Ann Thorac Surg 1996;62:385
© 1996 The Society of Thoracic Surgeons
Discussion
Discussion
See also page 378.
DR MEHMET C. OZ (New York, NY): I have spent a fair amount of my research career studying nitric oxide and am still confused by its effects. Even in this meeting's program there are several great things that nitric oxide does and several terrible things. You are always trying to figure out, even when you work in the field, which side of the cutting edge you are on. Do you have any evidence that inducing nitric oxide actually accelerates rejection? For example, did you give l-arginine or any other kind of nitric oxide inducer?
DR WORRALL: Many of the actions of nitric oxide depend on the conditions under which it is produced, including the local redox potential and the concentration of nitric oxide produced. Most of the pathologic effects of nitric oxide, particularly in tissue injury, result from high levels of nitric oxide, as are produced during acute cardiac allograft rejection. We have not specifically examined whether we can accelerate acute rejection through increasing the concentration of l-arginine, which is the substrate for nitric oxide synthase, in the rat's diet or through transfection of the inducible nitric oxide synthase gene into isografts, for example, although that would be interesting to examine.
DR JAMES K. KIRKLIN (Birmingham, AL): If you had a systemic blocker of inducible nitric oxide synthase, what sort of systemic or whole organism effects would you anticipate?
DR WORRALL: Systemic administration of nonselective nitric oxide synthase inhibitors such as L-NMAAu: spell out or L-NAMEAu: spell out to animals at doses high enough to inhibit high levels of pathologic nitric oxide produced by inducible nitric oxide synthase expression in the allograft heart, as would be required during allograft rejection, would also cause peripheral vasoconstriction through inhibition of constitutive nitric oxide synthase. This would result in reduced blood flow to the allograft, which would probably end up being deleterious. Aminoguanidine and other newer inducible nitric oxide synthase inhibitors that are currently under development are at least 10- to 100-fold selective for the inducible nitric oxide synthase versus the constitutive nitric oxide synthase. So one would expect minimal side effects.
Related Article
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Inhibition of Inducible Nitric Oxide Synthase Attenuates Established Acute Cardiac Allograft Rejection
- Neil K. Worrall, Thomas P. Misko, Patrick M. Sullivan, Jia-J. Hui, and T. Bruce Ferguson, Jr
Ann. Thorac. Surg. 1996 62: 378-385.
[Abstract]
[Full Text]
