ardiovascular diseases are thought to result from the interaction of multiple environmental and genetic factors. [1][2][3] The ECTIM study showed that the ACE DD genotype was more frequent in patients with myocardial infarction than in control subjects, 4 and Tiret et al also showed that the association between the ACE DD genotype and myocardial infarction was increased in a subset of patients who also carried the angiotensin II type 1 C allele. 5 Other studies have confirmed the association of the ACE D allele and angiotensin II type 1 receptor C allele with an increased risk of myocardial infarction, 6-10 and furthermore, there have been several reports of the association of some nuclear genes with coronary heart diseases in Japanese subjects. 11-13 However, few have addressed the association between polymorphisms of the mitochondria (mt) and coronary heart disease.Human mitochondrial DNA (mtDNA) consists of 16,569 base pairs (bp) located on the circular double strand of the H-and L-chains: 13 types of proteins, 22 types of transfer RNA (tRNA) and 2 types of liposome RNAs are densely coded in a region other than the non-coding region of approximately 1 kb. The mtDNA is highly polymorphic and controls the oxidative phosphorylation system regulating the oxygen metabolism.Tanaka et al reported a mutation specifically seen in Japanese subjects at nucleotide 5178 within the NADH dehydrogenase in the mitochondrial electron transport system Complex 1; mitochdrial 5178A/C is involved in a Met to Leu substitution. [14][15][16][17][18] According to them, the ratio of adenine (A) is approximately half that in healthy people and Japanese centenarians mostly carry A at 5178, which is rarely seen in Europeans or non-Japanese Asians. Based on their findings, they suggested that the high ratio of 5178A may be specific to the Japanese population and possibly related to the fact that the life expectancy at birth in Japan is among the highest in the world.Maternally transmitted mitochondrial genotypes may influence oxidative damage and 5178A/C may be relevant to common diseases. The aim of the present research was to examine the association between genetic factors and the incidence of myocardial infarction. In particular, we focused on the association between mitochondrial genotypes and coronary heart disease; in order to demonstrate a contribution of mitochondrial single nucleotide polymorphisms (SNPs) to the susceptibility to acute myocardial infarction (AMI), we investigated the association of mitochondrial 5178A/C polymorphism with the occurrence of AMI. Methods Study PopulationParticipants were randomly selected inpatients and outpatients treated at the University Hospital and affiliated hospitals in Tokyo, Japan. We divided the study subjects, all of them Japanese, into 4 groups.(1) AMI group, which consisted of 150 patients (102 men, mean age: 64 years old) who underwent coronary angiography at our University Hospital from 1997 to 1999. AMI was diagnosed from clinical evidence of cardiac attack, electrocardiographic findi...

Abstract-The appearance of cough in association with angiotensin-converting enzyme (ACE) inhibitors is thought to be related to bradykinin, and it has been speculated that the elicitation of adverse effects is genetically predetermined. Several polymorphisms of the human bradykinin B 2 receptor gene may be involved in ACE inhibitor-related cough. To investigate this possibility, we identified the Ϫ58 thymine (T)/cytosine (C) polymorphism in subjects with ACE inhibitor-related cough. We classified the study population into 4 groups: subjects with and without cough that were treated with ACE inhibitors (nϭ30/30), nontreated essential hypertensive subjects (nϭ100), and normotensive subjects (nϭ100). The Ϫ58T/C was genotyped by the polymerase chain reaction single-strand conformation polymorphism method. The frequencies of the CC genotype and C allele of Ϫ58T/C were significantly higher in the nontreated hypertensive subjects than in the normotensive subjects. Conversely, the frequencies of the TT genotype and T allele were significantly higher in the subjects with cough than in the subjects without cough. These tendencies were more pronounced in females. Among the promoter assays of the human bradykinin B 2 receptor, Ϫ58T was found to have a higher transcription rate than that of Ϫ58C. This finding seems to suggest that the transcriptional activity of promoter might be involved in the appearance of ACE inhibitor-related cough. A genetic variant of the bradykinin receptor is involved in the elicitation of ACE inhibitor-related cough. It may be possible to predict the side effects of ACE inhibitors in advance. Key Words: bradykinin Ⅲ genes Ⅲ polymorphism Ⅲ promoter A ngiotensin-converting enzyme (ACE) inhibitors have been widely used in therapy for hypertension, congestive heart failure, and myocardial infarction, and several large clinical trials have confirmed that ACE inhibitors reduce mortality and morbidity in patients with congestive heart failure. [1][2][3][4][5] Several studies also suggest that ACE inhibitors are efficient in left ventricular remodeling after acute myocardial infarction and congestive heart failure. 6,7 The ability of ACE inhibitors to decrease angiotensin II production and increase kinin activity has been considered to be critically important. Reduced formation of angiotensin II seems to play a major role in the antihypertensive action of ACE inhibitors, but increased kinin levels have also been proposed to contribute to other beneficial effects of ACE inhibitors, including cardioprotection. However, ACE inhibitors also have adverse effects, the most common of which are cough and angioedema. ACE inhibitor-related cough is a side effect in Ϸ10% of treated patients, 8 -10 and in some instances, an unexplained persistent cough limits the use of these drugs. Women are more likely to have this side effect, which may occur at any time from a few days to several months after the initiation of treatment. Why ACE inhibitors cause coughing is not completely understood. Accumulation of kinins has bee...

