angiotensinogen and Alcoholism

The objective of this study was to explore the association between coronary artery disease and genetic polymorphisms of the renin-angiotensin-aldosterone system (RAAS) pathway. In addition, we examined the interactions between demographic and lifestyle risk factors (environmental factors including age, sex, smoking status, alcohol intake) and RAAS polymorphisms on disease risk.. A total of 1089 subjects who underwent coronary angiography were enrolled in this study. Eight RAAS polymorphisms were genotyped in this population: the G2350A (rs4343) polymorphism in exon 17 of the angiotensin converting enzyme (ACE) gene, 1166A→C (rs5186) and 573C/T (rs5182) in the angiotensin II type 1 receptor (AGTR1) gene, the -344C→T transversion (rs1799998) in the aldosterone synthase (CYP11B2) gene, and the G-217A (rs5049), G-6A (rs5051), M235T (rs699; T4072C), and T174M (rs4762; C3889T) polymorphisms in the angiotensinogen (AGT) gene. Subjects with coronary heart disease were defined as those with at least 50% stenosis in at least one major coronary artery, and, the severity of coronary atherosclerosis was defined by the Gensini scoring system.. Compared to the subjects with AA genotype, the subjects with AG + GG genotype of rs1799998 had significant lower gensini score (p=0.029). After adjusting for age, gender, cigarette smoking, and alcohol intake status, the AG genotype (OR 0.717 95%CI 0.541-0.950, p=0.021) and the AG + GG genotype (OR 0.730 95%CI 0.559-0.954, p=0.021) distributions of rs1799998 were significantly different between the cases and controls compare to the AA genotype. Subjects with three at-risk loci had increased risk of coronary artery disease compared to subjects carrying 0 or 1 risk-associated polymorphism (OR [95% CI]:1.579 [1.077-2.316], p=0. 019), and the significance of the association was not reduced after adjusting for age, sex, cigarette smoking, or alcohol intake (adjusted OR [95% CI]: 1.673 [1.116-2.507], p=0.013). The results of multifactor-dimensionality reduction analysis revealed an interaction effect of CYP11B2 -344C→T, age, and smoking status on the risk of coronary heart disease (training OR [95% CI]: 3.7685 [2.8463-4.9895], p<0.0001; testing OR [95% CI]: 2.7583 [1.2038-6.3203], p=0.015).. Subjects who carried the G allele of the rs1799998 polymorphism significantly associated with coronary heart disease and severity of coronary atherosclerosis estimated by the Gensini score in the whole population of the study. And, multiple RAAS gene polymorphisms are associated with coronary artery disease. The interaction of the CYP11B2 -344C→T polymorphism (rs1799998), age, and smoking status is also associated with enhanced risk of coronary artery disease.

Topics: Age Factors; Aged; Alcoholism; Alleles; Angiotensinogen; Case-Control Studies; Coronary Angiography; Coronary Artery Disease; Cytochrome P-450 CYP11B2; Epistasis, Genetic; Exons; Female; Gene-Environment Interaction; Genetic Loci; Genotype; Humans; Life Style; Male; Middle Aged; Odds Ratio; Peptidyl-Dipeptidase A; Polymorphism, Genetic; Receptor, Angiotensin, Type 1; Renin-Angiotensin System; Risk Factors; Smoking

Pharmacological and genetic interference with the renin-angiotensin system (RAS) seems to alter voluntary ethanol consumption. However, understanding the influence of the RAS on ethanol dependence and its treatment requires modeling the neuroadaptations that occur with prolonged exposure to ethanol. Increased ethanol consumption was induced in rats through repeated cycles of intoxication and withdrawal. Expression of angiotensinogen, angiotensin-converting enzyme, and the angiotensin II receptor, AT1a, was examined by quantitative reverse transcription polymerase chain reaction. Increased ethanol consumption after a history of dependence was associated with increased angiotensinogen expression in medial prefrontal cortex but not in nucleus accumbens or amygdala. Increased angiotensinogen expression also demonstrates that the astroglia is an integral part of the plasticity underlying the development of dependence. The effects of low central RAS activity on increased ethanol consumption were investigated using either spirapril, a blood-brain barrier-penetrating inhibitor of angiotensin-converting enzyme, or transgenic rats (TGR(ASrAOGEN)680) with reduced central angiotensinogen expression. Spirapril reduced ethanol intake in dependent rats compared to controls. After induction of dependence, TGR(ASrAOGEN)680 rats had increased ethanol consumption but to a lesser degree than Wistar rats with the same history of dependence. These data suggest that the central RAS is sensitized in its modulatory control of ethanol consumption in the dependent state, but pharmacological or genetic blockade of the system appears to be insufficient to halt the progression of dependence.

Topics: Adaptation, Physiological; Alcoholism; Angiotensin II; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Angiotensinogen; Animals; Animals, Genetically Modified; Central Nervous System; Disease Models, Animal; Enalapril; Ethanol; Humans; Neuronal Plasticity; Rats; Rats, Wistar; Receptors, Angiotensin; Renin-Angiotensin System; RNA, Antisense

We have altered the method for measuring plasma renin concentration (P.R.C.) originated by Haas, et al (7) by using radioimmunoassay of angiotensin I and avoiding the addition of extrinsic renin substrate. Thus modified, the method gives values for P.R.A. (plasma renin activity), P.R.C. (plasma renin concentration), and also P.R.R. (plasma renin reactivity), which is the rate of reaction of renin substrate in the plasma with added extrinsic renin. By applying this modified method to a wide variety of plasma samples and independently measuring plasma renin substrate concentration (P.R.S.) in the same samples, we found a good correlation between P.R.R. and P.R.S. Our results indicate that the rate of the renin - renin substrate reaction in human plasma is proportional to renin substrate concentration over a wide range of values up to 5000 ng angiotensin I/ml or higher. Thus, first order reaction kinetics with respect to substrate concentration is followed even at high substrate levels and the Km must be high. An additional finding was that pregnant women have elevated P.R.C. levels in contrast with women taking oral contraceptives who have P.R.C. levels lower than normal.

Topics: Alcoholism; Angiotensin I; Angiotensinogen; Contraceptives, Oral; Depression, Chemical; Diabetes Mellitus; Female; Humans; Liver Cirrhosis; Male; Pregnancy; Radioimmunoassay; Renin; Sex Factors

Ten patients with severe liver disease and the hepatorenal syndrome underwent exchange transfusions with 9 to 16 units of fresh heparinized blood to improve renal function by either removing a vasoconstrictive substance or adding a vasodilatory substance. One patient recovered from renal failure within ten days without showing natriuresis. The renal function of one patient improved somewhat, but he died 35 days after the transfusion. The other eight aptients died from 1 to 35 days after exchange transfusion, without any appreciable improvement in renal function. In six patients, renin substrate levels increased after the transfusion, but renal function remained unchanged. The results of this study failed to support a humoral concept of pathogenesis of the hepatorenal syndrome.

Topics: Acute Kidney Injury; Adult; Alcoholism; Angiotensinogen; Chemical and Drug Induced Liver Injury; Creatinine; Exchange Transfusion, Whole Blood; Female; Hepatic Encephalopathy; Humans; Male; Middle Aged