5-hydroxytryptamine receptors mediating contraction in human small muscular pulmonary arteries:: importance of the 5-HT1B receptor

1 The 5-hydroxytryptamine (5-HT) receptors mediating vasoconstriction in isolated human small muscular pulmonary arteries (SMPAs) were determined using techniques of wire myography and reverse transcription-polymerase chain reaction (RT-PCR). 2 The agonists 5-HT, 5-carboxamidotryptamine (5- CT,unselective for 5-HT1 receptors) and sumatriptan (selective for 5-HT1B/D-receptors) all caused-contraction and were equipotent (pEC(50)s: 7.0+/-0.2, 7.1+/-0.3 and 6.7+/-0.1, respectively) suggesting the presence of a 5-HT1 receptor. 3 Ketanserin (5-HT2A-selective antagonist, 0.1 mu M) inhibited 5-HT-induced contractions only at non-physiological/pathological concentrations of 5-HT (>0.1 mu M) whilst GR55562 (5-HT1B/ID-selective antagonist, 1 mu M) inhibited 5-HT-induced contractions at all concentrations of 5-HT (estimated pK(B) =7.7+/-0.2). SB-224289 (5-HT1B-selective antagonist, 0.2 mu M) inhibited sumatriptan-induced contractions (estimated pK(B) = 8.4+/- 0.1) whilst these were unaffected by the 5-HT1D-selective antagonist BRL15572 (0.5 mu M) suggesting that the 5-HT1B receptor mediates vasoconstriction in this vessel. 4 RT-PCR confirmed the presence of substantial amounts of mRNA for the 5-HT2A and 5-HT1B receptor subtypes in these arteries whilst only trace amounts of 5-HT1D receptor message were evident. 5 These findings suggest that a heterogeneous population of 5-HT2A and 5-HT1B receptors co-exist in human small muscular pulmonary arteries but that the 5-HT1B receptor mediates 5-HT-induced vasoconstriction at physiological and pathophysiological concentrations of 5-MT. These results have important implications for the treatment of pulmonary hypertension in which the 5-HT1B receptor may provide a novel and potentially important therapeutic target.