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Anesthesiology:
Correspondence

Nitrous Oxide and Preconditioning

Weber, Nina C. Ph.D.; Preckel, Benedikt M.D., D.E.A.A.; Schlack, Wolfgang M.D., D.E.A.A.*

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In Reply:—

We thank Drs. Pagel and Warltier for their comments on our work and for drawing our attention to their previous article in 1992.1 In that work, 70% nitrous oxide given before and during ischemia and then continued for 15 min during reperfusion impaired the functional recovery of “stunned” myocardium after a brief coronary artery occlusion (15 min) and reperfusion period of 3 h in open-chest, barbiturate-anesthetized dogs. This study thus addressed a combined effect of preischemic, intraischemic, and postischemic treatment, whereas our study addressed the effects of nitrous oxide on the defined mechanism of preconditioning. For this purpose, the gas was administered only during 3 × 5 min before ischemia2 as a preconditioning stimulus followed by a washout before ischemia. We could show that nitrous oxide provided no cardioprotection by anesthetic preconditioning and that it did not interfere with the cardioprotection by isoflurane preconditioning.2
Siker et al.1 investigated regional hemodynamics, myocardial tissue perfusion, and myocardial oxygen consumption in an animal model with myocardial collateral circulation. Their endpoint was the functional recovery of stunned myocardium. In contrast, we used an in vivo rat model and assessed lethal cell damage, i.e., infarct size as the classic endpoint of ischemia–reperfusion injury. In addition, we were mainly interested in the molecular mechanisms involved.2 The results clearly demonstrated that nitrous oxide in a clinically relevant dose does not produce any preconditioning effect on the heart and that none of the most discussed molecular targets, such as protein kinase C-ϵ and Src kinase, are affected by nitrous oxide—in contrast to the volatile anesthetic isoflurane.2 Therefore, our study showed for the first time that nitrous oxide is, until today, the only inhalational anesthetic that offers no myocardial protection by preconditioning. It is difficult to directly compare both studies, because they are looking at different phenomena of myocardial ischemia–reperfusion injury in different experimental settings using different administration protocols; e.g., as pointed out in the letter, in our study hemodynamic determinants of myocardial oxygen consumption such as myocardial contractility or left ventricular preload were not measured. In our experimental setting, these regional hemodynamics might not be as relevant as in the study from Siker et al. because the preconditioning stimulus (3 × 5 min of nitrous oxide inhalation) was ended 5 min before ischemia–reperfusion and, in addition, did not alter global hemodynamics as the longer administration protocol during ischemia–reperfusion in the study of Siker et al. Therefore, we cannot conclude that similar hemodynamic effects as previously demonstrated by Siker et al. in their dog model of myocardial stunning are relevant for our rat model investigating myocardial preconditioning.
In conclusion, although addressing different topics, at least both studies demonstrated that nitrous oxide is—in contrast to volatile anesthetics and the inert gas xenon3,4—the only inhalational anesthetic without myocardial protective effects in an ischemia–reperfusion situation.
Nina C. Weber, Ph.D.
Benedikt Preckel, M.D., D.E.A.A.
Wolfgang Schlack, M.D., D.E.A.A.*
*University of Amsterdam, Amsterdam, The Netherlands. w.s.schlack@amc.uva.nl
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References

1. Siker D, Pagel PS, Pelc LR, Kampine JP, Schmeling WT, Warltier DC: Nitrous oxide impairs functional recovery of stunned myocardium in barbiturate-anesthetized, acutely instrumented dogs. Anesth Analg 1992; 75:539–48

2. Weber NC, Toma O, Awab S, Fräßdorf J, Preckel B, Schlack W: Effects of nitrous oxide on the rat heart in vivo: Another inhalational anesthetic that preconditions the heart? Anesthesiology 2005; 103:1174–82

3. Weber NC, Toma O, Wolter JI, Obal D, Müllenheim J, Preckel B, Schlack W: The noble gas Xenon induces pharmacological preconditioning in the rat heart in vivo via induction of PKC-epsilon and p38 MAPK. Br J Pharmacol 2005; 144:123–32

4. Weber NC, Toma O, Wolter JI, Wirthle NM, Schlack W, Preckel B: Mechanisms of xenon and isoflurane induced preconditioning: A potential link to the cytoskeleton via the MAPKAPK-2 HSP27 pathway. Br J Pharmacol 2005; 146:445–55

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