British journal of pharmacology · 2021
Carbenoxolone and 18β-glycyrrhetinic acid inhibit inositol 1,4,5-trisphosphate-mediated endothelial cell calcium signalling and depolarise mitochondria.
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Buckley Charlotte, Zhang Xun, Wilson Calum, McCarron John G
Аннотация
BACKGROUND AND PURPOSE: Coordinated endothelial control of cardiovascular function is proposed to occur by endothelial cell communication via gap junctions and connexins. To study intercellular communication, the pharmacological agents carbenoxolone (CBX) and 18β-glycyrrhetinic acid (18βGA) are used widely as connexin inhibitors and gap junction blockers.
EXPERIMENTAL APPROACH: We investigated the effects of CBX and 18βGA on intercellular Ca2+ waves, evoked by inositol 1,4,5-trisphosphate (IP3 ) in the endothelium of intact mesenteric resistance arteries.
KEY RESULTS: Acetycholine-evoked IP3 -mediated Ca2+ release and propagated waves were inhibited by CBX (100 μM) and 18βGA (40 μM). Unexpectedly, the Ca2+ signals were inhibited uniformly in all cells, suggesting that CBX and 18βGA reduced Ca2+ release. Localised photolysis of caged IP3 (cIP3 ) was used to provide precise spatiotemporal control of site of cell activation. Local cIP3 photolysis generated reproducible Ca2+ increases and Ca2+ waves that propagated across cells distant to the photolysis site. CBX and 18βGA each blocked Ca2+ waves in a time-dependent manner by inhibiting the initiating IP3 -evoked Ca2+ release event rather than block of gap junctions. This effect was reversed on drug washout and was unaffected by small or intermediate K+ -channel blockers. Furthermore, CBX and 18βGA each rapidly and reversibly collapsed the mitochondrial membrane potential.
CONCLUSION AND IMPLICATIONS: CBX and 18βGA inhibit IP3 -mediated Ca2+ release and depolarise the mitochondrial membrane potential. These results suggest that CBX and 18βGA may block cell-cell communication by acting at sites that are unrelated to gap junctions.
EXPERIMENTAL APPROACH: We investigated the effects of CBX and 18βGA on intercellular Ca2+ waves, evoked by inositol 1,4,5-trisphosphate (IP3 ) in the endothelium of intact mesenteric resistance arteries.
KEY RESULTS: Acetycholine-evoked IP3 -mediated Ca2+ release and propagated waves were inhibited by CBX (100 μM) and 18βGA (40 μM). Unexpectedly, the Ca2+ signals were inhibited uniformly in all cells, suggesting that CBX and 18βGA reduced Ca2+ release. Localised photolysis of caged IP3 (cIP3 ) was used to provide precise spatiotemporal control of site of cell activation. Local cIP3 photolysis generated reproducible Ca2+ increases and Ca2+ waves that propagated across cells distant to the photolysis site. CBX and 18βGA each blocked Ca2+ waves in a time-dependent manner by inhibiting the initiating IP3 -evoked Ca2+ release event rather than block of gap junctions. This effect was reversed on drug washout and was unaffected by small or intermediate K+ -channel blockers. Furthermore, CBX and 18βGA each rapidly and reversibly collapsed the mitochondrial membrane potential.
CONCLUSION AND IMPLICATIONS: CBX and 18βGA inhibit IP3 -mediated Ca2+ release and depolarise the mitochondrial membrane potential. These results suggest that CBX and 18βGA may block cell-cell communication by acting at sites that are unrelated to gap junctions.