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)P3 generation 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)P3 generation was observed after 2 min of reperfusion following 30 min of zero-flow ischaemia. No Ins(1,4,5)P3 response 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)P3 generation 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)P3 generation after 30 min of ischaemic insult in α1A-WT mice. However, the precursor lipid PtdIns(4,5)P2 was also reduced by preconditioning, whereas heightened α1A-AR activity did not influence PtdIns(4,5)P2 responses in reperfusion. Thus preconditioning and α1A-AR overexpression have different effects on early signalling responses, even though both prevented Ins(1,4,5)P3 generation. These studies demonstrate a selective inhibitory action of heightened α1A-AR activity on immediate post-receptor signalling responses in early post-ischaemic reperfusion.
Heightened α1A-adrenergic receptor activity suppresses ischaemia/reperfusion-induced Ins(1,4,5)P3 generation in the mouse heart: a comparison with ischaemic preconditioning
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Fatemeh Amirahmadi, Lynne Turnbull, Xiao-Jun Du, Robert M. Graham, Elizabeth A. Woodcock; Heightened α1A-adrenergic receptor activity suppresses ischaemia/reperfusion-induced Ins(1,4,5)P3 generation in the mouse heart: a comparison with ischaemic preconditioning. Clin Sci (Lond) 1 January 2008; 114 (2): 157–164. doi: https://doi.org/10.1042/CS20070110
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