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Figure 4 shows responses of isolated perfused rat hearts to perfusion with Krebs-Henseleit buffer at 15 ml/min at a Po, of 325 to 350 mm Hg (ie, 95% 02 + 5% COJ for 10 min followed by hypoxia (95% Na + 5% CO*), resulting in a Pos of 40-50 mm Hg for 30 min, and then reoxygenation with 95% 0*+5% COa for 20 min. At the beginning and at the end of this protocol, hearts were tested for their ability to dilate in response to ACh and NTG, compared with initial control responses. Hypoxia and reoxygenation clearly resulted in a marked decrease in vasorelaxation in response to ACh but not to NTG. This observation also indicates that a selective endothelial dysfunction was induced by hypoxia similar to that resulting after ischemia. Since the introduction of Oa is known to produce oxygen-derived free radicals following a period of oxygen deprivation, we also perfused hypoxic hearts with recombinant human superoxide dismutase (hSOD). Clearly, hSOD prevented the endothelial dysfunction in rat hearts subjected to hypoxia-reoxygenation, suggesting that hypoxia-reoxygenation induces the rat heart to generate superoxide radicals, which then produce endothelium dysfunction (ie, impaired EDRF responses). These results strongly point to the generation of superoxide radicals by the rat coronary endothelium, resulting in endothelial dysfunction (loss of EDRF). These results are consistent with our knowledge of the rat endothelium, a known source of xanthine oxidase-producing free radicals. Scavengers of superoxide ions (eg, SOD) or endothelial protective agents (eg, TGF-p) can protect the endothelium from the potentially dangerous effects of superoxide anions. Thus, monitoring the ability of a vascular bed to respond completely to endothelial-dependent dilators can be informative about the state of that vascular bed and perhaps about the state of health of the organism. Figure 4. Summary of responses of isolated perfused hypoxic rat hearts to acetylcholine ACh) and nitroglycerin (NTG). Hearts were perfused with 95% N,+5% CO, for 30 min, followed by reoxygenation with 95% Of+5% CO, for 20 min. Data on the right were obtained from hearts perfused with 5 mg hSOD during the hypoxic period.