Thromboxane (TXA2), is a powerful vasoconstrictor and aggregator of platelets and leukocytes, and appears to promote lymphocyte proliferation. These characteristics imply it may have a causal role in rejection. The hypothesis will be tested by using the rat cardiac allograft model and treating the animals with both thromboxane synthase inhibitors and receptor antagonists. Feasibility studies have shown that the TXA2 receptor antagonist L640,035 as well as the TXA2 synthase inhibitor, OKY-1581, prolong allograft survival in this rat experimental model. The involvement of other arachidonate metabolites, namely the leukotrienes, will be tested by similar treatment with receptor antagonists and various lipoxygenase inhibitors. Since these arachidonate metabolites exert their pharmacologic effects in part by promoting Ca++ influx, we will also test the effects of the clinically available calcium blocking drugs in prolonging allograft survival. Preliminary data indicate that the calcium blocker nifedipine prolongs rat cardiac allograft survival in a dose dependent manner. Because arachidonate metabolites are believed to be involved in the development of arteriosclerosis, we will also test the aforementioned drugs in the cyclosporine-treated rat cardiac allograft model in order to reduce the development of arteriosclerosis. A feature of the application will be evaluation of the effect of the pharmacological manipulation of arachidonic acid metabolism on the relationship between urinary i-TXB2, cytotoxicity, T cell subsets and the differential count of the inflammatory cells invading the cardiac allograft. The results will be directly applicable to the organ transplanted patient, especially those receiving cadaver allografts. The long term objective is to improve allograft function and the survival of the patients.
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| Foegh, M L; Hartmann, D P; Rowles, J R et al. (1987) Leukotrienes, thromboxane, and platelet activating factor in organ transplantation. Adv Prostaglandin Thromboxane Leukot Res 17A:140-6 |
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| Foegh, M L; Alijani, M R; Friedman, R M et al. (1986) Eicosanoids, gamma-interferon and inflammatory cells in kidney transplant patients. Adv Prostaglandin Thromboxane Leukot Res 16:205-14 |
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