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CLINICAL RESEARCH: GENETICS AND GENOMICS

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

Department of Pharmacology, School of Pharmaceutical Science, Central South University, Changsha, Hunan, China

Manuscript received February 1, 2008; revised manuscript received April 28, 2008, accepted May 19, 2008.

^_* Reprint requests and correspondence: Dr. Yuan-Jian Li, Department of Pharmacology, School of Pharmaceutical Science, Central South University, Changsha, Hunan 410008, China (Email: yuan_jianli{at}yahoo.com).

Objectives: 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.

Background: 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.

Methods: 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.

Results: 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 (SBP) and HR (HR) 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 SBP and HR, 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.

Conclusions: We found that CGRP is associated with the cardiovascular effect of GTN through an ALDH2-dependent pathway in humans.

Key Words: calcitonin gene-related peptide • mitochondrial aldehyde dehydrogenase-2 • nitroglycerin • genetic polymorphism • peripheral blood mononuclear cells

Abbreviations and Acronyms   DBP = absolute decrease in diastolic blood pressure from baseline   HR = absolute increase in heart rate from baseline   SBP = absolute decrease in systolic blood pressure from baseline   ALDH2 (mtALDH) = mitochondrial aldehyde dehydrogenase-2   CGRP = calcitonin gene-related peptide   CH = chloral hydrate   GTN = glyceryl trinitrate   HR = heart rate   NO = nitric oxide   PBMC = peripheral blood mononuclear cell

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