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Enkephalins are opioid peptides that act as neurotransmitters and modulators of cardiac function. Plasma enkephalin levels increase in response to ischemia and exercise. The level of bioactive peptides in blood is regulated at many levels, including inactivation by plasma or cell-associated peptidases. Previous studies showed that Met-enkephalin (ME) and Leu-enkephalin (LE) bound to plasma proteins, and that binding to these proteins protected LE from proteolysis. We found that Met-enkephalin-Arg-Phe (MEAP), and Met-enkephalin-Arg-Gly-Leu (MEAGL) also bound to human serum proteins; however, this binding was of significantly higher affinity that that of ME and LE. In addition, the enkephalin binding capacity of plasma was considerably greater than that of serum from the same donor, suggesting that enkephalins avidly bind to proteins that are present in plasma but not in serum. Finally, we observed a unique degradation pattern when MEAP was hydrolyzed by plasma carboxypeptidases, as compared to ME, LE and MEAGL. Together, our data suggest complex mechanisms by which enkephalin-plasma interactions may regulate systemic enkephalin bioactivity. [ABSTRACT FROM AUTHOR]

Ischemia-reperfusion injury contributes to the pathophysiology of numerous diseases. Ischemic preconditioning increases tissue resistance to ischemia-reperfusion injury. Among the mediators of ischemic preconditioning are opioid peptides called enkephalins. We found that numerous non-neuronal tissues express the enkephalin precursor protein proenkephalin. Additionally, using isolated heart, intestine, and skeletal muscle, we found a tissue-specific pattern of enkephalin release. We also found that ischemia increased cardiac enkephalin release, and that exercise altered the efficiency of enkephalin processing and release. In addition to acting as potential sources for enkephalin release, heart, intestine, and skeletal muscle all express mRNAs for opioid receptors, suggesting that these tissues are also targets for opioid-mediated effects. Consistent with this conclusion, purified enkephalins induced opioid-dependent decreases in intestinal contractility. Taken together, our data suggest that skeletal muscle, heart, and intestine may release enkephalins that may in turn mediate autocrine, paracrine, and systemic effects, including ischemic preconditiong. [ABSTRACT FROM AUTHOR]

Ischemic heart disease is a major contributor to death worldwide. Ischemic preconditioning (IPC) is a natural process that protects the heart from ischemic injury. The goal of our laboratory is to determine the mechanisms by which mediators of IPC exert their protective effects. Among the mediators of IPC are small opioid peptides called enkephalins. We found that numerous tissues, including skeletal muscle, express the precursor protein proenkephalin (PENK), and release enkephalins in a tissue-specific manner. We also found that exercise, which is potently cardioprotective, alters PENK levels in both heart and skeletal muscle, but not in intestine. Moreover, ischemia-induced enkephalin release is higher in hearts from exercised animals, as compared to control animals. Together, our data support a model wherein numerous non-neuronal tissues release enkephalins in response to ischemia and ischemic-like stresses (e.g., exercise). These enkephalins may then act locally or systemically to increase ischemic tolerance of the heart and other tissues. Our findings further suggest that enhancing or mimicking the protective effects of enkephalins may benefit patients with ischemic disease. [ABSTRACT FROM AUTHOR]

Exercise is associated with both increased serum opioid levels and improvements in cardiovascular health. We hypothesize that one class of opioids, the enkephalins, contributes to the acute cardioprotective effects of exercise. We further hypothesize that enkephalins are released from skeletal muscle in response to exercise, and act hormonally to evoke a cardioprotective effect. To test these hypotheses, we assessed the effect of exercise on skeletal and cardiac muscle proenkephalin (PENK) expression, as well as on myocardial ischemic tolerance. We found that exercise was profoundly cardioprotective in the rat. Additionally, exercise was associated with a change in PENK levels in skeletal and cardiac muscle, but not in intestine. Finally, hearts from exercised animals appeared to have an enhanced ischemia-induced enkephalin release relative to control animals. These findings, coupled with our recent report that enkephalins can be absorbed from skeletal muscle and can induce a cardioprotective effect, strongly support our hypothesis that exercise-induced enkephalin release from skeletal muscle, acting hormonally, contributes to acute cardioprotection. [ABSTRACT FROM AUTHOR]