5‐hydroxytryptamine receptors mediating contraction in human small muscular pulmonary arteries: importance of the 5‐HT_1B receptor

Abstract

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-HT 1 receptors) and sumatriptan (selective for 5-HT 1B/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-HT 1 receptor. 3 Ketanserin (5-HT 2A -selective antagonist, 0.1 mM) inhibited 5-HT-induced contractions only at non-physiological/pathological concentrations of 5-HT (40.1 mM) whilst GR55562 (5-HT 1B/1D -selective antagonist, 1 mM) inhibited 5-HT-induced contractions at all concentrations of 5-HT (estimated pK B =7.7+0.2). SB-224289 (5-HT 1B -selective antagonist, 0.2 mM) inhibited sumatriptaninduced contractions (estimated pK B =8.4+0.1) whilst these were una ected by the 5-HT 1D -selective antagonist BRL15572 (0.5 mM) suggesting that the 5-HT 1B receptor mediates vasoconstriction in this vessel. 4 RT ± PCR con®rmed the presence of substantial amounts of mRNA for the 5-HT 2A and 5-HT 1B receptor subtypes in these arteries whilst only trace amounts of 5-HT 1D receptor message were evident. 5 These ®ndings suggest that a heterogeneous population of 5-HT 2A and 5-HT 1B receptors co-exist in human small muscular pulmonary arteries but that the 5-HT 1B receptor mediates 5-HT-induced vasoconstriction at physiological and pathophysiological concentrations of 5-HT. These results have important implications for the treatment of pulmonary hypertension in which the 5-HT 1B receptor may provide a novel and potentially important therapeutic target.

Responses to serotonin (5HT) in isolated corpus cavernosum penis of rabbit

“…3 We are investigating whether 5HT 2B and/or 5HT 2C receptors participate in the 5HT-induced contraction. Lack of effect of LY278584 (a potent 5HT 3 receptor antagonist 8 ) on the concentrationresponse curve of 5HT suggests that 5HT 3 receptor does not participate in the 5HT-induced contraction. SDZ205557 (5HT 4 receptor antagonist) showed a tendency to potentiate the 5HT-induced contraction.…”

Why drugs fail in clinical trials in pulmonary arterial hypertension, and strategies to succeed in the future

“…The 5-HT 2A receptor has been explored in animal models (Cogolludo et al, 2006;Hironaka et al, 2003;Morecroft et al, 2005) and pulmonary arterial fibroblasts in culture (Welsh et al, 2004). Although present in human pulmonary arteries, it may only participate in vasoconstriction when exposed to high 5-HT concentrations (Morecroft et al, 1999). However, given that 5-HT levels are significantly increased in PAH, this may be relevant (Dumitrascu et al, 2011).…”

Genetic, cellular and molecular mechanisms of pulmonary arterial hypertension

“…5-HT1 reseptörleri aracılığıyla büyük çaplı pulmoner arterlerde kontraksiyona neden olur. Daha sonradan gelen çalış-malarda 5-HT1B reseptörleri aracılığı ile küçük çaplı pulmoner arterlerde kontraksiyona neden olduğu gösterilmiştir (33). Ratlar üzerine yapılan çalışmalarda kontrol grubu sıçanlarda pulmoner arter kontraktil cevabı 5-HT1A reseptörleri aracılığı ile olmaktayken, kronik hipoksiye maruz bırakılan ratlarda kontraktil cevabın abartılı olduğu ve de bunun 5-HT1B reseptörleri aracılığı ile gerçekleştiği gösterilmiştir (34).…”