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

Angiotensin IV (Val Tyr Ile His Pro Phe), administered centrally, increases memory retrieval and induces c-fos expression in the hippocampus and piriform cortex. Angiotensin IV binds to a high affinity site that is quite distinct in pharmacology and distribution from the angiotensin II AT1 and AT2 receptors and is known as the AT4 receptor. These observations suggest that the AT4 receptor may have multiple central effects. The present study uses in vitro receptor autoradiography, and employs [125I]angiotensin IV to map AT4 receptors in the macaca fascicularis brain. The distribution of the AT4 receptor is remarkable in that its distribution extends throughout several neural systems. Most striking is its localization in motor nuclei and motor associated regions. These include the ventral horn spinal motor neurons, all cranial motor nuclei including the oculomotor, abducens, facial and hypoglossal nuclei, and the dorsal motor nucleus of the vagus. Receptors are also present in the vestibular, reticular and inferior olivary nuclei, the granular layer of the cerebellum, and the Betz cells of the motor cortex. Moderate AT4 receptor density is seen in all cerebellar nuclei, ventral thalamic nuclei and the substantia nigra pars compacta, with lower receptor density observed in the caudate nucleus and putamen. Abundant AT4 receptors are also found in areas associated with cholinergic nuclei and their projections, including the nucleus basalis of Meynert, ventral limb of the diagonal band and the hippocampus, somatic motor nuclei and autonomic preganglionic motor nuclei. AT4 receptors are also observed in sensory regions, with moderate levels in spinal trigeminal, gracile, cuneate and thalamic ventral posterior nuclei, and the somatosensory cortex. The abundance of the AT4 receptor in motor and cholinergic neurons, and to a lesser extent, in sensory neurons, suggests multiple roles for the AT4 receptor in the primate brain.
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PMID:Distribution of AT4 receptors in the Macaca fascicularis brain. 881 7

The present study describes the influence of carbocyclic thromboxane A2 on the proliferative effects of angiotensin II on vascular smooth muscle cells. Angiotensin II (10(-7) M) and carbocyclic thromboxane A2 (10(-6) M) per se caused an increase in [3H]thymidine incorporation and cell number. The exposure of cells to both agonists resulted in a 2.5-fold elevation of the angiotensin II dependent effect on DNA synthesis and a 1.6-fold increase in cell number. 2-Ethoxy-1-[[2'-(1 H-tetrazol-5-yl)biphenyl-4-yl]methyl]-1 H-benzimidazole-7-carboxylic acid (CV-11974), the active metabolite of the specific non-peptide angiotensin AT1 receptor antagonist (+/-)-1-(cyclohexyloxycarbonyloxy)ethyl 2-ethoxy-1-[[2'-(1 H-tetrazol-5-yl)biphenyl-4-yl]methyl]-1 H-benzimidazole-7-carboxylate (TCV-116, Candesartan) suppressed the effect of angiotensin II on cell growth as well as reduced the synergistic effect of carbocyclic thromboxane A2. Simultaneous cell stimulation with carbocyclic thromboxane A2 and angiotensin II for 30 min resulted in a 26 +/- 9% elevation of the angiotensin II-induced increase of c-fos mRNA (100%).
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PMID:Carbocyclic thromboxane A2 enhances the angiotensin II-induced DNA synthesis in smooth muscle cells. 883 Nov 14

In addition to its vasoconstrictor and aldosterone-stimulating action, angiotensin II also drives cell growth and replication in the cardiovascular system, which may result in myocardial hypertrophy and hypertrophy or hyperplasia of conduit and resistance vessels in certain subjects. These actions are mediated through angiotensin II receptors (subtype AT1), which activate the G protein, phospholipase C, diacylglycerol and inositol trisphosphate pathway, to increase the expression of certain protooncogenes (c-fos, c-myc and c-jun) and growth factors (platelet-derived growth factor-A-chain, transforming growth factor-beta 1 and basic fibroblast growth factor). The cellular responses to angiotensin II in vascular smooth muscle have been shown in different hypertensive vessels to be either hypertrophy alone, hypertrophy and DNA synthesis without cell division (polyploidy) or DNA synthesis with cell division (hyperplasia). In genetic hypertension, the altered structure of small arteries is due to either cellular hyperplasia or remodeling, whereas in renovascular hypertension there is hypertrophy of vascular smooth muscle cells. Angiotensin II also increases synthesis of some matrix components, activates blood monocytes and is thrombogenic. Angiotensin-converting enzyme (ACE) inhibitors prevent or reverse vascular hypertrophy in animal models of hypertension; this seems to be a class effect, shared to some extent with calcium channel blocking agents. In human hypertension, ACE inhibitors reduce the increased media/lumen ratio of large and small arteries in hypertension and increase arterial compliance. These properties are also shared by losartan, the first of the new class of angiotensin II receptor (AT1) antagonists. The clinical implications of these findings need to be tested through rigorous and prospective clinical trials.
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PMID:The renin-angiotensin system and vascular hypertrophy. 883 52

