Long-term angiotensin-converting enzyme inhibition reduces plasma asymmetric dimethylarginine and improves endothelial nitric oxide bioavailability and coronary microvascular function in patients with syndrome X

Am J Cardiol. 2002 Nov 1;90(9):974-82. doi: 10.1016/s0002-9149(02)02664-4.


Angiotensin-converting enzyme (ACE) inhibition has been shown to improve clinical myocardial ischemia in patients with syndrome X (angina pectoris, positive treadmill exercise test, normal coronary angiograms, and no evidence of coronary spasm). This study was conducted to investigate the effects of long-term ACE inhibitors on endothelial nitric oxide (NO) metabolism and coronary microvascular function in patients with syndrome X. After a 2-week washout period, 20 patients with syndrome X were randomized to receive either enalapril, an ACE inhibitor, 5 mg twice daily (n = 10) or placebo (n = 10) in a double-blind design for 8 weeks. Another 6 age- and gender-matched subjects with negative treadmill exercise tests were also studied as controls. Compared with control subjects, patients with syndrome X had significantly reduced coronary flow reserve, reduced plasma levels of nitrate and nitrite (NOx), and a reduced plasma L-arginine to asymmetric dimethylarginine (ADMA) ratio (an index of systemic NO metabolism), as well as reduced endothelial function. These patients also had increased plasma levels of ADMA, which is an endogenous inhibitor of NO synthase and of von Willebrand factor, a marker of endothelial injury. Baseline characteristics including exercise performance and coronary flow reserve were similar between enalapril and placebo groups. After an 8-week treatment period, exercise duration (p = 0.001) and coronary flow reserve (p = 0.001) significantly improved with enalapril but not with placebo. Enalapril treatment, but not placebo, reduced plasma von Willebrand factor (p = 0.03) and ADMA levels (p = 0.01) and increased NOx levels (p = 0.01) and the ratio of L-arginine to ADMA (p <0.01). In patients with syndrome X, the plasma NOx level was positively and ADMA level inversely correlated with coronary flow reserve before and after the treatment. In conclusion, long-term ACE inhibitor treatment with enalapril improved coronary microvascular function as well as myocardial ischemia in patients with syndrome X. This may be related to the improvement of endothelial NO bioavailability with the reduction of plasma ADMA levels.

Publication types

  • Clinical Trial
  • Comparative Study
  • Evaluation Study
  • Randomized Controlled Trial

MeSH terms

  • Aged
  • Angiotensin-Converting Enzyme Inhibitors / pharmacokinetics*
  • Arginine / analogs & derivatives*
  • Arginine / blood*
  • Arginine / drug effects*
  • Biological Availability
  • Coronary Circulation / drug effects*
  • Coronary Circulation / physiology*
  • Double-Blind Method
  • Enalapril / pharmacokinetics
  • Endothelium, Vascular / drug effects*
  • Endothelium, Vascular / metabolism*
  • Exercise Test
  • Female
  • Hemodynamics / drug effects
  • Humans
  • Male
  • Microcirculation / drug effects*
  • Microcirculation / physiology*
  • Microvascular Angina / blood*
  • Microvascular Angina / drug therapy*
  • Middle Aged
  • Nitric Oxide / metabolism*
  • Statistics as Topic
  • Time
  • Treatment Outcome
  • von Willebrand Factor / drug effects


  • Angiotensin-Converting Enzyme Inhibitors
  • von Willebrand Factor
  • Nitric Oxide
  • N,N-dimethylarginine
  • Enalapril
  • Arginine