Heightened α<inf>IA</inf>-adrenergic receptor activity suppresses ischaemia/reperfusion-induced Ins(1,4,5)P<inf>3</inf>generation in the mouse heart: A comparison with ischaemic preconditioning

Publication Type:
Journal Article
Citation:
Clinical Science, 2008, 114 (1-2), pp. 157 - 164
Issue Date:
2008-01-01
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Reperfusion of ischaemic rat or mouse hearts causes NE [noradrenaline ('norepinephrine')] release, stimulation of α1-ARs (α1-adrenergic receptors), PLC (phospholipase C) activation, Ins(1,4,5)P3generation and the development of arrhythmias. In the present study, we examined the effect of increased α1A-AR drive on these responses. In hearts from non-transgenic mice (α1A- WT), Ins(1,4,5)P3generation was observed after 2 min of reperfusion following 30 min of zero-flow ischaemia. No Ins(1,4,5)P3response was observed in hearts from transgenic mice with 66-fold overexpression of α1A-AR (α1A-TG). This was despite the fact that α1A-TG hearts had 8-10-fold higher PLC responses to NE than α1A-WT under normoxic conditions. The immediate phospholipid precursor of Ins(1,4,5)P3, PtdIns(4,5)P2, responded to ischaemia and reperfusion similarly in α1A-WT and α1A-TG mice. Thus the lack of Ins(1,4,5)P3generation in α1A-TG mice is not caused by limited availability of PtdIns(4,5)P2. Overall, α1-AR-mediated PLC activity was markedly enhanced in α1A-WT mice under reperfusion conditions, but responses in α1A-TG mice were not significantly different in normoxia and post-ischaemic reperfusion. Ischaemic preconditioning prevented Ins(1,4,5)P3generation after 30 min of ischaemic insult in α1A-WT mice. However, the precursor lipid PtdIns(4,5)P2was also reduced by preconditioning, whereas heightened α1A-AR activity did not influence PtdIns(4,5)P2responses in reperfusion. Thus preconditioning and α1A-AR overexpression have different effects on early signalling responses, even though both prevented Ins(1,4,5)P3generation. These studies demonstrate a selective inhibitory action of heightened α1A-AR activity on immediate post-receptor signalling responses in early post-ischaemic reperfusion. © The Authors.
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