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.
|Tidsskrift||Basic & clinical pharmacology & toxicology|
|Status||Udgivet - apr. 2005|