Hongwei Gao, Mirna Mourtada, Noel G Morgan
Context Certain imidazoline drugs stimulate insulin secretion acutely but their longer term effects on the viability of pancreatic beta-cells are less well characterised. Indeed, some reports have suggested that imidazolines can be toxic to beta-cells while others have reported protective effects against other cytotoxic agents. Objective In order to address these discrepancies, the effects of two structurally related imidazolines, efaroxan and idazoxan, on the viability of clonal BRIN-BD11 betacells, were compared. Design and main outcome measures BRINBD11 cells were exposed to test reagents and their viability monitored by measuring cellular reducing ability and DNA fragmentation. Nitric oxide was measured indirectly via medium nitrite formation. Results (up to 100 ìM) did not directly affect BRIN-BD11 cell viability in the absence of other agents and it did not protect these cells against the cytotoxic effects of interleukin-1beta. Indeed, analysis of DNA fragmentation in BRIN-BD11 cells revealed that efaroxan enhanced the level of damage caused by interleukin-1beta. Idazoxan caused a time- and dose-dependent loss of BRIN-BD11 cell viability in the absence of other ligands. This was associated with marked DNA degradation but was not associated with formation of nitric oxide. The effects of idazoxan were insensitive to blockade of alpha2-adrenoceptors or 5-HT1A (5-hydroxytryptamine; serotonin) receptors. Conclusions : The results confirm that idazoxan is cytotoxic to beta-cells but show that efaroxan is better tolerated. However, since efaroxan enhanced the cytotoxic effects of interleukin-1beta, it appears that this imidazoline may sensitise BRIN-BD11 cells to the damaging effects of certain cytokines.
