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.