Endothelin-1 exerts a preconditioning-like cardioprotective effect against ischaemia/reperfusion injuryviathe ETA receptor and the mitochondrial KATP channel in the ratin vivo

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In vitro studies have demonstrated that endothelin-1 (ET-1) given before myocardial ischaemia may evoke a preconditioning (PC)-like cardioprotective effect. The first aim of this study was to investigate whether administration of ET-1 before ischaemia exerts cardioprotection against ischaemia/reperfusion injury in vivo and to determine involvement of the ET-1 receptor subtype. The second aim was to examine the role of mitochondrial ATP-sensitive K+ channels (mitoKATP) as a mediator of this cardioprotection.Anaesthetised open-chest Wistar rats were subjected to 30 min of coronary artery occlusion followed by 2 h reperfusion (I/R). In protocol I, the first group was subjected to I/R only (control, n=10). In the second (n=10) group, PC was elicited by three 5 min cycles of coronary artery occlusion, separated by 5 min reperfusion before I/R. The third (n=6) and fourth (n=7) groups were given ET-1 intravenous (i.v.) during three 5 min infusion periods separated by 5 min before I/R. The fourth group was in addition given the ETA receptor antagonist LU 135252 5 min before the infusions of ET-1. In protocol II, the first group was I/R control as in protocol I (n=8). The second (n=6), third (n=7) and fourth (n=7) groups were given ET-1 as in protocol I. The third group was in addition given the nonselective KATP channel antagonist glibenclamide (Glib) 30 min before the ET-1 infusions and the fourth group the selective mitoKATP channel antagonist 5-hydroxydecanoic acid (5-HD) 5 min before I/R.There were no significant differences in MAP or heart rate between the groups during I/R. In protocol I, PC reduced IS compared to the control group (10±3 vs 35±5%, P<0.01). Infusion of ET-1 also reduced IS (to 14±3%, P<0.05 vs control). The ETA receptor antagonist blocked the reduction in IS induced by ET-1 (IS 47±8% after LU+ET-1; P< 0.05 vs ET-1). In protocol II, Glib and 5-HD abolished the cardioprotective effect induced by ET-1 (IS 48±7% after Glib+ET-1 and 42±5% after ET-1+5-HD vs 18±4% after ET-1 alone; P<0.05).In conclusion, administration of ET-1 before ischaemia resulted in a PC-like cardioprotective effect. This effect is mediated via the ETA receptor and activation of mitoKATP channels.British Journal of Pharmacology (2005) 144, 331–337. doi:10.1038/sj.bjp.0706050

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