Possible mechanisms for the protective action of alpha-tocopherol in vascular hypoxia.

1. The mechanism of the protective action of alpha-tocopherol (vitamin E) in sustaining noradrenaline-induced responses in vascular hypoxia was investigated using pharmacological methods. 2. Four vascular spasmogenic agents, methoxamine, acetylcholine, histamine and potassium, each with a different mode of action were used to produce responses in guinea-pig isolated portal vein. In each case the responses were significantly reduced by hypoxia or hypoxia and a substrate-free environment. 3. Pre-incubation of the vein with alpha-tocopherol protected the noradrenaline-induced responses against hypoxia in the substrate-free environment, However, at the EC50 concentration for protection of noradrenaline, alpha-tocopherol failed to protect the responses of each agent from the inhibitory effects of hypoxia, suggesting a mechanism of protection involving noradrenaline. 4. Drugs known to interfere with the disposition of noradrenaline in sympathetically innervated tissues, cocaine, hydrocortisone and tyramine did not affect the response to alpha-tocopherol. 5. Responses to calcium were unaffected by alpha-tocopherol in normoxia and hypoxia. 6. The protective action of alpha-tocopherol was not mimicked by the chromanol ring of the vitamin structure, Trolox C, suggesting that the vascular protection in hypoxia was not dependent on an antioxidant mechanism. 7. However, the glycolytic enzyme inhibitor, iodoacetic acid, prevented the protective action of the vitamin in hypoxia, suggesting that alpha-tocopherol enhanced noradrenaline-mediated activity in hypoxia through an iodoacetic acid-sensitive pathway.