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)

Since 1) renin-angiotensin-aldosterone systems play an critical role in the development and progression of chronic heart failure, and 2) inhibitors of angiotensin converting enzyme (ACEIs) are proved to be effective for the treatment of chronic heart failure, angiotensin II receptor antagonists may be more effective than ACEIs. This is because angiotensin II receptor antagonists can inhibit the effects of angiotensin II via ACE-independent pathways, e.g., chymase. On the other hand, ACEIs can increase bradykinin, and thus, nitric oxide, which may cause potent cardioprotection. Therefore, angiotensin II receptor antagonists and ACEIs may mediate cardioprotection via different mechanisms, which may hint the combination therapy of both drugs in the pathophysiology of chronic heart failure. Angiotensin II receptor antagonists may open a new era for the treatment of chronic heart failure.
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PMID:[Efficacy of angiotensin II receptor antagonists as a novel drug for the treatment of chronic heart failure--in comparison with ACE inhibitors]. 1036 49

During administration of the anthracycline antitumour agents, their cardiotoxicity can progress from cardiac dysfunction to heart failure. Cardiomyopathy can also develop years after receiving anthracyclines. To determine if persistent and/or progressive anthracycline effect(s) are referable to anthracycline effects on cardiac gene expression, steady-state mRNA levels were determined 4 days (n=8), 4 weeks (n=7) and 10 weeks (n=7) after doxorubicin (DOX; 2 mg/kg IV) in a well-characterized rabbit model. Levels of mRNA for alpha -actin, beta -myosin heavy chain and the calcium pump of the sarcoplasmic reticulum (SERCA2a) in the left ventricle (LV) were determined by Northern blot hybridization and expressed relative to an 18S constitutive marker. The mRNA levels for the high molecular weight subunit (cardiac isoform) of the ryanodine receptor (RyR2), sarcolemmal calcium channel (dihydropyridine receptor; DHPR), angiotensin-converting enzyme (ACE), angiotensin II receptor (ATR) and atrial naturetic peptide prohormone (ANP) were determined by reverse transcription-polymerase chain reaction (RT-PCR) and Southern blot analysis, and expressed relative to GAPDH, a constitutive marker. Histopathologic evidence for anthracycline-induced myocardial cell injury was absent (score <1) in all hearts examined except one (score=1.1; 4 weeks post-DOX), which was considered separately. Relative mRNA levels for beta -myosin heavy chain 4 days after DOX increased 1.9-fold compared to the vehicle-treated group, but by 4 weeks levels had returned to baseline. Relative mRNA levels for DHPR were increased 1.2-fold 4 days after DOX and were persistently increased 1.9- and 2.2-fold 4 and 10 weeks after DOX, respectively. The mRNA levels for ANP were first decreased (4.5-fold) 4 days after DOX. Four weeks after DOX, ANP message levels approached Control in seven out of eight rabbits. The one rabbit with early LV histopathology 4 weeks post-DOX had increased mRNA for DHPR (2.7-fold) and ANP (80-fold). Between 4 and 10 weeks after DOX, mRNA levels for ANP increased C 16-fold: evidence for late progression. In situ hybridization with specific riboprobes localized the persistent increase in DHPR and the progressive increase in ANP to myocytes. Thus, DOX alters steady-state mRNA levels in LV that are referable to both persistent and progressive anthracycline effects on myocellular gene expression.
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PMID:Persistent effects of doxorubicin on cardiac gene expression. 1042 42

Hypertension is a very common disease and represents a major risk factor for cardiovascular adverse events such as stroke and heart failure. In recent years, a big effort has been put into detecting and treating patients with hypertension. Several classes of drugs acting by different pharmacological mechanisms can be chosen for the treatment of hypertension. However, the long term use of all anti-hypertensive agents is sometimes limited by the occurrence of adverse effects. Thanks to continuous pharmacological research, new compounds are regularly developed and become available in clinical practice. Recently, several new, nonpeptide, orally active angiotensin II receptor antagonists have reached the market. Today, these substances represent the most specific way to block the renin angiotensin system. Numerous studies have now demonstrated that these angiotensin II antagonists are as effective as ACE inhibitors, calcium antagonists, beta-blockers or diuretics in lowering blood pressure in patients with hypertension. Given the increasing use of angiotensin II receptor antagonists in the treatment of hypertension, it is important to review their safety and tolerability. Based on the actual level of knowledge, the striking feature of this class of agents is their favourable safety and tolerability profile which appears to be equivalent to that observed with placebo. Indeed, so far, no clear class-specific adverse effect has been attributed to the angiotensin II receptor antagonists. Thus, if angiotensin II antagonists prevent target organ damage and reduce the morbidity and mortality of patients with hypertension, they may well become a first-line treatment of hypertension.
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PMID:Comparative safety and tolerability of angiotensin II receptor antagonists. 1043 51

