Characterization of 5-HT receptor subtypes mediating contraction in human umbilical vein. 1. Evidence of involvement of 5-HT2A receptors using functional and radioligand binding assays

xED;a#Rogines-Velo, Mar&; Pelorosso, Facundo; Zold, Camila; Nowak, Wanda; Pesce, Guido; Sardi, Sergio; Brodsky, Paula; Rothlin, Rodolfo
December 2002
Naunyn-Schmiedeberg's Archives of Pharmacology;Dec2002, Vol. 366 Issue 6, p587
Academic Journal
This study attempted to characterize pharmacologically the involvement of 5-HT2A receptors in 5-HT-induced contractile responses in human umbilical vein (HUV) rings employing functional and radioligand binding assays. In HUV rings, prazosin 1 µM did not affect contractile responses elicited by 5-HT, ruling out the involvement of α1-adrenoceptors in contractile responses to 5-HT. 5-HT-induced contractions were competitively blocked by ketanserin, a 5-HT2A-selective antagonist. The apparent pA2 value was 9.8 and the Schild slope significantly less than unity, suggesting that 5-HT-induced responses are mediated by a heterogeneous receptor population. α-methyl-5-HT, a selective 5-HT2 receptor agonist, induced contractions that were antagonized in a competitive manner by ketanserin. The slope regression was not significantly different from unity and the pA2 value was 8.8. The selective 5-HT2A ligand spiperone produced a parallel rightward shift on 5-HT CRCs in HUV rings. The calculated pA2 was 9.0, which is in accord for an interaction with the 5-HT2A receptor subtype. α-methyl-5-HT CRCs were competitively blocked by spiperone treatment. The Schild analysis yielded a pA2 of 9.1 with a slope not significantly different from unity. The 5-HT2C/2A antagonist mesulergine 10 nM did not affect 5-HT CRCs, suggesting that 5-HT2C receptors are not involved in 5-HT-elicited contractions. Higher concentrations of mesulergine showed a parallel rightward shift on 5-HT responses. The calculated pA2 was 7.44, which suggests an interaction with the 5-HT2A receptor subtype. In addition, mesulergine competitively blocked α-methyl-5-HT CRCs. The Schild slope was not significantly different from unity and the pA2 value was 7.98. The binding of [3H]ketanserin to HUV membranes was saturable and of high affinity. Ketanserin displayed a monophasic curve which was best fit with a single component of binding. Nonlinear least squares analysis of the binding curves revealed a high affinity Kd of 0.30 nM and a Bmax of 134 fmol/mg protein. These findings provide strong pharmacological evidence of the involvement of 5-HT2A receptors in 5-HT-induced vasoconstriction in HUV. In addition, the contribution of another receptor population cannot be excluded. The results also suggest that this receptor population is neither an α1-adrenoceptor nor a 5-HT2C receptor subtype.


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