Relation between the angiotensin-converting enzyme insertion/deletion polymorphism and blood pressure in Japanese male subjects.

Inconsistent results have been reported regarding the association of the angiotensin-converting enzyme (ACE) insertion/deletion (I/D) polymorphism and hypertension. Recent studies of population-based samples of three different areas in Japan presented conflicting results regarding this association. We, thus, investigated the relation between the ACE I/D polymorphism and blood pressure (BP), or the frequency of hypertension, respectively, in 706 Japanese male subjects who participated in the health check-up programme of our hospital. The ACE I/D polymorphism was determined by the polymerase chain reaction technique. Of 706 subjects, 203 were found to have hypertension and the other 503 were found to be normotensive. In all subjects, the frequencies of the DD, ID, and II genotypes were 0.123, 0.432, and 0.445, respectively, and the allelic frequency of the D allele was 0.339. In the younger subjects aged <50 years (n=264), neither systolic nor diastolic BP differed significantly among the genotypes. Conversely, in the older subjects aged > or =50 years (n=442), the systolic BP was significantly higher by 5.9 mmHg in the subjects with the ID genotype than those with the II genotype (P<0.01), and the diastolic BP was significantly higher in the subjects with the DD and ID genotypes by 5.1 and 3.3 mmHg, respectively than those with the II genotype (P<0.05 for each), although age, BMI, percentage of smoking habits, drinking habits, or the use of antihypertensive drugs did not differ significantly among the genotypes. In addition, in the older subjects, the hypertensive subjects showed significantly higher frequencies of the DD and ID genotypes and the D allele than the normotensive subjects. These results demonstrated that there was no significant association of the ACE I/D polymorphism with BP or a prevalence of hypertension in younger Japanese men aged <50 years but there was in older Japanese men aged > or =50 years.

Positive association of CYP11B2 gene polymorphism with genetic predisposition to essential hypertension.

Predispositions to essential hypertension and cardiovascular diseases are possibly associated with gene polymorphisms of the renin-angiotensin system. Gene polymorphisms of angiotensinogen and angiotensin-converting enzyme genes have been suggested to be risk factors for hypertension and myocardial infarction. Concerning the polymorphism of aldosterone synthase (CYP11B2) gene, earlier studies have shown inconsistent results in terms of its relation to hypertension. In the present case-control study, we investigated the association of -344T/C polymorphism in the promoter region of human CYP11B2 gene with genetic predisposition to hypertension. The genotype of -344T/C polymorphism was determined in essential hypertension subjects (n=250) and normotensive subjects (n=221). The distributions of three genotypes (TT, TC, and CC) were significantly different between the hypertensive and the normotensive groups (chi(2)=9.61, P=0.008). Namely, the frequency of C allele was higher in the hypertensive patients than in the normotensive subjects (34.2 vs 26.5%, P=0.010). Our data suggest that the -344C allele of CYP11B2 gene polymorphism is associated with the genetic predisposition to develop essential hypertension.

Microsatellite DNA polymorphism of human adrenomedullin gene in normotensive subjects and patients with essential hypertension.

Adrenomedullin (AM) is a hypotensive peptide widely produced in the cardiovascular organs and tissues. We have cloned and sequenced the genomic DNA encoding the human AM gene and have determined that the gene is located in the short arm of chromosome 11. The 3'-end of the gene is flanked by the microsatellite marker of cytosine adenine (CA) repeats. In this study, we investigated the association between DNA variations in AM gene and the predisposition to hypertension. Genomic DNA was obtained from 272 healthy normotensive subjects (NT) age 57+/-5 years and 266 patients with essential hypertension (EH) age 53+/-11 years. The DNA was subject to PCR using a fluorescence-labeled primer, and the number of CA repeats were determined by poly-acrylamide gel electrophoresis. The averaged blood pressure was 117+/-13/73+/-9 mm Hg in NT and 170+/-23/104+/-12 mm Hg in EH. In Japanese, there existed 4 types of alleles with different CA-repeat numbers: 11, 13, 14, and 19. The frequencies of these alleles were significantly different between NT and EH (chi(2)=9.43, P=0.024). Namely, 13.5% of EH carried the 19-repeat allele, whereas the frequency was 6.2% in NT (chi(2)=7.62, P=0.007). In NT, plasma AM concentrations were not significantly different between the genotypes. In conclusion, microsatellite DNA polymorphism of AM gene may be associated with the genetic predisposition to EH, although the gene expression is not likely to be affected by the genotypes.

[Analysis of factors influencing left ventricular mass and diastolic function in normotensive men].

