Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0018801 (heart failure)
 72,216 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In many types of cardiovascular pathophysiology such as hypercholesterolemia and atherosclerosis, diabetes, cigarette smoking, or hypertension (with its sequelae stroke and heart failure) the expression of endothelial NO synthase (eNOS) is altered. Both up- and downregulation of eNOS have been observed, depending on the underlying disease. When eNOS is upregulated, the upregulation is often futile and goes along with a reduction in bioactive NO. This is due to an increased production of superoxide generated by NAD(P)H oxidase and by an uncoupled eNOS. A number of drugs with favorable effects on cardiovascular disease upregulate eNOS expression. The resulting increase in vascular NO production may contribute to their beneficial effects. These compounds include statins, angiotensin-converting enzyme inhibitors, AT1 receptor antagonists, calcium channel blockers, and some antioxidants. Other drugs such as glucocorticoids, whose administration is associated with cardiovascular side effects, downregulate eNOS expression. Stills others such as the immunosuppressants cyclosporine A and FK506/tacrolimus or erythropoietin have inconsistent effects on eNOS. Thus regulation of eNOS expression and activity contributes to the overall action of several classes of drugs, and the development of compounds that specifically upregulate this protective enzyme appears as a desirable target for drug development.
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PMID:Regulation of endothelial-type NO synthase expression in pathophysiology and in response to drugs. 1238 13

L-arginine is the substrate for endothelial nitric oxide synthase (eNOS), and the precursor for the synthesis of nitric oxide (NO). This amino acid exerts a number of actions in the cardiovascular system, mainly through the production of NO. However, it also has a number of NO-independent properties, such as the ability to regulate blood and intracellular pH and the effect on the depolarization of endothelial cell membranes. It also has antihypertensive and antioxidant properties, it influences blood viscosity and the coagulation/fibrinolysis system, and it affects the metabolism of glucose, lipids and proteins. L-arginine influences a number of atherosclerosis risk factors such as hypercholesterolemia, hypertension and smoking, improving endothelial function in these patients. However, it does not affect endothelial function in patients with diabetes mellitus. The role of L-arginine in coronary artery disease is still controversial, but it seems that oral or parenteral administration of this amino acid restores endothelial function in the brachial artery and improves coronary microcirculation. The role of L-arginine in heart failure is currently under investigation, and the first results are rather hopeful. In conclusion, L-arginine seems to provide a hopeful prospect for the treatment of cardiovascular diseases. However, more data derived from large-scale prospective studies evaluating the effects of long-term treatment with L-arginine are needed.
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PMID:L-arginine in cardiovascular disease: dream or reality? 1255 44

Endothelial dysfunction plays an important role in a number of cardiovascular diseases. An important pathogenetic factor for the development of endothelial dysfunction is lack of nitric oxide (NO), which is a potent endothelium-derived vasodilating substance. 3-Hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors (statins), originally designed to lower plasma cholesterol levels, seem to ameliorate endothelial dysfunction by a mechanism so far only partly understood. However, statins increase nitric oxide synthase activity. It has been speculated that this and other "side effects" of statin treatment are due to inhibition of Rho, an intracellular signalling protein that initiates Rho kinase transcription. Moreover, statins possess anti-inflammatory characteristics. Some statins have proven to lower plasma levels of C-reactive protein, which is induced by pro-inflammatory cytokines. Other statins have been demonstrated to directly inhibit pro-inflammatory cytokine induction. Finally, some data suggest that statins might be able to counterbalance an increased production of oxygen free radicals. Since chronic heart failure is accompanied not only by endothelial dysfunction, but also by pro-inflammatory cytokine activation and enhanced formation of oxygen free radicals, it is tempting to speculate that statins might be an ideal candidate to treat certain features of this disease. The doses needed to achieve the desired effects might be much lower than those needed to treat hypercholesterolemia.
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PMID:Statins and the role of nitric oxide in chronic heart failure. 1265 63

