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

Angiotensin II (AII) participates in regulation of arterial blood pressure through its binding to AII receptors distributing among its target organs. In addition, locally produced AII appears to play a major role in the pathogenesis of cardiovascular hypertrophy via mechanism not related to blood pressure. Two subtypes of AII receptors, AT1 and AT2, are recognized as distinct in both molecular and pharmacological basis. In adult, AT1 is a dominant subtype in cardiovascular system, and mediates virtually all the previously known actions of AII, including vasoconstriction, production of growth factors, hypertrophy of smooth muscle and cardiomyocyte, proliferation of smooth muscle and fibroblast, production of extracellular matrix and so on. Recently, upregulation of AT2 expression is revealed under certain pathological conditions, such as vascular injury, myocardial infarction, and heart failure. Biological significance of AT2 are still under investigation, however, countering actions against AT1 are often suggested.
 ...
PMID:[Distribution and function of angiotensin receptor subtypes in cardiovascular system]. 1036 30

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.
 ...
PMID:Pharmacological mechanism of angiotensin II receptor antagonists: implications for the treatment of elevated systolic blood pressure. 1046 64

Expression levels of angiotensin II type 1 and type 2 receptors (AT1, AT2) vary at different cardiac localizations and are regulated in cardiac diseases. Differential splicing of the 5' untranslated exons of the primary AT1 mRNA transcripts may modulate translational efficiency and thus receptor expression. We therefore searched for AT1 and AT2 mRNA splice patterns specific to chamber localization or to cardiac performance and analyzed their effect on protein expression in transfection experiments. The exon composition of the AT1 and AT2 mRNA transcripts in normal and diseased human hearts were analyzed using a reverse transcription polymerase chain reaction followed by HPLC quantitation of the amplificates. We compared atrial (n=18) and ventricular (n=28) samples and endomyocardial biopsies (n=10) from patients with normal and severely impaired cardiac function and one donor heart, which was not used for transplantation. AT1 transcripts with the exon composition 1/2/5 and 1/5 represented about 93-98% of all AT1 mRNAs; transcript 1/2/3/5 represented 8% in the atria and 2% in ventricles. Since exon 2 reduces translational efficiency in vitro, the ratios of transcripts with and without exon 2, (1/2/5+1/2/3/5) to (1/5), were compared. These were 1.24+/-0.07 in normal atria, 0.96+/-0.09 in atria from failing hearts (P<0.05), 0.68 in the left ventricle of the donor heart, and 0.58+/-0.03 in failing left ventricles. Endomyocardial biopsy specimens showed significant differences between controls and heart failure (controls 0.63+/-0.04 vs. heart failure 0.52+/-0.02, P<0.05). Of the two identified AT2 transcripts, mRNA 1/2/3 was the most abundant in the human heart (92%). Luciferase reporter gene assays were performed to test the effect of the various 5' untranslated regions (5' UTRs) on protein expression. Among the constructs which contained the AT1 promoter/AT1 5' UTRs the plasmid Ex 1/2/5 exhibited 27% lower luciferase activity than Ex 1/5 (n=24, P<0.001), and Ex 1/2/3/5 expressed only 35.9% of Ex 1/5 activity (P<0.001). Among the reporter gene plasmids with the AT2 promoter/AT2 5' UTRs the construct Ex 1/2/3 expressed a 31% lower luciferase activity than Ex 1/3 (n=20, P<0.001). In conclusion, alternative splicing may represent a mechanism of ATR regulation in vivo. In the human heart, AT1 splice patterns differ distinctly between atria and ventricles and to a lesser degree between controls and failing hearts. This may lead to differences in AT1 mRNA translation into protein in the various cardiac areas and under different pathophysiological conditions.
 ...
PMID:Analysis and functional characterization of alternatively spliced angiotensin II type 1 and 2 receptor transcripts in the human heart. 1060 7

The renin-angiotensin system (RAS) is a widely studied hormonal system that comprises substrate-enzyme interactions, the end result of which is production of the active peptide angiotensin II (Ang II). Because Ang II affects blood pressure control, sodium and water homeostasis, and cardiovascular function and structure, a great deal of research effort has been directed toward blocking the RAS. Angiotensin II may also be involved in end-organ damage in hypertension, heart failure, and vascular disease. At least two subtypes of angiotensin II receptors have been identified: AT1 and AT2. The AT1 mediates all of the known actions of Ang II on blood pressure control. Additionally, research has indicated that the AT1 receptor modulates cardiac contractility and glomerular filtration, and increases renal tubular sodium reabsorption, and cardiac and vascular hypertrophy. Less is known regarding the function of the AT2 receptor. Evidence suggests that the AT2 receptor inhibits cell proliferation and reverses AT1-induced hypertrophy. Indeed, these receptors are thought to exert opposing effects. Angiotensin II AT1 receptor antagonists (AT1RA) inhibit the RAS at the receptor level by specifically blocking the AT1 receptor subtype. These drugs induce a dose-dependent blockade of Ang II effects, resulting in reduced blood pressure, urinary protein, and glomerular sclerosis. It is postulated that AT1RA may provide end-organ protection by blocking Ang II effects via the AT1 receptor, yet leaving the AT2 receptor unopposed. Consequently, these agents may reduce the morbidity and mortality that result from myocardial infarction (MI) and other conditions resulting from structural alterations in the heart, kidney, and vasculature.
 ...
PMID:Angiotensin II receptor blockade and end-organ protection. 1061 95

