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

5‐HT moduline (5‐HTm) is tetrapeptide (Leu‐Ser‐Ala‐Leu) previously shown to act as a specific endogenous antagonist to central 5‐HT 1B/1D receptors. Its effects were investigated in rat and rabbit pulmonary arteries (PAs). In rabbit PAs, contractile responses to the 5‐HT 1B/1D receptor agonist 5‐carboxamidotryptamine (5‐CT) were inhibited by 1 and 10 μ M 5‐HTm in a non‐competitive fashion with the maximum contractile response (E max , per cent of response to 50 m M 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 μ M ). In the rabbit PAs, the nitric oxide synthase inhibitor, N ω ‐nitro‐ L ‐arginine methylester ( L ‐NAME) potentiated responses to 5‐CT (E max : 106±22.5 ( n =4)) and this response was also inhibited by 10 μ M 5‐HTm (E max : 38±13% ( n =8)). 5‐HTm (10 μ M ) inhibited responses to 5‐CT in rat PAs, the E max 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 p IC 50 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 (E max before 5‐HTm: 100.5±16% ( n =5), E max 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‐HT 1B/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