiology*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D018100:Receptors, Histamine H3 / Q000502:physiology*; D018047:Receptors, Purinergic P1 / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D009435:Synaptic Transmission / Q000502:physiology
D002121:Calcium Channel Blockers; D017442:Histamine Agonists; D008762:Methylhistidines; D018100:Receptors, Histamine H3; D018047:Receptors, Purinergic P1; D000242:Cyclic AMP; D006152:Cyclic GMP; D000241:Adenosine; D000109:Acetylcholine