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1 5-HT moduline (5-HTm) is tetrapeptide (Leu-Ser-Ala-Leu) previously shown to act as a speci®c endogenous antagonist to central 5-HT 1B/1D receptors. Its e ects were investigated in rat and rabbit pulmonary arteries (PAs). 2 In rabbit PAs, contractile responses to the 5-HT 1B/1D receptor agonist 5-carboxamidotryptamine (5-CT) were inhibited by 1 and 10 mM 5-HTm in a non-competitive fashion with the maximum contractile response (E max , 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 mM). 3 In the rabbit PAs, the nitric oxide synthase inhibitor, N o -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 mM 5-HTm (E max : 38+13% (n=8)). 4 5-HTm (10 mM) 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 pIC 50 of 9.0+0.6 (n=9). 5 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)). 6 In conclusion we show here for the ®rst 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 e ect of 5-HTm.

BY 785