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Serotonin increases the production of inositol phosphates and mobilises calcium via the 5-HT2 receptor in A7r5 smooth muscle cells

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Summary

  1. 1.

    Serotonin (5-HT) induces inositol phosphate production and the efflux of 45Ca2+ in a smooth muscle cell line (A7r5) derived from rat aorta. These effects were pharmacologically characterised and compared to data obtained in radioligand binding studies performed with the 5-HT2 ligand [3H]ketanserin in rat brain cortex membranes.

  2. 2.

    5-HT causes in increase in the levels of inositol trisphosphate (InsP3), inositol bisphosphate (InsP2) and inositol phosphate (InsP1). InsP3 production was rapid and transient whereas InsP1 accumulated in a time and concentration dependent manner. The 5-HT stimulated InsP1 accumulation (pEC50=6.48) was potently and competitively inhibited by the 5-HT2 specific antagonists, pirenperone and ketanserin, whereas antagonists of other 5-HT receptors were active only at high concentrations. There was a significant correlation between inhibition of 5-HT stimulated InsP1 accumulation and 5-HT2 binding (r=0.98, P=0.0035).

  3. 3.

    5-HT stimulated the efflux of 45Ca2+ from preloaded cells with a pEC50 of 7.59. The rank order of potency for agonist induced Ca2+ efflux, 5-HT > α-methyl-5-HT > 1-methyl-5-HT > RU 24969 (5-methoxy-3[1,2,3,6-tetrahy-dropyridin-4-yl]-1-H indole) > 8-OH-DPAT (8-hydroxy-2-(di-n-propylamino)tetralin) > 5-CT (5-carboxamidotryptamine) is typical for a 5-HT2 receptor mediated event. The effect of 5-HT was competitively blocked by ketanserin (pA2=8.22). There was a very good correlation (r=0.94; P=0.0001) between antagonism of Ca2+ release and 5-HT2 binding as measured using a series of 13 antagonists.

  4. 4.

    The values obtained with selective agonists and antagonists exclude that the 5-HT mediated effects described here involve 5-HT1A, 1B, 1C, 5-HTM receptors, α-or β-adrenoceptors. The data suggests that 5-HT mobilises intracellular Ca2+ via the production of InsP3 in this smooth muscle cell line, an effect mediated by a 5-HT2 receptor.

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Authors and Affiliations

  1. Preclinical Research, Sandoz Ltd., 386/525, CH-4002, Basel, Switzerland

    Valerie M. Doyle, Judith A. Creba, Urs T. Rüegg & Daniel Hoyer

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  1. Valerie M. Doyle
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  2. Judith A. Creba
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  3. Urs T. Rüegg
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  4. Daniel Hoyer
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Part of this work has been presented in London, December 1985, at the winter meeting of the British Pharmacological Society

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Doyle, V.M., Creba, J.A., Rüegg, U.T. et al. Serotonin increases the production of inositol phosphates and mobilises calcium via the 5-HT2 receptor in A7r5 smooth muscle cells. Naunyn-Schmiedeberg's Arch. Pharmacol. 333, 98–103 (1986). https://doi.org/10.1007/BF00506510

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  • DOI: https://doi.org/10.1007/BF00506510

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