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J Thorac Cardiovasc Surg 2002;124:418-419
© 2002 The American Association for Thoracic Surgery

Letters to the Editor

Role of cardiopulmonary bypass and cardioplegic arrest in the regulation of cardiac nitric oxide synthase activity

Department of Cardiothoracic Surgery^a, Institute I for Anatomy^b, University of Cologne, Germany

To the Editor:

We read with interest the article by Mayers and coworkers ¹ on the role of cardiopulmonary bypass (CPB) and cardioplegic arrest in the activity of both myocardial nitric oxide synthase (NOS) isoforms, the endothelial (eNOS) or Ca⁺⁺-dependent NOS, synonymously termed constitutive NOS or NOS-III, and the inducible NOS (iNOS), the Ca⁺⁺-independent NOS or NOS-II. In human right atrial samples, they found increased total NOS activity at CPB termination compared with CPB onset. ¹ They state that even though they cannot distinguish between the effects of CPB on NOS activity from those attributable to "grafting," their previous canine study, ² in which they demonstrated increased iNOS activity resulting from CPB, suggests that CPB is responsible for increased NOS activity. ¹

We would like to comment on their data interpretation, because we have investigated this very issue. We have shown in human left ventricular myocardium that eNOS activity increased after ischemia/reperfusion induced by blood cardioplegia in patients undergoing coronary artery surgery on CPB. ³ In contrast, eNOS activity was not affected when patients were subjected to continuous coronary perfusion with normothermic oxygenated blood enriched with the ß-blocker esmolol on CPB, a nonischemic myocardial protection method. ³ These data suggested that myocardial ischemia but not CPB acts as a stimulus resulting in eNOS activation during initial reperfusion. ³ We and others have further investigated the effects of myocardial ischemia on eNOS activity in rat hearts and found that only 5 minutes of ischemia is sufficient to increase detectable eNOS activity. ^4,5 This fast eNOS activation suggests a conformational change of the enzyme eNOS from an inactive, not detectable state to an active form that can be detected by immunocytochemistry. ⁴ In contrast to this fast eNOS activation, investigators have shown that iNOS activation requires 4 to 6 hours. ⁶ This is in agreement with the previous work by Mayers and coworkers, ² in which they showed increased iNOS activity at 4 hours after CPB but no change in eNOS activity. Thus, our present knowledge of NOS activity regulation during cardiac surgery suggests that (1) myocardial ischemia but not CPB acts as a trigger for rapid eNOS activation and (2) CPB induces a much slower iNOS activation, probably through release of various mediators including cytokines and endotoxins. ⁷ Future studies are required to further elucidate the time courses of eNOS and iNOS activation and inactivation, respectively, and to evaluate the potentially dose-dependent cardioprotective effects of selective eNOS and/or iNOS inhibition.

12/8/126040

doi:10.1067/mtc.2002.126040

References

1. Mayers I, Hurst T, Puttagunta L, Radomski A, Mycyk T, Sawicki G, et al. Cardiac surgery increases the activity of matrix metalloproteinases and nitric oxide synthase in human hearts. J Thorac Cardiovasc Surg. 2001;122:746-52.[Abstract/Free Full Text]
   
2. Mayers I, Salas E, Hurst T, Johnson D, Radomski MW. Increased nitric oxide synthase activity after canine cardiopulmonary bypass is suppressed by S-nitrosoglutathione. J Thorac Cardiovasc Surg. 1999;117:1009-16.[Abstract/Free Full Text]
   
3. Mehlhorn U, Bloch W, Krahwinkel A, LaRose K, Geissler HJ, Hekmat K, et al. Activation of myocardial constitutive nitric oxide synthase during coronary artery surgery. Eur J Cardiothorac Surg. 2000;17:305-11.[Abstract/Free Full Text]
   
4. Bloch W, Mehlhorn U, Krahwinkel A, Reiner M, Dittrich M, Özkara C, et al. Ischemia increases detectable endothelial nitric oxide synthase in rat and human myocardium. Nitric Oxide. 2001;5:317-33.[Medline]
   
5. Depré C, Fierain L, Hue L. Activation of nitric oxide synthase by ischaemia in the perfused heart. Cardiovasc Res. 1997;33:82-7.[Medline]
   
6. Balligand JL, Ungureanu-Longrois D, Simmons WW, Pimental D, Malinski TA, Kapturczak M, et al. Cytokine-inducible nitric oxide synthase (iNOS) expression in cardiac myocytes: characterization and regulation of iNOS expression and detection of iNOS activity in single cardiac myocytes in vitro. J Biol Chem. 1994;269:27580-8.[Abstract/Free Full Text]
   
7. Ungureanu-Longrois D, Balligand JL, Kelly RA, Smith TW. Myocardial contractile dysfunction in the systemic inflammatory response syndrome: role of a cytokine-inducible nitric oxide synthase in cardiac myocytes. J Mol Cell Cardiol. 1995;27:155-67.[Medline]
   

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 Similar articles in PubMed Alert me to new issues of the journal Add to Personal Folders Download to citation manager Author home page(s): Uwe Mehlhorn Permission Requests Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Mehlhorn, U. Articles by Bloch, W. Search for Related Content PubMed PubMed Citation Articles by Mehlhorn, U. Articles by Bloch, W.