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In cultured neonatal rat cardiac fibroblasts and CHO-K1 cells expressing angiotensin II (Ang II) type 1 receptors (AT1) (T3CHO/AT1A cell line), Ang II induced a delayed tyrosine phosphorylation of Stat3 (Signal Transducers and Activators of Transcription) with maximal activation at 2 h. This was in contrast to the rapid tyrosine phosphorylation (15-30 min) of Stat3 by the cytokine interleukin-6 (IL-6). Using T3CHO/AT1A cells, we tested the hypothesis that the delayed tyrosine phosphorylation of Stat3 by Ang II resulted from the induction of an inhibitory pathway (0-30 min) prior to activation (1-2 h). In support of this hypothesis, we observed that a short treatment of cells with Ang II transiently inhibited the IL-6-induced Stat3 tyrosine phosphorylation. The inhibitory effect of Ang II could be attenuated by exposing the cells to a specific inhibitor of MAP kinase kinase 1, PD98059. Such modulatory cross-talk between Ang II and IL-6 may have relevance in pathophysiological conditions such as cardiac hypertrophy, and in acute phase and inflammatory responses.
Basic Res Cardiol 1998
PMID:Cross-talk between angiotensin II and interleukin-6-induced signaling through Stat3 transcription factor. 987 41

The progression of left ventricular (LV) dilation with congestive heart failure (CHF) is associated with an increased incidence of morbidity and mortality. The LV myocardial extracellular matrix has been implicated to play an important role in maintaining chamber shape and myocyte alignment. While angiotensin II AT1 receptor (Ang AT1) receptor activation has been demonstrated to contribute to increased vascular resistance with the CHF, whether activation of the myocardial Ang AT1 receptor system contributes to LV dilation and myocardial collagen remodelling with CHF remains unclear. The goal of this study was to examine the effects of Ang AT1 receptor inhibition on LV geometry and myocardial collagen content and structure with the development of pacing CHF. Pigs (25 kg) were instrumented in order to measure LV function in the conscious state and were assigned to one of three groups: (1) Pacing CHF: rapid atrial pacing (240 bpm) for 3 weeks (n = 7); (2) Pacing CHF and Ang AT1 Block: concomitant Ang AT1 receptor blockade (valsartan, Novartis, Basel 60 mg/day) and rapid pacing (n = 7); (3) sham controls (n = 7). The Ang AT1 receptor antagonist was delivered by osmotic minipump and this dose has been demonstrated previously to significantly blunt the Ang-II pressor response. LV pump function and geometry was assessed by echocardiography and LV myocardial collagen content by computer assisted histomorphometry and biochemistry. In the pacing CHF group, LV fractional shortening was reduced (17 +/- 2 v 45 +/- 1%) and LV end-diastolic dimension increased (5.91 +/- 0.09 v 3.75 +/- 0.07 cm) compared to controls (P<0.05). In the pacing CHF and Ang AT1 blockade group, LV pump function and dimensions were similar to untreated pacing CHF values. The relative content of LV myocardial fibrillar collagen was reduced with pacing CHF (7.6 +/- 0.4 v 11.3 +/- 0.6%) compared to controls (P<0.05), and was similarly reduced in the pacing CHF and Ang AT1 receptor blockade group (8.3 +/- 0.4%, P<0.05). LV myocardial hydroxyproline was reduced with pacing CHF compared to controls (2.35 +/- 0.21 v 2.89 +/- 0.42 mg/gdwt, P<0.05). While reduced with pacing CHF and Ang AT1 receptor blockade (2.54 +/- 0.25 mg/gdwt), this was not significantly different from controls (P=0.23). Ang AT1 receptor inhibition in this model of CHF did not appear to favorably affect the degree of LV dilation and myocardial collagen structure. These results suggest that activation of the myocardial Ang AT1 receptor may not significantly contribute to LV remodelling with pacing CHF.
J Mol Cell Cardiol 1998 Nov
PMID:Angiotensin AT1 receptor inhibition in pacing induced heart failure: effects on left ventricular myocardial collagen content and composition. 992 71