Systolic hypertension is a major risk factor for cardiovascular disease. The determinants of systolic blood pressure are peripheral resistance and arterial compliance. Arterial vasoconstriction, vascular growth and fluid retention, induced by the renin-angiotensin system directly or indirectly by enhancing sympathetic nervous system activity, are important factors in increasing peripheral resistance, decreasing arterial compliance and, consequently, elevating systolic blood pressure. Selective blockade of the angiotensin II type 1 (AT1) receptor represents a novel mechanism for interrupting the renin-angiotensin system. This provides the additional benefit of blocking angiotensin II generated by non-angiotensin-converting-enzyme pathways without altering either bradykinin metabolism or the potential beneficial effects of AT2 receptor stimulation. Eprosartan is a potent (1.4 nmol/l) AT1 receptor antagonist that inhibits angiotensin-II-induced vascular contraction in a competitive manner. Eprosartan is effective in reducing disease progression in animal models of hypertension, heart failure, renal disease and stroke. Furthermore, eprosartan causes a large increase in arterial compliance in hypertensive rats fed high-salt and high-fat diets. Eprosartan also possesses sympathoinhibitory activity as demonstrated by an inhibition of the pressor responses induced by activation of sympathetic outflow through spinal cord stimulation in pithed rats. In contrast, other angiotensin II receptor antagonists, such as losartan, used at equivalent angiotensin II blocking activity, do not appear to alter sympathetic nervous system activity. Angiotensin II receptor antagonists, such as eprosartan, that have the ability to block both the direct effects of angiotensin II and the indirect effects mediated by enhanced sympathetic neurotransmission, may represent an important advance in the treatment of elevated systolic blood pressure.
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PMID:Pharmacological mechanism of angiotensin II receptor antagonists: implications for the treatment of elevated systolic blood pressure. 1046 64

Losartan is the first orally active angiotensin II receptor type 1 antagonist for a new class of cardiovascular therapeutic agent. Losartan is converted to an active metabolite (E3174) after oral administration in humans and rats. Both losartan and E3174 contribute to the net angiotensin II receptor blockade and produce anti-hypertensive effect. Losartan not only blocks the vasoconstrictive effect of angiotensin II but also inhibits its mitogenic effect; thus losartan is expected to protect against end-organ-damage-related hypertension and chronic heart failure. Unlike angiotensin-coverting-enzyme inhibitor, losartan does not elicit adverse effects of cough and angioneurotic edema by its blockade of angiotensin II receptor. It is also expected to reduce proteinuria in nephropathy. In addition to its blockade of angiotensin II receptor, losartan blocks thromboxane A2 receptor and facilitates excretion of uric acid, although therapeutic importance of these effects are under investigation. In summary, losartan, an angiotensin II type 1 receptor antagonist is a new class of antihypertensive agent and its therapeutic potentials are not merely reduction of blood pressure but total protection from end-organ damage resulting from activation of both the systemic and local renin-angiotensin system.
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PMID:[Pharmacological characteristics and clinical application of losartan, an orally active AT1 angiotensin II receptor antagonist]. 1052 59

The prevention and treatment of hypertension remain as major challenges for clinicians all over the world. The recently published Sixth Report of the Joint National Committee for the Prevention, Detection, Evaluation and Treatment of High Blood Pressure (JNC-VI) uses evidence-based medicine in providing guidelines to aid clinicians in the prevention, detection and treatment of high blood pressure, including pharmacological approaches. Calcium antagonists are used widely for the treatment of hypertension, and JNC-VI focuses on specific situations where calcium antagonists could be considered as preferred treatments. There are a large number of calcium antagonists available, with a variety of pharmacodynamic and pharmacokinetic actions. Several sustained-release formulations of these drugs are also available. In terms of blood pressure control, calcium antagonists are more effective as antihypertensive treatments than beta-blockers, ACE inhibitors and angiotensin II receptor blockers in Black patients. The dihydropyridine calcium antagonists have been shown to reduce morbidity and mortality in elderly patients with isolated systolic hypertension. The rate-lowering calcium antagonists can be used as alternatives to beta-blockers in patients with coronary artery disease and hypertension. Calcium antagonists can be used as alternatives to ACE inhibitors in patients with hypertension and concomitant diabetes mellitus and/or renal disease. Some dihydropyridine calcium antagonists may be useful as alternatives to ACE inhibitors in patients with hypertension and systolic heart failure. Calcium antagonists appear to be extremely useful in patients with cyclosporin-induced hypertension, and in patients with hypertension and concomitant Raynaud's phenomenon and/or migraine. The rate-lowering agents can be used in patients with atrial tachyarrhythmias and hypertension. Clinicians should be aware of drug-drug interactions involving calcium antagonists, especially after the recent problems with mibefradil. Although retrospective studies have caused controversy regarding the safety of calcium antagonists in patients with hypertension, recent prospective studies have revealed no major safety concerns with these drugs.
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PMID:How to use calcium antagonists in hypertension: putting the JNC-VI guidelines into practice. Joint National Committee for the Prevention, Detection, Evaluation and Treatment of High Blood Pressure. 1055 31

