cyclic-gmp and 6-hydroxy-2-5-7-8-tetramethylchroman-2-carboxylic-acid

Myeloperoxidase (MPO) is an abundant mammalian phagocyte hemoprotein thought to primarily mediate host defense reactions. Although its microbicidal functions are well established in vitro, humans deficient in MPO are not at unusual risk of infection. MPO was observed herein to modulate the vascular signaling and vasodilatory functions of nitric oxide (NO) during acute inflammation. After leukocyte degranulation, MPO localized in and around vascular endothelial cells in a rodent model of acute endotoxemia and impaired endothelium-dependent relaxant responses, to which MPO-deficient mice were resistant. Altered vascular responsiveness was due to catalytic consumption of NO by substrate radicals generated by MPO. Thus MPO can directly modulate vascular inflammatory responses by regulating NO bioavailability.

Topics: Animals; Aorta; Catalysis; Cattle; Cells, Cultured; Chromans; Coculture Techniques; Cyclic GMP; Endothelium, Vascular; Endotoxemia; Humans; Hydrogen Peroxide; Inflammation; Leukocytes; Mice; Mice, Inbred C57BL; Muscle, Smooth, Vascular; Mutation; Nitric Oxide; Oxidation-Reduction; Peroxidase; Rats; Rats, Sprague-Dawley; Signal Transduction; Transfection; Tumor Cells, Cultured; Vasodilation

The effects of Trolox C (6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid), a vitamin E analogue, (60-900 microM) and SIN-1 (3-morpholino sydnonimine), a nitric oxide donor, (30-3000 microM) on arachidonic acid metabolism and on cyclic GMP formation in calcium ionophore A23187 (calcimycin)-stimulated human polymorphonuclear leukocytes were investigated. Trolox C elicited a dose dependent decrease in leukotriene B4 levels and increase in prostaglandin E2 levels but did not affect cyclic GMP levels. SIN-1 dose dependently inhibited leukotriene B4 and stimulated prostaglandin E2 and cyclic GMP formation. Dibutyryl cyclic GMP did not affect the formation of leukotriene B4 and prostaglandin E2. Trolox C (180 microM), which itself had no effect on cyclic GMP levels, enhanced the effect of SIN-1 (100 microM) on cyclic GMP levels more than 5-fold. The effects of SIN-1 on arachidonic acid metabolism seem to be independent of cyclic GMP and are probably due to nitric oxide. In this experimental model both Trolox C and SIN-1 have similar actions on the prostaglandin/leukotriene ratio, and Trolox C potentiates the SIN-1-induced increase in cyclic GMP levels.

Topics: Antioxidants; Arachidonic Acid; Calcimycin; Centrifugation, Density Gradient; Chromans; Cyclic GMP; Dibutyryl Cyclic GMP; Dinoprostone; Dose-Response Relationship, Drug; Guanylate Cyclase; Humans; Leukotriene B4; Molsidomine; Neutrophils; Radioimmunoassay; Vasodilator Agents; Vitamin E

The effects of exogenous guanosine 5'-triphosphate (GTP), guanosine 5'-(gamma-thio)triphosphate (GTP gamma S), cysteine and Trolox C, a water soluble vitamin E analogue, were studied on basal and nitrovasodilator-induced cyclic GMP formation in isolated human lymphocytes. Incubation of lymphocytes in the presence of GTP (0.1 mM) and GTP gamma S (0.1 mM) increased cyclic GMP more than twofold. SIN-1 and sodium nitroprusside dose-dependently increased cyclic GMP, but nitroglycerin and sodium nitrite were ineffective. GTP and GTP gamma S potentiated SIN-1 and sodium nitroprusside-induced cyclic GMP formation. In the presence of GTP and GTP gamma S, nitroglycerin, but not sodium nitrite, was able to increase lymphocyte cyclic GMP. Cysteine (1 mM) enhanced cyclic GMP formation induced by sodium nitroprusside and nitroglycerin. Trolox C (0.1 mM) potentiated SIN-1-induced cyclic GMP formation. These results indicate that exogenous GTP and GTP gamma S enhance guanylate cyclase stimulation by spontaneous nitric oxide releasers and nitroglycerin in lymphocytes. Cysteine, a redox-compound and Trolox C, an antioxidant, have different effects on guanylate cyclase activation by nitric oxide releasers, SIN-1 and sodium nitroprusside.

Topics: Chromans; Cyclic GMP; Cysteine; Dose-Response Relationship, Drug; Drug Interactions; Enzyme Activation; Guanosine 5'-O-(3-Thiotriphosphate); Guanosine Triphosphate; Guanylate Cyclase; Humans; L-Lactate Dehydrogenase; Lymphocytes; Molsidomine; Nitroprusside; Vasodilator Agents