Endothelial venodilator response in carriers of genetic polymorphisms involved in NO synthesis and degradation

Abstract

Aims: Polymorphisms of the NOSIII gene and of the CYBA gene have been associated with a number of pathological conditions such as arterial hypertension, coronary artery disease, and myocardial infarction. Because endothelium-dependent vasodilation is impaired in these disorders, we hypothesized that polymorphisms of NOSIII or CYBA might modulate endothelial function of venous capacitance vessels already before cardiovascular disease becomes overt.

Methods: Endothelium-dependent and -independent venodilation was assessed by measuring local vascular responses to bradykinin and sodium nitroprusside in the dorsal hand vein after preconstriction with phenylephrine in 72 healthy male Caucasians after careful exclusion of cardiovascular risk factors. Genotyping was performed for polymorphisms of the NOSIII gene (T-786C, G894T, (CA)(n)) and the CYBA gene (C242T).

Results: Genotype distribution for each polymorphism followed the Hardy-Weinberg equilibrium. In all studied single nucleotide polymorphisms no significant difference between the respective genotypes and the venodilator response to either sodium nitroprusside or bradykinin was observed, and the number of CA repeat copies was not related to the venodilator response to bradykinin. Mean venodilation induced by bradykinin 50 ng min(-1) (+/-SEM) for homozygote carriers of the single nucleotide polymorphisms was 48.9 +/- 8.5% venodilation (G894T; wild type: 49.8 +/- 6.9), 50.3 +/- 11.0% venodilation (T-786C; wild type: 42.6 +/- 5.2), and 30.4 +/- 9.1% venodilation (C242T; wild type: 49.2 +/- 6.0), respectively.

Conclusions: This study suggests that the studied polymorphisms of NOSIII and CYBA do not significantly modulate endothelium-dependent venodilation in individuals without vascular risk factors.

Figures

Figure 1

T-786C polymorphism of the NOSIII gene detected by PdiI restriction digestion of the 163 bp PCR product: Lane 1: molecular size marker pUC19/MspI; lane 2: no template control; lanes 3 +8 + 9: restriction pattern corresponding to homozygosity for the T-allele; lanes 4 +6: restriction pattern corresponding to homozygosity for the C-allele; lanes 5 +7: restriction pattern corresponding to heterozygosity

Figure 2

Response of dorsal hand veins of 72 healthy males to bradykinin (1, 50, and 250 ng min-1) during preconstriction with phenylephrine with regard to the NOSIII G894T (a) GG (G894T wild type) (▪), GT (•), TT (▾); and T-786C (b) TT (T-786C wild type) (▪), TC (•), CC (▾); genotypes and the CYBA C242T genotype (c) CC (242T wild type) (▪), CT (•), TT (▾)

Figure 3

Relationship between response of preconstricted dorsal hand veins to bradykinin (50 ng min−1) and CA repeat copy number of NOSIII (univariate correlation analysis; P = NS). The straight line is the linear regression line, curved lines indicate the 95% confidence interval