Involvement of 5‐HT 1B/1D and 5‐HT 2A receptors in 5‐HT‐induced contraction of endothelium‐denuded rabbit epicardial coronary arteries

1 The receptors responsible for 5‐hydroxytryptamine (5‐HT)‐mediated contraction of rabbit isolated epicardial coronary artery denuded of endothelium was examined by bioassay. 2 A variety of 5‐HT mimetics caused concentration‐dependent contractions. The rank order of agonist potency was 5‐carboxamidotryptamine (5‐CT)>5‐HT>(±)‐α‐methyl‐5‐hydroxytryptamine ((±)‐α‐me‐5‐HT)=sumatriptan. This was not consistent with relative potencies at any single recognized 5‐HT receptor, suggesting the presence of a mixed receptor population. In one subset of preparations precontracted with U46619 (10–30 n M ) with the endothelium intact, none of the agonists caused a relaxation. 3 Contractions to 5‐HT were antagonized by ketanserin, a 5‐HT 2A ‐selective antagonist, but the displacement of concentration‐response curves was inconsistent with an interaction between 5‐HT and a single receptor population; the slope of regression between antagonist log M concentration and agonist log (concentration‐ratio −1) was shallow (0.57). Responses to 5‐HT were also antagonized by the 5‐HT 1B/1D ‐receptor antagonist GR127935 and, again, the slope of regression was shallow (0.68). These data suggest a possible involvement of 5‐HT 2A and 5‐HT 1B or 5‐HT 1D receptors in the response to 5‐HT. 4 Contractions to (±)‐α‐me‐5‐HT, which is selective for 5‐HT 2A over 5‐HT 1B and 5‐HT 1D receptors, were competitively antagonized by low concentrations of ketanserin. The regression between antagonist log  M concentration and agonist log (concentration‐ratio −1) fitted the Schild equation with a slope that was not significantly different from unity (0.95), giving a pA 2 value of 9.0. GR127935 (3–30 n M ), had no effect on the contractile response to (±)‐α‐me‐5‐HT. These data establish, unequivocally, the presence of 5‐HT 2A receptors in the tissue. 5 Sumatriptan, a relatively selective 5‐HT 1B/1D ‐receptor agonist, induced contractions that were antagonized competitively by GR127935 (3–30 n M ), although there was a reduction in the maximum response when concentrations of GR127935 exceeded 3 n M . The apparent pA 2 (estimated by imposing a unit slope on the log agonist (concentration‐ratio −1) value in the presence of 3 n M GR127935) was 8.92. Contractions to sumatriptan were not affected by low (5‐HT 2A receptor‐selective) concentrations of ketanserin, but were antagonized in a competitive manner at higher concentrations (pA 2 6.5). These data appear to confirm the presence of 5‐HT 1B and/or 5‐HT 1D receptors in the tissue. 6 Antagonism of 5‐HT responses by GR127935 was reassessed after blockade of 5‐HT 2A receptors with 1 μ M ketanserin. Under these conditions, GR127935 was able to antagonize 5‐HT‐induced contractions fully. The slope of regression between log M antagonist concentration and log agonist (concentration‐ratio −1) fitted the Schild equation with a slope not significantly different from unity (1.1) (albeit there was still a reduction in maximum response when GR127935 concentration exceeded 3 n M ). The apparent pA 2 value was 8.8. This reinforces the evidence that 5‐HT 1B and/or 5‐HT 1D receptors contribute to the effects of 5‐HT in the tissue. 7 In conclusion, in endothelium denuded rabbit epicardial coronary arteries, 5‐HT activates 5‐HT 2A and 5‐HT 1D and/or 5‐HT 1B receptors to cause contraction. This appears to be similar to the situation in man.British Journal of Pharmacology (1997) 122 , 875–884; doi: 10.1038/sj.bjp.0701470