ischaemic preconditioning of the human heart. - Leicester Research ...

4.1 INTRODUCTION
The basis of card
ioprotect ion by ischaernic preconditioning is not fully elucidated despite
intensive investigation. The most favoured current hypothesis for preconditioning
suggests that a variety of endogenous figands such as adenosine, bradykinin.
catecholamines and opoids activate receptors linked to protein kinase C to initiate an
intracellular signal transduction pathway. PKC may activate a tyrosine kinase, which in
turn activates MAP or JUN kinases leading finally to phosphorylation of an effector
protein, which ultimately leads to protection [461
The ATP-sensitive K' channel (K..,.
I-p) has been suggested as a possible end-effector in
the mechanism of ischaemic preconditioning [ 1181 . This evidence arises primarily from
pharmacological studies [8,107,2731. K.. %. I-p channels exist in the sarcolemma and in
mitochondria as described in Chapter I- However, since the effects of sarcolemmal K. ý I.,.
channels [109,111,1151 on excitability cannot alone account for the protection of
preconditioning it has been suggested that
, mitochondrial K.
%., -,, channels may be the true
effectors mediating the beneficial action of preconditioning. This hypothesis is supported
by recent reports by Garfid et a] [991 showing that diazoxide opens reconstituted
mitochondrial K., N-1-p channels at cardioprotective concentrations but much less potent on
sarcolemmal channels and by Liu et al [ 1961, who showed that dia7oxide caused
oxidation of mitochondrial flavoproteins in isolated cardiac myocytes, consistent with
activation of mitochondrial K. N-rp
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