and specific aims) This proposal is a revised renewal application to further characterize the mechanisms underlying anoxic endothelium (EC)-dependent contractions of canine coronary arteries and EC-dependent responses following ischemia in acute versus chronic reperfused vessels.
Specific aims focus on two major areas: A) EC-dependent anoxic contractions: 1) Whether the production of nitric oxide (EDRF) or endothelin (ET) by ECs or cGMP by VSM participate in EC-dependent vasoconstriction under anoxic conditions; 2) Whether a critical concentration of cGMP unmasks an activation of the contractile process in VSM by anoxia; and B) EC-dependent responses after reperfusion injury: 1) Whether the blunted EC-dependent relaxation after reperfusion injury is dueto reduced release ofa hyperpolarizing factor (EDHF), an augmented production of ET, or by reduced production of nitric oxide; 2) Whether impairment of the pertussis toxin-sensitive release of EDRF contributes to the acute and chronic blunting of EC-dependent relaxations to aggregating platelets with reperfusion; 3) Studies as to why EC- dependent anoxic contractions are exacerbated inchronically reperfused coronary arteries; and 4) Whether chronic treatment with nitric oxide donors or with omega- unsaturated fatty acids influence altered EC-dependent responsiveness and/or adhesiveness of formed elements to the endothelium after reperfusion. Conventional techniques are proposed to measure isometric tension in intact versus denuded canine coronary arteries, nitric oxide, ET, cGMP, as well as bioassays in cascade or """"""""sandwich"""""""" preparations, and possible cell culture methodologies.
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