5‐HT moduline: an endogenous inhibitor of 5‐HT1B/1D‐mediated contraction in pulmonary arteries

• Published in: British journal of pharmacology 2003-03, Vol.138 (5), p.795-800
• Main Authors: Murdoch, R, Morecroft, I, MacLean, M R
• Format: Article
• Language: English
• Subjects: 5‐HT moduline; 5‐HT1B/1D receptors; Biological and medical sciences; contraction; Medical sciences; pulmonary artery
• ISSN: 0007-1188; 1476-5381
• DOI: 10.1038/sj.bjp.0705123

5‐HT moduline (5‐HTm) is tetrapeptide (Leu‐Ser‐Ala‐Leu) previously shown to act as a specific endogenous antagonist to central 5‐HT1B/1D receptors. Its effects were investigated in rat and rabbit pulmonary arteries (PAs). In rabbit PAs, contractile responses to the 5‐HT1B/1D receptor agonist 5‐carboxamidotryptamine (5‐CT) were inhibited by 1 and 10 μM 5‐HTm in a non‐competitive fashion with the maximum contractile response (Emax, per cent of response to 50 mM KCl) being reduced from 65.6±7% (n=6) to 39.7±6.5% (n=6) and 25.2±7.9 (n=4), respectively. The ability of 5‐HTm to inhibit responses to 5‐CT was increased by the aminopeptidase inhibitor bestatin (10 μM). In the rabbit PAs, the nitric oxide synthase inhibitor, Nω‐nitro‐L‐arginine methylester (L‐NAME) potentiated responses to 5‐CT (Emax: 106±22.5 (n=4)) and this response was also inhibited by 10 μM 5‐HTm (Emax: 38±13% (n=8)). 5‐HTm (10 μM) inhibited responses to 5‐CT in rat PAs, the Emax being reduced from 24.8±4.1% (n=7) to 15.5±3.7% (n=9). 5‐HTm induced relaxation of 5‐CT‐pre‐constricted rat PAs with a pIC50 of 9.0±0.6 (n=9). In PAs from chronic hypoxic, pulmonary hypertensive rats, the maximum response to 5‐CT was increased to 80±8.5% (n=11). 5‐HTm reduced this response to 34.4±6.3% (n=12). L‐NAME markedly inhibited the ability of 5‐HTm to inhibit responses to 5‐CT (Emax before 5‐HTm: 100.5±16% (n=5), Emax after 5‐HTm: 107±11.3% (n=4)). In conclusion we show here for the first time that 5‐HTm is a non‐competitive inhibitor of 5‐HT1B/1D receptor‐mediated constriction in PAs. In rat PAs, L‐NAME can inhibit this effect of 5‐HTm. British Journal of Pharmacology (2003) 138, 795–800. doi:10.1038/sj.bjp.0705123