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Differential effects of organic nitrates on arterial diameter among healthy Japanese participants with different mitochondrial aldehyde dehydrogenase 2 genotypes: randomised crossover trial.

ABSTRACT: To determine whether polymorphisms at codon 487 (*1, GAA=Glu; *2, AAA=Lys) of mitochondrial aldehyde dehydrogenase 2 (ALDH2) influence nitroglycerine (glyceryl trinitrate (GTN))-induced vasodilation, and whether GTN or isosorbide dinitrate (ISDN) is a more effective antianginal agent in each ALDH2 genotype.A randomised, open-label, crossover trial with 117 healthy Japanese (20-39 years) whose genotypes were determined (*1/*1, n=47; *1/*2, n=48; *2/*2, n=22) was performed at Kyushu University Hospital, Fukuoka, Japan. Participants were randomly assigned to treatment: sublingual spray of GTN (0.3 mg) or ISDN (1.25 mg). After ? 1 week, measurements were repeated using the other drug. The main outcome measures were the maximal rate of increase in the brachial artery diameter determined by ultrasonography, the time required to attain maximal dilation (T(max)) and the time required to attain 90% maximal dilation (T(0.9)).The maximal artery diameter increase in response to GTN or ISDN did not differ among genotypes. However, GTN T(max) was significantly longer for *2/*2 (299.7 s, 269.0-330.4) than *1/*1 (254.7 s, 238.6-273.4; p=0.0190). GTN T(0.9) was significantly longer in the *1/*2 (206.1 s, 191.7-219.3) and *2/*2 (231.4 s, 211.8-251.0) genotypes than *1/*1 (174.9 s, 161.5-188.3; p=0.0068, p<0.0001, respectively). In contrast, the time-course of ISDN-induced vasodilation did not differ among genotypes. GTN T(max) and T(0.9) among *1 allele carriers (*1/*1 and *1/*2) were significantly shorter than those of ISDN, whereas the time course of GTN and ISDN vasodilation did not differ among participants carrying *2/*2.The amplitude of GTN-induced vasodilation was not influenced by the ALDH2 genotype, but the response was significantly delayed in *2 allele carriers, especially *2/*2. GTN dilated the artery more quickly than ISDN in *1/*1 and *1/*2, but not in *2/*2. Trial registration number UMIN000001492 (UMIN-CTR database).

SUBMITTER: Sakata S

PROVIDER: S-EPMC3191425 | biostudies-other | 2011 Jan

REPOSITORIES: biostudies-other

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Differential effects of organic nitrates on arterial diameter among healthy Japanese participants with different mitochondrial aldehyde dehydrogenase 2 genotypes: randomised crossover trial.

Sakata Satoko S Yoshihara Tatsuya T Arima Hisatomi H Shiraishi Fumie F Oniki Hideyuki H Takahashi-Yanaga Fumi F Matsumura Kiyoshi K Sasaguri Toshiyuki T

BMJ open 20110718 1

<h4>Objectives</h4>To determine whether polymorphisms at codon 487 (*1, GAA=Glu; *2, AAA=Lys) of mitochondrial aldehyde dehydrogenase 2 (ALDH2) influence nitroglycerine (glyceryl trinitrate (GTN))-induced vasodilation, and whether GTN or isosorbide dinitrate (ISDN) is a more effective antianginal agent in each ALDH2 genotype.<h4>Design</h4>A randomised, open-label, crossover trial with 117 healthy Japanese (20-39 years) whose genotypes were determined (*1/*1, n=47; *1/*2, n=48; *2/*2, n=22) was ...[more]

