Rapid-onset endothelial dysfunction with adriamycin: Evidence for a dysfunctional nitric oxide synthase

Damon Duquaine, Glenn A. Hirsch, Anjan Chakrabarti, Zhenguo Han, Chris Kehrer, Robert Brook, Joy Joseph, Anne Schott, B. Kalyanaraman, Jeanette Vasquez-Vivar, Sanjay Rajagopalan

Research output: Contribution to journalArticlepeer-review

Abstract

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 2 .- 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 μM) but not L-NMMA (10 μM). Brachial artery flow-mediated dilation (FMD) in patients undergoing chemotherapy with ADR was markedly attenuated after a single dose of ADR (6.5 ± 1.0 to 2.5 ± 1.1% (p = 0.0004, time to end of infusion 27 ± 8 min) while endothelial-independent dilatation with nitroglycerin was unchanged (16.3 ± 3.1 and 14.33 ± 2.1% respectively, p = 0.36). Serum nitrite and nitrate concentrations fell from 50 ± 6 μmol/l pre-ADR to 33 ± 6 nmol/l post-ADR infusion (p = 0.0005) while serum concentrations of CD141 thrombomodulin and von Willebrand factor (vWF) activity remained unchanged after ADR infusion (36 ± 13 to 52 ± 22% ng/ml versus 3.25 ± 0.98 to 3.01 ± 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 findings may have implications for cardiovascular complications noted with ADR.

Original languageEnglish (US)
Pages (from-to)101-107
Number of pages7
JournalVascular Medicine
Volume8
Issue number2
DOIs
StatePublished - 2003

Keywords

  • Adriamycin
  • Endothelium
  • Free radicals
  • Nitric oxide
  • Superoxide

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Fingerprint Dive into the research topics of 'Rapid-onset endothelial dysfunction with adriamycin: Evidence for a dysfunctional nitric oxide synthase'. Together they form a unique fingerprint.

Cite this