Pharmacological profile of the 5-HT-induced inhibition of cardioaccelerator sympathetic outflow in pithed rats: correlation with 5-HT1 and putative 5-ht5A/5B receptors.
Continuous infusions of 5-hydroxytryptamine (5-HT) inhibit the tachycardiac responses to preganglionic (C7-T1) sympathetic stimulation in pithed rats pretreated with desipramine. The present study identified the pharmacological profile of this inhibitory action of 5-HT. The inhibition induced by intravenous (i.v.) continuous infusions of 5-HT (5.6 microg x kg-1x min-1) on sympathetically induced tachycardiac responses remained unaltered after i.v. treatment with saline or the antagonists GR 127935 (5-HT1B/1D), the combination of WAY 100635 (5-HT1A) plus GR 127935, ritanserin (5-HT2), tropisetron (5-HT3/4), LY215840 (5-HT7) or a cocktail of antagonists/inhibitors consisting of yohimbine (alpha2), prazosin (alpha1), ritanserin, GR 127935, WAY 100635 and indomethacin (cyclooxygenase), but was abolished by methiothepin (5-HT1/2/6/7 and recombinant 5-ht5A/5B). These drugs, used in doses high enough to block their respective receptors/mechanisms, did not modify the sympathetically induced tachycardiac responses per se. I.v. continuous infusions of the agonists 5-carboxamidotryptamine (5-CT; 5-HT1/7 and recombinant 5-ht5A/5B), CP 93129 (r5-HT1B), sumatriptan (5-HT1B/1D), PNU-142633 (5-HT1D) and ergotamine (5-HT1B/1D and recombinant 5-ht5A/5B) mimicked the above sympatho-inhibition to 5-HT. In contrast, the agonists indorenate (5-HT1A) and LY344864 (5-ht1F) were inactive. Interestingly, 5-CT-induced cardiac sympatho-inhibition was abolished by methiothepin, the cocktail of antagonists/inhibitors, GR 127935 or the combination of SB224289 (5-HT1B) plus BRL15572 (5-HT1D), but remained unchanged when SB224289 or BRL15572 were given separately. Therefore, 5-HT-induced cardiac sympatho-inhibition, being unrelated to 5-HT2, 5-HT3, 5-HT4, 5-ht6, 5-HT7 receptors, alpha1/2-adrenoceptor or prostaglandin synthesis, seems to be primarily mediated by (i). 5-HT1 (probably 5-HT1B/1D) receptors and (ii). a novel mechanism antagonized by methiothepin that, most likely, involves putative 5-ht5A/5B receptors.
D000818:Animals; D001339:Autonomic Fibers, Preganglionic / Q000187:drug effects / Q000502:physiology; D001794:Blood Pressure / Q000187:drug effects; D003655:Decerebrate State / Q000503:physiopathology*; D003891:Desipramine / Q000008:administration & dosage / Q000493:pharmacokinetics; D004195:Disease Models, Animal; D004359:Drug Therapy, Combination; D004558:Electric Stimulation / Q000379:methods; D004878:Ergotamine / Q000008:administration & dosage / Q000493:pharmacokinetics; D007262:Infusions, Intravenous; D007275:Injections, Intravenous; D008297:Male; D010069:Oxadiazoles / Q000008:administration & dosage / Q000493:pharmacokinetics; D010879:Piperazines / Q000008:administration & dosage / Q000493:pharmacokinetics; D011725:Pyridines / Q000008:administration & dosage / Q000493:pharmacokinetics; D051381:Rats; D017208:Rats, Wistar; D011985:Receptors, Serotonin / Q000145:classification / Q000187:drug effects* / Q000502:physiology; D044263:Receptors, Serotonin, 5-HT1 / Q000145:classification / Q000187:drug effects* / Q000502:physiology; D012701:Serotonin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics*; D012702:Serotonin Antagonists / Q000008:administration & dosage / Q000493:pharmacokinetics; D017366:Serotonin Receptor Agonists / Q000008:administration & dosage / Q000493:pharmacokinetics; D013564:Sympathetic Nervous System / Q000187:drug effects* / Q000503:physiopathology*; D013610:Tachycardia / Q000188:drug therapy / Q000503:physiopathology
D010069:Oxadiazoles; D010879:Piperazines; D011725:Pyridines; D011985:Receptors, Serotonin; D044263:Receptors, Serotonin, 5-HT1; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; C078730:serotonin 5 receptor; C090701:GR 127935; D012701:Serotonin; C090413:N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide; C047087:5-carboxamidotryptamine; D004878:Ergotamine; D003891:Desipramine