Clinical study: polymorphisms and cardiovascular disease
The T-786C and Glu298Asp polymorphisms of the endothelial nitric oxide gene affect the forearm blood flow responses of Caucasian hypertensive patients

https://doi.org/10.1016/S0735-1097(02)03011-5Get rights and content
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Abstract

Objectives

We sought to investigate whether two polymorphisms located in the promoter (T-786C) and exon 7 (Glu298Asp) of the endothelial nitric oxide (NO) synthase (eNOS) gene affected agonists-mediated NO release.

Background

Endothelial dysfunction can be genetically determined. Therefore, we investigated whether two polymorphisms located in the eNOS gene affected agonists-mediated NO release.

Methods

We compared endothelial-dependent and -independent vasodilation of the different eNOS genotypes in a cross-sectional study on 187 subjects, of whom 137 were uncomplicated essential hypertensive patients (PH) (49 ± 9 years, 151 ± 11/99 ± 5 mm Hg) and 50 healthy normotensive subjects (NT) (43 ± 16 years, 123 ± 10/78 ± 7 mm Hg). Endothelial-dependent and -independent vasodilation was assessed as the forearm blood flow response to incrementally increasing doses of acetylcholine (0.15, 0.45, 1.5, 4.5, 15 μg/100 ml/min) and sodium nitroprusside (1, 2, 4 μg/100 ml/min), respectively. Genotyping was performed with melting curve analysis (Lightcycler) of polymerase chain reaction products from acceptor (5′ end-labeled with LCRed 640) and donor probes (3′ end-labeled with fluorescein) specific for each polymorphism.

Results

The genotype distribution of T-786C (CC = 21.9%, CT = 48.7%, TT = 29.4%) and Glu298Asp (GG = 39.0%, GT =51.9%, TT = 9.1%) was similar in PH and NT. A repeated measure analysis of variance showed a blunting of endothelium-dependent vasodilation in PH compared with NT (p < 0.001). A significant effect of the T-786C (p = 0.002) but not of the Glu298Asp (p = NS) eNOS polymorphism on endothelial-dependent vasodilation was found. However, we also detected a significant interaction between the T-786C and Glu298Asp polymorphism (p < 0.001). No effect on either polymorphism on endothelial-independent vasodilation was seen.

Conclusions

The T-786C promoter polymorphism and its interaction with exon 7 Glu298Asp affect endothelium-dependent vasodilation in mild-to-moderate PH patients and NT Caucasian subjects.

Abbreviations

ACH
acetylcholine
ANOVA
analysis of variance
BP
blood pressure
DNA
deoxyribonucleic acid
EDV
endothelium-dependent vasodilation
EIV
endothelium-independent vasodilation
eNOS
endothelial nitric oxide synthase
FBF
forearm blood flow
NO
nitric oxide
NT
normotensive
PCR
polymerase chain reaction
PH
primary (essential) hypertension
SNP
sodium nitroprusside

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Supported by grants from the Italian Cabinet of University and Scientific Research (MURST) to Drs. Pessina (9906193152-001/06) and Salvetti (9906193152-003/06) and by research grants from Regione Veneto and from F.O.R.I.C.A. (FOundation for advanced Research In hypertension and CArdiovascular diseases) to Dr. Rossi (863/01/98).