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Medientyp:
E-Artikel
Titel:
Carbenoxolone and 18β‐glycyrrhetinic acid inhibit inositol 1,4,5‐trisphosphate‐mediated endothelial cell calcium signalling and depolarise mitochondria
Beteiligte:
Buckley, Charlotte;
Zhang, Xun;
Wilson, Calum;
McCarron, John G.
Erschienen:
Wiley, 2021
Erschienen in:
British Journal of Pharmacology, 178 (2021) 4, Seite 896-912
Sprache:
Englisch
DOI:
10.1111/bph.15329
ISSN:
0007-1188;
1476-5381
Entstehung:
Anmerkungen:
Beschreibung:
Background and PurposeCoordinated 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 ApproachWe 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 ResultsAcetycholine‐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 ImplicationsCBX 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.