Gene/Protein Disease Symptom Drug Enzyme Compound
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 23,843 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The rising incidence of stroke, congestive heart failure (CHF) and end stage renal disease (ESRD) has signalled a need to increase awareness, treatment and control of hypertension. There continues to be a need for effective antihypertensive medications since hypertension is a major precursor to various forms of cardiovascular disease. The renin-angiotensin (AT) aldosterone system (RAAS) is a key component to the development of hypertension and can be one target of drug therapy. Angotensin II (ATII) receptor blockers (ARBs) are the most recent class of agents available to treat hypertension, which work by by inhibiting ATII at the receptor level. Currently, national consensus guidelines recommend that ARBs should be reserved for hypertensive patients who cannot tolerate angiotensin converting enzyme (ACE) inhibitors (ACEIs). ARBs, however, are moving to the forefront of therapy with a promising role in the area of renoprotection and CHF. Recent trials such as the The Renoprotective Effect of the Angiotensin-Receptor Antagonist Irbesartan in Patients with Nephropathy Due to Type 2 Diabetes Trial (IDNT), the Effect of Irbesartan on the Development of Diabetic Nephropathy in Patients with Type 2 Diabetes (IRMA2), and The Effects of Losartan on Renal and Cardiovascular Outcomes in Patients with Type 2 Diabetes and Nephropathy (RENAAL) study have demonstrated the renoprotective effects of ARBs in patients with Type 2 diabetes. The Valsartan Heart Failure Trial (Val-HeFT) adds to the growing body of evidence that ARBs may improve morbidity and mortality in CHF patients. As a class, ARBs are well tolerated and have a lower incidence of cough and angioedema compared to ACEIs. This article reviews the differences among the ARBs, existing efficacy data in hypertension, and explores the role of ARBs in CHF and renal disease.
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PMID:Angiotensin II receptor blockers for the treatment of hypertension. 1182 17

Cardiovascular disease is the major cause of morbidity and mortality in Westernised societies. It is well known that the aetiology of this devastating disorder involves both genetic and environmental factors. Sequence variants of the components of the renin-angiotensin-aldosterone system and the kallikrein-kinin system are suggested to have significant influences on cardiovascular homeostasis. Both gene targeting and transgenic studies in mice have clearly suggested a critical role of the angiotensin converting enzyme (ACE) gene in blood pressure regulation. Furthermore, an up-regulation of myocardial ACE gene expression has been observed in patients with heart failure. Thus, the ACE gene has been recognised as a top candidate gene for cardiovascular research. Over the past decade, the insertion/deletion (I/D) polymorphism of a 287-bp Alu element in intron 16 of the ACE gene has attracted significant attention and has been extensively investigated in a spectrum of cardiovascular phenotypes, because of its correlation with serum ACE activity. A large majority of previous studies have shown a positive association between the DD genotype and an increased risk of myocardial infarction, but results in hypertension, left ventricular hypertrophy, cardiomyopathy and restenosis after percutaneous transluminal coronary angioplasty remain quite controversial. Since ACE inhibitors are widely used in hypertension and congestive heart failure, we also review the literature on the relationship of ACE I/D polymorphism with ACE inhibitor response. It appears that this polymorphism has some moderate impact on the cardiovascular response to ACE inhibitors but there is no consensus as to which allele confers a more pronounced effect. In addition, previous data are suggestive of an association between the ACE I allele and a greater risk of increased occurrence of ACE inhibitor-induced cough, but such a relationship needs further confirmation. Overall, since ACE I/D is only an intronic marker, the true locus that controls the ACE enzyme activity remains to be identified, and could be located within either the ACE gene or another nearby gene such as the human growth hormone gene. We note that since associations tend to vary across different gender or ethnic groups, or across different socio-ecological settings, consideration of potential gene-gene and gene-environment interactions should be made. Furthermore, the dissection of the genetic underpinning of cardiovascular disease needs delineation of all molecular variants of the key physiological pathways that influence cardiovascular function.
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PMID:Angiotensin converting enzyme gene insertion/deletion polymorphism and cardiovascular disease: therapeutic implications. 1198 86