The angiotensin II receptor blockers (ARBs) are safe and effective agents in the treatment of hypertension, and they have potential in treating other cardiovascular disorders such as heart failure. These drugs share a common mechanism of action: They selectively block the angiotensin type 1 (AT1) receptor. A new ARB, candesartan cilexetil is a prodrug that is converted completely into the active metabolite candesartan during gastrointestinal absorption, whereas losartan is converted partially by hepatic metabolism into the more active compound EXP 3174. Valsartan and irbesartan are active in their own right. These ARBs differ pharmacologically in terms of their affinity for the AT1 receptor, the mechanism by which they block the receptor, and the duration of their receptor-blocking activity. In radioligand-binding studies, candesartan had a slightly higher affinity for the AT1 receptor than the other ARBs. In the rabbit aorta, candesartan blocked angiotensin II-induced contractions in an insurmountable manner, whereas losartan blocked the contractions competitively, and EXP 3174, valsortan and irbesartan blocked the contractions in a manner intermediate between competitive and insurmountable antagonism. The insurmountable antagonism exhibited by candesartan likely reflects its long-lasting blockade of the AT1 receptor due to a slow dissociation rate. This suggests that candesartan will exhibit a longer duration of action than would be predicted simply from its pharmacokinetic elimination half-life. Comparative clinical trials with several ARBs are needed to define the clinical significance of these pharmacologic differences.
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PMID:Significance of angiotensin type 1 receptor blockade: why are angiotensin II receptor blockers different? 1058 89

The treatment of hypertension and heart failure has evolved in recent years. It may no longer be sufficient to lower blood pressure per se or correct hemodynamics alone in these conditions to achieve optimal long-term outcomes; rather, the effects of drugs on the cellular events and structural alterations that occur in the vasculature, heart, and kidney must be considered. Drugs that target angiotensin II, which include the angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs), may protect target organs from damage and thereby improve outcomes. Nevertheless, it remains to be demonstrated whether these agents are more effective in reducing cardiovascular morbidity and mortality in hypertensive patients than conventional treatment with diuretics and beta blockers. In certain subgroups of hypertensive patients, including those with heart failure, type 1 diabetes with proteinuria, or after myocardial infarction with systolic dysfunction, there is compelling evidence for use of ACE inhibitors. The results from animal models and initial clinical studies suggest that ARBs are also highly effective in these patients. Several large-scale clinical studies, comparing the effect of ARBs and other drug classes on morbidity and mortality outcomes, have been initiated to better define the long-term benefit of ARBs in the treatment of hypertension and heart failure.
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PMID:Long-term benefits of angiotensin II blockade: is the consensus changing? 1058 90

New guidelines for managing heart failure urge physicians to identify patients likely to benefit from therapy, obtain an echocardiogram to measure the ejection fraction, and, in patients with systolic dysfunction (i.e., an ejection fraction < or = 40%), institute therapy with an angiotensin-converting enzyme (ACE) inhibitor and a beta-blocker if at all possible. Digoxin and diuretics can relieve symptoms but do not affect the mortality rate. Spironolactone in low nondiuretic doses may reduce mortality when added to baseline drug regimens. The proper role of angiotensin II receptor blocking agents has yet to be determined.
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PMID:Heart failure: highlights from new consensus guidelines. 1064 72

The renin-angiotensin system plays a central role in the regulation of blood pressure through its primary effector hormone angiotensin II. Studies conducted nearly 30 years ago with peptidic angiotensin II receptor blockers (ARB) suggested that disruption of the renin-angiotensin system offered considerable promise for the treatment of hypertension as well as heart failure. This promise was initially realized with the advent of angiotensin converting enzyme inhibitors, and more recently with nonpeptidic ARB that selectively antagonize the AT1-angiotensin receptor subtype. The potent and long-acting agent candesartan cilexetil illustrates how these new ARB fulfill the promises suggested by the early studies. Candesartan cilexetil provides a clinically relevant, dose-dependent reduction in diastolic and systolic blood pressure at doses of 4 to 16 mg once daily in patients with mild to moderate hypertension. Recent studies suggest that further blood pressure lowering is obtained with a 32-mg once daily dose. In comparative clinical trials, 8 mg of candesartan cilexetil and 10 to 20 mg of enalapril provided comparable antihypertensive effects. The safety and tolerability profile of candesartan cilexetil is comparable to placebo. Notably, this agent does not produce the dry, nonproductive cough that often limits use of angiotensin converting enzyme inhibitors, nor does it cause side effects that limit other antihypertensive drug classes. On the basis of the results of initial clinical studies, ARB also possess cardioprotective and renoprotective properties that promise to expand the role that these new agents will play in treating cardiovascular disorders.
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PMID:Update on the clinical pharmacology of candesartan cilexetil. 1067 85


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