Thromboxane synthetase inhibitors reduce infarct size by a platelet-dependent, aspirin-sensitive mechanism.

Abstract

Platelets are suggested to exacerbate ischemia-induced myocardial injury, which has led to the study of various antiplatelet therapies including thromboxane synthetase inhibitors (TXSI). Two such agents, benzylimidazole and OKY-046, reduce infarct size commensurate with a diminution in serum thromboxane B2 formation in anesthetized dogs subjected to 90 minutes of coronary artery occlusion followed by 5 hours of reperfusion. In contrast, platelet depletion with specific antiserum does not reduce infarct size but prevents the cardioprotection afforded by the TXSI. Platelet-derived prostaglandin endoperoxides (PGG2 and PGH2), which cannot be converted to thromboxane A2 in the inhibited platelet, can be transformed to PGE2 and PGD2 in plasma and to PGI2 by the blood vessel wall. These prostaglandins are considered "cardioprotective." Consequently, a low dose of aspirin (3-5 mg/kg) given 24 hours before coronary occlusion was used to selectively block the platelet cyclooxygenase enzyme. Aspirin, by itself, does not reduce infarct size, but it suppresses the myocardial salvage induced by OKY-046. Thus, TXSI reduce infarct size by platelet-dependent, aspirin-sensitive mechanism that depends on the redirection of platelet-derived PGG2 and PGH2 to protective metabolites, rather than inhibition of thromboxane A2 per se. Moreover, myocardial salvage induced by the TXSI is accompanied by a reduction in neutrophil accumulation in the myocardium, as indicated by the levels of the neutrophil-specific myeloperoxidase enzyme. Platelet depletion or pretreatment with aspirin prevents the TXSI-induced suppression of neutrophil accumulation. Consequently, it is proposed that the prostaglandin-mediated protective effects of TXSI can be resolved, at least in part, in terms of a braking action on neutrophil activation to prevent leukocyte-dependent tissue injury.

• Authors: K M Mullane, D Fornabaio
• Journal: Circulation research (Circ Res) Vol. 62 Issue 4 Pg. 668-78 (Apr 1988) ISSN: 0009-7330 [Print] United States
• PMID: 3127073 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Acrylates
• Cyclooxygenase Inhibitors
• Imidazoles
• Methacrylates
• 1-benzylimidazole
• Thromboxane-A Synthase
• ozagrel
• Aspirin

Topics

• Acrylates (pharmacology)
• Animals
• Aspirin (pharmacology)
• Biomechanical Phenomena
• Blood Platelets (metabolism, physiology)
• Coronary Disease (drug therapy, pathology)
• Cyclooxygenase Inhibitors
• Dogs
• Imidazoles (pharmacology)
• Methacrylates (pharmacology)
• Myocardial Infarction (pathology)
• Thromboxane-A Synthase (antagonists & inhibitors)