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Query: UMLS:C0004135 (ATM)
 13,001 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Angiotensin II (AII) elicits a positive inotropic response in cardiac muscle preparations from several species including humans. The purpose of this study was to characterize the AII binding sites and inotropic responses in rabbit ventricle using the selective AII receptor antagonists/ligands, DuP 753 (AT1) and PD 121981 (AT2). Biphasic displacement of specific 125I-Sar1,Ile8-AII binding was observed with both DuP 753 and PD 121981, suggesting the presence of two AII binding sites. The high affinity site for DuP 753 (29 nM) was a low affinity site for PD 121981 (91 microM), and the high affinity site for PD 121981 (78 nM) was a low affinity site for DuP 753 (81 microM). Of the specific AII binding, 70% was DuP 753 (AT1)-sensitive sites. Positive inotropic responses to AII in isolated papillary muscles from rabbit heart were antagonized competitively by both DuP 753 and PD 121981. The potencies of DuP 753 (pA2 = 7.99) and PD 121981 (pA2 = 4.28) to antagonize AII inotropic responses were similar to their potencies to displace 125I-Sar1,Ile8-AII from AT1 sites. There was no apparent functional consequence of AII interaction with AT2 site. Inotropic responses to isoproterenol were unaffected by DuP 753 and PD 121981. Therefore, there are two binding sites for AII in rabbit ventricle; however, only one site, AT1, participates in the inotropic response to AII. The roles of these receptor subtypes in other cardiac responses to AII have yet to be determined. Also, DuP 753 and PD 121981 are useful tools to study these two AII binding sites in cardiac preparations.
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PMID:Cardiac angiotensin receptors: effects of selective angiotensin II receptor antagonists, DUP 753 and PD 121981, in rabbit heart. 160 98

Cardiac hypertrophy of diverse etiologies is associated with two remodeling events: an increase in cardiac muscle mass, and the abnormal accumulation of fibrillar collagen, which results in increased myocardial stiffness and eventual ventricular dysfunction. Clinical and animal studies have implicated angiotensin II (A II) as a growth promoter of both cardiac myocytes and fibroblasts during the cardiac remodeling that occurs with hypertension and myocardial infarction. The growth-promoting effects of A II occur, in part, independent of effects on hemodynamic load. Tissue culture studies have shown that cardiac myocytes and fibroblasts are targets for the actions of A II. In these cells. A II activates phospholipases C, D, and A2, leading in turn to the activation of multiple, conventional second-messenger pathways. By an undefined process. A II also increases the tyrosine phosphorylation of cytosolic proteins, and activates the STAT family of transcription factors, which may mediate an inflammatory or stress response. A II has been shown to affect gene expression of cultured cardiac myocytes and fibroblasts, induce either cellular hyperplasia or hypertrophy, and increase expression of other growth factors. Cardiac fibroblasts have been shown to respond to A II with increased expression of integrins and the extracellular matrix proteins, collagen and fibronectin. Recently, stretch of cardiac myocytes was shown to induce hypertrophy, through an autocrine release of A II. All of the aforementioned actions of A II are mediated by the AT1 receptor.
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PMID:The role of the renin-angiotensin system in the pathophysiology of cardiac remodeling. 891 34

TGR(mREN2)27 is a transgenic rat harboring the murine Ren-2 gene and exhibit fulminant hypertension and marked heart hypertrophy. In order to study the role of angiotensin II in the increase of cardiac mass, these animals were treated with antihypertensive and non-antihypertensive doses of the angiotensin II receptor AT1 antagonist Telmisartan for 9 weeks. All doses led to significant reductions of heart hypertrophy detected by the evaluation of the diameter of cardiac muscle bundles. We conclude from this study that cardiac hypertrophy in TGR(mREN2)27 is characterized by an increased volume of cardiomyocytes and an unchanged amount of fibrous tissue and that angiotensin II plays an important role in the mechanisms leading to this phenotype.
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PMID:Reduction of cardiac hypertrophy in TGR(mREN2)27 by angiotensin II receptor blockade. 897 60