From March to July 1999, 940 private cardiologists in France recruited 100,429 patients of whom 30,430 (30%) had a previous history of atherothrombotic disease. The prevalence of patients with a previous history of Myocardial Infarction (MI), Ischemic Stroke (IS) or Peripheral Arterial Disease (PAD) was 19.7%, 7.2% and 10.7% respectively. Among patients with a history of atherothrombotic disease, myocardial infarction was the most frequent diagnosis responsible for 65% of all consultations. Each cardiologist described the secondary prevention treatment for 3 consecutive patients among whom 1 corresponded to each of the 3 atherothrombotic territories. The most frequent cardiovascular risk factors were hypercholesterolemia for myocardial infarction (77.9%), smoking for PAD (32.5%) and hypertension for IS (73.2%). Diabetes mellitus (1/4 patients), obesity (1/3) and sedentary way of life (1/3) were equally prevalent for each of the atherothrombotic territories. More than 90% of the patients received an antithrombotic drug. Antiplatelet agents were largely prescribed, anticoagulants being more frequently used for patients with atrial fibrillation, symptomatic cardiac heart failure or stroke of embolic origin. Thienopyridines represent 17.9% of the prescriptions. The prescription rate of statins after MI (58.9%) is lower than in published studies in secondary prevention. The lack of lipid measurement and the delay since last measurement are non-prescription factors. The rates of prescription are even lower in case of PAD (44.6%) or IS history (33.3%). More than half of the patients (56.6%) are treated with beta-blockers and 40.1% with ACE inhibitors. These rates are similar to what has been published. Atherothrombotic disease represents a large part of the daily activity of private cardiologists and is not limited to coronary heart disease. Despite their proven efficacy, drugs for secondary prevention for MI, except antithrombotic drugs, are insufficiently prescribed. This under-prescription is even higher in patients with PAD or IS history and may be related to the lack of clinical trials in these specific territories.
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PMID:[Factors influencing secondary prevention of atherothrombotic disease in the private outpatient cardiology setting: results of the Prisma survey]. 1271 Feb 91

Mice with homozygous null mutations in the high-density lipoprotein receptor SR-BI (scavenger receptor class B, type I) and apolipoprotein E genes fed a low-fat diet exhibit a constellation of pathologies shared with human atherosclerotic coronary heart disease (CHD): hypercholesterolemia, occlusive coronary atherosclerosis, myocardial infarctions, cardiac dysfunction (heart enlargement, reduced systolic function and ejection fraction, and ECG abnormalities), and premature death (mean age 6 weeks). They also exhibit a block in RBC maturation and abnormally high plasma unesterified-to-total cholesterol ratio (0.8) with associated abnormal lipoprotein morphology (lamellar/vesicular and stacked discoidal particles reminiscent of those in lecithin/cholesterol acyltransferase deficiency and cholestasis). Treatment with the lipid-lowering, antiatherosclerosis, and antioxidation drug probucol extended life to as long as 60 weeks (mean 36 weeks), and at 5-6 weeks of age, virtually completely reversed the cardiac and most RBC pathologies and corrected the unesterified to total cholesterol ratio (0.3) and associated distinctive abnormal lipoprotein morphologies. Manipulation of the timing of administration and withdrawal of probucol could control the onset of death and suggested that critical pathological changes usually occurred in untreated double knockout mice between approximately 3 (weaning) and 5 weeks of age and that probucol delayed heart failure even after development of substantial CHD. The ability of probucol treatment to modulate pathophysiology in the double knockout mice enhances the potential of this murine system for analysis of the pathophysiology of CHD and preclinical testing of new approaches for the prevention and treatment of cardiovascular disease.
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PMID:Probucol prevents early coronary heart disease and death in the high-density lipoprotein receptor SR-BI/apolipoprotein E double knockout mouse. 1277 86

