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 13,001 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The renin-angiotensin system is a major contributor to the pathophysiology of cardiovascular diseases such as congestive heart failure and hypertension. Antagonizing angiotensin (Ang) II at the receptor site may produce fewer side effects than inhibition of the promiscuous converting enzyme. The present study was designed to assess in healthy human subjects the effect of LRB081, a new orally active AT1-receptor antagonist, on the pressor action of exogenous Ang II. At the same time, plasma hormones and drug levels were monitored. At 1-week intervals and in a double-blind randomized fashion, 8 male volunteers received three doses of LRB081 (10, 40, and 80 mg) and placebo. Blood pressure (BP) was measured at a finger by photoplethysmograph. The peak BP response to intravenous injection of a standard dose of Ang II was determined before and for < or = 24 h after administration of an oral dose of LRB081 or placebo. After drug administration, the blood BP response to Ang II was expressed in percent of the response before drug administration. At the same time, plasma renin activity (PRA), Ang II, aldosterone, catecholamine (radioassays), and drug levels (by high-performance liquid chromatography) were monitored. After LRB081 administration, a dose dependent inhibition of the BP response to Ang II was observed. Maximal inhibition of the systolic BP response was 54 +/- 3 (mean +/- SEM), 63 +/- 2, and 93 +/- 1% with 10, 40, and 80 mg LRB081, respectively. The time to peak was 3 h for 6 subjects and 4 and 6 h for 2 others. Preliminary plasma half-life (t1/2) was calculated at 2 h. With the highest dose, the inhibition remained significant for 24 h (31 +/- 5%, p < 0.05). Maximal BP-blocking effect and maximal plasma drug level coincided, suggesting that the unmetabolized LRB081 is responsible for the antagonistic effect. PRA and Ang II increased dose dependently after LRB081 intake. Aldosterone, epinephrine, and norepinephrine concentrations remained unchanged. No clinically significant adverse reaction was observed during the study. LRB081 is a well-tolerated, orally active, potent, and long-acting Ang II receptor antagonist. Unlike in the case of losartan, no active metabolite of LRB081 has been shown to be responsible for the main effects.
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PMID:Clinical and hormonal effects of the new angiotensin II receptor antagonist LRB081. 885 81

The renin-angiotensin system (RAS) is an important factor in the pathogenesis of cardiovascular diseases, including hypertension and congestive heart failure. The RAS also contributes to media hypertrophy and neointima formation. The recent development of specific, highly selective, nonpeptide angiotensin II (A II)-receptor ligands/antagonists was the basis for the identification of the A II-receptor subtypes, AT1 and AT2, which display a heterogeneous distribution. Virtually all known physiologic actions of A II have been attributed to AT1 receptors; much less is known about AT2 receptors. Cell growth, proliferation, or both are mediated by AT1 receptors, whereas stimulation of AT2 receptors leads to an inhibition of cell proliferation and possibly induces cell differentiation. Under physiologic conditions. AT1 receptors may facilitate angiogenesis while AT2 receptors inhibit it. Under pathophysiologic conditions. AT2 receptors could be up-regulated to control excessive growth mediated in part by AT1 receptors. Characterization of the angiotensin-receptor subtypes has advanced our knowledge of the various functions of A II in the pathogenesis of hypertension and related diseases. It is hoped that eventually we will be able to develop even more specific blocking agents of the pathogenic effects of A II.
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PMID:Physiologic and pharmacologic implications of AT1 versus AT2 receptors. 891 40

Angiotensin II is an active peptide of the renin-angiotensin system, whose biological actions are mediated through cell surface receptors. It is an important hormone in the regulation of blood pressure, fluid and electrolyte balance. This report describes the historical development of non-peptide angiotensin II receptor antagonists and angiotensin II receptor subtypes. Previous receptor antagonists for angiotensin II are angiotensin-like peptides with limitations of short duration, lack of oral bioavailability and partial agonistic activity. Recently, we have developed the first long-acting and orally-active non-peptide angiotensin II receptor antagonist losartan (DuP 753) which does not have agonistic activities. The discovery of losartan provides a potentially important therapy for the treatment of hypertension and congestive heart failure. Moreover, the use of losartan and other angiotensin II receptor antagonists in research has rapidly expanded our understanding of the physiological and pathophysiological roles of angiotensin II and led to the identification of receptor subtypes, AT1 and AT2. All the known physiological effects of angiotensin II including vasoconstriction and aldosterone release, which can be inhibited by losartan, are attributable to the AT1 receptor subtype. Whether the AT2 receptors serve any important physiological functions remain to be determined.
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PMID:Historical development of losartan (DuP 753) and angiotensin II receptor subtypes. 897 60