OBJECTIVES: Increase in left ventricular weight is an important risk factor for the incidence of cardiovascular diseases, and reduction in diastolic function of the left ventricle is an early marker for cardiac dysfunction. Factors related to the left ventricular mass and diastolic function were analyzed in middle-aged normotensive men. METHODS: The subjects were 126 normotensive men aged 49 +/- 1 years who were hospitalized for health-checkup. In addition to physical examination and routine laboratory tests, echocardiography including the pulse-Doppler method was performed and urinary electrolyte excretions, plasma angiotensin II, plasma noradrenaline and the angiotensin converting enzyme genotype were examined. RESULTS: Left ventricular mass index was positively correlated with mean blood pressure (r = 0.249, p < 0.006) and body mass index (r = 0.279, p < 0.002). With regard to the index of left ventricular diastolic dysfunction, the late to early peak transmitral flow velocity ratio (A/E) was positively correlated with age (r = 0.465, p < 0.001) and urinary sodium excretion (r = 0.240, p < 0.007). Neither left ventricular mass index or A/E was affected by the angiotensin converting enzyme genotype and was not significantly correlated with plasma angiotensin II or noradrenaline. CONCLUSIONS: Increase in left ventricular mass is influenced by blood pressure and obesity, whereas reduction in left ventricular diastolic function is affected by greater age and salt intake.

Molecular forms of plasma and urinary adrenomedullin in normal, essential hypertension and chronic renal failure.

OBJECTIVES: Human adrenomedullin precursor is converted to glycine-extended adrenomedullin (AM-Gly), an intermediate inactive form of adrenomedullin. Subsequently, AM-Gly is converted to active form of mature adrenomedullin (AM-m). The aim of the present study was to investigate (i) whether sex or age influences plasma and urinary AM-m and AM-Gly levels in normal subjects; (ii) the daytime variability of plasma AM-m and AM-Gly levels in normal subjects; (iii) AM-m and AM-Gly levels and its ratio in plasma and urine in normal subjects, individuals with essential hypertension (HT), and chronic renal failure (CRF); and (iv) the ratio of AM-m and AM-total (T) in plasma of various veins and aorta. METHODS: We measured plasma levels and urinary excretions of AM-m, AM-Gly and AM-T (AM-m + AM-Gly) by recently developed immunoradiometric assay in normal subjects (n = 81), HT (n = 28) and CRF (n = 30). We also determined the molecular forms of plasma adrenomedullin taken from various sites during angiography in patients with suspected renovascular hypertension (n = 9). RESULTS: There were no differences in plasma and urinary excretions of two molecular forms of adrenomedullin among sexes or ages in normal subjects. There was no daytime variation of plasma two molecular forms of adrenomedullin in normal subjects. Plasma AM-m, AM-Gly and AM-T levels were increased in patients with HT and CRF compared with normal subjects, whereas urinary AM-m, AM-Gly and AM-T excretions were decreased in patients with HT and CRF compared with normal subjects. Urinary AM-m: AM-T ratios were significantly higher than plasma AM-m: AM-T ratios. Plasma AM-m and AM-T levels taken from various veins were similar, and they were significantly higher than those of aorta, although there were no differences in plasma AM-Gly levels between aorta and veins. CONCLUSIONS: These results suggest that in normal subjects, and individuals with HT and CRF: (i) plasma and urinary excretions of AM-m and AM-Gly are not affected by age or sex; (ii) AM-m in parallel with AM-Gly is increased; (iii) urine contains a higher percentage of active adrenomedullin than plasma; and (iv) plasma AM-m may be partly metabolized in the lung.

Chromosomal sublocalization and microsatellite DNA polymorphism of human adrenomedullin gene.

Adrenomedullin (AM) is a hypotensive peptide widely produced in the cardiovascular organs and tissues such as the heart, kidney and vascular cells. We have cloned and sequenced genomic DNA encoding the human AM gene. In this study, we determined that the AM gene was located in the short arm of chromosome 11 (p15.1-3). The 3'-end of the gene is flanked by a microsatellite marker of cytosine adenine (CA) repeats. Moreover, we analyzed this DNA variation in the AM gene in the general Japanese population. Genomic DNA was obtained from the peripheral leukocytes of healthy normotensive subjects, 327 men and 149 women, aged 51 +/- 8 years (mean +/- SD). The genomic DNA was subject to PCR using a fluorescence-labeled primer, and the number of CA repeats were determined via polyacrylamide gel electrophoresis (PAGE). Plasma AM concentration was measured by RIA and compared with respect to the number of CA repeats adjacent to the AM gene. In Japanese, four types of alleles with different CA-repeat numbers; 11, 13, 14 and 19, appear to exist. The frequencies of these alleles were as follows: 11 repeats, 28.8%; 13 repeats, 33.1%; 14 repeats, 35.0% and 19 repeats, 3.1%. This DNA variation does not seem to affect the transcription of the AM gene, because plasma concentrations of AM were not significantly different between the genotypes.

