Enhanced transcription of contractile 5-hydroxytryptamine 2A receptors via extracellular signal-regulated kinase 1/2 after organ culture of rat mesenteric artery.
5-Hydroxytryptamine (5-HT) has been found to elicit enhanced contractile effects in some vascular disorders. The present study was designed to examine if vascular 5-HT2A receptors are up-regulated during organ culture and if the extracellular signal-regulated protein kinase 1/2 (ERK1/2) pathways are involved. Compared with fresh rat mesenteric artery ring segments, the contractile responses to 5-HT were significantly increased in the segments cultured for 6, 24 or 48 hr (P<0.05, P<0.01, P<0.01, respectively). The 5-HT-induced contraction occurred via 5-HT2A receptors, since the selective 5-HT2A antagonist ketanserin blocked the 5-HT-induced contraction in the fresh segments with a pA2 value 9.5 (slope was 0.98 with 95% confidence intervals from 0.8 to 1.1). A similar result was obtained in the segments cultured for 24 hr with a pA2 value of 9.43 (slope=0.91 and 95% confidence intervals between 0.45 to 2.3). In addition, the enhanced 5-HT2A receptor contraction occurred with a significant increase of 5-HT2A receptor mRNA (P<0.05). Organ culture of the mesenteric artery was found to activate ERK1/2 already within 1 and 3 hr. It is likely that the ERK1/2 pathways were involved as a initial switch, since the selective ERK1/2 pathway inhibitor SB386023 abolished both up-regulation of 5-HT2A mRNA transcription and the enhanced contractile response to 5-HT. These data reveal a role of ERK1/2 in up-regulation of 5-HT2A receptors and suggest a possibility to inhibit the enhanced responses to 5-HT by inhibition of the ERK1/2 pathway.
Cao
Yong-Xiao
YX
Division of Experimental Vascular Research, Department of Medicine, Lund University, Sweden.
He
Lang-Chong
LC
Xu
Cang-Bao
CB
Luo
Guo-Gang
GG
Edvinsson
Lars
L
D000818:Animals; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000502:physiology*; D007650:Ketanserin / Q000494:pharmacology; D008297:Male; D008638:Mesenteric Arteries / Q000187:drug effects / Q000473:pathology* / Q000502:physiology; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000473:pathology / Q000502:physiology; D009924:Organ Culture Techniques / Q000379:methods*; D012333:RNA, Messenger / Q000032:analysis / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D044402:Receptor, Serotonin, 5-HT2A / Q000187:drug effects* / Q000235:genetics; D012701:Serotonin / Q000031:analogs & derivatives / Q000494:pharmacology; D058830:Serotonin 5-HT2 Receptor Antagonists; D013997:Time Factors; D014158:Transcription, Genetic / Q000502:physiology*; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology; D014661:Vasoconstriction / Q000187:drug effects
D004791:Enzyme Inhibitors; D012333:RNA, Messenger; D044402:Receptor, Serotonin, 5-HT2A; D058830:Serotonin 5-HT2 Receptor Antagonists; D012701:Serotonin; C047087:5-carboxamidotryptamine; D007650:Ketanserin; D048049:Extracellular Signal-Regulated MAP Kinases