Exercise for Cardiovascular Disease Prevention and Treatment From Molecular to Clinical, Part 1

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More recently, a great deal of interest has focused on KAT P channels as underlying

mechanism for exercise-induced cardioprotection. Convincing data exist demon-

strating that short-term [ 26 ] and long-term exercise [ 25 , 110 ] increase the expres-

sion of cardiac sarcolemmal KAT P, and that pharmacological blockage of

mitochondrial and sarcolemmal KAT P channels impairs cardioprotection [ 25 ,

111 – 114 ].

Interestingly, sex specific levels of KAT P channel expression were reported [ 115 ],

suggesting varying degrees of exercise-induced cardioprotection between genders.

Due to estrogen, female animals have higher levels of KAT P channels, which subse-

quently provide enhanced cardioprotection against IRI following exercise [ 23 ].

Although association of exercise-induced cardioprotection and KAT P channel

opening is well established, the intracellular signaling cascade triggered by exercise

and responsible for the opening of these channels remains unclear [ 54 ]. It is believed

that phosphorylation of KAT P channels by protein kinases, especially PKC via acti-

vation of opioid receptors, results in channel activity modulation [ 116 , 117 ].

Previous data indicate that inhibiting both KAT P channels and PKC do not provide

additional protection, suggesting that activation of PKC and KAT P channels are dif-

ferent components of the same signaling pathway [ 23 ].

5.4 Opioids System

Opioid receptors belong to the G-protein coupled receptor family and are tradition-

ally known by their anti-nociceptive effect. However, more recently, it was discov-

ered that an exogenous opioid ligand (morphine) apart from treating pain associated

with myocardial infarct, may also help in reducing myocardial infarct size area.

Since then, the putative negative inotropic action of opioid receptors has gained

importance [ 116 ].

Interestingly, it is well established that stressful situations (e.g. ischemia and

exercise) increase endogenous opioid peptide levels [ 11 , 118 – 121 ]. Howlett et al.

[ 122 ], for instance, observed that an acute bout of treadmill exercise markedly

increased beta-endorphin (an opioid ligand) levels in young women either before

and after an 8-week exercise training. In theory, this response could act as a com-

pensatory mechanism aiming to counteract the high levels of catecholamines

released during these stressful situation, and thus minimize potential damage in the

heart.

Recent and exciting literature has provided evidence that opioid receptors may

be another limb of exercise preconditioning [ 107 ]. Opioid receptor blockage pre-

cluded short [ 11 ] and long-term [ 80 ] exercise-induced ischemic tolerance. Posterior

data [ 10 , 77 ] have demonstrated that delta opioid receptor plays a key role in this

response. Borges et al. [ 10 ] revealed that four consecutive days of exercise reduced

the myocardial infarct size by approximately 34%. Exercise-induced cardiopro-

tection against IRI was not blunted by pharmacological blockade of the kappa or mu

10 Cardiac Ischemia/Reperfusion Injury: The Bene cial Effects of Exercise