Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023890 (cirrhosis)
 42,195 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Valsartan is a highly selective, orally available antagonist of the angiotensin Type 1 (AT1) receptor. It is indicated for treatment of mild to moderate essential hypertension. Experimental studies have confirmed the abolition or attenuation of angiotensin II (AII)-related effects, such as vasoconstriction, cell growth promotion and aldosterone release. In humans, valsartan is rapidly absorbed with maximal plasma concentrations occurring 1-2 h after oral administration. The elimination half-life comes to about 7-8 h, valsartan is metabolised to a negligible extent and most of the drug is excreted via the faeces. There is no dose adjustment required for patients with a creatinine clearance > 10 ml/min. The dose should not exceed 80 mg o.d. in patients with hepatic dysfunction, valsartan is not recommended for patients with severe hepatic dysfunction and/or biliary cirrhosis. At present, no clinically relevant pharmacokinetic drug interactions have been observed. Valsartan produces persistent blood pressure reductions in patients with mild to moderate hypertension, the recommended starting dose is 80 mg o.d. If required, the dose may either be increased to 160 mg o.d. or hydrochlorothiazide may be added. In comparison to other antihypertensive drugs valsartan therapy leads to similar blood pressure reductions, while exhibiting a favourable tolerability profile. Preliminary studies suggest beneficial effects in patients with hypertensive end-organ damage such as renal disease and left ventricular hypertrophy. Furthermore, the drug is evaluated for its efficacy in heart failure and patients post-myocardial infarction.
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PMID:Valsartan: a novel angiotensin type 1 receptor antagonist. 1124 53

Although the aldosterone-responsive segments of the nephron together reabsorb <10% of the filtered Na+, certain single-gene defects that affect the epithelial Na+ channel (ENaC) in the luminal membrane of the collecting duct (CD) or its regulation by aldosterone cause severe hypertension, whereas others cause salt wasting and hypotension. These rare defects illustrate the key role of the distal nephron in maintaining normal extracellular volume and blood pressure. Genetic defects that increase the Cl- conductance of the junctional complexes may also lead to salt retention and hypertension. Less dramatic alterations in regulatory actions of other hormones such as vasopressin (VP), either alone or with other genetic variations, diet, or environmental factors, may also produce Na+ retention or loss. Although VP acts primarily to regulate water balance, it is also an antinatriuretic hormone. Elevated basal plasma VP levels, and/or augmented VP release with increased Na+ intake, have been linked to essential hypertension in humans and in animal models of congestive heart failure and cirrhosis. Norepinephrine, dopamine, and prostaglandin E2 can inhibit the antinatriuretic effects of VP, and changes in the actions of these autocrine and paracrine regulators may also be involved in abnormal regulation of Na+ reabsorption.
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PMID:Abnormal regulation of ENaC: syndromes of salt retention and salt wasting by the collecting duct. 1211 May 5

Urea cycle disorders (UCD) are human conditions caused by the dysregulation of nitrogen transfer from ammonia nitrogen into urea. The biochemistry and the genetics of these disorders were well elucidated. Earlier diagnosis and improved treatments led to an emerging, longer-lived cohort of patients. The natural history of some of these disorders began to point to pathophysiological processes that may be unrelated to the primary cause of acute morbidity and mortality, i.e., hyperammonemia. Carbamyl phosphate synthetase I single nucleotide polymorphisms may be associated with altered vascular resistance that becomes clinically relevant when specific environmental stressors are present. Patients with argininosuccinic aciduria due to a deficiency of argininosuccinic acid lyase are uniquely prone to chronic hepatitis, potentially leading to cirrhosis. Moreover, our recent observations suggest that there may be an increased prevalence of essential hypertension. In contrast, hyperargininemia found in patients with arginase 1 deficiency is associated with pyramidal tract findings and spasticity, without significant hyperammonemia. An intriguing potential pathophysiological link is the dysregulation of intracellular arginine availability and its potential effect on nitric oxide (NO) metabolism. By combining detailed natural history studies with the development of tissue-specific null mouse models for urea cycle enzymes and measurement of nitrogen flux through the cycle to urea and NO in UCD patients, we may begin to dissect the contribution of different sources of arginine to NO production and the consequences on both rare genetic and common multifactorial diseases.
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PMID:Clinical consequences of urea cycle enzyme deficiencies and potential links to arginine and nitric oxide metabolism. 1546 84

The renin-angiotensin-aldosterone system (RAAS) is characterized by a circadian rhythm (CR) whose acrophase is detectable early in the morning. The prorenin and angiotensin converting enzyme (ACE) show a CR as well. However, while the prorenin is in phase with the RAAS the ACE shows its circadian acrophase in the afternoon suggesting a negative feed-back. The RAAS CR is influenced by many factors. Its mesor is modified by sodium intake. The physical activity and rest affect both the mesor and acrophase. The variations in mesor amplitude and acrophase in aged subjects are conditioned by sex and physical activity. Moreover, the RAAS CR seems to be influenced by the race. In addition, it is abolished by the beta-adrenergic blockade, suggesting the existence of an adrenergic clock. Interestingly, the RAAS CR seems not to be a pacemaker for the blood pressure CR, whose acrophase is early in the afternoon. The RAAS CR is not substantially modified has in essential hypertension. However, the CR of plasma renin activity is disappeared in the low-renin essential hypertension, while the CR of plasma aldosterone is detectable. On the contrary, the aldosterone CR is not detectable in ascitic liver cirrhosis; but, it is restored when the ascites is removed by peritoneal-jugular shunt. No significant variation of the RAAS CR seems to occur in obesity and Cushing's syndrome. The RAAS CR has disappeared in Conn's disease as well as in Bartter's syndrome and Liddle's syndrome. The administration of indomethacine in Bartter's syndrome and of triamterene in Liddle's syndrome is able to restore the RAAS CR. Finally, the RAAS CR is not detectable in the heart or kidney transplanted patients; such a phenomenon could be attributed to cyclosporine and corticosteroids administration and to the denervation of the transplanted organs.
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PMID:[Circadian rhythm of the renin-angiotensin-aldosterone system: a summary of our research studies]. 1555 56