This study was designed to assess the influence of the activation status of the renin angiotensin system (RAS) on the hemodynamic effects of EXP 3174 (an angiotensin AT1 receptor antagonist) and enalaprilat (an angiotensin converting enzyme inhibitor) in tachycardia-induced heart failure. Thirteen dogs were chronically instrumented to measure left ventricular (LV) pressure, its first time derivative (LV dP/dt), atrial and aortic pressures, and cardiac output. EXP 3174 (0.1 mg/kg, i.v.) or enalaprilat (1 mg/kg, i.v.) were administered in conscious dogs with heart failure induced by right ventricular pacing (250 beats/min, 3 weeks). EXP 3174 and enalaprilat produced significant vasodilation but the effects of EXP 3174 on mean aortic pressure (MAP), cardiac output, and total peripheral resistance (TPR) were only 50% of those produced by enalaprilat. When dogs were grouped according to their baseline plasma renin activity (PRA) values, in dogs with normal PRA (0.5 +/- 0.1 ng/ml/h) EXP 3174 did not produce significant change in MAP and TPR, while enalaprilat decreased significantly MAP and TPR. In contrast, in dogs with high PRA (6.7 +/- 3.2 ng/ml/h), EXP 3174 produced significant reductions in MAP and TPR, which were similar to those produced by enalaprilat. Thus, in conscious dogs with heart failure, enalaprilat is effective whether the RAS is activated or not. In contrast, EXP 3174 is effective only when the RAS is activated. These results may help in the choice of inhibitors of the RAS in heart failure.
Basic Res Cardiol 1999 Apr
PMID:Comparison between angiotensin receptor antagonism and converting enzyme inhibition in heart failure. Differential acute effects according to the renin-angiotensin system activation. 1032 61

In response to humoral and mechanical stimuli, the myocardium adapts to increased work load through hypertrophy of individual muscle cells. Myocardial hypertrophy is characterized by an increase in cell size in the absence of cell division and is accompanied by changes in gene expression. 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 growth in rats. In this review, the role of RAS on the myocyte protein synthesis (myocyte hypertrophy) and on the induction of gene expression will be discussed in rat cardiomyocytes in culture. The traditional RAS can be considered as a system in which circulating ANG II is delivered to target tissues or cells. However, a local RAS has also been described in cardiac cells and evidence has been accumulated for autocrine and/or paracrine pathways by which biological actions of ANG II can be mediated. These actions of ANG II are primarily mediated through ANG II receptors of the subtype I (AT1-R). When evaluating the effects of ANG II in situ, both changes in circulating levels and local production have to be taken into account. Discrepant findings on the in vitro effect of ANG II on the protein synthesis in cardiac myocytes are described and can be at least partly be attributed to methodological problems such as assay of the de novo protein synthesis, isolation and the separation procedure of cardiac myocytes. The ANG II-induced hypertrophic effect also depends on the existence of non-myocytes in a cardiocyte culture. In rat cardiocytes ANG II also causes induction of many immediately-early genes (c-fos, c-jun, jun-B, Egr-1 and c-myc) and induces also late markers of cardiac hypertrophy (skeletal alpha-actin and atrial natriuretic peptide expression) and growth factors (TGF-beta1 gene expression). In vivo ANG II via AT1-R, causes not only ventricular hypertrophy, independently of blood pressure, but also a shift to the fetal phenotype of the myocardium. Angiotensin-converting enzyme inhibitors and ANG II receptor antagonists of the subtype I not only induce the regression, but also prevent the development of cardiac hypertrophy in experimental rat models.
J Mol Cell Cardiol 1999 May
PMID:Renin-angiotensin system, hypertrophy and gene expression in cardiac myocytes. 1033 36

Angiotensin II antagonists block the actions of angiotensin II by occupying the AT1 receptors. With this blockade there is no bradykinin increase, the angiotensin II synthetized by the cardiac chymase is also blocked, and the AT2 receptor is stimulated (antiproliferative effect). In animal experiments, losartan reverses left ventricular hypertrophy, inhibits myocardial fibrosis and diabetic glomerulosclerosis and significantly protects from vascular cerebral diseases. In humans, the efficacy of the angiotensin II antagonists and that of other antihypertensives is similar and is potentiated by the addition of a thiazide. They are very well tolerated and no important adverse reactions are reported. Losartan decreases insulin resistance, has a very favourable hemodynamic and neurohormonal profile in patients with cardiac insuficiency, reverses proteinuria and has a uricosuric effect. Angiotensin II antagonists are a step forward towards the ideal antihypertensive drugs.
Rev Port Cardiol 1999 Apr
PMID:[Therapy of arterial hypertension with angiotensin receptor blockers]. 1037 49

