A T-786-->C mutation in the 5'-flanking region of the endothelial nitric oxide synthase gene and coronary arterial vasomotility.
In the endothelium, synthesis of nitric oxide (NO) from the amino acid L-arginine is catalyzed by the endothelial NO synthase (eNOS), and the continuously generated NO serves to maintain basal vascular tone. Recently, we discovered a T-786-->C mutation in the 5'-flanking region of the eNOS gene; this mutation reduced the promoter activity of the eNOS gene and was associated with coronary spasm. We examined the vasomotility of the epicardial coronary artery in subjects with and without T-736-->C mutation. We examined vasomotility in 32 consecutive subjects who were heterozygotes for the T-786-->C mutation and in 68 subjects without the T-786-->C mutation who had equivalent age, sex, and smoking status at the proximal and distal segments of the left descending coronary artery by performing quantitative coronary angiography. In subjects with the mutant allele (-786C allele), basal diameters of proximal and distal segments before intracoronary injection of acetylcholine (ACh) were less than diameters in subjects without the mutant allele (p <0.05), although there was no difference between subjects with and without the mutant allele in the diameters of coronary arteries after isosorbide dinitrate (ISDN) administration. When we compared the changes in diameters, both ACh-induced vasoconstriction and ISDN-induced vasodilatation in subjects with the mutant allele were significantly increased in the proximal (p <0.01, p <0.001, respectively) and distal segments (p <0.03, p <0.01, respectively). Taken together, these findings strongly suggest that the T-786-->C mutation increases the basal tone of the coronary artery, and enhances the response to the constrictor effects of ACh and the dilator effect of ISDN because of reducing the endothelial NO synthesis.
Yoshimura
M
M
Department of Cardiovascular Medicine, Kumamoto University School of Medicine, Japan. bnp@kumamoto-u.ac.jp
Nakayama
M
M
Shimasaki
Y
Y
Ogawa
H
H
Kugiyama
K
K
Nakamura
S
S
Ito
T
T
Mizuno
Y
Y
Harada
E
E
Yasue
H
H
Miyamoto
Y
Y
Saito
Y
Y
Nakao
K
K
D024506:5' Flanking Region / Q000235:genetics*; D000109:Acetylcholine / Q000494:pharmacology; D016022:Case-Control Studies; D003329:Coronary Vasospasm / Q000235:genetics; D003331:Coronary Vessels / Q000502:physiology*; D005260:Female; D006579:Heterozygote; D006801:Humans; D007548:Isosorbide Dinitrate / Q000494:pharmacology; D008297:Male; D008875:Middle Aged; D009154:Mutation; D019001:Nitric Oxide Synthase / Q000235:genetics*; D052250:Nitric Oxide Synthase Type III; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D014665:Vasodilator Agents / Q000494:pharmacology; D014666:Vasomotor System / Q000187:drug effects / Q000503:physiopathology
D014662:Vasoconstrictor Agents; D014665:Vasodilator Agents; C496314:NOS3 protein, human; D019001:Nitric Oxide Synthase; D052250:Nitric Oxide Synthase Type III; D007548:Isosorbide Dinitrate; D000109:Acetylcholine