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J Thorac Cardiovasc Surg 2000;120:830
© 2000 The American Association for Thoracic Surgery
Letters to the Editor |
Associate Professor
Departments of Physiology and Biophysics, and Surgery
University of Illinois College of Medicine at Chicago Chicago, IL 60612
Reply to the Editor:
Miyamoto and Miyamoto close their letter by raising a very important issue that relates to the heart of their question. Until the mechanisms underlying the protective effects of adenosine are thoroughly understood, adenosine's application cannot be optimized to be effective in the diverse population in which it would be used. Miyamoto and Miyamoto raise two examples that might be of concern if an individual's adenosine handling is altered or if the second messenger system is based on adenylate cyclase. If our working hypothesis is correct, and protein kinase C (PKC) is involved,
1 individuals with conditions or inborn variances that affect this pathway may be unresponsive or may demonstrate adverse effects that are not seen in controlled experiments performed in otherwise normal, healthy animals, organs, or cellular systems. Such matters must be closely considered and investigated as the use of adenosine supplementation advances into clinical use.
It will be important to determine which adenosine receptor subtype(s) are responsible for the actions of adenosine in cardioplegic arrest. The A2 receptor is thought to primarily reside in the coronary vasculature, effecting vasodilation. Such an effect would contribute to benefits afforded by adenosine, but my colleagues and I found no evidence of postarrest perfusion benefits with adenosine supplementation. The myocardium contains both A1 and A3 receptors, either of which may play a role. The cyclic adenosine monophosphate (cAMP)–inhibiting actions of the A1 receptor have generally been linked to conditions wherein adenylate cyclase is concurrently stimulated, as by ß-agonists, and has little or no activity alone. 2 Thus, although we cannot rule out cAMP as a primary mediator of protection, this appears less likely. The A1 and A3 receptors can also be linked to other cellular mechanisms. Our primary focus is PKC.
In a recent publication, 1 my associates and I presented evidence that adenosine supplementation of cardioplegic solution differentially alters PKC isozyme responses to cardioplegic arrest. We demonstrated that cardioplegic arrest results in the translocation of the PKC-delta isozyme. When we added adenosine to the cardioplegic solution, the translocation of PKC-delta was suppressed, whereas the PKC-epsilon isozyme translocated. Our working hypothesis is that such differential actions on PKC isozymes, suppression of PKC-delta and activation of PKC-epsilon, play a significant role in the protection afforded by adenosine in this setting. For example, PKC-delta–mediated phosphorylation of one or more myofilament proteins may explain the decreased Hill coefficient we have observed. Adenosine's suppression of this PKC isozyme would then explain the prevention of altered myofilament activity that we reported in the article referenced by Miyamoto and Miyamoto. 3 The activation of PKC-epsilon by adenosine may also play a role in the increased glyolysis we observe when adenosine is added to cardioplegic solution.
Clearly, more work is needed to tease out the mechanisms responsible for the beneficial effects of adenosine in cardioplegic solutions, and only two cellular pathways have been named herein. We look forward to continued progress toward this end.
12/8/109550
doi:10.1067/mtc.2000.109550
References
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