Relationship between birth weight and cardiovascular risk factors in Japanese young adults.

A number of studies have recently shown a significant inverse relationship between birth weight and incidences of chronic and metabolic disorders such as hypertension and type 2 diabetes, though the findings are not consistent. So far, few investigations have been performed to determine whether this relationship exists in Japanese young adults. We investigated the influence of birth weight on cardiovascular risk factors such as blood pressure and several metabolic variables in Japanese young adults. The data of 299 medical students of Dokkyo University School of Medicine (207 men, 92 women; mean age +/- SD: 23 +/- 2 years) who underwent a medical check-up in 1998 were analyzed. Information on pregnancies and measurements at birth were obtained from The Maternal and Child Health Handbook, which is provided to every pregnant woman by the Ministry of Health and Welfare of Japan. Blood pressure was measured twice in the sitting position using an automated device based on the cuff-oscillometric method. The systolic and diastolic blood pressure in young adulthood was positively correlated with current body weight and body mass index (BMI) in both genders. Although birth weight was not significantly correlated with blood pressure in the young adults examined in the present study, male birth weight was inversely correlated with serum total cholesterol and triglyceride concentrations in young adulthood, independently of current BMI. These results partly support the hypothesis for the first time that low birth weight may be one of the risk factors for subsequent cardiovascular disease in Japanese men.

[Implications of obesity for target organ injuries and cardiovascular risk factors in hypertensive subjects].

The effects of obesity on target organ injuries and cardiovascular risk factors were examined in hypertensive subjects. The subjects were 22 obese (OB-HT) and 54 nonobese (NO-HT) men with never-treated essential hypertension, and 37 obese (OB-NT) and 50 nonobese (NO-NT) normotensive men. In these 4 groups with the average age of about 50 years, we evaluated serum lipids, glucose tolerance, and hypertensive organ injuries in the heart, kidney, and optic fundus. Although the fasting blood glucose levels were similar in the 4 groups, the area under the blood glucose curve after 75 g glucose ingestion (NO-NT 15.6, OB-NT 17.5, NO-HT 15.8, OB-HT 17.6 x 10(3) mg/dl.min; p < 0.02) and the fast serum insulin level (NO-NT 7.3, OB-NT 10.1, NO-HT 7.7, OB-HT 12.2 mU/l; p < 0.001) were increased in obese men. In OB-HT, serum HDL-cholesterol was decreased (-11%, p < 0.05) and triglycerides were increased (+ 58%, p < 0.01) comparing with NO-NT. The incidence of electrocardiographic left ventricular hypertrophy was not significantly different among the 4 groups, however, urinary albumin excretion was increased in OB-HT (NO-NT 3.0, OB-NT 3.4, NO-HT 3.6, OB-HT 4.3 mg/g creatinine; p < 0.05) and sclerotic lesions of the retinal arteries were observed even in normotensive OB-NT. These data suggest that obesity unfavorably alters lipid and glucose metabolism, and facilitates organ injuries such as arteriosclerosis and renal dysfunction in hypertensive subjects.

Effects of alcohol intake on organ injuries in normotensive and hypertensive human subjects.

1. This cross-sectional study examined the influence of alcohol intake on organ injuries in normotensive and hypertensive subjects. 2. A total of 514 normotensive subjects and 302 never-treated hypertensive subjects were screened from 4557 men who entered the health check programme of our institute during the period 1990 to 1994. According to the daily alcohol consumption data reported by a self-administered questionnaire, the normotensive and hypertensive subjects were both classified into four categories; very light and non- (0-10 ml of ethanol), light (11-29 ml), moderate (30-58 ml) and heavy (> or = 59 ml) drinker groups. In these four pairs of groups, organ injuries in the heart, kidney and optic fundus were evaluated and serum lipids were measured. 3. Although the blood pressure levels were similar among the four groups of hypertensive subjects, the electrocardiographic findings of left ventricular hypertrophy were significantly more common among the moderate and heavy drinkers but not in the light drinkers compared with the very light and non-drinkers (very light and non-drinkers 25%, light drinkers 23%, moderate drinkers 38%, heavy drinkers 40%; P = 0.026). The alcohol intake increased the serum level of high-density lipoprotein cholesterol in a dose-dependent manner without changing the total cholesterol level; however, the serum gamma-glutamyl transpeptidase and triacylglycerol levels were increased in the moderate and heavy drinkers. Urinary albumin excretion and fundoscopic lesions were not associated with the drinking habit in either the normotensive or hypertensive subjects. 4. These data suggest that habitual alcohol consumption exceeding 29 ml per day facilitates the development of left ventricular hypertrophy in hypertensive patients. Among the hypertensive subjects, light drinkers consuming 11 to 29 ml of ethanol daily showed preferable profiles in terms of organ injuries and risks of cardiovascular diseases.