The use of angiotensin-converting enzyme (ACE) inhibitors to treat hypertension has recently increased. However, their use is associated with a persistent dry cough in a significant percentage of such patients. The present study was designed to assess the contribution of polymorphisms as a genetic marker of ACE-inhibitorrelated cough in a Japanese hypertensive population. Genotyping was carried out in 190 patients, 70 with cough and 120 without cough, who had been treated with ACE inhibitors. Polymorphisms of ACE insertion/ deletion (I/D), angiotensin II type 1 receptor (1166A/C), type 2 receptor (3123C/A), and bradykinin B2 receptor (À58T/C, exon 1, I/D), were analyzed in these subjects. The TT genotype and T allele of bradykinin B2 receptor (À58T/C) were identified at a significantly higher frequency in the cough (+) patients than in the cough (À) patients. This difference was even more pronounced in women. However, there was no significant relationship between polymorphisms of ACE, angiotensin II receptors, or bradykinin B2 receptor exon 1, and occurrence of ACE-inhibitor-related cough. The transcriptional activity of the bradykinin B2 receptor promoter is involved in the occurrence of cough, and this new marker may provide a valuable tool to detect patients at risk of developing this side effect of ACE inhibitors. In conclusion, Susceptibility to develop cough is associated with a genetic variant of the bradykinin B2 receptor promoter; thus, it may be possible to identify those patients who will develop this adverse reaction to ACE inhibitors in advance.

The purpose of this study was to examine mitochondrial respiratory impairment in the diabetic heart. Diabetes mellitus was induced in male Wistar rats by intravenous injection of streptozotocin (STZ) for 2 to 16 weeks (Group D). In some of the diabetic rats, insulin was injected for 2 or 3 weeks prior to sacrifice (Group I). Fasting blood glucose was markedly elevated to greater than 300 mg/dl in Group D and was similar to normal glucose levels in Group I. At 2 weeks after STZ injection, state 3 was only 59.1% of that in the control. Complex I and complex V activities were also significantly reduced to 43.4% and 71.7% of those in the control, respectively. These reductions recovered with insulin treatment. This phenomenon persisted for 16 weeks. Morphological studies revealed swelling of the mitochondria and an increase in lipid droplets in diabetic cardiomyocytes, and these were also improved with insulin treatment. We conclude that in the diabetic heart, disturbance of energy production in cardiac mitochondria is generated by the impairment of oxidative phosphorylation due to depression of complex I and complex V. These changes may contribute the cardiac dysfunction that is a complication of diabetes mellitus.

he past few decades have seen remarkable developments in the field of molecular biology, and the genetic epidemiologic approach has identified many hereditary diseases. Human essential hypertension is thought to result from the interaction of multiple environmental and genetic factors. 1 The renin-angiotensin system (RAS) is an important component of blood pressure regulation 2 and its components, such as angiotensin-converting enzyme (ACE), angiotensinogen, and angiotensin-II type 1 and type 2 receptors, are suspected to play a role in the pathogenesis of human essential hypertension at the genetic level. Therefore the RAS has been the focus of numerous genetic studies of the cause of essential hypertension. [3][4][5][6][7][8][9][10][11] On the other hand, the vascular kallikrein-kinin system (KKS) also seems to be involved in the development of human essential hypertension. From the results of experimental hypertension, 12,13 the kinins may possibly gain importance in blood pressure regulation in cases where elevated blood pressure is maintained by circulating pressure agents (eg,. Bradykinin is a vasoactive nonapeptide of the kinin family released from kininogenes via the proteolytic activity of kallikreins, [15][16][17] and it has been implicated in a variety of physiological processes (eg, vasodilation, cardiovascular permeability, inflammatory pain, edema, smooth muscle contraction, neurotransmission and cell proliferation 18,19 ). Human bradykinin receptors are cell surface, G-protein-coupled receptors of the 7-transmembrane domained superfamily, and the existence of 2 subtypes, 1 and 2, has been confirmed 15 and Japanese Circulation Journal Vol.63, October 1999 the majority of bradykinin effects are mediated by the 2-subtype receptor. 17,[20][21][22] The human 2 bradykinin receptor cDNA was recently cloned by Hess et al 23 and a study of the genomic structure has shown that it is characterized by 4 polymorphisms located in each of the 3 exons and 1 polymorphism in the promoter region. [24][25][26] Therefore, the 2 bradykinin receptor gene has been implicated as one of the candidate genes involved in the complex genetic underpinnings of essential hypertension.To assess the role of 2 bradykinin receptor gene polymorphism in essential hypertension, we examined the distribution of a nucleotide polymorphism in the core promoter of the gene in a Japanese population. Methods Patient PopulationThe participants were randomly selected outpatients at the Hatiouji Health Care Center in Tokyo. They were all Japanese and consisted of 100 hypertensive subjects and 100 normotensive subjects matched for age and sex. Written informed consent was obtained from each subject. Hypertensive subjects were selected according to the following criteria.(1) Systolic blood presssure >140 mmHg or a diastolic blood presssure >90 mmHg without antihypertensive treatment.(2) Absence of clinical or biological signs of secondary hypertension.(3) Absence of diabetes mellitus, hyperlipidemia, coronary heart disease, etc requiring treatment.(...