PMID: 22021773

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Project description:RATIONALE:An increasing body of evidence links the occurrence of sleep continuity disturbances with increased inflammation and both sleep disturbances and inflammation are associated with clinical depression. Typhoid vaccination results in a mild inflammatory response that significantly increases levels of the proinflammatory cytokine, interleukin (IL)-6. OBJECTIVES:The present exploratory study aimed to enhance our understanding of the link between inflammation, sleep and depression by examining the effects of typhoid vaccine on the sleep polysomnogram. METHODS:We studied the effects of a single injection of typhoid polysaccharide vaccine and placebo (saline solution) on sleep in 16 healthy male and female participants aged 20-38 years, sleeping at home in a randomized, double-blind, balanced order, crossover design. Subjective measures of mood, sleep and adverse effects were elicited and plasma samples analysed for IL-6 levels. RESULTS:IL-6 levels (in picogramme per millilitre) significantly increased 2 h post vaccine compared to placebo (0.90 vs 0.53, p = 0.026, r = 0.55). Relative to placebo, typhoid vaccination produced significant impairment in several measures of sleep continuity. Total sleep time (in minute) (426.1 vs 410.7, p = 0.005, r = 0.62) and sleep efficiency percent (94.3 vs 91.5, p = 0.007, r = 0.65) were decreased; with increases in wake after sleep onset (in minute) (25.5 vs 38.8, p = 0.007,r = 0.65), total wake (in minute) (34.9 vs 50.3, p = 0.005,r = 0.67), sleep stage transitions (155.9 vs 173.1, p = 0.026, r = 0.56), number of awakenings (27.2 vs 36.1, p = 0.007, r = 0.64) and awakening index (3.8 vs 5.3, p = 0.005, r = 0.67) (means, significance level and effect size). CONCLUSIONS:Inflammatory mechanisms may underlie the impairment in sleep efficiency which is a hallmark of major depression. Because impaired sleep is also a predictor of major depression, there may be a role for suitable anti-inflammatory approaches in strategies designed to prevent the onset of depression. ClinicalTrials.gov ( http://www.clinicaltrials.gov ): NCT02628054.

Project description:Elevated serum triglyceride (TG) and high-density-lipoprotein cholesterol (HDL-C) levels are common in drinkers. The fast-metabolizing alcohol dehydrogenase-1B encoded by the ADH1B*2 allele (vs. ADH1B*1/*1 genotype) and inactive aldehyde dehydrogenase-2 encoded by the ALDH2*2 allele (vs. ALDH2*1/*1 genotype) modify ethanol metabolism and are prevalent (?90% and ?40%, respectively) in East Asians. We attempted to evaluate the associations between the ADH1B and ALDH2 genotypes and lipid levels in alcoholics.The population consisted of 1806 Japanese alcoholic men (?40 years) who had undergone ADH1B and ALDH2 genotyping and whose serum TG, total cholesterol, and HDL-C levels in the fasting state had been measured within 3 days after admission.High serum levels of TG (?150 mg/dl), HDL-C (>80 mg/dl), and low-density-lipoprotein cholesterol (LDL-C calculated by the Friedewald formula ?140 mg/dl) were observed in 24.3%, 16.8%, and 15.6%, respectively, of the subjects. Diabetes, cirrhosis, smoking, and body mass index (BMI) affected the serum lipid levels. Multivariate analysis revealed that the presence of the ADH1B*2 allele and the active ALDH2*1/*1 genotype increased the odds ratio (OR; 95% confidence interval) for a high TG level (2.22 [1.67-2.94] and 1.39 [0.99-1.96], respectively), and decreased the OR for a high HDL-C level (0.37 [0.28-0.49] and 0.51 [0.37-0.69], respectively). The presence of the ADH1B*2 allele decreased the OR for a high LDL-C level (0.60 [0.45-0.80]). The ADH1B*2 plus ALDH2*1/*1 combination yielded the highest ORs for high TG levels and lowest OR for a high HDL-C level. The genotype effects were more prominent in relation to the higher levels of TG (?220 mg/dl) and HDL-C (?100 mg/dl).The fast-metabolizing ADH1B and active ALDH2, and especially a combination of the two were strongly associated with higher serum TG levels and lower serum HDL-C levels of alcoholics. The fast-metabolizing ADH1B was associated with lower serum LDL-C levels.

Dataset Information

Differential effects of organic nitrates on arterial diameter among healthy Japanese participants with different mitochondrial aldehyde dehydrogenase 2 genotypes: randomised crossover trial.

Publications

Differential effects of organic nitrates on arterial diameter among healthy Japanese participants with different mitochondrial aldehyde dehydrogenase 2 genotypes: randomised crossover trial.

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