1. While the haemodynamic influences that cause cardiac hypertrophy are well known, the cellular and molecular mechanisms by which a mechanical stimulus is translated into a growth response by cardiac muscle have remained uncertain. 2. Current evidence suggests that a number of trophic factors may be released by cellular constituents of the heart, acting in an autocrine or paracrine manner to influence the growth response and phenotype of neighbouring cells. 3. Angiotensin II, acting via the AT1 receptor subtype, and both basic fibroblast growth factor and heparin-binding epidermal growth factor have been shown to exert hypertrophic actions in vivo and in vitro. Studies also indicate that cardiac myocytes themselves are capable of releasing all of these cytokines in response to increased mechanical load.
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PMID:Cytokines and cardiac hypertrophy: roles of angiotensin II and basic fibroblast growth factor. 899 53

1. Transgenic(TG) (mRen-2) rats overexpressing the mouse renin gene develop fulminant hypertension and cardiac hypertrophy. Since the activation of AT1 receptor by angiotensin II is involved in blood pressure regulation, cardiac performance and myocardial growth, we investigated the biological effects of angiotensin II and the regulation of the AT1 receptor in the heart and aorta of TGR (mRen-2)27 rats in comparison to control animals. 2. Contraction studies on isolated cardiac muscle strips reveal that angiotensin II exerts no positive inotropic effect on the left ventricular myocardium of both, transgenic and control rats. In contrast, angiotensin II leads via AT1 receptor activation in the left atrium of control rats to a significant contraction (130 +/- 5% of basal contraction) which is not detectable in left atrium preparations of the transgenic animals. Furthermore, AT1 receptor activation causes a profound contraction of aortic rings isolated from control rats amounting to 1.39 +/- 0.2 mN mg-1 wet weight, whereas aortic rings from TGR (mRen-2)27 rats contract only minimally upon angiotensin II stimulation (0.2 +/- 0.02 mN mg-1 wet weight). 3. These altered physiological responses of angiotensin II in the transgenic rats are in part due to a marked down-regulation of the AT1 receptor in atrial, ventricular and aortic tissue of these transgenic animals in comparison to control Sprague-Dawley rats, as shown by radioligand binding assays and quantitative polymerase chain reaction (PCR) experiments. The AT1 receptor density Bmax in the left atrium was 1.3 +/- 0.08 fmol mg-1 protein in control rats (KD 1.1 +/- 0.18 nmol l-1) and 0.94 +/- 0.15 fmol mg-1 protein (KD 2.1 +/- 0.3 nmol l-1. In the aorta Bmax values were 15.1 +/- 0.5 fmol mg-1 protein (KD 1.9 +/- 0.27 nmol l-1) for control rats and 11.3 +/- 0.76 fmol mg-1 protein (KD 1.9 +/- 0.27 nmol l-1) for the TGR(mRen-2)27 rats AT1 receptor mRNA was reduced in the transgenic animals to 46 +/- 3% in the left atrium, 50 +/- 11% in the left ventricle and 40 +/- 3% in the aorta, respectively. 4. Together, the AT1 receptor is down-regulated in TGR (mRen-2)27 rats in comparison to wildtype Sprague Dawley rats leading to a profoundly decreased response of cardiac and aortic tissue upon stimulation with angiotensin II.
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PMID:Down-regulation of aortic and cardiac AT1 receptor gene expression in transgenic (mRen-2) 27 rats. 914 97

