Glutathione S-transferase mu polymorphism does not explain variation in nitroglycerin responsiveness

Area of Science:

• Pharmacology
• Genetics
• Cardiovascular Physiology

Background:

• Interindividual variability in nitroglycerin-induced venodilation is significant.
• Vascular glutathione S-transferase mu (GST mu) is a polymorphic enzyme (present in ~60% of the population) with high in vitro activity towards nitroglycerin.
• The clinical relevance of GST mu in nitroglycerin metabolism and vasodilation is unknown.

Purpose of the Study:

• To investigate if the polymorphic expression of glutathione S-transferase mu (GST mu) explains the variability in nitroglycerin-induced venodilation in humans.
• To assess the in vivo role of GST mu in nitroglycerin metabolism and its impact on vascular response.

Main Methods:

• Dose-response curves for nitroglycerin were generated in 26 healthy volunteers by measuring dorsal hand vein compliance during local nitroglycerin infusion.
• Polymerase chain reaction was used to detect the presence or absence of the gene coding for GST mu in blood samples.

Main Results:

• The GST mu isozyme was detected in 58% of subjects and absent in 42%.
• No significant differences in maximum venodilation (Emax) or the dose rate to achieve 50% of Emax (ED50) were observed between subjects with or without GST mu.
• Mean Emax was 98-103% dilation, and mean ED50 was 9-16 ng/min, with no gender-specific differences in response.

Conclusions:

• Individuals lacking GST mu exhibit normal venodilatory responses to nitroglycerin.
• The significant interindividual variability in nitroglycerin potency is not attributable to the polymorphic expression of GST mu.
• Other vascular enzymes or downstream pathways in the venodilatory cascade are likely responsible for the observed variability.