Abstract

The major objective of this research project is to evaluate synthetic analogs of thromboxanes in terms of their cardiovascular and biochemical properties relevant to their potential usefulness in life-threatening ischemic situations such as myocardial ischemia, hemorrhagic and traumatic shock. First, each analog, after its structure is confirmed, will be classified as an agonist, antagonist, activator, or inhibitor of classical prostaglandins, prostacyclin (PGI2) or thromboxane (TxA2). Secondly, each compound will be assigned a biological profile based on key biological actions (i.e., inhibition of platelet aggregation, lysosomal membrane stabilization, coronary vasoactivity and cardiac inotropicity). Thirdly, each promising compound will be studied in several well-defined pathophysiologic models including acute myocardial ischemia in cats, traumatic shock in rats, and arachidonic acid-induced thrombosis in rabbits, for prolongation of survival, reduction in ischemic tissue damage, prevention of proteolysis and toxic products of proteolysis, and formation of thromboxane A2 and prostacyclin. In this manner, we should be able to find useful new therapeutic agents (e.g., prostacyclin analogs, thromboxane inhibitors) as well as useful biological tools for prostaglandin research (e.g., thromboxane agonists, prostacyclin synthetase inhibitors).

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL025575-06
Application #
3338135
Study Section
Experimental Cardiovascular Sciences Study Section (ECS)
Project Start
1981-07-01
Project End
1988-06-30
Budget Start
1986-07-01
Budget End
1987-06-30
Support Year
6
Fiscal Year
1986
Total Cost
Indirect Cost

  Institution

Name
Thomas Jefferson University
Department
Type
Schools of Medicine
DUNS #
061197161
City
Philadelphia
State
PA
Country
United States
Zip Code
19107

  Publications

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
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
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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