The distributions of angiotensin AT1 and AT2 receptors have been mapped by in vitro autoradiography throughout most tissues of many mammals, including humans. In addition to confirming that AT1 receptors occur in sites known to be targets for the physiologic actions of angiotensin, such as the adrenal cortex and medulla, renal glomeruli and proximal tubules, vascular and cardiac muscle, and brain circumventricular organs, many new sites of action have been demonstrated. In the kidney, AT1 receptors occur in high density in renal medullary interstitial cells. The function of these cells, which span the interstitial space between the tubules and the vasa rectae, remains to be determined. Renal medullary interstitial cells possess receptors for a number of vasoactive hormones in addition to AT1 receptors and this, in concert with their anatomical location, suggest that they may be important for the regulation of fluid reabsorption or renal medullary blood flow. In the heart, the highest densities of AT1 receptors occur in association with the conduction system and vagal ganglia. In the central nervous system, high AT1 receptor densities occur in many regions behind the blood-brain barrier, supporting a role for neurally derived angiotensin as a neuromodulator. The physiologic role of angiotensin in many of these brain sites remains to be determined. The AT2 receptor also has a characteristic distribution in several tissues including the adrenal gland, heart, and brain. The role of this receptor in physiology is being elucidated, but it appears to participate in development. Thus, receptor binding studies, localizing the distribution of AT1 and AT2 receptors, outline a number of regions where the actions of angiotensin are known but also provide many insights into novel physiologic roles of this peptide.
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PMID:Localization of angiotensin AT1 and AT2 receptors. 989 37

Myocardial hypertrophy is one of the basic mechanisms by which the heart compensates for hemodynamic overload. The mechanisms by which hemodynamic overload is transduced by the cardiac muscle cell and translated into cardiac hypertrophy are not completely understood. Candidates include activation of the renin-angiotensin system (RAS) and angiotensin II receptor (AT1) stimulation. In this study, we tested the hypothesis that load, independent of the RAS, is sufficient to stimulate cardiac growth. Four groups of cats were studied: 14 normal controls, 20 pulmonary artery-banded (PAB) cats, 7 PAB cats in whom the AT1 was concomitantly and continuously blocked with losartan, and 8 PAB cats in whom the angiotensin-converting enzyme (ACE) was concomitantly and continuously blocked with captopril. Losartan cats had at least a one-log order increase in the ED50 of the blood pressure response to angiotensin II infusion. Right ventricular (RV) hypertrophy was assessed using the RV mass-to-body weight ratio and ventricular cardiocyte size. RV hemodynamic overload was assessed by measuring RV systolic and diastolic pressures. Neither the extent of RV pressure overload nor RV hypertrophy that resulted from PAB was affected by AT1 blockade with losartan or ACE inhibition with captopril. RV systolic pressure was increased from 21 +/- 3 mmHg in normals to 68 +/- 4 mmHg in PAB, 65 +/- 5 mmHg in PAB plus losartan and 62 +/- 3 mmHg in PAB plus captopril. RV-to-body weight ratio increased from 0.52 +/- 0.04 g/kg in normals to 1.11 +/- 0.06 g/kg in PAB, 1.06 +/- 0.06 g/kg in PAB plus losartan and 1.06 +/- 0.06 g/kg in PAB plus captopril. Thus 1) pharmacological modulation of the RAS with losartan and captopril did not change the extent of the hemodynamic overload or the hypertrophic response induced by PAB; 2) neither RAS activation nor angiotensin II receptor stimulation is an obligatory and necessary component of the signaling pathway that acts as an intermediary coupling load to the hypertrophic response; and 3) load, independent of the RAS, is capable of stimulating cardiac growth.
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PMID:Hypertrophic response to hemodynamic overload: role of load vs. renin-angiotensin system activation. 995 Aug 33