Primary diastolic failure is typically seen in patients with hypertensive or valvular heart disease as well as in hypertrophic or restrictive cardiomyopathy but can also occur in a variety of clinical disorders, especially tachycardia and ischemia. Diastolic dysfunction has a particularly high prevalence in elderly patients and is generally associated, with low mortality but high morbidity. The pathophysiology of diastolic dysfunction includes delayed relaxation, impaired LV filling and/or increased stiffness. These conditions result typically in an upward displacement of the diastolic pressure-volume relationship with increased end-diastolic, left atrial and pulmo-capillary wedge pressure leading to symptoms of pulmonary congestion. Diagnosis of diastolic heart failure requires three conditions: (1) presence of signs or symptoms of heart failure; (2) presence of normal or slightly reduced LV ejection fraction (EF > 50%) and (3) presence of increased diastolic filling pressure. Assessment of diastolic function can be performed with several non-invasive (2D- and Doppler-echocardiography, color Doppler M-mode, Doppler tissue imaging, MR-myocardial tagging, radionuclide ventriculography) and invasive techniques (micromanometry, angiography, conductance method). Doppler-echocardiography is the most useful tool to routinely measure diastolic function. Different techniques can be used alone or in combination to assess LV diastolic function, but most of them are dependent on heart rate, pre- and afterload. The transmitral flow pattern remains the starting point, since it is easy to acquire and rapidly categorizes patients into normal (E > A), delayed relaxation (E < A), and restrictive (E >> A) filling patterns. Invasive assessment of diastolic function allows determination of the time constant of relaxation from the exponential pressure decay during isovolumic relaxation, and the evaluation of the passive elastic properties from the slope of the diastolic pressure-volume (= constant of chamber stiffness) and stress-strain relationship (= constant of myocardial stiffness). The prognosis of diastolic heart failure is usually better than for systolic dysfunction. Diastolic heart failure is associated with a lower annual mortality rate of approximately 8% as compared to annual mortality of 19% in heart failure with systolic dysfunction, however, morbidity rate can be substantial. Thus, diastolic heart failure is an important clinical disorder mainly seen in the elderly patients with hypertensive heart disease. Early recognition and appropriate therapy of diastolic dysfunction is advisable to prevent further progression to diastolic heart failure and death. There is no specific therapy to improve LV diastolic function directly. Medical therapy of diastolic dysfunction is often empirical and lacks clear-cut pathophysiologic concepts. Nevertheless, there is growing evidence that calcium channel blockers, beta-blockers, ACE-inhibitors and AT2-blockers as well as nitric oxide donors can be beneficial. Treatment of the underlying disease is currently the most important therapeutic approach.
 ...
PMID:Diastolic heart failure. 1072 7

RENIN-ANGIOTENSIN SYSTEM: This system plays a major role in regulation of blood pressure. Angiotensin converting enzyme inhibitors (CEI) modify the balance between the vasocilator and diuretic properties of bradykinin and the vasoconstrictor and antidiuretic properties of angiotensin II, favoring vasodilatation and natriuresis. Angiotensin II receptor antagonists (ARAII) block AT1 receptors and stimulate AT2 receptors with favorable vasodilator and natriuretic affects. CEI: Converting enzyme inhibitors play an indispensable role in the treatment of heart failure and should be prescribed at high dosage. They have a long-term beneficial effect. ARAII: These compound could play a role in the future, but studies conducted to date comparing ARAII and CEI have been unable to demonstrate superior or equivalent effects with ARAII, and do not warrant their prescription for hypertension.
 ...
PMID:[Chronic cardiac insufficiency. Treatment with angiotensin I converting enzyme inhibitors and angiotensin II receptor antagonists]. 1079 30

