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Abstract-A recent report based on the results of 2 epidemiological studies, the Etude Cas-Temoin de l'Infarctus Myocarde (ECTIM) and the Glasgow Heart Scan Study, revealed that a G/T polymorphism with an amino acid substitution (Lys3 Asn) at codon 198 in exon 5 of the endothelin-1 gene (ET-1) is associated with blood pressure in overweight people. They suggested that G/T polymorphism of ET-1 strongly interacted with body mass index (BMI) in the determination of BP levels. To examine interaction among G/T polymorphism of ET-1, BMI, and BP, we performed an association study in a general Japanese population. Subjects (nϭ1250) were recruited from Ohasama, a cohort in a rural community of northern Japan. DNA was extracted from buffy coat of participants, and G/T polymorphism of ET-1 was determined by the TaqMan probe polymerase chain reaction method, a powerful tool for semiautomatic genotype determination of a large number of samples. Frequency of T (Asn 198) allele in Japanese (27%) was slightly but significantly higher than in whites (24%). Baseline characteristics (age, BMI, systolic and diastolic BP, and antihypertensive treatment) of all subjects were not significantly different according to the genotype of G/T polymorphism. However, in obese subjects (Ն25 kg/m 2 ) diastolic BPs were significantly associated with G/T polymorphism of ET-1. After adjustment for confounding factors, significant association remained; for overweight subjects, diastolic BP level in those with T allele (GT ϩ TT) was 1.8 mm Hg (Pϭ0.04) higher than in those with GG genotype. That similar results were obtained from subjects of different races suggests that the Lys198Asn polymorphism of ET-1 is involved in determination of BP levels in obese subjects. Key Words: genetics Ⅲ hypertension, essential Ⅲ insulin resistance Ⅲ polymerase chain reaction Ⅲ polymorphism Ⅲ receptors, endothelin E ndothelin (ET) originally was isolated in 1988 from a supernatant of porcine aortic endothelial cell cultures and demonstrated strong vasoconstrictive peptide. 1 ET has 3 isoforms (ET-1, ET-2, and ET-3) translated from 3 independent genes 2 and is produced by endothelium and many tissues. 3 ET-1 plays a role in increasing BP, cell proliferation, and modulation of vasomotor tone; it also interacts with the pathophysiology of a variety of vascular diseases, such as hypertension, arteriosclerosis, and ischemic heart disease. Because ET-1 concentration in the blood is increased by standing and decreased by volume overload, it is considered to be modulated by body fluid volume through the renin-angiotensin-aldosterone system. 4 Because of its vasoconstrictive actions for vessels and hypertrophic actions for heart, ET-1 has been examined as an important risk for hypertension. [5][6][7] Plasma level of ET-1 was higher in patients with essential hypertension than in normotensive subjects 8 and paralleled the level of target organ damage. ET A receptor gene was overexpressed in arteries of hypertensive patients, 9 -10 which suggests that ET-1 contributes to the patho...

Excessive alcohol consumption is a potent risk factor for high blood pressure. About half of Japanese show an extremely high sensitivity to alcohol, which is due to a genetic deficiency in an isoenzyme of aldehydede-hydrogenase with a low Km (ALDH2). It is possible that the effects of alcohol consumption on blood pressure differ according to the ALDH2 genotype. The purpose of the present study was to assess the influence of the ALDH2 genotype on the pressor effects of alcohol. The influence of the ALDH2 genotype on blood pressure was investigated in a large cohort (4,000 subjects) representing the general population in Japan. The genotype was determined by the TaqMan method. The genotype was significantly associated with alcohol consumption, gamma-GTP level, and HDL cholesterol level in both males and females. The odds ratio for the presence of hypertension for the Glu/Glu genotype in comparison to other genotypes was 1.67 (p< 0.0001, odds ratio=1.37-2.08, 95% confidence interval) among males. In contrast, the ALDH2 genotype had no significant effects on blood pressure among females. To investigate whether the ALDH2 genotype affected the sensitivity to the pressor effects of alcohol, we analyzed the effects of the ALDH2 genotype (Lys/Lys+Lys/Glu=0, Glu/Glu=1) and the level of alcohol consumption on blood pressure values after adjusting for age and BMI (residuals after adjusting for age and BMI). Among males, while the level of alcohol consumption significantly affected systolic, diastolic and pulse pressure, no significant interaction was observed between the ALDH2 genotype and the level of alcohol consumption in determining blood pressure levels. These results suggest that the Glu/Glu genotype is a potent risk factor for hypertension among males mainly through its association with the level of alcohol consumption, and that the ALDH2 genotype does not affect the sensitivity to the pressor effects of alcohol.

The effect of torasemide and furosemide therapy was compared in 50 patients who had chronic heart failure and symptoms [NYHA class II-III] despite long-term therapy with both low-dose furosemide and angiotensin-converting enzyme inhibitors. In this randomized 6-month, open-label trial, baseline and follow-up echocardiograms and neurohumoral assays were obtained in 25 group F patients (continued same dose of oral furosemide at 20-40 mg/day) and in 25 group T patients (received torasemide at 4-8 mg/day in place of furosemide). At 6 months, parameters were unchanged in group F whereas the group T patients had a lower left ventricular end-diastolic diameter (p<0.005) and left ventricular mass index (p<0.005) with improved Doppler filling parameters, decreased plasma B-type natriuretic concentration (p<0.001) and increased plasma concentrations of active renin (p<0.005) and aldosterone (p<0.001). The magnitude of these changes appeared dose dependent and it is suggested these favorable effects of switching from furosemide to torasemide may be related to aldosterone receptor blockade.

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