Evidence for Involvement of Calcitonin Gene-Related Peptide in Nitroglycerin Response and Association With Mitochondrial Aldehyde Dehydrogenase-2 (ALDH2) Glu504Lys Polymorphism

Abstract

This study sought to determine whether calcitonin gene-related peptide (CGRP) is involved in glyceryl trinitrate (GTN) response in humans, and its association with mitochondrial aldehyde dehydrogenase-2 (ALDH2) Glu504Lys (ALDH2*2) polymorphism. In animal models, CGRP contributes to the cardiovascular effects of GTN. The enzyme principally responsible for GTN bioactivation is ALDH2. The common ALDH2*2 polymorphism is associated with a lack of GTN efficacy. In 18 ALDH2*2-genotyped Chinese volunteers, we observed the changes in plasma concentrations of CGRP after sublingual GTN administration and its correlation with GTN response, and assessed the expression of CGRP messenger ribonucleic acid (mRNA) in cultured peripheral blood mononuclear cells (PBMCs) pre-treated with 10(-5) mol/l GTN. In contrast to carriers of the ALDH2*2 allele, ALDH2*1/*1 homozygotes showed a significantly higher extent of absolute changes in both systolic blood pressure (DeltaSBP) and HR (DeltaHR) at several time points after GTN administration. Plasma concentrations of CGRP were increased significantly 12 min after GTN administration, the percentage increase in plasma concentrations of CGRP correlated positively with both DeltaSBP and DeltaHR, and percentage increase in plasma concentrations of CGRP was significantly higher in ALDH2*1/*1 homozygotes. In addition, PBMCs from ALDH2*1/*1 homozygotes showed a higher-fold increase in both CGRP I and CGRP II mRNA after GTN stimulation, and the GTN-induced increase in CGRP mRNA expression in PBMCs from ALDH2*1/*1 homozygotes was inhibited by the ALDH2 inhibitor chloral hydrate. We found that CGRP is associated with the cardiovascular effect of GTN through an ALDH2-dependent pathway in humans.