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Rapid-onset endothelial dysfunction with adriamycin: evidence for a dysfunctional nitric oxide synthaseDepartment of Internal Medicine, University of Michigan School of Medicine, Ann Arbor, MI, USA
Division of Cardiology Johns Hopkins University, Baltimore, MD, USA
Department of Internal Medicine, University of Michigan School of Medicine, Ann Arbor, MI, USA
Department of Internal Medicine, University of Michigan School of Medicine, Ann Arbor, MI, USA
Department of Internal Medicine, University of Michigan School of Medicine, Ann Arbor, MI, USA
Department of Internal Medicine, University of Michigan School of Medicine, Ann Arbor, MI, USA
Biophysics Research Institute and Free radical Research Center. Medical College of Wisconsin, Milwaukee, WI 53226, USA
Department of Internal Medicine, University of Michigan School of Medicine, Ann Arbor, MI, USA
Biophysics Research Institute and Free radical Research Center. Medical College of Wisconsin, Milwaukee, WI 53226, USA
Biophysics Research Institute and Free radical Research Center. Medical College of Wisconsin, Milwaukee, WI 53226, USA
Department of Internal Medicine, University of Michigan School of Medicine, Ann Arbor, MI, USA, srajagop{at}umich.edu Adriamycin (ADR) is a commonly used chemotherapeutic agent that is believed to exert its effects through the generation of oxygen free radicals. We hypothesized that administration of a single dose of ADR results in endothelial nitric oxide synthase (eNOS)-dependent generation of superoxide (O2·-) and acute endothelial dysfunction. A single dose of ADR (10 mg/kg i.v.) administered to rabbits resulted in rapid attenuation of agonist-dependent responses to acetylcholine and calcium ionophore (A23187). In vitro exposure of ring segments to ADR for <30 min resulted in O2·- generation measured by electron spin resonance (ESR) with the spin trap segments 5-tert-butoxycarbonyl-5-methyl-1-pyrroline N-oxide (BMPO) that was abolished by endothelial denudation and incubation with diphenyliodonium (DPI) (10 mM) but not L-NMMA (10 mM). Brachial artery flow-mediated dilation (FMD) in patients undergoing chemotherapy with ADR was markedly attenuated after a single dose of ADR (6.5 6 1.0 to 2.5 6 1.1% (p = 0.0004, time to end of infusion 27 6 8 min) while endothelial-independent dilatation with nitroglycerin was unchanged (16.3 6 3.1 and 14.33 6 2.1% respectively, p = 0.36). Serum nitrite and nitrate concentrations fell from 50 6 6 mmol/l pre-ADR to 33 6 6 mmol/l post-ADR infusion (p = 0.0005) while serum concentrations of CD141 thrombomodulin and von Wille-brand factor (vWF) activity remained unchanged after ADR infusion (36 6 13 to 52 6 22% ng/ml versus 3.25 6 0.98 to 3.01 6 0.91%, respectively, p = NS for pre versus post for both). Doppler indices of diastolic function (IVRT, DT and E/A ratios) were not altered in response to ADR. In conclusion, ADR administration results in rapid depletion of systemic NO· levels and attenuation of agonist-dependent responses in rabbits and flow-mediated dilation in the brachial artery of humans. ESR measurements in rabbit ring suggest an endothelial origin for radical production via flavin-containing oxido-reductases such as eNOS or NADPH cytochrome P450 reductase. These fi ndings may have implications for cardiovascular complications noted with ADR.
Key Words: adriamycin • endothelium • nitric oxide • superoxide • free radicals
Vascular Medicine, Vol. 8, No. 2,
101-107 (2003) This article has been cited by other articles:
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