Tetrahydrobiopterin (BH4) is an essential cofactor for nitric oxide synthase (NOS) and a scavenger of oxygen-derived free radicals. Decreased availability of BH4 leads, under in vitro conditions, to reduced nitric oxide (NO) production and increased superoxide formation. We studied the effect of exogenous BH4 on endothelial function of angiographically normal vessel segments in patients with coronary artery disease. Nineteen patients with coronary artery disease underwent quantitative coronary angiography with simultaneous coronary flow velocity measurements (Cardiometrics FloWire). Data were obtained in angiographically normal segments of the left coronary artery at baseline, after intracoronary (i.c.) administration of acetylcholine (Ach; 10(-4) M), after infusion of BH4 (10(-2) M), and after co-infusion of ACh and BH4. At the end of the study, 300 microg nitroglycerin (NTG) i.c. was administered to obtain maximal vasodilation. At each step, flow velocity was determined before and after 18 microg adenosine i.c. to assess coronary flow velocity reserve. In 15 patients, ACh induced coronary vasoconstriction of -18 +/- 3% (endothelial dysfunction; p < 0.0001 vs. baseline), and in four patients, vasodilation of +39 +/- 20%. In the 15 patients with endothelial dysfunction, BH4 alone did not influence vessel area but prevented vasoconstriction to ACh (+2 +/- 3%, NS, vs. baseline). Correspondingly, calculated volume flow showed the highest value after co-infusion of ACh and BH4. Coronary flow velocity reserve was comparable during the various infusion steps. BH4 prevents ACh-induced vasoconstriction of angiographically normal vessels in patients with coronary artery disease. Thus substitution of this cofactor of NOS may represent a new approach for the treatment of endothelial dysfunction.
Background-Stenting has proved beneficial for treating threatened closure and reducing restenosis after balloon angioplasty. However, the implantation of a coronary metallic prosthesis has been related to impaired vasomotion distal to the stent as assessed by acetylcholine infusion. Thus, the purpose of the present study was to determine the vasomotion of stented coronary arteries and to assess its influence on the vasomotion of adjacent vessel segments during bicycle exercise. Methods and Results-Biplane quantitative coronary angiography was performed at rest and during bicycle exercise in 26 patients with coronary artery disease. Twelve patients had single vessel disease with stable angina pectoris (controls; group 1). Fourteen patients underwent coronary stenting for therapeutic reasons and were studied 10Ϯ3 months after the intervention (group 2). Minimal luminal area, stent area, and proximal and distal vessel areas were determined. In controls (group 1), vasoconstriction of the stenotic artery (Ϫ29Ϯ4%; PϽ0.001) was observed during exercise, whereas the normal segment showed vasodilation (15Ϯ4%; PϽ0.05). In group 2, vasomotion of the stented segment was eliminated (0Ϯ1%), whereas the proximal and distal segments showed exercise-induced vasodilation (8Ϯ2% and 11Ϯ3%, respectively; PϽ0.005), which was not different from control segments (10Ϯ2%). Sublingual nitroglycerin was associated with maximal vasodilation of the proximal and distal vessel segments (30Ϯ8% and 38Ϯ13%, respectively; PϽ0.005). Conclusions-In contrast to the vasoconstriction of vessels in control patients, normal vasodilation of proximal and distal segments occurred during the physiological stress of exercise in patients with coronary stent placement. As expected, vasomotion was abolished in the stented region.
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