An elevation in angiotensin II (Ang II) levels is a common occurrence in a diverse number of cardiovascular diseases including hypertension, hypercholesterolaemia, atherosclerotic coronary artery disease, left ventricular hypertrophy (LVH), heart failure and diabetes. An important effect of Ang II is activation of the NAD(P)H oxidase, a major source of reactive oxygen species (ROS) production by vascular cells. This increase in cellular ROS contributes to the pathogenesis of vascular disease by altering endothelial cell function, enhancing smooth muscle cell growth and proliferation, stimulating inflammatory proteins, including macrophage chemoattractant agents, growth factors and cytokines, and modulating matrix remodelling. Studies of genetically-altered mice have unequivocally shown that activation of the NAD(P)H oxidase by Ang II contributes to hypertension, LVH and atherosclerosis. Furthermore, increasing evidence suggest that the NAD(P)H oxidase contributes to human disease, suggesting that it is a potential target for future therapeutic intervention.
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PMID:Interactions of angiotensin II with NAD(P)H oxidase, oxidant stress and cardiovascular disease. 1280 86

There is abundant evidence that the endothelium plays a crucial role in the maintenance of vascular tone and structure. One of the major endothelium-derived vasoactive mediators is nitric oxide (NO). Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of NO synthase. ADMA inhibits vascular NO production at concentrations found in pathophysiological conditions (i.e., 3-15 micromol/l); ADMA also causes local vasoconstriction when it is infused intraarterially. The biochemical and physiological pathways related to ADMA are now well understood: dimethylarginines are the result of the degradation of methylated proteins; the methyl group is derived from S-adenosylmethionine. Both ADMA and its regioisomer, SDMA, are eliminated from the body by renal excretion, whereas only ADMA, but not SDMA, is metabolized via hydrolytic degradation to citrulline and dimethylamine by the enzyme dimethylarginine dimethylaminohydrolase (DDAH). DDAH activity and/or expression may therefore contribute to the pathogenesis of endothelial dysfunction in various diseases. ADMA is increased in the plasma of humans with hypercholesterolemia, atherosclerosis, hypertension, chronic renal failure, and chronic heart failure. Increased ADMA levels are associated with reduced NO synthesis as assessed by impaired endothelium-dependent vasodilation. In several prospective and cross-sectional studies, ADMA evolved as a marker of cardiovascular risk. With our increasing knowledge of the role of ADMA in the pathogenesis of cardiovascular disease, ADMA is becoming a goal for pharmacotherapeutic intervention. Among other treatments, the administration of L-arginine has been shown to improve endothelium-dependent vascular function in subjects with high ADMA levels.
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PMID:The emerging role of asymmetric dimethylarginine as a novel cardiovascular risk factor. 1455 22

There is abundant evidence now that the endothelium plays a crucial role in the maintenance of vascular tone and structure. One of the major endothelium-derived vasoactive mediators is nitric oxide (NO). Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of NO synthase. ADMA inhibits vascular NO production at concentrations found in pathophysiological conditions; ADMA also causes local vasoconstriction when it is infused intra-arterially. ADMA is increased in plasma of humans with hypercholesterolemia, atherosclerosis, hypertension, chronic renal failure, and chronic heart failure. Increased ADMA levels are associated with reduced NO synthesis as assessed by impaired endothelium-dependent vasodilation. In several prospective and cross-sectional studies, ADMA evolved as a marker of cardiovascular risk in certain populations like hemodialysis patients, non-smoking men, or intensive-care patients. The CARDIAC study is a multicenter case-control study designed to address the hypothesis that ADMA may be a suitable and sensitive marker of cardiovascular risk in a large, unselected population of both sexes, and with a broad range of established cardiovascular risk factors. The population included in the CARDIAC study will be prospectively followed for a scheduled follow-up period of 4 years, and the data of the CARDIAC-PRO study will then provide definite evidence whether ADMA may be prospectively determined as a cardiovascular risk factor.
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PMID:Plasma concentration of asymmetric dimethylarginine and the risk of coronary heart disease: rationale and design of the multicenter CARDIAC study. 1466

