prostaglandin-h2 and Hypoxia

Thromboxane A2 (TxA2) appears to be an important mediator of ischemia and hypoxia. Despite its short half-life and the fact that it may not circulate in the blood until its values become quite high, TxA2 contributes to the pathogenesis of cardiopulmonary diseases (e.g., sudden death, myocardial ischemia, circulatory shock). It does so because it propagates its own formation by activating platelets and constricting blood vessels, thus activating more TxA2 and trapping it locally within an ischemic or hypoxic region. TxA2 concentrations in the extracellular fluid of lymph of ischemic regions may be much higher than that occurring in nonischemic, normally perfused regions. Specific and potent Tx receptor antagonists (TxRA) have recently become available for study. The TxRA are useful tools in the study of the pathophysiology of Tx-dependent disease processes and have been found to be effective in a variety of ischemic disorders including circulatory shock, myocardial ischemia, and sudden cardiopulmonary death. Moreover, inasmuch as early work indicates that these agents are both safe and effective in humans, Tx receptor antagonists may be employed as therapeutic agents in several cardiovascular disease states. Further investigation is necessary to clarify the role of TxRA as therapeutic agents.

Topics: Animals; Bronchial Spasm; Cardiovascular Diseases; Cell Membrane; Humans; Hypoxia; Ischemia; Platelet Aggregation; Prostaglandin Endoperoxides, Synthetic; Prostaglandin H2; Prostaglandins H; Receptors, Prostaglandin; Receptors, Thromboxane; Vasoconstriction

We have investigated the effect of ONO-3144 (2:aminomethyl-4-tert-butyl-propionylphenol), which accelerates the conversion of prostaglandin G2 to H2 and acts as a scavenger for free radicals, on the reoxygenation injury in the anoxic heart. Rat hearts were perfused retrogradely with Krebs-Henseleit (KH) medium for 30 minutes in Group I. In Group II, the hearts which were perfused with anoxic KH medium for 40 minutes were reoxygenated for 30 minutes. Group III was similar to Group II except that 4 mg ONO-3144/liter was added in anoxic medium. Group IV was similar to group III except ONO-3144 was present both during anoxia and reoxygenation. Coronary effluent was collected for the measurement of creatine phosphokinase (CPK). Tissue from each group was processed for electron microscopy, adenosine triphosphate (ATP), and tissue calcium. A six-fold increase in CPK leakage that was observed after reoxygenation of anoxic heart was prevented by ONO-3144. Tissue ATP was reduced from 21.65 +/- 1.1 mumol/gm dry weight (Group I) to 4.83 +/- 0.8 mumol/gm dry weight (Group II). A significant amount of ATP (9.05 +/- 1.22 mumol/gm dry weight) was preserved in the treated Group IV. The number of normal cells obtained by morphometrical analysis increased significantly from 24.2 +/- 8.4% (Group II) to 70.00 +/- 4.0% (Group IV), and severely injured cells were also reduced to 19.8 +/- 2.8% in the same group as compared to 54.8% in the untreated Group II. At the electron microscopic level, the cellular membranes, mitochondria, vascular endothelium, and glycogen deposits were well preserved in Group IV. The treatment during anoxia only did not minimize the reoxygenation damage (Group III). Thus, treatment with ONO-3144 provides a great protection against reoxygenation injury to the myocyte and vascular endothelium of the anoxic myocardium, perhaps by scavenging active oxygen species.

Topics: Adenosine Triphosphate; Animals; Calcium; Coronary Circulation; Creatine Kinase; Heart; Hypoxia; Myocardial Reperfusion Injury; Myocardium; Oxygen; Propiophenones; Prostaglandin Endoperoxides, Synthetic; Prostaglandin H2; Prostaglandins G; Prostaglandins H; Rats; Rats, Inbred Strains

Arachidonic acid causes dose-dependent increases in pulmonary vascular resistance in perinatal lambs. The specific metabolites that produce this effect are not known; however, a role for thromboxanes (TX's), potent constrictors of vascular smooth muscle, has been proposed. The effects of a specific inhibitor of TX synthase, OKY-1581, were tested in newborn and ventilated fetal lambs using an in situ pump-perfused lower left lobe preparation. Pulmonary and systemic responses of newborns and ventilated fetuses to infusions of arachidonic acid were evaluated in the presence and absence of OKY-1581. Increases in pulmonary vascular resistance caused by arachidonic acid were diminished by TX synthase inhibition. The degree of systemic hypotension observed with arachidonic acid infusions was significantly greater in animals receiving OKY-1581 than in animals without the inhibitor. The effect of OKY-1581 on periods of hypoxia was also evaluated in newborn lambs. There were no significant differences in the hypoxic pressor response in lambs with and without TX synthase inhibition. These results suggest that OKY-1581 can reduce most of the pulmonary vasoconstriction produced by arachidonic acid in perinatal lambs.

Topics: Acrylates; Animals; Animals, Newborn; Arachidonic Acid; Arachidonic Acids; Fetus; Hypoxia; Lung; Methacrylates; Oxidoreductases; Prostaglandin Endoperoxides, Synthetic; Prostaglandin H2; Prostaglandins H; Pulmonary Circulation; Respiration, Artificial; Sheep; Thromboxane A2; Thromboxane-A Synthase; Time Factors; Vascular Resistance; Vasoconstriction