Asymmetric dimethylarginine (ADMA) induces vascular endothelium impairment and aggravates post-ischemic ventricular dysfunction in rats

Vito De Gennaro Colonna, Sara Bonomo, Paolo Ferrario, Mauro Bianchi, Marco Berti, Marco Guazzi, Barbara Manfredi, Eugenio E. Muller, Ferruccio Berti, Giuseppe Rossoni

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Abstract

Asymmetric dimethylarginine (ADMA) is an endogenous nitric oxide (NO) inhibitor recognized as an independent risk factor for endothelial dysfunction and coronary heart diseases. This study investigated whether ADMA (10 mg/kg day for 14 days) affected endothelial function and aggravated post-ischemic ventricular dysfunction in the perfused rat heart. Systolic blood pressure and heart rate, plasma levels of ADMA and nitrite/nitrate were measured in vehicle- and ADMA-treated rats. Perfused hearts were submitted to global ischemia-reperfusion and vascular endothelial dysfunction was examined with angiotensin II in coronary vessels and aortic rings. Endothelial NO synthase (eNOS) and angiotensin-converting enzyme (ACE) mRNA expression in aortic and cardiac tissues were measured. ADMA-treated rats had higher systolic blood pressure (1.3-fold, P <0.01) and slower heart rate (16%, P <0.05) than controls. Plasma ADMA rose (1.9-fold, P <0.01) and nitrite/nitrate concentration decreased 59% (P <0.001). Ventricular contraction (stiffness) increased significantly, with worsening of post-ischemic ventricular dysfunction. In preparations from ADMA-treated rats the coronary vasculature's response to angiotensin II was almost doubled (P <0.01) and the maximal vasorelaxant effect of acetylcholine in aortic rings was significantly lower than in preparations from vehicle-treated rats. In cardiac and aortic tissues eNOS mRNA and ACE mRNA levels were similar in controls and ADMA-treated rats. The increased plasma levels of ADMA presumably cause endothelial dysfunction because of a deficiency in NO production, which also appears involved in the aggravation of myocardial ischemia-reperfusion injury.

Original languageEnglish
Pages (from-to)178-185
Number of pages8
JournalEuropean Journal of Pharmacology
Volume557
Issue number2-3
DOIs
Publication statusPublished - Feb 28 2007

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Keywords

  • (Rat)
  • Asymmetric dimethylarginine
  • Endothelial dysfunction
  • Myocardial ischemia-reperfusion

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience
  • Pharmacology

Cite this

De Gennaro Colonna, V., Bonomo, S., Ferrario, P., Bianchi, M., Berti, M., Guazzi, M., Manfredi, B., Muller, E. E., Berti, F., & Rossoni, G. (2007). Asymmetric dimethylarginine (ADMA) induces vascular endothelium impairment and aggravates post-ischemic ventricular dysfunction in rats. European Journal of Pharmacology, 557(2-3), 178-185. https://doi.org/10.1016/j.ejphar.2006.11.034