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Ann Thorac Surg 1997;64:1659-1660
© 1997 The Society of Thoracic Surgeons
DR JAKOB VINTEN-JOHANSEN (Atlanta, GA): That was a very nice presentation, and as you have alluded to, it is a very controversial issue whether nitric oxide is beneficial or deleterious in ischemia reperfusion. Did you try to use authentic nitric oxide in the perfusate so that there are no other confounding effects of donors, and to reproduce your results with these conditions?
DR COPE: No, we did not. However, I am aware of at least one previous study in which the authentic gas was used and, in fact, it showed beneficial effects.
DR RICHARD M. ENGELMAN (Springfield, MA): I likewise enjoyed your presentation. Did you administer this nitric oxide donor, the sodium nitroprusside, during reperfusion only? Do you think that your results would have been any different if this had been administered before ischemia?
DR COPE:It is a possibility. The experimental protocols vary widely between different studies. Although some initiate the donor at the end of ischemia and continue it into reperfusion, others begin at the inception of reperfusion, as did ours.
The importance of the time at which infusion of the nitric oxide donor is begun would certainly be interesting to examine in a future study.
DR BRADLEY S. ALLEN (Chicago, IL): This is a very nice study. However, several investigators have recently shown that l-arginine, which is also a nitric oxide donor, seems to prevent or modify the reperfusion injury. Therefore, I am wondering how you explain the discrepancy between your results and these other studies, as one nitric oxide donor (l-arginine) seems to improve the reperfusion injury, and another nitric oxide donor (sodium nitroprusside) does not, no matter what the dose.
DR COPE: That is a very good question, and, unfortunately, it is not answered with this study. The reason we chose sodium nitroprusside is so that we could achieve supraphysiologic concentrations of nitric oxide in the coronary circulation, whereas if you relied just on endogenous production with l-arginine, one would think that supraphysiologic levels would not be achieved.
I suspect a lot of the differences between the studies are related to model differences. I do not know that for a fact, but I suspect there may be an element of that involved.
DR VINTEN-JOHANSEN: Did you look at neutrophils in these rabbits? Sometimes neutrophils get activated by the Langendorff type of preparation by surface contact reactions with plastics or glass. If they were preactivated, then this may not have been overcome by nitric oxide donor administration at reperfusion. Therefore, nitroprusside may not have exerted an antineutrophil mechanism.
DR COPE: Actually, we do have some late-breaking data with regard to that question. We did measure myeloperoxidase in the ventricular myocardium, and there were no significant differences between any of the groups with regard to myeloperoxidase.
DR DUKE E. CAMERON (Baltimore, MD): I enjoyed this paper very much. I have two questions. First, could you elaborate on how you chose your dose of sodium nitroprusside? Second, have you tried this with a cold arrested heart rather than normothermic ischemia, a situation we have all sworn to avoid?
DR COPE: With regard to the second question, no, we did not. We went with straight-up warm ischemia, and as I mentioned, there may be a role played by model differences here. Perhaps the results might have been different had we used hypothermic arrest.
As I mentioned, a previous study found that the approximate intracoronary nitric oxide concentration in a nonischemic heart without the presence of ischemia is approximately 1 nmol/L. Therefore, we chose our physiologic dose as 1 nmol • L-1 • min hoping to put us somewhere close to the physiologic range after ischemia.
DR JOHN E. MAYER JR (Boston, MA): I have one last minor technical question. What was the effect of the nitroprusside on the donor animal? Were there any hemodynamic effects that you know of?
DR COPE: Actually, during the 20 minutes of reperfusion we diverted the blood away from the support animal and wasted it because otherwise the animal succumbed to hypotension.
DR J. KENT TRINKLE (San Antonio, TX): This may be a matter of timing of the nitroprusside. If you look at lung transplantation as an experimental model, if you give extrinsic nitric oxide to the donor animal, you will get less ischemia–reperfusion injury. If you wait and put it in the flush solution, you get less injury. If you wait and put it in the storage solution, you get less injury. If you wait and give it to the recipient animal before reperfusion you have less injury. But if you wait until you take your clamps off and reperfuse that organ, then add the nitric oxide donor, you get worse injury. The reason is peroxynitrite, plus possibly up-regulation of inorganic nitric oxide synthase as opposed to the endothelial nitric oxide synthase, which in turn depresses myocardial function.
So if you had just given it a little bit earlier, it would probably have been good instead of bad.
Related Article
Ann. Thorac. Surg. 1997 64: 1656-1659.
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