Alterations of arachidonate metabolism in cardiovascular system by cigarette smoking.
Male rats were exposed to freshly generated cigarette smoke once daily for various lengths of time. Inhalation of smoke was verified by elevated levels of carboxyhemoglobin. Metabolism of arachidonate in the cardiovascular system to thromboxane and prostacyclin through the cyclooxygenase pathway and their further metabolism to 15-keto-derivatives, and to 12-hydroxyeicosatetraenoic acid (12-HETE) through lipoxygenase pathway was investigated. Synthesis of thromboxane and prostacyclin in platelets and aortas respectively was not changed within 8 weeks of smoke exposure. However, formation of 12-HETE in platelets was significantly increased after 4 weeks of smoke exposure. Catabolism of thromboxane and prostacyclin as determined by NAD(+)-dependent 15-hydroxyprostaglandin dehydrogenase activity was greatly decreased in lung but not in kidney and stomach following 4 weeks of smoke exposure. Increased 12-lipoxygenase activity in platelets may lead to stimulation of migration and proliferation of smooth muscle cells and to increased synthesis of leukotrienes in neutrophils. Decreased pulmonary prostaglandin catabolic activity may result in increase in circulating thromboxane/prostacyclin ratio and subsequently alteration of vascular homeostasis. The consequence of these biochemical changes may contribute to the development of atherosclerosis, thromboembolism and emphysema commonly found in smokers.
Tai
H H
HH
Division of Medicinal Chemistry and Pharmaceutics, College of Pharmacy, University of Kentucky, Lexington 40536-0082.
Chang
W C
WC
Liu
Y
Y
Fukuda
S
S
D000171:Acrolein / Q000494:pharmacology; D000818:Animals; D001011:Aorta / Q000378:metabolism; D001092:Arachidonate 12-Lipoxygenase / Q000378:metabolism; D016718:Arachidonic Acid; D001095:Arachidonic Acids / Q000378:metabolism*; D001792:Blood Platelets / Q000201:enzymology / Q000378:metabolism; D001835:Body Weight / Q000187:drug effects; D002263:Carboxyhemoglobin / Q000378:metabolism; D002319:Cardiovascular System / Q000378:metabolism*; D003600:Cytosol / Q000378:metabolism; D011464:Epoprostenol / Q000096:biosynthesis; D005978:Glutathione / Q000494:pharmacology; D006911:Hydroxyprostaglandin Dehydrogenases / Q000378:metabolism; D008168:Lung / Q000201:enzymology; D009243:NAD / Q000378:metabolism; D051381:Rats; D012907:Smoking / Q000378:metabolism*; D013552:Swine; D013931:Thromboxanes / Q000096:biosynthesis
D001095:Arachidonic Acids; D013931:Thromboxanes; D009243:NAD; D016718:Arachidonic Acid; D000171:Acrolein; D002263:Carboxyhemoglobin; D011464:Epoprostenol; D006911:Hydroxyprostaglandin Dehydrogenases; D001092:Arachidonate 12-Lipoxygenase; D005978:Glutathione