We tested the hypothesis that a combination of angiotensin-converting enzyme inhibitor (ACEi) and angiotensin II type 1 receptor antagonist (AT1-ant) may have an additive cardioprotective effect in mice with heart failure (HF), because these two agents could have other mechanisms of action besides interrupting the renin-angiotensin system. ACEi prevent degradation of bradykinin. During treatment with AT1-ant, increased angiotensin II could activate AT2 receptors, with an antitrophic effect. To test this hypothesis, we used a mouse model of HF induced by myocardial infarction. Seven days after surgery, mice were divided into six groups and treated for 23 weeks: (a) sham ligation; (b) HF-vehicle; (c) HF-ACEi; (d) HF-AT1-ant; (e) HF-ACEi + AT1-ant (half dose of each); and (f) HF-ACEi + AT1-ant (full dose of each). Cardiac function was evaluated in conscious mice during the treatment period. The HF-vehicle group showed significantly decreased left ventricular (LV) ejection fraction (EF), shortening fraction (SF), and cardiac output (CO) and increased LV dimensions, interstitial collagen, and myocyte cross-sectional area (MCSA) compared with controls. Treatment with ACEi or AT1-ant significantly increased EF, SF, and CO and decreased LV dimensions and MCSA in mice with HF. However, a combination of these drugs did not improve cardiac function more than ACEi or AT1-ant alone. We concluded that ACEi and AT1-ant have similar cardioprotective effects and may reach maximal effect when given individually; thus no further improvement can be achieved with combined therapy in mice with HF.
 ...
PMID:Effects of ACE inhibitor, AT1 antagonist, and combined treatment in mice with heart failure. 1102 48

The renin-angiotensin system plays a pivotal role in the regulation of fluid, electrolyte metabolism and blood pressure. Molecular cloning and pharmacological studies have defined two major classes of Angiotensin II (Ang II) receptors, designated AT1 and AT2. Recently, it has been well recognized that Ang II, beside its classical physiological actions, is a profibrogenic peptide and displays characteristics of a growth factor. The emerging picture suggests that angiotensin receptor subtypes exert opposing features in many aspects of their biological function, most importantly in cellular growth and proliferation. Accordingly, the proliferative and/or growth-promoting effects of Ang II are thought to be mediated by AT1 receptor, whereas the AT2 receptor subtype may have growth-inhibitory properties. The novel finding that Ang II is able to induce apoptosis by AT2 receptors in diverse cell types is of great scientific interest, as recent studies revealed a role for apoptosis as a deliberate form of cell death in the pathogenesis of various cardiovascular diseases such as heart failure and vascular remodeling. Furthermore apoptotic cell death might occur during the development of progressive glomerulosclerosis. It is tempting to speculate that autocrine-paracrine vasoactive substances such as Ang II might regulate these apoptotic processes during pathogenic conditions.
 ...
PMID:Apoptosis induction and inhibition of cellular proliferation by angiotensin II: possible implication and perspectives. 1103 44

After recalling the fundamental importance of ACE inhibitors in the treatment of heart failure, the author analyzes the scientific evidence supporting the use of beta-adrenergic blockers in the treatment of this syndrome. He describes the complications involved in prescribing these drugs for patients in functional class IV and reviews the current literature on the problem. He then considers the possibility of beta-blockers (particularly carvedilol) being used instead of ACE inhibitors. He reviews the conclusions of studies on the benefits of adding an AT1 receptor antagonist to ACE inhibitor therapy, including the results of the RESOLVD studies. He also concludes that there is no evidence that AT2 receptor antagonists are as good as or better than ACE inhibitors in the treatment of heart failure.
 ...
PMID:[Options in drug combinations]. 1140 73

Olmesartan medoxomil is a new non-peptide angiotensin (A) II antagonist under development for treating hypertension. It is a pro-drug containing an ester moiety that, after oral administration, is rapidly cleaved to release the active form olmesartan (RNH-6270). In vitro, olmesartan is a highly potent, competitive and selective All AT1 receptor antagonist with almost no antagonistic activity on AT2 and AT4 receptors. Olmesartan produces selective insurmountable inhibition of All-induced contractions of the guinea-pig aorta and is much more potent than losartan in reducing maximal responses. In vivo, intravenous olmesartan produces a rapid and long-lasting inhibition of All-induced pressor responses in conscious rats. Oral olmesartan medoxomil also inhibits All-pressor response but onset of the action is slower compared with intravenous administration. Following oral administration, olmesartan has a faster onset but similar potency when compared with candesartan cilexetil, and clearly exceeds losartan in both respects. Oral olmesartan medoxomil exhibits dose-dependent antihypertensive effects in several rat and dog models, with the most marked effects seen in high plasma renin models, when compared with normal or low renin types. Haemodynamic studies in spontaneously hypertensive rats and normotensive dogs showed intravenous olmesartan selectively reduces renal vascular resistance, which suggests that vasodilatation in the renal vascular bed contributes most to the antihypertensive action of the drug. Long-term treatment with olmesartan medoxomil exhibits, beside antihypertensive effects, beneficial effects in animal models of various types of nephrosis and heart failure, and anti-atherogenic effects in hyperlipidaemic animals. Olmesartan medoxomil is worthy of clinical development in essential and renal hypertension, particularly where renal function is threatened by underlying diabetic disease.
 ...
PMID:In vitro and in vivo pharmacology of olmesartan medoxomil, an angiotensin II type AT1 receptor antagonist. 1145 Dec 12


<< Previous 1 2 3 4 5 6 Next >>