Rats with congestive heart failure demonstrate striking intrarenal vasoconstriction that contributes to reduced renal excretory function. The importance of specific angiotensin II receptor subtypes (AT1, AT2) for mediating changes in renal hemodynamics was studied in anesthetized rats 1 mo after myocardial infarction (MI) created by coronary artery ligation. AT1 antagonism with losartan alone decreased mean arterial pressure (MAP), total peripheral resistance (TPR), and renal resistance (RR) in control and MI rats to a similar extent without affecting renal blood flow (RBF) or RBF as a percentage of cardiac output (%RBF/CO). In contrast, AT2 antagonism with PD-123319 alone significantly reduced MAP and RR in MI rats without affecting these parameters in control rats. TPR and %RBF/CO were not changed significantly in either group. In contrast, combined AT1- and AT2-receptor inhibition lowered TPR and RR and increased RBF and %RBF/CO, thus the effects of renin or ACE inhibition were mimicked in MI rats. We conclude that angiotensin II acts at both AT1 and AT2 receptor sites in rats with reduced cardiac mass to modulate renal hemodynamics.
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PMID:Renal hemodynamics in rats with myocardial infarction: selective antagonism of angiotensin receptor subtypes. 899 87

Nonpeptide angiotensin II type 1-receptor antagonists, AT1 receptor antagonists are newly developed and useful drugs for hypertension and congestive heart failure. In Japan, the efficacy and safety of losartan and candesartan cilexetil in patients with essential hypertension have been evaluated by the double-blind, parallel group-comparison study using enalapril as control drug. Both trials revealed that these drugs showed a hypotensive effect comparable to that of enalapril with a high safety since the adverse drug reaction of cough was recognized in very few patients. Furthermore, a recent randomised trial of losartan versus captopril in patients over 65 with heart failure, evaluation of losartan in the elderly study (ELITE), showed that losartan was associated with a lower mortality than that found with captopril. Further studies will clarify differences in protection of cardiovascular system with a long-term treatment between AT1, receptor antagonists and angiotensin-converting enzyme inhibitors.
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PMID:[Angiotensin receptor antagonist for therapy of patients with hypertension]. 928 26

Congestive heart failure (CHF) patients share several similar features, such as reduced cardiac contractility and neurohumoral activation to compensate the impaired cardiac function. In CHF patients, the cardiac renin-angitensin (RA) system, receptors, GTP-binding proteins, and their effector molecules are inevitably exposed to chronically elevated neurohumoral stimulation. A widely recognized concept is that a chronic increase in such stimulation can desensitize target cell receptors and the post-receptor signal transducing pathway. Recently, reports of several studies have indicated that the inhibitory GTP-binding protein (Gi) can be increased in CHF patients and animal models. Although direct evidence for a change in catalytic protein of adenylyl cyclase has not been found, limited information has suggested a reduced catalytic activity in terminally failing hearts. In this paper, we have assessed the changes in beta AR, GTP-binding protein, catalytic protein and beta ARK. We also examined angiotensinogen mRNA expression in failing heart. It was detected not only in the liver, but also in both the atrial and ventricular heart tissues, suggesting that angiotensinogen is synthesized in the human heart. Immunohistochemical studies revealed a stronger reaction in the endocardial layer of the human left ventricle than in the epicardial layer, and intense immunoreactivity in the conduction system and right atrium. Our experiments revealed a widespread immunopositive reaction for angiotensinogen in the left ventricle of diseased hearts. In the non-diseased heart, ACE and AT1 receptor RNA are present in ventricular muscles. Renin and Ao mRNA could not be detected in the subendocardium of non-diseased left ventricle, but both were present in the left ventricle of diseased hearts. These data indicate that the cardiac RA system plays an important role in the deterioration of cardiac function.
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PMID:Alterations of signal transduction system in heart failure. 929 May 67

The purpose of our study was test the hypothesis that endogenous angiotensin II contributes to the basal coronary artery tone by acting at vascular ATP-sensitive K+ (K+ATP) channels. Coronary blood flow (CBF) and other hemodynamic parameters were measured in anesthetized dogs. Intracoronary infusion of the selective antagonists of angiotensin II AT1 receptors (L-158,809 and E4177) increased CHF without affecting other hemodynamic parameters, indicating that endogenous angiotensin II caused coronary vaso-constriction through the AT1 subtype receptors. Coronary vasodilation in response to AT1 receptor antagonists was blunted by pretreatment with glibenclamide (a specific inhibitor of K+ATP channels; p < 0.01) but not by either an adenosine-receptor antagonist or an inhibitor of nitric oxide synthesis. Coronary vasodilation in response to AT1-receptor antagonists was partly reduced (p < 0.01) by PD-123319 (the AT2-receptor antagonist). Glibenclamide had no effect on coronary vasodilation induced by sodium nitroprusside. These results indicate that in dogs in vivo, coronary vasodilation in response to AT 1-receptor antagonists inhibited markedly by glibenclamide and partly by PD-123319, suggesting that endogenous angiotensin II contributes to the maintenance of basal coronary vascular tone by acting at K+ATP channels through its receptors.
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PMID:Glibenclamide, a specific inhibitor of ATP-sensitive K+ channels, inhibits coronary vasodilation induced by angiotensin II-receptor antagonists. 930 Mar 14

