Prostaglandins, platelets, and atherosclerosis.
Metabolism of arachidonic acid (AA) in blood platelets and in vascular endothelium does not lead to prostaglandins, but thromboxane A2 and prostacyclin are generated. These labile metabolites of AA antagonize each other: thromboxane A2 is a vasoconstrictor and proaggregatory agent, whereas prostacyclin dilates arteries, prevents platelets from aggregation, and dissipates the preformed platelet clumps. Prostacyclin is a powerful stimulator of adenylate cyclase in platelets and therefore its antiplatelet action is potentiated by phosphodiesterase inhibitors such as theophylline or dipyridamole. Cyclo-oxygenase of AA is inhibited by aspirin, thromboxane synthetase by analogues of prostaglandin endoperoxides, and prostacyclin synthetase by linear lipid peroxides. A hypothesis is put forward that atherosclerosis develops because of pathological, nonenzymic lipid peroxides. A hypothesis is put forward that atherosclerosis develops because of pathological, nonenzymic lipid peroxydation in the body and the subsequent molecular damage to prostacyclin synthetase in the rheologically determined areas of arterial walls. Endothelium deprived of prostacyclin is the basis for microthrombi formation, and follows a sequence of events described by Rokitansky and later by Ross. Prostacyclin is also a circulating hormone which is generated by the lungs. Thereby a damage of this "endocrine gland" by respiratory disorders, air pollution, or tobacco smoking are likely to contribute to pathogenesis of atherosclerosis, myocardial infarction, and arterial thromboembolism. Pharmacological treatment and prevention of these diseases should logically include antioxydants, prostacyclin and its analogues, thromboxane synthetase inhibitors and perhaps cyclooxygenase inhibitors (aspirin ?). Prostacyclin was already infused intravenously to men and its powerful antiaggregatory and deaggregatory actions were demonstrated. These properties of prostacyclin along with its vasodilator and positive inotropic actions destine this hormone to be a new type of antithrombotic drug in acute myocardial infarction.
D000818:Animals; D001095:Arachidonic Acids / Q000378:metabolism*; D001161:Arteriosclerosis / Q000378:metabolism*; D001241:Aspirin / Q000494:pharmacology; D001775:Blood Circulation / Q000187:drug effects; D001808:Blood Vessels / Q000187:drug effects; D002341:Carotid Artery Thrombosis / Q000378:metabolism; D016861:Cyclooxygenase Inhibitors; D004285:Dogs; D011464:Epoprostenol / Q000378:metabolism*; D005260:Female; D006801:Humans; D007263:Infusions, Parenteral; D008297:Male; D051379:Mice; D009203:Myocardial Infarction / Q000378:metabolism; D010974:Platelet Aggregation / Q000187:drug effects*; D011453:Prostaglandins / Q000378:metabolism*; D011817:Rabbits; D051381:Rats; D013329:Structure-Activity Relationship; D013923:Thromboembolism / Q000378:metabolism; D013928:Thromboxane A2 / Q000502:physiology*; D013931:Thromboxanes / Q000502:physiology*
D001095:Arachidonic Acids; D016861:Cyclooxygenase Inhibitors; D011453:Prostaglandins; D013931:Thromboxanes; D013928:Thromboxane A2; D011464:Epoprostenol; D001241:Aspirin