Opioid peptides and exogenous
opioids such as
morphine are known to exert important cardiovascular effects. However, until recently, it was not appreciated that activation of specific receptors results in a potent cardioprotective effect to reduce
infarct size in experimental animals and to reduce cell death in isolated cardiomyocytes. In intact rat and rabbit hearts, nonselective
opioid receptor antagonists such as
naloxone and a selective delta1-opioid receptor antagonist,
7-benzylidenenaltrexone, have been shown to inhibit the cardioprotective effect of ischemic preconditioning, a phenomenon in which brief periods of
ischemia protect the heart against a more prolonged period of
ischemia. Selective delta(1) specific agonists such
as 2-methyl-4a-alpha-(3-hydroxyphenyl)-1,2,3,4,4a,5,12,12a-alpha-octahydroquinolino[2,3,3-g]
isoquinoline have been shown to exert potent cardioprotective effects in intact animals and cardiac myocytes via activation of Gi/o
proteins,
protein kinase C, and ultimately, the mitochondrial
KATP channel. These protective effects occur immediately following drug administration, and reappear 24-48 hr post treatment. Although further studies are needed to more clearly define the mechanisms by which
opioids exert their cardioprotective effects, the data accumulated and summarized in this review suggest that this class of drugs may not only be useful in alleviating the
pain associated with a
myocardial infarction, but may also be simultaneously reducing the size of the ultimate
infarct. Since many of these drugs are already clinically available, a long period of drug development may not be necessary before the use of these drugs reaches the patient with signs of
myocardial ischemia.