Endothelial dysfunction might be related to an increase in superoxide anion production in patients with hypertension, hypercholesterolemia, diabetes mellitus, and heart failure. Studies in animal models indicate that angiotensin II increases superoxide anion production by vascular tissues. We examined whether angiotensin II attenuates endothelium-dependent vasodilation via an increase in superoxide anion production in human forearm vessels in vivo. Forearm blood flow was measured in 23 healthy young men. We examined forearm vasodilator responses to an intra-arterial infusion of acetylcholine (4, 8, and 16 microg/min) and sodium nitroprusside (0.8, 1.6, and 3.2 microg/min) before and during an intra-arterial infusion of anglotensin II (n=8), angiotensin II plus vitamin C (n=8), and vitamin C alone (n=4). Angiotensin II attenuated the forearm vasodilatory response to acetylcholine (p<0.05), and this attenuated response was abolished by vitamin C. Angiotensin II did not alter the forearm vasodilatory response to sodium nitroprusside, and vitamin C infusion did not affect the forearm vasodilatory response to either acetylcholine or sodium nitroprusside. The forearm vasodilator response to acetylcholine did not change during infusion of norepinephrine (n=3), which reduced forearm blood flow to a degree similar to that by angiotensin II infusion. These results suggest that angiotensin II attenuates endothelium-dependent forearm vasodilation, and vitamin C improves this impairment. Thus, angiotensin II likely attenuates endothelium-dependent vasodilation via an increase of superoxide anion production in the human forearm in vivo.
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PMID:Vitamin C improves attenuated angiotensin II-induced endothelium-dependent vasodilation in human forearm vessels. 1471 37

The endothelins are synthesized in vascular endothelial and smooth muscle cells, as well as in neural, renal, pulmonal, and inflammatory cells. These peptides are converted by endothelin-converting enzymes (ECE-1 and -2) from 'big endothelins' originating from large preproendothelin peptides cleaved by endopeptidases. Endothelin (ET)-1 has major influence on the function and structure of the vasculature as it favors vasoconstriction and cell proliferation through activation of specific ET(A) and ET(B) receptors on vascular smooth muscle cells. In contrast, ET(B )receptors on endothelial cells cause vasodilation via release of nitric oxide (NO) and prostacyclin. Additionally, ET(B) receptors in the lung are a major pathway for the clearance of ET-1 from plasma. Indeed, ET-1 contributes to the pathogenesis of important disorders as arterial hypertension, atherosclerosis, and heart failure. In patients with atherosclerotic vascular disease (as well as in many other disease states), ET-1 levels are elevated and correlate with the number of involved sites. In patients with acute myocardial infarction, they correlate with 1-year prognosis. ET receptor antagonists have been widely studied in experimental models of cardiovascular disease. In arterial hypertension, they prevent vascular and myocardial hypertrophy. Experimentally, ET receptor blockade also prevents endothelial dysfunction and structural vascular changes in atherosclerosis due to hypercholesterolemia. In experimental myocardial ischemia, treatment with an ET receptor antagonist reduced infarct size and prevented left ventricular remodeling after myocardial infarction. Most impressively, treatment with the selective ET(A) receptor antagonist BQ123 significantly improved survival in an experimental model of heart failure. In many clinical conditions, such as congestive heart failure, both mixed ET(A/B )as well as selective ET(A) receptor antagonism ameliorates the clinical status of patients, i.e. symptoms and hemodynamics. A randomized clinical trial showed that a mixed ET(A/B) receptor antagonist effectively lowered arterial blood pressure in patients with arterial hypertension. In patients with primary pulmonary hypertension or pulmonary hypertension related to scleroderma, treatment with a mixed ET(A/B) receptor antagonist resulted in an improvement in exercise capacity. ET receptor blockers thus hold the potential to improve the outcome in patients with various cardiovascular disorders. Randomized clinical trials are under way to evaluate the effects of ET receptor antagonism on morbidity and mortality.
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PMID:Therapeutic potential for endothelin receptor antagonists in cardiovascular disorders. 1472 28


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