Angiotensin II receptor antagonists (AAIIs) are the most specific inhibitors of the renin-angiotensin-aldosterone system. There are two types of angiotensin II (Ang II) receptors, the AT(1) receptor, which is responsible for all the classical physiological properties of Ang II, and the AT(2) receptor, whose function in humans remains unclear. The different AAIIs used in clinical practice vary depending on their pharmacodynamic and pharmacokinetic properties, and, for some of them, depending on their metabolism in vivo into an active metabolite. AAIIs are relatively well tolerated, and, unlike angiotensin-converting enzyme inhibitors (ACEIs), do not induce cough. AAIIs are indicated in mild, moderate and severe essential hypertension, where their efficacy has been proven in many studies. The maximal antihypertensive effect is obtained in a few days or weeks, and is somewhat retarded when compared with ACEIs. Their effect is independent of age and sex, but does depend to a certain extent on ethnic origin, since Afro-American patients are less sensitive to AAIIs than Caucasians. In general, the antihypertensive and haemodynamic response to blockers of the renin-angiotensin system is potentiated in presence of a negative salt balance and attenuated in case of a positive salt balance. This means that AAII efficiency is improved by salt depletion induced by a salt-free diet or thiazide diuretics. AAIIs induce short-term improvement of haemodynamic parameters in cardiac insufficiency. Several ongoing clinical trials have been designed to compare their efficacy in cardiac insufficiency and myocardial infarction with those of reference treatments. Valsartan has been recently shown to improve morbimortality in patients with cardiac insufficiency and receiving a conventional treatment including an ACEI. It has been convincingly shown that blockade of the renin-aldosterone system by ACEIs decreases proteinuria and slows down the progression of renal insufficiency, especially in type 2 diabetic nephropathy. Recent trials have shown that AAIIs share the same properties as ACEIs in these indications. It appears that the beneficial effect of AAIIs and ACEIs is not entirely explained by the blood pressure lowering effect of these drugs. AAII administration increases renin release and Ang II production, which may overcome Ang II blockade. On this basis, the combination of an AAII and an ACEI has been proposed to achieve a maximal renin-angiotensin system blockade. Several experimental studies in animals and preliminary clinical studies all indicate that the combination of the two drugs may be more beneficial than either drug used alone in hypertension, cardiac insufficiency and post-myocardial infarction. Clinical trials are necessary to further document the putative advantages of such a combined therapy. The future of AAIIs depends on the following: progress made in the understanding of the molecular and cellular activities of angiotensin (angiotensin receptor signalling, receptor dimerisation, presence of other angiotensin receptor subtypes, role of AT(2) receptor, etc.);a comprehensive view of the role of the local renin system in various organs (local generation and effect of Ang II on cellular proliferation, fibrosis, inflammation, angiogenesis, etc.);predictability of the response to AAII treatment (genetic predisposition to AAII treatment, in conjunction with environmental factors); andresults of the ongoing clinical trials designed to assess the long-term effects of AAIIs in cardiovascular mortality and morbidity, in comparison with reference treatments.
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PMID:[Angiotensin II receptor blockers: current status and future prospects]. 1203 89

The renin-angiotensin-aldosterone system plays a key role in the regulation of fluid and electrolyte balance. Angiotensin-converting enzyme inhibitors inhibit angiotensin-converting enzyme and have been shown to be effective in many cardiovascular diseases. They should be considered for the treatment of hypertension in patients with heart failure, previous myocardial infarction, diabetes, or proteinuria. There are a number of side-effects associated with angiotensin-converting enzyme inhibitors, especially persistent dry cough. Angiotensin II receptor antagonists (sartans) provide a more specific blockade of the renin-angiotensin-aldosterone system and are associated with fewer side-effects, including cough. Their long-term efficacy and tolerability in the treatment of patients with hypertension has, however, yet to be established. Periodic monitoring of renal function and electrolytes is required in patients treated with an angiotensin-converting enzyme inhibitor or a sartan.
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PMID:Blockade of the renin-angiotensin system. 1205 64

