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The Arachidonic Acid Cascade: Thromboxane A2 Antagonism and Synthetase Inhibition in Experimental Myocardial Infarction

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Pathophysiology of Cardiovascular Disease

Part of the book series: Progress in Experimental Cardiology ((PREC,volume 10))

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Summary

The pathogenesis of myocardial ischemia depends on the factors that upset the balance between myocardial oxygen supply and demand. Arachidonic acid accumulation in the ischemic myocardial tissue, its release and subsequent metabolisation into several classes of eicosanoids and lipid peroxides occurs simultaneously with the development of myocardial ischemic injury. Eicosanoid release in acute ischemia is primarily deleterious and enhances inflammatory-type reactions and functional disturbances of the myocardium. Endoperoxide intermediates (i.e. prostaglandin H2), thromboxane A2 (TXA2) and other eicosanoids having vasoconstrictor and proaggregatory properties are thought to contribute to the pathophysiology of acute myocardial ischemia. Consequently, inhibition of the formation and/or action of TXA2 and other deleterious eicosanoids have been shown to reduce the severity of myocardial ischemia in models of coronary occlusion. In the present study the effects of the specific thromboxane synthetase inhibitor UK 38485 (dazmegrel) and the TXA2/prostaglandin endoperoxide receptor antagonist SQ 29548 on myocardial infarct size, cardiometabolic correlates and hemodynamics were determined in a canine model of 24 h acute myocardial infarction. Anesthetised open-chest dogs were subjected to left anterior descending coronary artery ligation. Twenty minutes post-ligation the dogs were given (i) intravenous saline (0.9% NaCl solution) (n = 12), (ii) UK 38485 (3mg/kg i.v.) (n = 10) or SQ 29548 (0.2mg/kg i.v. loading dose with 0.2mg/kg/h i.v. for 4 hours) (n = 10). UK 38485 and SQ 29548 treatment resulted in a significant (p < 0.01) reduction in infarct size as compared to the controls, UK 38485 salvaged 51% and SQ 29548 salvaged 45% of the left ventricular area at risk of infarction. Borh drugs significantly reduced the accumulation of lactate and restored the activity of myocardial enzymes creatine phosphokinase and lactate dehydrogenase in the ischemic zone of the myocardium. Heart rate. systolic blood pressure and the pressure-rate index were not markedly affected by these drugs. The sharp rise in the left ventricular end diastolic pressure in the saline-treated animals was significantly lowered by UK 38485 and SQ 29548 treatment. The ischemia-induced lowering of the maximal rate of rise of left ventricular pressure (LV dP/dtmax) observed in the saline-treated animals was corrected, albeit non-significantly, by SQ 29548 treatment. These results showing the beneficial effects of UK 38485 and SQ 29548 indicate that thromboxane A2 may be involved in the pathogenesis of myocardial ischemia, The study suggests that attenuation of TXA2 synthesis and action may have potential as a mode of therapy for ischemic heart disease.

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Authors and Affiliations

  1. Indian Council of Medical Research, Ansari Nagar, New Delhi, 110 029, India

    Professor Shiva D. Seth (National Professor & Chair in Clinical Pharmacology)

  2. Departments of Pharmacology, All India Institute of Medical Sciences, New Delhi, 110 029, India

    Uma Singh

  3. Departments of Cardiology, All India Institute of Medical Sciences, New Delhi, 110 029, India

    Sandeep Seth

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  1. Professor Shiva D. Seth
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  2. Uma Singh
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  3. Sandeep Seth
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Correspondence to Shiva D. Seth .

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Editors and Affiliations

  1. Institute of Cardiovascular Sciences St. Boniface General Hospital Research Centre Faculty of Medicine, University of Manitoba, Winnipeg, Canada

    Naranjan S. Dhalla PhD, MD (Hon), DSc (Hon) (Distinguished Professor and Director) (Distinguished Professor and Director)

  2. Philipps University of Marburg, Marburg, Germany

    Heinz Rupp PhD (Professor of Medicine) (Professor of Medicine)

  3. Faculty of Medicine, University of Manitoba, Winnipeg, Canada

    Aubie Angel MD (Professor of Internal Medicine) (Professor of Internal Medicine)

  4. Division of Stroke & Vascular Disease St. Boniface General Hospital Research Centre Faculty of Medicine, University of Manitoba, Winnipeg, Canada

    Grant N. Pierce PhD, FACC (Professor & Director) (Professor & Director)

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© 2004 Springer Science+Business Media Dordrecht

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Seth, S.D., Singh, U., Seth, S. (2004). The Arachidonic Acid Cascade: Thromboxane A2 Antagonism and Synthetase Inhibition in Experimental Myocardial Infarction. In: Dhalla, N.S., Rupp, H., Angel, A., Pierce, G.N. (eds) Pathophysiology of Cardiovascular Disease. Progress in Experimental Cardiology, vol 10. Springer, Boston, MA. https://doi.org/10.1007/978-1-4615-0453-5_32

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