Pyrrolizidine alkaloids such as monocrotaline (MCT) are produced by plants which intoxicate humans and livestock in the U.S. and other countries. MCT produces lung injury accompanied by pulmonary hypertension and right ventricular hypertrophy (RVH) in experimental animals. Its pathophysiology shares much in common with certain types of chronic pulmonary hypertension in humans, and thus provides a good animal model for such human disease. A reactive pyrrole metabolite (MCTP) of MCT is thought to be the proximate toxicant, but its mechanism of toxicity is unknown. The most striking changes in pulmonary morphology in MCT intoxication includes alterations in vascular endothelium and accumulation in vessels of thrombi containing large numbers of platelets. The endothelial cell injury is associated with diminished capacity of the lungs to inactivate circulating 5-hydroxytryptamine (5HT). Thrombocytopenia reduces the degree of RVH following treatment with MCTP, suggesting a role for the platelet in the toxicology of this agent. The overall goal of the proposed research is to elucidate the role of the platelet in the cardiopulmonary toxicology of MCTP. Although the platelet could be involved in many ways, efforts for this granting period will focus upon the involvement of 5HT and of thromboxane A2 (TxA2). These are released by platelets and cause pulmonary vasoconstriction and platelet activation and thus may mediate the pulmonary hypertensive response to MCTP. Experiments will be performed to determine platelet kinetics and 5HT turnover in MCTP-intoxicated rats. The distribution of 5HT between platelets and plasma will also be examined. The isolated lung preparation will be used to determine if altered interactions between perfused platelets and lung occur after MCTP treatment which affect 5HT distribution, disposition or action or which alter the balance between TxA2 and prostacyclin (PGI2). Experiments with platelet-rich plasma will test whether uptake or release of 5HT by platelets is altered and whether the ability of platelets to generate and release TxA2 in changed in rats intoxicated with MCTP. The cardiopulmonary toxicity of MCTP will be compared in the fawn-hooded rat, a strain with a defect in 5HT storage and release. Finally, studies in vivo will determine effects on MCTP toxicity of drugs which are 5HT or thromboxane biosynthesis inhibitors or receptor antagonists. These studies will increase understanding of the role of the platelet in the responses of lung to chronic vascular injury from toxic agents. Such an understanding may lead to useful measures to prevent or to treat human pulmonary hypertension and right heart failure.
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