The effect of AT1 receptor blockade on myocardial stunning is still somewhat ambiguous. In some prior studies, coronary occlusion was of too long duration such that the effects of infarction and stunning on the recovery of contractile function could not be distinguished. In others, blood pressure was decreased such that the improved wall excursion could be the consequence of reduced afterload and/or of attenuated stunning. The present study, therefore, investigated the effect of the AT1 receptor antagonist candesartan in a pure model of myocardial stunning with controlled systemic hemodynamics. Fourteen anesthetized open-chest dogs were subjected to 15 minutes occlusion of the left circumflex coronary artery (LCx) and 4 hours subsequent reperfusion. Systemic hemodynamics (micromanometer), regional myocardial blood flow (colored microspheres), and posterior wall thickening (PWT, sonomicrometry) were measured, and data were compared between 7 placebo controls (group 1) and 7 dogs receiving 1 mg/kg candesartan i.v. before LCx occlusion (group 2). Left ventricular peak pressure was kept constant by an intra-aortic balloon, and heart rate did not change throughout the protocol. Regional myocardial blood flow was not different between the groups under control conditions, increased in response to candesartan in group 2 (posterior subendocardial blood flow from 0.99 +/- 0.18 to 1.57 +/- 0.45; p < 0.05 vs. control conditions), but was not different during myocardial ischemia and at 4 hours of reperfusion between the groups. Under control conditions and during myocardial ischemia, PWT was also not different between the groups. At 4 hours of reperfusion, PWT was still depressed in group 1 (-1.5 +/- 3.4% vs. 17.7 +/- 5.6% during control conditions, p < 0.05), whereas PWT had recovered in group 2 (11.4 +/- 3.7% at 4 hours reperfusion vs. 18.3 +/- 2.7 during control conditions, NS, p < 0.05 vs. group 1). In conclusion, pretreatment with the AT1 receptor antagonist candesartan improved the functional recovery of reperfused myocardium. This attenuation of myocardial stunning was not based on more favorable systemic hemodynamics or regional myocardial blood flow.
Basic Res Cardiol 1999 Jun
PMID:Attenuation of myocardial stunning by the AT1 receptor antagonist candesartan. 1042 39

The renin-angiotensin system (RAS) plays an important role in the regulation of blood pressure. Angiotensin II is the principal effector hormone in the RAS, causing vasoconstriction and increased sodium and water retention, leading to increased blood pressure. Angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor antagonists both inhibit the actions of angiotensin II. ACE inhibitors prevent the formation of angiotensin II from angiotensin I, whereas angiotensin II receptor antagonists inhibit the final crucial step of angiotensin II binding with the AT1 receptor site. This article discusses the efficacy of angiotensin II receptor antagonists and their possible role in organ protection.
Am J Cardiol 1999 Jul 22
PMID:How do angiotensin II receptor antagonists affect blood pressure? 1043 37

