The atypical 5-HT2 receptor mediating tachycardia in pithed rats: pharmacological correlation with the 5-HT2A receptor subtype.
1. In pithed rats, 5-HT mediates tachycardia both directly (by 5-HT(2) receptors) and indirectly (by a tyramine-like effect). The receptor mediating tachycardia directly has been classified as an 'atypical' 5-HT(2) receptor since it was 'weakly' blocked by ketanserin. Moreover, 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI), a 5-HT(2) agonist, failed to mimic 5-HT-induced tachycardia. Since 5-HT(2) receptors consist of 5-HT(2A), 5-HT(2B) and 5-HT(2C) subtypes, this study investigated if these subtypes mediate the above response. 2. In pithed rats, intraperitoneally (i.p.) pre-treated with reserpine (5 mg kg(-1)), intravenous (i.v.) administration of 5-HT, 5-methoxytryptamine (5-MeO-T), 1-(3-chlorophenyl) piperazine (mCPP) and 5-carboxamidotryptamine (5-CT) (10, 30, 100 and 300 microg kg(-1) each), produced dose-dependent tachycardic responses. Interestingly, DOI (10 - 1000 microg kg(-1), i.v.) induced only slight, dose-unrelated, tachycardic responses, whilst the 5-HT(2C) agonist, Ro 60-0175 (10 - 1000 microg kg(-1), i.v.), produced a slight tachycardia only at 300 and 1000 microg kg(-1). In contrast, sumatriptan and 1-(m-trifluoromethylphenyl)- piperazine (TFMPP) were inactive. The rank order of potency was: 5-HT > or =5-MeO-T> mCPP > or =5-CT > or =DOI > Ro 60-0175. 3. The tachycardic responses to 5-HT, which remained unaffected after i.v. saline (0.3 and 1 ml kg(-1)) or propranolol (3 mg kg(-1)), were selectively blocked by the 5-HT(2A) antagonists ketanserin (30 and 100 microg kg(-1)) or spiperone (10 and 30 microg kg(-1)) as well as by the non-selective 5-HT(2) antagonists, ritanserin (10 and 30 microg kg(-1)) or mesulergine (100 microg kg(-1)). Remarkably, these responses were unaffected by the antagonists rauwolscine (5-HT(2B)), SB204741 (5-HT(2B/2C)) or Ro 04-6790 (5-ht(6)) (300 and 1000 microg kg(-1) each). 4. These results suggest that the 'atypical' 5-HT(2) receptors mediating tachycardia in reserpinized pithed rats are pharmacologically similar to the 5-HT(2A) receptor subtype.
Centurión
David
D
Departamento de Farmacobiología, CINVESTAV-IPN, Czda. de los Tenorios 235, Col. Granjas Coapa, Deleg. Tlalpan, C.P. 14330, México D.F., México.
Ortiz
Mario I
MI
Saxena
Pramod R
PR
Villalón
Carlos M
CM
D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D001794:Blood Pressure / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D016166:Free Radical Scavengers / Q000494:pharmacology; D006339:Heart Rate / Q000187:drug effects / Q000502:physiology; D007275:Injections, Intravenous; D008297:Male; D009638:Norepinephrine / Q000494:pharmacology / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D044402:Receptor, Serotonin, 5-HT2A; D011985:Receptors, Serotonin / Q000502:physiology*; D012110:Reserpine / Q000494:pharmacology; D012701:Serotonin / Q000494:pharmacology / Q000502:physiology; D017366:Serotonin Receptor Agonists / Q000494:pharmacology; D013610:Tachycardia / Q000378:metabolism*; D014662:Vasoconstrictor Agents / Q000494:pharmacology
D000959:Antihypertensive Agents; D016166:Free Radical Scavengers; D044402:Receptor, Serotonin, 5-HT2A; D011985:Receptors, Serotonin; D017366:Serotonin Receptor Agonists; D014662:Vasoconstrictor Agents; D012701:Serotonin; D012110:Reserpine; D009638:Norepinephrine