Relevance of the NOS3 T–786C and G894T variants for cholinergic and adrenergic coronary vasomotor responses in man

Abstract

We investigated the impact of the -786C allele at the promoter and the 894T allele in exon 7 of the gene encoding the endothelial nitric oxide synthase (NOS3) on coronary vasomotor responses to exogenous and endogenous stimuli. In 47 individuals undergoing coronary angiography for chest pain, but without significant stenosis in the left anterior descending artery (LAD), nitroglycerine and acetylcholine were infused intracoronarily, and a cold pressor test (CPT) was performed. Coronary blood flow (CBF) in the LAD was calculated from quantitative coronary angiography and intracoronary Doppler measurements. Aortic and coronary sinus lactate levels were determined in 18 individuals. To analyze the impact of NOS3 genotypes, a logistic regression model was used. In response to acetylcholine (p = 0.002) and CPT (p = 0.015) CBF reduction was associated with homocygosity for the -786C allele. Myocardial lactate uptake was reversed into net lactate production in CC homocygotes. No independent effects of the G894T polymorphism were observed in the present study. Haplotype analysis revealed a significant linkage disequilibrium between both polymorphisms (p < 0.001). Our findings suggest a pathophysiologically relevant role for the T-786C polymorphism in human coronary vasomotion. The observed linkage disequilibrium between both NOS3 genotypes deserves further research in future studies.