Perindopril is a long-acting ACE inhibitor, acting through its only active metabolite perindoprilat. It inhibits the renin-angiotensin system by preventing both the conversion of angiotensin I to angiotensin II and the degradation of bradykinin, thereby reducing the vasoconstriction and left ventricular remodelling characteristic of heart failure. Perindopril 4mg significantly improved a range of haemodynamic parameters in single-dose and long-term (8 weeks and 3 months) studies involving patients with congestive heart failure (CHF), with little or no effect on blood pressure or heart rate. In randomised, double-blind, placebo-controlled clinical trials conducted over 3 months and a large noncomparative study (up to 30 months), perindopril 4mg once daily significantly increased exercise tolerance and reduced symptoms of heart failure in patients with mild to moderate CHF. Perindopril 4mg once daily is generally well tolerated in patients with mild to moderate CHF. In a large noncomparative study the most commonly reported adverse clinical event was cough, which led to 2.8% of patients discontinuing treatment. In short-term comparative trials there was a significantly lower incidence of first-dose hypotension following the recommended starting dose of perindopril 2mg than after the equivalent starting doses of captopril, enalapril and lisinopril.
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PMID:Perindopril: in congestive heart failure. 1207 91

Systemic pseudohypoaldosteronism type I (PHAI) is an autosomal recessive disorder that arises from loss of function mutations of the alpha, beta, or gamma subunit of Epithelial Na(+) Channel (ENaC). In addition to a severe renal phenotype in the neonatal period, patients with PHAI develop a childhood pulmonary syndrome characterized by cough and frequent respiratory infections. We tested a patient, born to consanguineous parents, who presented with dehydration, metabolic acidosis, hyperkalemia, elevated renin and aldosterone levels at birth, and recurrent respiratory symptoms in his first year. He demonstrated defective epithelial Na(+) transport in multiple organs (raised sweat Cl(-), 120 mM; raised salivary Na(+) and Cl(-), 118 and 111 mM, respectively; and little nasal amiloride-sensitive potential difference). No deleterious mutation was identified in the coding region of the three ENaC subunits. Reverse transcriptase-polymerase chain reaction of nasal epithelial RNA showed reduced betaENaC expression, and inability to amplify promoter elements indicated the possibility of a deletion in the 5' region. Using a probe that corresponded to exon 1A of betaENaC, we confirmed a large deletion (> 1,300 bp). In summary, a homozygous mutation in the promoter region of betaENaC leads to PHAI, the first description of a mutation in the regulatory regions of an ENaC subunit leading to a clinical phenotype.
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PMID:Systemic pseudohypoaldosteronism from deletion of the promoter region of the human Beta epithelial na(+) channel subunit. 1220 93

Recently, both researchers and clinicians have focused their attention to the blockade of the renin-angiotensin system (RAS). Their efforts resulted in discovery of ACE inhibitors. ACE inhibitors proved to be effective antihypertensive drugs. However, their excellent antihypertensive efficacy has been limited by frequent occurrence of adverse effects, among which cough occupies a prominent place. Angiotensin II receptor antagonists could completely block RAS, having significantly less adverse effects than ACE inhibitors. Clinical studies have demonstrated that angiotensin II receptor antagonists are equally effective in the treatment of hypertension as diuretics, beta blockers, calcium antagonists and ACE inhibitors. Also the studies showed angiotensin II receptor antagonists to have an additional advantage, i.e. the frequency of their adverse effects matches that of placebo. All today available angiotensin II receptor antagonists--losartan, valsartan, irbesartan, candesartan, eprosartan, and telmisartan--equally lower both systolic and diastolic pressure. This new class of drugs can be used as monotherapy or can be combined with other antihypertensive drugs, especially with diuretics. Trials now underway will demonstrate whether angiotensin II receptor antagonists can prevent target-organ damage and reduce cardiovascular morbidity and mortality.
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PMID:[Role of angiotensin II antagonists in the treatment of hypertension]. 1237 64

