The major long-term objective of this proposed research project is to synthesize and evaluate a variety of potential lipid mediators of circulatory disease, including (a) thromboxane A2 (TxA2) and thromboxane analogs, (b) platelet activating factor (PAF) and PAF analogs, and (c) lipoxins (Lx) (e.g., LxA4, LxB4, LxA5, LxB5). These lipid compounds will be studied as mediators or inhibitors of ischemic (e.g., myocardial ischemia) and shock (e.g., hemorrhagic, endotoxic) disorders. The primary purpose will be to define the potential role of these purported mediators in these disease states and to develop analogs or other agents as pharmacologic antagonists against these mediators. In order to achieve these objectives, studies are planned in which TxA2 and a key TxA2 analog, number of PAF analogs, and a series of lipoxins will be synthesized. These compounds will then be studied in terms of their biochemical interaction with other classes of lipid mediators (e.g., PAF analogs will be studied for their ability to release leukotrienes and thromboxanes; TxA2 analogs will be studied for PAF and leukotriene release). In a comprehensive manner, these analogs will then be studied in selected models of circulatory disease in which the parent mediator has been shown to be involved. These models constitute both in vitro preparations (e.g., isolated perfused cat coronary arteries, isolated guinea pig pulmonary parenchymal strips, isolated perfused rat hearts) and in vivo models (e.g., cat myocardial ischemia, rabbit endotoxic shock, guinea pig anaphylactic shock, and rat hemorrhagic shock). We hope to obtain potentially useful compounds in this manner. Successful investigations should lead to (a) useful tools in studying the role of these lipid mediators in pathphysiologic processes,and (b) potentially valuable therapeutic agents in the treatment of ischemia and shock-like disorders.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL025575-09
Application #
3338137
Study Section
Experimental Cardiovascular Sciences Study Section (ECS)
Project Start
1981-07-01
Project End
1992-06-30
Budget Start
1989-07-01
Budget End
1990-06-30
Support Year
9
Fiscal Year
1989
Total Cost
Indirect Cost
Name
Thomas Jefferson University
Department
Type
Schools of Medicine
DUNS #
061197161
City
Philadelphia
State
PA
Country
United States
Zip Code
19107
Christopher, T A; Ma, X L; Lefer, A M (1994) Beneficial actions of S-nitroso-N-acetylpenicillamine, a nitric oxide donor, in murine traumatic shock. Shock 1:19-24
Christopher, T A; Ma, X L; Gauthier, T W et al. (1994) Beneficial actions of CP-0127, a novel bradykinin receptor antagonist, in murine traumatic shock. Am J Physiol 266:H867-73
Guo, J P; Milhoan, K A; Tuan, R S et al. (1994) Beneficial effect of SPM-5185, a cysteine-containing nitric oxide donor, in rat carotid artery intimal injury. Circ Res 75:77-84
Buerke, M; Weyrich, A S; Lefer, A M (1994) Isolated cardiac myocytes are sensitized by hypoxia-reoxygenation to neutrophil-released mediators. Am J Physiol 266:H128-36
Lefer, A M; Siegfried, M R; Ma, X L (1993) Protection of ischemia-reperfusion injury by sydnonimine NO donors via inhibition of neutrophil-endothelium interaction. J Cardiovasc Pharmacol 22 Suppl 7:S27-33
Ma, X L; Weyrich, A S; Krantz, S et al. (1992) Mechanisms of the cardioprotective actions of WEB-2170, bepafant, a platelet activating factor antagonist, in myocardial ischemia and reperfusion. J Pharmacol Exp Ther 260:1229-36
Karasawa, A; Rochester, J A; Lefer, A M (1992) Effects of adenosine, an adenosine-A1 antagonist, and their combination in splanchnic occlusion shock in rats. Circ Shock 36:154-61
Siegfried, M R; Erhardt, J; Rider, T et al. (1992) Cardioprotection and attenuation of endothelial dysfunction by organic nitric oxide donors in myocardial ischemia-reperfusion. J Pharmacol Exp Ther 260:668-75
Carey, C; Siegfried, M R; Ma, X L et al. (1992) Antishock and endothelial protective actions of a NO donor in mesenteric ischemia and reperfusion. Circ Shock 38:209-16
Ma, X L; Lefer, D J; Lefer, A M et al. (1992) Coronary endothelial and cardiac protective effects of a monoclonal antibody to intercellular adhesion molecule-1 in myocardial ischemia and reperfusion. Circulation 86:937-46

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