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Inhibition of vascular oxidative stress in hypercholesterolemia by eccentric isosorbide mononitrate

Senta Müller, DVM^*, Ilona König, PharmD^*, Wilfried Meyer, PhD and Georg Kojda, PharmD, PhD^*,*

^* Institut fuer Pharmakologie und Klinische Pharmakologie, Heinrich-Heine-Universitaet, Duesseldorf, Germany
Institut fuer Anatomie, Tieraerztliche Hochschule, Hannover, Germany

View larger version (18K): [in a new window]   Figure 1 Effect of a four months' lasting oral treatment with isosorbide mononitrate (ISMN) on changes of aortic superoxide induced by hypercholesterolemia. Given are the cumulative counts/mg tissue measured during incubation with 5 µM lucigenin. The significant increase of superoxide in cholesterol chow group (CHOL) was completely abolished by treatment with ISMN (*p < 0.01 CHOL vs. control and CHOL-ISMN).

View larger version (49K): [in a new window]   Figure 2 Area of intimal lesions in the aorta stained with sudan IV (black areas, panels B and C). Given are representative examples of aortic segments of (A) control, (B) cholesterol chow (CHOL), and (C) cholesterol chow-isosorbide mononitrate (CHOL-ISMN), and (D) the mean values of aortic arch segments of CHOL and CHOL-ISMN (*p = 0.0094).

View larger version (54K): [in a new window]   Figure 3 Cross-sections of thoracic aortic rings stained with sudan black B to visualize atherosclerotic areas (black areas). Given are representative examples of aortic cross-sections (* = lumen) of (A) control, (B) cholesterol chow (CHOL), and (C) cholesterol chow-isosorbide mononitrate (CHOL-ISMN), and (D) the mean values of the intima-media thickness (*p < 0.001, vs. control, #p < 0.001 CHOL-ISMN vs. CHOL).

View larger version (17K): [in a new window]   Figure 4 Effect of a four months' lasting oral treatment with isosorbide mononitrate (ISMN) on changes of endothelium-dependent vasorelaxation induced by hypercholesterolemia in (A) endothelium-intact aortic rings. The significant impairment of endothelium-dependent vasodilation in cholesterol chow (CHOL) as compared with controls was partially reversed by ISMN (*p < 0.001 CHOL vs. CHOL-ISMN; #p < 0.001 CHOL-ISMN vs. control). In (B) endothelium-denuded rings, acetylcholine induced vasoconstrictions.

View larger version (26K): [in a new window]   Figure 5 Effect of a four months' lasting oral treatment with isosorbide mononitrate (ISMN) on changes of vasorelaxations to the nitric oxide (NO) donor S-nitroso-N-acetyl-D,L-penicillamine (SNAP) induced by hypercholesterolemia. The significant reduction of the vascular sensitivity against NO-dependent vasodilation induced by SNAP (rightward-shift, *p < 0.0001, control vs. cholesterol chow [CHOL]) was partially reversed by ISMN (CHOL vs. CHOL-ISMN: #p < 0.001).

View larger version (25K): [in a new window]   Figure 6 Effect of a four months' lasting oral treatment with isosorbide mononitrate (ISMN) on vasorelaxations to ISMN. There was a rightward shift of the ISMN concentration response curve in cholesterol chow (CHOL)-ISMN as compared with controls and with CHOL (*p < 0.0001, each). This significantly less vasodilator response to ISMN indicates the development of nitrate tolerance in CHOL-ISMN.