Reperfusion of ischaemic rat or mouse hearts causes NE [noradrenaline (‘norepinephrine’)] release, stimulation of α 1 -ARs (α 1 -adrenergic receptors), PLC (phospholipase C) activation, Ins(1,4,5) P 3 generation and the development of arrhythmias. In the present study, we examined the effect of increased α 1A -AR drive on these responses. In hearts from non-transgenic mice (α 1A -WT), Ins(1,4,5) P 3 generation was observed after 2 min of reperfusion following 30 min of zero-flow ischaemia. No Ins(1,4,5) P 3 response was observed in hearts from transgenic mice with 66-fold overexpression of α 1A -AR (α 1A -TG). This was despite the fact that α 1A -TG hearts had 8–10-fold higher PLC responses to NE than α 1A -WT under normoxic conditions. The immediate phospholipid precursor of Ins(1,4,5) P 3 , PtdIns(4,5) P 2 , responded to ischaemia and reperfusion similarly in α 1A -WT and α 1A -TG mice. Thus the lack of Ins(1,4,5) P 3 generation in α 1A -TG mice is not caused by limited availability of PtdIns(4,5) P 2 . Overall, α 1 -AR-mediated PLC activity was markedly enhanced in α 1A -WT mice under reperfusion conditions, but responses in α 1A -TG mice were not significantly different in normoxia and post-ischaemic reperfusion. Ischaemic preconditioning prevented Ins(1,4,5) P 3 generation after 30 min of ischaemic insult in α 1A -WT mice. However, the precursor lipid PtdIns(4,5) P 2 was also reduced by preconditioning, whereas heightened α 1A -AR activity did not influence PtdIns(4,5) P 2 responses in reperfusion. Thus preconditioning and α 1A -AR overexpression have different effects on early signalling responses, even though both prevented Ins(1,4,5) P 3 generation. These studies demonstrate a selective inhibitory action of heightened α 1A -AR activity on immediate post-receptor signalling responses in early post-ischaemic reperfusion.