Inhibitory mechanism of xestospongin‐C on contraction and ion channels in the intestinal smooth muscle

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Abstract
Xestospongin‐C isolated from a marine sponge, Xestospongia sp., has recently been shown to be a membrane‐permeable IP3 receptor inhibitor. In this study we examined the effects of this compound on smooth muscle from guinea‐pig ileum. In guinea‐pig ileum permeabilized with α‐toxin, xestospongin‐C (3 μM) inhibited contractions induced by Ca2+ mobilized from sarcoplasmic reticulum (SR) with IP3 or carbachol with GTP, but not with caffeine. In intact smooth muscle tissue, xestospongin‐C (3–10 μM) inhibited carbachol‐ and high‐K+‐induced increases in [Ca2+]i and contractions at sustained phase. It also inhibited voltage‐dependent inward Ba2+ currents in a concentration‐dependent manner with an IC50 of 0.63 μM. Xestospongin‐C (3–10 μM) had no effect on carbachol‐induced inward Ca2+ currents via non‐selective cation channels; but it did reduce voltage‐dependent K+ currents in a concentration‐dependent manner with an IC50 of 0.13 μM. These results suggest that xestospongin‐C inhibits the IP3 receptor but not the ryanodine receptor in smooth muscle SR membrane. In intact smooth muscle cells, however, xestospongin‐C appears to inhibit voltage‐dependent Ca2+ and K+ currents at a concentration range similar to that at which it inhibits the IP3 receptor. Xestospongin‐C is a selective blocker of the IP3 receptor in permeabilised cells but not in cells with intact plasma membrane. British Journal of Pharmacology (2002) 137, 1207–1212. doi:10.1038/sj.bjp.0704988

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