Combined therapy with an angiotensin-II type I receptor (AT1) antagonist and an angiotensin-converting enzyme (ACE) inhibitor results in more complete suppression of the renin-angiotensin system. Accordingly, the blood-pressure response and safety of combining AT1-receptor blockade with losartan for ACE inhibition were evaluated in patients with congestive heart failure who were already treated with maximally recommended or tolerated doses of an ACE inhibitor. Forty-three patients with symptomatic congestive heart failure were evaluated biweekly for 1 month before addition of losartan and weekly during administration of losartan at a daily dose of 25 mg for the first week and 50 mg for the second week. Systolic blood pressure, which remained unchanged before addition of losartan, decreased from 122 +/- 18 mm Hg to 112 +/- 17 and 107 +/- 17 mm Hg (p < 0.001) after 1 week of 25 mg and 1 week of 50 mg losartan, respectively. Diastolic blood pressure also significantly decreased. The decreases in blood pressure were well tolerated by all patients, even by those in whom symptomatic hypotension developed during uptitration of ACE inhibition. Serum potassium and sodium and parameters of renal function remained unchanged. Combining AT1-receptor blockade with losartan to maximally recommended or tolerated ACE inhibition appears safe and leads to further vasodilatation in symptomatic patients with congestive heart failure.
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PMID:Angiotensin II-receptor blockade further reduces afterload safely in patients maximally treated with angiotensin-converting enzyme inhibitors for heart failure. 933 16

Angiotensin II (Ang II), the effector peptide of the renin-angiotensin system (RAS), regulates volume and electrolyte homeostasis and is involved in cardiac and vascular cellular growth in humans and other species. This system, which has been conserved throughout evolution, plays an important role in cardiac and vascular pathology associated with hypertension, coronary heart disease, myocarditis and congestive heart failure. The traditional RAS is viewed as a system in which circulating Ang II is delivered to target organs and cells. However, in the past decade, a local RAS has been described in cardiac cells, providing evidence for autocrine and paracrine pathways by which biological actions of Ang II could be mediated. The critical actions of Ang II are mediated primarily through the AT1, G-protein (guanylyl nucleotide binding protein) coupled receptor. In addition to coupling to conventional G-protein signal transduction pathways, the AT1 receptor was recently shown to increase the tyrosine phosphorylation of several intracellular substrates, including the STAT (Signal Transducers and Activators of Transcription) family of novel transcription factors, in rat cardiac fibroblasts, myocytes and vascular smooth muscle cells, and AT1 receptor transfected CHO cells. It has been shown that Ang II stimulates the tyrosine phosphorylation and nuclear translocation of Stat1 (Stat 91) and Stat3 (Stat 92). Angiotensin II acting directly through the AT1 receptor, induces the formation of a complex of STAT proteins termed SIF (sis-inducing factor) which binds the DNA sequence, SIE (sis-inducing element) present in the promotor element of many genes. This provides evidence for a direct role of Ang II in mediating inflammatory and remodeling responses through the JAK-STAT pathway. Thus, it is likely that the JAK-STAT pathway has an important role in Ang II-mediated effects on gene transcription, cardiac and vascular cellular growth/development, and inflammatory responses.
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PMID:Molecular mechanisms of angiotensin II in modulating cardiac function: intracardiac effects and signal transduction pathways. 940 64

In congestive heart failure (CHF), some of the effects of angiotensin-converting enzyme (ACE) inhibitors, such as an increase in exercise oxygen uptake (VO2), are mediated through prostaglandins. Angiotensin (AT1) receptor blockers apparently do not share potentiation of this biosystem. We tested whether losartan improves exercise VO2 in CHF and if the effect is the same as for enalapril. Sixteen men with CHF and 8 volunteers, all nonsmokers and not taking ACE, AT1 receptor, or cyclooxygenase inhibitors, were randomized to receive placebo, enalapril (10 mg 2 times daily), losartan (50 mg/day), each of these 2 drugs plus aspirin (325 mg/day), aspirin, or the same preparations in a reverse order, each for 3 weeks, with a 3-week washout period between treatments. Pulmonary function and VO2 were assessed at the end of each treatment. In CHF, losartan and enalapril caused a similar improvement of VO2 and exercise tolerance, which was absent in controls and was counteracted by aspirin (prostaglandin inhibition) when obtained with enalapril and not with losartan. While on enalapril, we also detected an increase in the diffusing lung capacity for carbon monoxide, which correlated with changes in VO2 and was antagonized by aspirin, suggesting the possibility that a prostaglandin-mediated functional improvement of the alveolar capillary membrane contributes to the rise in VO2. Thus, losartan is as effective as enalapril for exercise VO2 and exercise tolerance, but the mechanism seems to be dissociated from a prostaglandin biosystem activation. Losartan may represent an advancement in CHF because its efficacy on VO2 is similar to that of enalapril, but is not antagonized by aspirin.
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PMID:Comparison of changes in respiratory function and exercise oxygen uptake with losartan versus enalapril in congestive heart failure secondary to ischemic or idiopathic dilated cardiomyopathy. 941 38


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