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Ann Thorac Surg 2001;72:843-844
© 2001 The Society of Thoracic Surgeons

Invited commentary

^a Human Physiology, University of California–Davis, 4147A Tupper Hall, Davis, CA 95616, USA

e-mail: seanderson{at}ucdavis.edu

This paper is one of numerous recently published which underscores our incomplete understanding of the roles of Na and the Na/H exchanger (NHE1) in myocardial injury induced by ischemia/reperfusion. The hypothesis tested here arises from ample evidence that untreated ischemia leads to increases in cytosolic H, Na, and Ca concentrations with the first two ions linked by NHE1 and the latter two by sarcolemmal Na/Ca exchange. There is also ample evidence that in otherwise untreated hearts limiting cytosolic Na accumulation (and in particular inhibiting NHE1) limits cytosolic Ca accumulation and diminishes injury induced by ischemia/reperfusion.

Given this background it is reasonable to predict that including HOE 642 (accepted as a specific NHE1 inhibitor) in cardioplegia is likely to be cytoprotective. However, it is well established that cardioplegia alone diminishes cytosolic proton accumulation which, in and of itself, is expected to diminish NHE1 activity, and thus decrease cytosolic Na and thereby Ca accumulation compared to untreated ischemia. Thus, when proton accumulation is limited by cardioplegia, pharmacological inhibition of NHE1 may be of little or no benefit, and, to the extent NHE1 inhibitors are not specific, their addition to cardioplegia or subsequently during reperfusion may be counterproductive. For example, if the inhibitor added with or after cardioplegia has a small inhibitory effect on Na/Ca exchange, the major pathway for Ca efflux may be sufficiently limited to offset any benefit gained from limiting proton and Na accumulation.

Unfortunately, because this study failed to measure any of the ion concentrations affected by NHE1 inhibition, conclusions concerning mechanism are speculative. Furthermore, because the cardioplegic solution used here is hypertonic compared to the control perfusate and the effects on Na uptake and NHE1 caused by exposing heart cells to hypertonic solutions depend upon tonicity and oxygen availability [1], any attempt to characterize the added effect of NHE1 inhibition with this cardioplegia is confounded.

Nevertheless, the work is important because it demonstrates that under the conditions of this study HOE 642 combined with cardioplegia is less cytoprotective than cardioplegia alone. In doing so it underscores the continued need for studies which measure the changes in the ions pertinent to the hypothesis so mechanism(s) can be determined and treatments can be tailored for the disturbance.

References

1. Ho H.S., Liu H., Cala P.M., Anderson S.E. Hypertonic perfusion inhibits intracellular Na and Ca accumulation in hypoxic myocardium. Am J Physiol 2000;278:C953-C964.[Abstract/Free Full Text]

This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Alert me to new issues of the journal Add to Personal Folders Download to citation manager Permission Requests Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Anderson, S. E. Search for Related Content PubMed Articles by Anderson, S. E. Related Collections Myocardial protection Related Article