This review looks at the alterations in the systemic haemodynamics of patients with chronic liver disease (cirrhosis) in relation to essential hypertension and arterial hypertension of renal origin. Characteristic findings in patients with cirrhosis are vasodilatation with low overall systemic vascular resistance, high arterial compliance, increased cardiac output, secondary activation of counterregulatory systems (renin-angiotensin-aldosterone system, sympathetic nervous system, release of vasopressin), and resistance to vasopressors. The vasodilatory state is mediated through adrenomedullin, calcitonin gene-related peptide, nitric oxide, and other vasodilators, and is most pronounced in the splanchnic area. This provides an effective (although relative) counterbalance to raised arterial blood pressure. Subjects with arterial hypertension (essential, secondary) may become normotensive during the development of chronic liver disease, and arterial hypertension is rarely manifested in patients with cirrhosis, even in those with renovascular disease and high circulating renin activity. There is much dispute as to the understanding of homoeostatic regulation in cirrhotic patients with manifest arterial hypertension. This probably includes the combination of vasodilatation and vasoconstriction in parallel.
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PMID:Arterial hypertension and chronic liver disease. 1617 91

Characteristic findings in patients with cirrhosis are vasodilatation with low overall systemic vascular resistance, high arterial compliance, increased cardiac output, secondary activation of counter-regulatory systems (renin-angiotensin-aldosterone system, sympathetic nervous system, release of vasopressin), and resistance to vasopressors. The vasodilatory state is mediated through adrenomedullin, calcitonin gene-related peptide, nitric oxide, and other vasodilators, and is most pronounced in the splanchnic area. This constitutes an effective (although relative) counterbalance to increased arterial blood pressure. This review considers the alterations in systemic hemodynamics in patients with cirrhosis in relation to essential hypertension and arterial hypertension of the renal origin. Subjects with arterial hypertension (essential, secondary) may become normotensive during the development of cirrhosis, and arterial hypertension is rarely manifested in patients with cirrhosis, even in cases with renovascular disease and high circulating renin activity. There is much dispute as to the understanding of homoeostatic regulation in cirrhotic patients with manifest arterial hypertension. This most likely includes the combination of vasodilatation and vasoconstriction in parallel.
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PMID:Liver cirrhosis and arterial hypertension. 1652 Nov 78

Essential hypertension is associated with the metabolic syndrome, insulin resistance and the development of fatty liver. Fatty liver disease is a spectrum of liver diseases ranging from simple hepatic steatosis through steato-hepatitis to cirrhosis and hepatoma. The purpose of this review is to discuss the evidence for an association between essential hypertension and non-alcoholic fatty liver disease, and to consider the diagnosis and management of non-alcoholic fatty liver disease. We conclude that it is important to consider the diagnosis of fatty liver disease in hypertensive patients, to measure the liver function tests at diagnosis and not to ignore minor elevations of serum aminotransferases. Hypertensive patients with raised liver enzymes should be referred for further assessment, particularly if risk factors for progressive liver disease, such as obesity and diabetes, are present.
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PMID:Hypertension and fatty liver: guilty by association? 1727 55

Nonalcoholic fatty liver disease represents a spectrum of histopathologic abnormalities, the prevalence of which may be as high as 24% of the population of the United States. Nonalcoholic fatty liver disease will play a major role in the science and practice of gastroenterology in the near future. The fundamental derangement in nonalcoholic fatty liver disease is insulin resistance, a key component of the metabolic syndrome, which includes type 2 diabetes mellitus, hypertriglyceridemia, essential hypertension, low circulating high-density lipoprotein, and obesity. The natural history of fatty liver disease is not always benign, and causality for cirrhosis and chronic liver disease is well-founded in the literature. Treatment strategies are limited and, at present, are primarily focused on weight loss and use of insulin sensitizing agents, including the thiazolidenediones. Recent data clearly implicate hepatic insulin resistance as a culprit in accumulation of free fatty acids as triglycerides in hepatocytes. Hepatic insulin resistance is clearly exacerbated by systemic insulin resistance and impaired handling by skeletal muscle and adipose tissue of both glucose and free fatty acids. The key consequence of hepatic insulin resistance, impaired hepatocyte insulin signal transduction, results in adverse cellular and molecular changes exacerbating hepatocyte triglyceride storage. Cytokines secreted by white adipose tissue, adipokines, have emerged as key players in glucose and fat metabolism previously thought controlled largely by insulin. Modulation of adipokines may aid in further understanding of the pathophysiology and treatment of nonalcoholic fatty liver disease.
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PMID:Abnormal lipid and glucose metabolism in obesity: implications for nonalcoholic fatty liver disease. 1749 12


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