Oxygen consumption at peak exercise (peak VO2) is a strong independent predictor of the outcome in congestive heart failure (CHF). Renin-angiotensin system inhibition with either ACE or AT1 receptor blockers is effective on peak VO2. We evaluated whether mechanisms are similar for the 2 categories of drugs and whether their combination is able to produce a synergistic effect. Twenty CHF patients were randomized to receive, in a double-blind fashion, placebo + placebo (P+P), enalapril (20 mg/day) + placebo (E+P), losartan (50 mg/day) + placebo (L+P), and enalapril + losartan (E+L) or the same preparations in a reverse order, each for 8 weeks. Two patients did not complete the trial. Pulmonary function, cardiopulmonary exercise test, plasma neurohormones, and quality of life were assessed at the end of each treatment. Compared with P+P, E+P, and L+P similarly (16% and 15%, respectively) and significantly (p <0.01) augmented peak VO2. Enalapril improved lung function (reduced slope of ventilation vs carbon dioxide production and dead space to tidal volume ratio, and increased alveolar membrane conductance and tidal volume). Losartan likely activated the exercising muscle perfusion (raised delta VO2/delta work rate, which is a measure of aerobic work efficiency). In combination, they further increased peak VO2, 10% from E+P (p <0.05) and 11% from L+P (p <0.05). Compared with run-in, E+P and L+P significantly reduced plasma norepinephrine by 70 +/- 14 pg/ml and 100 +/- 16 pg/ml and aldosterone by 1.6 +/- 0.7 ng/dl and 1.6 +/- 0.8 ng/dl. These changes were significantly greater when the drugs were combined (140 +/- 20 pg/ml for norepinephrine, and 5.6 +/- 0.9 ng/dl for aldosterone). Quality-of-life score did not improve significantly at each treatment step. Thus, lorsartan and enalapril similarly increased peak VO2 in CHF patients, but mediators of this effect were, at least in part, different therapeutic targets that may be synergistic when the 2 drugs are combined.
Am J Cardiol 1999 Nov 01
PMID:Synergistic efficacy of enalapril and losartan on exercise performance and oxygen consumption at peak exercise in congestive heart failure. 1056 60

Advances in scientific research over the last century have permitted the recognition and characterization of the structure and function of an enzymatic pathway involved in cardiovascular homeostasis and blood pressure control, namely the renin-angiotensin-aldosterone system. This system may be reversibly blocked by drugs acting at different levels: renin inhibitors, angiotensin converting enzyme inhibitors and AT1 angiotensin II receptor antagonists. Lacking clinical experience with effects of AT1 angiotensin II receptor antagonists on the cardiovascular system are practically identical to those observed with angiotensin converting enzyme inhibitors. The efficacy and safety of drugs blocking the renin-angiotensin-aldosterone system in the reduction of blood pressure, the regression of cardiovascular remodeling, the prevention of progression of diabetic nephropathy to end-stage renal failure, and the prevention of cardiovascular morbidity and mortality is well established. These hemodynamic effects of AT1 angiotensin II receptor antagonists treatment are achieved with less adverse effects than with angiotensin converting enzyme inhibitors. Furthermore, the association of angiotensin converting enzyme inhibitors and AT1 angiotensin II receptor antagonists allows a more effective renin-angiotensin-aldosterone Systems blockade and improves the hemodynamic and non-hemodynamic effects. This possibility opens up new perspectives in the treatment of cardiovascular diseases, the most common cause of death at the end of the millennium in developed countries.
Rev Esp Cardiol 1999
PMID:[Antihypertensive advantages of angiotensin II AT1 receptor antagonism]. 1061 50

The in vivo activation of transcription factors, which is important for cell regulation by gene expression, has not been well examined in myocardial infarcted heart. The purpose of this study was to determine whether myocardial signal transducer and activator of transcription (STAT) pathway is activated as sis-inducing factor (SIF) in infarcted heart, and to assess the angiotensin blockade on SIF activity in ischemic and non-ischemic myocardium of rat. Myocardial infarction was made by ligation of the coronary artery in Wistar rats. In electrophoretic mobility shift assay, myocardial SIF DNA binding activities gradually increased and reached to peak at 1 week in infarcted and non-infarcted regions after myocardial infarction. Imidapril and candesartan cilexitil significantly prevented the increase in SIF DNA binding activity in infarcted and non-infarcted regions. This increased SIF DNA complex was supershifted by specific anti-STAT3 antibody, indicating that increased SIF complex at least contained activated STAT3 proteins in myocardial infarcted heart. Furthermore, immunoprecipitation-Western blot analysis revealed that STAT3 of infarcted and non-infarcted regions were tyrosine-phosphorylated at 1 week after myocardial infarction. Imidapril and candesartan cilexitil prevented the increase in phosphorylated STAT3. Thus, the transcriptional activation of STAT3 through AT1 receptor may be partially involved in cardiac remodeling after myocardial infarction.
J Mol Cell Cardiol 2000 Jan
PMID:Angiotensin blockade inhibits SIF DNA binding activities via STAT3 after myocardial infarction. 1065 87


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