We present a two-part review of the English-language literature pertaining to drug therapy for systemic high BP in patients with pulmonary diseases. Part I examines the literature pertaining to the use of antihypertensive drugs in patients with systemic hypertension and coexisting pulmonary conditions, especially COPD and asthma. Part II of the series reviews studies assessing the relationship between sleep-disordered breathing (including the role of the sympathetic nervous system) and systemic hypertension, and presents an approach to the management of these patients. It is the aim of both parts of this review to make qualified conclusions and recommendations applying a methodologic critique to assess the current literature. In the first part of this series, we review the demographics of hypertension in patients with COPD. This is followed by an extensive review of the use of specific classes of antihypertensive drug therapies in patients with pulmonary disease. The antihypertensive agents reviewed include diuretics, calcium antagonists, angiotensin-converting enzyme inhibitors, and angiotensin II receptor antagonists, beta-adrenergic blocking agents, and alpha-beta-blockers and other non-beta-blocker classes. Additionally, the renin angiotensin system is briefly reviewed, with a discussion of how angiotensin-converting enzyme inhibitors induce cough, especially in pulmonary and congestive heart failure patients.
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PMID:Treatment of systemic hypertension in patients with pulmonary disease: COPD and asthma. 1455 4

Angiotensin II (AII) receptor blockers offer an alternative means of blocking the renin-angiotensin-aldosterone system (RAAS) to angiotensin converting enzyme (ACE) inhibitors. Being highly selective for the AII receptor subtype AT(1), AII receptor blockers may avoid side-effects associated with ACE inhibitor treatment, such as cough. Eprosartan is a non-biphenyl, non-tetrazole competitive blocker that is chemically distinct from other AII receptor blockers, which may account for differences in its pharmacological properties. It induces dual blockade of AT(1) receptors both presynaptically and postsynaptically, reducing sympathetic nerve activity to a significantly greater degree than other AT(1) receptor blockers. At the recommended dose of 600 mg once daily, eprosartan effectively lowers blood pressure (BP) in hypertensive patients to a similar degree as seen with other AII receptor blockers and ACE inhibitors. However, a greater proportion of patients achieved adequate BP control compared with enalapril. When eprosartan is given in combination with hydrochlorothiazide (HCTZ), it provides a significantly greater BP reduction compared with eprosartan alone. Eprosartan has a side-effect profile that is similar to placebo and to other AII receptor blockers, but is better than that of enalapril because it lacks the propensity to cause dry cough. Eprosartan is not metabolized by the cytochrome P450 enzyme system, and so has no interaction with drugs that affect this system. Eprosartan completely reverses renal vasoconstriction induced by AII and may, therefore, have further applications in situations where stimulation of the RAAS is a problem. In summary, eprosartan, alone or in combination with HCTZ, provides an effective and well-tolerated approach to lowering BP in patients with all grades of hypertension. Further development of eprosartan may offer therapeutic opportunities that go far beyond the current recommendations.
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PMID:Clinical profile of eprosartan. 1276 89

Hypertension remains one of the most unmet medical needs of this century. While many drugs are available for treating hypertension, efforts are still insufficient to find potent therapeutic agents since cause for hypertension in all patients is not the same. Angiotensin-converting enzyme inhibitors (ACEIs) have emerged as an important class of drugs in the treatment of hypertension, congestive heart failure (CHF), protenuric renal disease, myocardial infarction and stroke. This class of drugs blocks the conversion of angiotensin I to angiotensin II and prevents bradykinin breakdown. However, the lack of specificity of ACEIs leads to the frequent side effects like cough and angio-oedema. Recently developed, specific non-peptide and orally active angiotensin receptor blockers (ARBs) have become the prime therapeutics as they alone or co-administration with ACE inhibitors can control the renin angiotensin disorders. This review explores recent developments in the design, synthesis, and structural modifications of ACE inhibitors as well as angiotensin receptor blockers.
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PMID:Advances in angiotensin converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs). 1287 Nov 64


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