Heterogeneity in hand veins responses to acetylcholine is not associated with polymorphisms in the G-protein beta(3)-subunit (C825T) and endothelial nitric oxide synthase (G894T) genes but with serum low density lipoprotein cholesterol

Vascular responses to acetylcholine (ACh) are notoriously variable, the rea son for this phenomenon is unknown, We tested the hypothesis that the varia bility in venous response to acetylcholine may be associated with two recen tly identified genetic polymorphisms for proteins involved in the signal tr ansduction pathway, i.e. the G-protein beta (3)-subunit (GNB3) and endothel ial nitric oxide synthase (eNOS). The dorsal hand vein technique was used i n 37 healthy subjects. Hand veins were preconstricted with the alpha (1)-ad renoceptor agonist phenylephrine and the venodilator response to local ACh infusion was measured with and without comedication of acetylsalicylic acid or co-infusion of N-G-monomethyl-L-arginine (L-NMMA). in addition, all sub jects received routine laboratory tests and 26 of them were genotyped for t he C825T polymorphism of the GNB3 gene and for the G894T polymorphism of th e eNOS gene, A striking variability in venous response to ACh was found wit h dilation observed in the low ACh concentration range and reduced dilation or even constriction at high concentrations. ACh-induced venodilation was mediated by muscarinic receptors and abolished in the presence of both acet ylsalicylic acid acid L-NMMA suggesting dependence on endothelium. We did n ot find any association of the variability in ACh response with GNB3 or eNO S allele status. On the other hand, a significant positive correlation betw een ACh responsiveness and low density lipoprotein-cholesterol status was d etected, Two recently discovered gene polymorphisms are not responsible for the profound heterogeneity in venodilator response to ACh, Surprisingly, t his variability appears to relate to the lipid status of the subjects. The exact nature of this new finding requires further study, Pharmacogenetics 1 1:307-316 (C) 2001 Lippincott Williams & Wilkins.