5‐HT moduline: an endogenous inhibitor of 5‐HT_1B/1D‐mediated contraction in pulmonary arteries

Abstract

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.

Heterogeneity in 5-HT-Induced Contractile and Proliferative Responses in Rat Pulmonary Arterial Bed

“…In small IPA from Wistar rats, EC 50 varies from 0.8 to 7.4 µ M [13,14,15, 33], which is also in accordance with our results (EC 50 of 3.9 and 4.9 µ M for IPA2 and IPA1, respectively). Although previous studies showed higher Emax in large PA than in small PA and inversely greater EC 50 in small PA than in large PA [5, 6], in our study, we described a higher Emax and EC 50 in IPA2 compared to MPA (fig.…”

“…However, this point remains controversial since 5-carboxamidotryptamine (5-CT), a selective 5-HT 1 receptor agonist, also induced a contraction [14]. In rat small intrapulmonary arteries (IPA), the contractile response to 5-HT is mainly mediated by the 5-HT 2A receptors, but the role of 5-HT 1B receptors cannot be ruled out [5, 15]. In similar vessels, nordexfenfluramine, a 5-HT 2B receptor agonist, induces a contraction in endothelium intact or denuded rings [16].…”

Commentary on the article presented by Murdoch et al.

“…Both central and peripheral 5‐HT 1B/1D receptors participate in these functional adaptative changes. Thus, together with previous results, the observations of Murdoch et al . (2002) provide a strong impetus to further explore the hypothesis that the interaction of 5‐HT‐moduline with 5‐HT 1B/1D receptors plays a role in the development of a co‐ordinated and efficient global response of the organism to external stimuli.…”

“…The experimental study reported by Murdoch et al . (2002) is the first demonstration that 5‐HT‐moduline, an endogenous tetrapeptide (Leu‐Ser‐Ala‐Leu), can regulate the contraction of arterial smooth muscle via an interaction with 5‐HT 1B/1D receptors.…”

“…However, the demonstration of a regulatory effect of 5‐HT‐moduline on peripheral targets was only recently reported when it was shown that the peptide affected multiplication of immunocompetent cells (Grimaldi & Fillion, 2000). Thus, the work of Murdoch et al . (2002) together with the previously published results, suggests that in the periphery, 5‐HT‐moduline may exert a similar regulatory role to that previously proposed in the brain.…”