Characterization of 5-hydroxytryptamine-induced depolarizations in rat isolated vagus nerve.
An additional component of the depolarization induced by 5-hydroxytryptamine (5-HT) in the rat isolated vagus nerve has recently been attributed to activation of 5-HT4 receptors. To confirm and extend this finding, extracellular recordings of D.C. potentials were made using the 'grease-gap' technique during continuous superfusion of the isolated nerve. Beginning at 1 nM, 5-HT induced small depolarizations that displayed a slow onset. At concentrations > or = 1 microM, large depolarizations with rapid onset were elicited. In the presence of the 5-HT3 receptor antagonists, granisetron or ondansetron, 5-HT responses were diminished and exhibited an increased latency to peak. These small, slow depolarization were not reduced by 5-HT1 or 5-HT2 receptor antagonists, but were potently inhibited by the 5-HT4 receptor antagonist GR 113808 (pA2 = 9.3), and mimicked by 5-methoxytryptamine (pEC50 = 5.3). 5-HT4-mediated responses were larger at 37 degrees C than at 31 degrees C, but also showed marked diminution with repeated 5-HT applications at concentrations greater than 1 microM. Conversely, 5-HT3 receptor responses were potentiated at lower temperatures (< or = 31 degrees C). Consistent with the reported positive coupling of 5-HT4 receptors to adenylyl cyclase, forskolin and 8-Br-cAMP produced slowly developing depolarizations which were qualitatively similar to 5-HT4 receptor activation. Pre-depolarization of nerves with 10 microM forskolin or 300 microM 8-Br-cAMP diminished the effect of 5-HT4 receptors. This study has confirmed the presence of 5-HT4 receptors on the vagus nerve of the rat and defined some conditions that optimize their pharmacological isolation.(ABSTRACT TRUNCATED AT 250 WORDS)
Bley
K R
KR
Department of Neurosciences, Institute of Pharmacology, Syntex Discovery Research, Palo Alto, CA 94305.
Eglen
R M
RM
Wong
E H
EH
D008735:5-Methoxytryptamine / Q000494:pharmacology; D015124:8-Bromo Cyclic Adenosine Monophosphate / Q000494:pharmacology; D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004357:Drug Synergism; D004594:Electrophysiology; D017829:Granisetron / Q000494:pharmacology; D066298:In Vitro Techniques; D007211:Indoles / Q000494:pharmacology; D008297:Male; D008719:Methiothepin / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011985:Receptors, Serotonin / Q000187:drug effects* / Q000378:metabolism; D012044:Regression Analysis; D012701:Serotonin / Q000031:analogs & derivatives / Q000494:pharmacology*; D012702:Serotonin Antagonists / Q000494:pharmacology*; D013449:Sulfonamides / Q000494:pharmacology; D013696:Temperature; D014630:Vagus Nerve / Q000187:drug effects* / Q000378:metabolism
D008735:5-Methoxytryptamine; D015124:8-Bromo Cyclic Adenosine Monophosphate; D017829:Granisetron; D007211:Indoles; D008719:Methiothepin; D011985:Receptors, Serotonin; D012701:Serotonin; D012702:Serotonin Antagonists; D013449:Sulfonamides; C045918:2-methyl-5-HT; C082871:GR 113808