Rm. Fryer et al., Differential activation of extracellular signal regulated kinase isoforms in preconditioning and opioid-induced cardioprotection, J PHARM EXP, 296(2), 2001, pp. 642-649
Citations number
40
Categorie Soggetti
Pharmacology & Toxicology
Journal title
JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Stimulation of the delta (1)-opioid receptor has been shown to trigger isch
emic preconditioning (IPC). Additionally, myocardial ischemia/reperfusion i
nduces the activation of extracellular signal-regulated kinase (ERK). There
fore, we examined the role of ERK in acute cardioprotection induced by delt
a (1)-opioid receptor stimulation or IPC. Infarct size (IS) was expressed a
s a percentage of the area at risk (AAR). Control animals had an IS/AAR of
60.6 +/- 1.8. IPC and delta (1)-opioid receptor stimulation with TAN-67 red
uced IS/AAR (8.2 +/- 1.3 and 30.2 +/- 2.4). Inhibition of ERK with the sele
ctive MEK-1 antagonist, PD 098059 during IPC or TAN-67 administration signi
ficantly reduced cardioprotection (41.5 +/- 6.4 and 63.0 +/- 4.8). Western
Blot analysis and subsequent densitometry corroborated these observations.
Control, TAN-67-, or IPC-treated hearts were harvested after 0, 5, 15, and
30 min of ischemia or 5, 30, and 60 min of reperfusion and separated into c
ytosolic and nuclear fractions. Both isoforms of ERK (p44 and p42) rapidly
increased to greater levels throughout reperfusion in the nuclear fraction
of IPC- and opioid-treated versus control rats, however, this increase was
not attenuated by PD 098059. Conversely, the rapid activation of the 44-kDa
isoform of ERK after 5 min of reperfusion in the cytosolic fraction was si
gnificantly increased in IPC- and opioid-treated hearts versus control, and
this increase was abolished by pretreatment with PD 098059. Additionally,
p42 was activated in the cytosolic fraction of IPC-treated animals. These r
esults suggest a key role for the 44-kDa isoform of ERK in the cytoplasm du
ring cardioprotection induced by either IPC or stimulation of the delta (1)
-opioid receptor.