ANGIOGRAPHIC CONTRAST-INDUCED VASCULAR AND RENAL TOXICITY A NANOMEDICAL APPROACH
Tadeusz Malinski, Ph.D., Ohio University, Athens, Ohio, USA
Background: Use of contrast media (CM) in angiography creates a paradoxical dilemma. Adsorption of CM molecules on endothelial cells is necessary to produce an x-ray image of the vasculature, but the adsorption process itself may contribute to cell dysfunction and serious vascular and renal damage. The molecular mechanism of CM induced toxicity is unknown. We hypothesized that CM toxicity can be due to an induced dysfunction of endothelial nitric oxide synthase (eNOS), low levels of cytoprotective NO and high levels of cytotoxic O2- and ONOO-
Methods and Results: A nanomedical approach, utilizing nanosensors (diameter of 150-250nm), was used to monitor the collision/adsorption of contrast molecules (iodixanol and iohexol) with cells and to measure the concentrations of NO, O2-, and ONOO-. Measurements were made at different concentrations of CM and at different incubation times with cellular models of different diseases: diabetes, hypertension and hypercholesterolemia. A ratio of concentrations [NO]/[ONOO-] was used to indicate the level of nitroxidative stress. Initially, the collision/adsorption of CM stimulated NO and ONOO-, peaking at about 400nM NO and 170nM ONOO- and a [NO]/[ONOO-] ratio of about 2.5. The maximal capacity of NO production decreased and ONOO- increased rapidly with time and [NO]/[ONOO-] reached about 0.8 after 2 hours. The decrease in [NO]/[ONOO-] directly correlates with increased incubation time, eNOS uncoupling, dysfunctional endothelium and CM concentration. An elevated glucose, angiotensin II or LDL decreased the [NO]/[ONOO-] ratio. This effect was additive to that observed for CM alone.
Conclusions: CM can hinder cytoprotective NO and increase cytotoxic O2- and ONOO-. It may also diminish the overall function of the vascular and renal system. The negative effect of CM increased in diabetes, hypertension and hypercholesterolemia, but can be mollified by preserving/restoring eNOS function with antioxidants or scavengers of ONOO- and O2- and/or increasing bioavailable NO.