The distributions of angiotensin AT1 and AT2 receptors have been mapped by in vitro autoradiography throughout most tissues of many mammals, including humans. In addition to confirming that AT1 receptors occur in sites known to be targets for the physiologic actions of angiotensin, such as the adrenal cortex and medulla, renal glomeruli and proximal tubules, vascular and cardiac muscle and brain circumventricular organs, many new sites of action have been demonstrated. In the kidney, AT1 receptors occur in high density in renal medullary interstitial cells. The function of these cells, which span the interstitial space between the tubules and the vasa rectae, remains to be determined. Renal medullary interstitial cells possess receptors for a number of vasoactive hormones in addition to AT1 receptors and this, in concert with their anatomic location, suggests they may be important for the regulation of fluid reabsorption or renal medullary blood flow. In the heart, the highest densities of AT1 receptors occur in association with the conduction system and vagal ganglia. In the central nervous system, high AT1 receptor densities occur in many regions behind the blood-brain barrier, supporting a role for neurally derived angiotensin as a neuromodulator. The physiologic role of angiotensin in many of these brain sites remains to be determined. The AT2 receptor also has a characteristic distribution in several tissues including the adrenal gland, heart, and brain. The role of this receptor in physiology is being elucidated, but it appears to inhibit proliferation and to participate in development. Thus, receptor-binding studies, localizing the distribution of AT1 and AT2 receptors, provide many insights into novel physiologic roles of angiotensin.
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PMID:Localization and function of angiotensin AT1 receptors. 1067 86

The purpose of this study was to characterize myosin light chain kinase (MLCK) expression in cardiac and skeletal muscle. The only classic MLCK detected in cardiac tissue, purified cardiac myocytes, and in a cardiac myocyte cell line (AT1) was identical to the 130-kDa smooth muscle MLCK (smMLCK). A complex pattern of MLCK expression was observed during differentiation of skeletal muscle in which the 220-kDa-long or "nonmuscle" form of MLCK is expressed in undifferentiated myoblasts. Subsequently, during myoblast differentiation, expression of the 220-kDa MLCK declines and expression of this form is replaced by the 130-kDa smMLCK and a skeletal muscle-specific isoform, skMLCK in adult skeletal muscle. These results demonstrate that the skMLCK is the only tissue-specific MLCK, being expressed in adult skeletal muscle but not in cardiac, smooth, or nonmuscle tissues. In contrast, the 130-kDa smMLCK is ubiquitous in all adult tissues, including skeletal and cardiac muscle, demonstrating that, although the 130-kDa smMLCK is expressed at highest levels in smooth muscle tissues, it is not a smooth muscle-specific protein.
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PMID:Smooth muscle myosin light chain kinase expression in cardiac and skeletal muscle. 1102 14

Mechanical forces have profound effects on cardiomyocytes. To test whether angiotensin II is a potential mediator of stretch-induced effects on gap junctions, we used the angiotensin II (AT1) receptor antagonist, losartan, to investigate the cyclical stretch-induced expression of connexin43 (Cx43), the major cardiac muscle gap junction channel protein. Cultured neonatal rat cardiomyocytes grown on a flexible membrane base were stretched by vacuum to 20% of maximum elongation, at 60 cycles/min. The levels of Cx43 protein began to increase as early as 2 h after stretch was applied, reached a maximum of six-fold over the control by 24 h and remained at this level another 24 h (i.e. up to 48 h after stretch was applied). These increases of Cx43 protein at 24 h were largely (73%) and completely (100%) attenuated (P<0.001) by the addition (30 min before stretch) of 10 n M and 100 n M losartan, respectively. Similarly, the Cx43 mRNA levels in stretched cardiomyocytes rose 89% (P<0.01) above control (non-stretched cells) mRNA levels. This increase also was blocked by losartan. Cyclical stretch increased (and losartan decreased) the immunohistochemical labeling of Cx43 and significantly increased release of angiotensin II into the culture media from 7.5+/-0.6 ng/ml to 23.8+/-1.0 ng/ml (P<0.01) after a 1 h stretch. These findings indicate that cyclical mechanical stretch augments angiotensin II production and Cx43 gene expression in cultured cardiomyocytes, partially through mediation of the AT1 receptors, and suggests interaction between the cardiomyocyte local rennin-angiotensin system and Cx43 in response to stretch.
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PMID:Angiotensin II receptor antagonist blocks the expression of connexin43 induced by cyclical mechanical stretch in cultured neonatal rat cardiac myocytes. 1127 22


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