| 12711621 |
Rabelo LA, Cortes SF, Alvarez-Leite JI, Lemos VS: Endothelium dysfunction in LDL receptor knockout mice: a role for H2O2. Br J Pharmacol. 2003 Apr;138(7):1215-20.
1. In this study, the role of endogenous H (2) O (2) as an endothelium-dependent relaxant factor was characterised in aortas from C57BL/6J and LDL receptor-deficient mice (LDLR (-/-)). 2. Aortic rings from LDLR (-/-) mice showed impaired endothelium-dependent relaxation to acetylcholine (ACh; 0.001-100 micro M) and to the Ca (2+) ionophore A23187 (0.001-3 micro M) compared with aortic rings from control mice. Endothelium-independent relaxation produced by the NO donor, 3-morpholino-sydnonimine (SIN-1) was not different between strains. 3. Pretreatment of vessels with L-NNA (100 micro M) or L-NNA (100 micro M) plus L-NAME (300 micro M) plus haemoglobin (10 micro M) markedly decreased, but did not abolish the relaxation to ACh in control mice. In the aortas from LDLR (-/-) mice treated with L-NNA (100 micro M), ACh induced a contractile effect. Catalase (800 and 2400 U ml (-1)) shifted to the right the endothelium-dependent relaxation to ACh in aortas from control but not from LDLR (-/-) mice. Aminotriazole (50 mM), which inhibits catalase, abolished its effect on control mice. Treatment of vessels with L-NNA and catalase abolished vasorelaxation induced by ACh. Indomethacin (10 micro M) did not modify the concentration-response curve to ACh. Superoxide dismutase (300 U ml (-1)) did not change ACh-induced relaxation in both strains. 4. Exogenous H (2) O (2) produced a concentration-dependent relaxation in endothelium-denuded aortic rings, which was not different between strains. 5. It is concluded that H (2) O (2) greatly contributes to relaxation to ACh in aorta from control mice. Endothelial-dependent relaxation to ACh is impaired in LDLR (-/-) mice. Reduced biosynthesis or increased inactivation of H (2) O (2) is the possible mechanism responsible for endothelial dysfunction in aortas of atherosclerosis-susceptible LDLR (-/-) mice. |
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