5-HT moduline: an endogenous inhibitor of 5-HT(1B/1D)-mediated contraction in pulmonary arteries.

(1) 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). (2) In rabbit PAs, contractile responses to the 5-HT(1B/1D) receptor agonist 5-carboxamidotryptamine (5-CT) were inhibited by 1 and 10 micro M 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 micro M). (3) In the rabbit PAs, the nitric oxide synthase inhibitor, N(omega)-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 micro M 5-HTm (E(max): 38+/-13% (n=8)). (4) 5-HTm (10 micro 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 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 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.