Angiotensin II stimulates phosphorylase a activity and c-fos expression in isolated rat hepatocytes. Both effects are mediated through AT1 receptors. However, the time-courses and the dose-dependencies of these responses were different. These effects of angiotensin II were blocked by Losartan when the antagonist was added to the cells before the hormone or when both the hormone and the antagonist were added simultaneously. Interestingly, when the antagonist was added 2 or 3 min after the peptide hormone, the action on phosphorylase a activity was markedly decreased but, in contrast, that on c-fos expression was not affected. The data suggest that angiotensin II-mediated activation of phosphorylase a was reversible and dependent on continuous receptor activation by the hormone whereas c-fos expression did not seem to have these characteristics, i.e., our data suggest that once protooncogene expression is triggered, the process becomes independent of the hormone-receptor interaction.
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PMID:Differences between rapid and longer-term actions of angiotensin II in isolated rat hepatocytes. Effects on phosphorylase a activity and c-fos expression. 884 49

Many lines of evidence have suggested that angiotensin II (Ang II)plays an important role in cardiac hypertrophy. Ang II not only increases protein synthesis but also induces the reprogramming of gene expression in cultured cardiac myocytes. In the present study, to elucidate the mechanism by which Ang II regulates gene expression in cardiac myocytes, we examined whether Ang II activates c-Jun NH2-terminal kinase (JNK), which is a member of the mitogen-activated protein kinase family and activates the transcription factor, activator protein-1 (AP-1). The activity of JNK increased 5 minutes after the addition of Ang II, peaked at 20 minutes, and gradually decreased thereafter. Examination of the Ang II dose-response relation revealed detectable JNK activation at 10(-9) mol/L and maximal activation at 10(-6) mol/L. Ang II activated JNK through the AT1 receptor, and the activation was attenuated by the downregulation of protein kinase C or the chelation of intracellular Ca2+. Although the addition of either Ca2+ ionophore or phorbol ester resulted in little or no activation of JNK, simultaneous addition of both Ca2+ ionophore and phorbol ester markedly activated JNK. Slight expressions of the c-jun gene were observed in unstimulated cardiac myocytes, and Ang II increased expressions of the c-jun gene as well as the c-fos gene. Ang II increased transcription of the endothelin-1 gene through the AP-1 binding site. In conclusion, Ang II may activate JNK in cultured cardiac myocytes through an increase in intracellular Ca2+ and activation of protein kinase C, and the activated JNK may regulate gene expression by activating AP-1 during Ang II-induced cardiac hypertrophy.
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PMID:Angiotensin II stimulates c-Jun NH2-terminal kinase in cultured cardiac myocytes of neonatal rats. 897 32

Accumulating evidence indicate that various growth-related genes, growth factors and extracellular matrix components play a central role in the pathogenesis of cardiovascular and renal diseases by regulating cellular phenotype, growth and migration or promoting tissue fibrosis. Treatment of hypertensive rats with an angiotensin II type 1-receptor (AT1-receptor) antagonist normalizes cardiac phenotypic modulation and the increased fibrosis-related gene expressions in hypertrophied heart, leading to the improvement of cardiac dysfunction. The AT1-receptor antagonist can inhibit protooncogenes (c-fos, c-jun and Egr-1) and fibronectin gene expressions in rat balloon-injured artery, which is associated with the inhibition of neointima formation. Furthermore, the AT1-receptor antagonist prevents either the phenotypic modulation of glomerular mesangial cells or the increase in transforming growth factor-beta 1 expression in nephrosclerosis. Thus, the AT1-receptor antagonist in vivo potently inhibits the expression of growth-related gene and extracellular matrix and inhibits cellular phenotypic modulation. The AT1-receptor is responsible for the pathogenesis and development of cardiovascular and renal diseases.
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PMID:[Role of the renin-angiotensin system in cardiovascular and renal diseases]. 921 48

Signaling mediated by the angiotensin (Ang) II and alpha1-adrenergic receptor (alpha1-AR) pathways is important for cardiovascular homeostasis. However, it is unknown whether Ang II has any direct effect on alpha1-AR expression and signaling in cardiac myocytes. In the present study, we determined alpha1-AR subtype mRNA levels by RNase protection; receptor density by competition binding with 5-methylurapidil; and alpha1-AR-mediated c-fos expression by Northern blot analysis. We found that Ang II had no effect on alpha1b- and alpha1d-AR mRNA levels but decreased the alpha1a-AR mRNA level in a time- and dose-dependent manner. The maximal effect occurred at 6 hours with 100 nmol/L Ang II (40.0+/-8.2% reduction, n=4, P<.01). The decrease in alpha1a-AR mRNA level induced by Ang II is mediated by the Ang II AT1 receptor subtype and is associated with decreased stability of alpha1a-AR mRNA. Corresponding to the changes in the alpha1a-AR mRNA level, Ang II (100 nmol/L, 24 hours) reduced the density of high-affinity sites for 5-methylurapidil (alpha1A-AR) by 29% (56.5+/-6.4 versus 79.0+/-11.6 fmol/mg protein, n=4, P<.05). Alpha1-AR-stimulated c-fos induction, which could be blocked by 5-methylurapidil but not by chloroethylclonidine, was attenuated by Ang II preincubation (100 nmol/L, 24 hours). We conclude that there is previously undescribed cross talk between AT1 receptors and alpha1-ARs. Ang II selectively downregulates alpha1a-AR subtype mRNA and its corresponding receptor as well as alpha1a-AR-mediated expression of the immediate-early gene c-fos in cardiac myocytes.
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PMID:Cross talk between angiotensin AT1 and alpha 1-adrenergic receptors: angiotensin II downregulates alpha 1a-adrenergic receptor subtype mRNA and density in neonatal rat cardiac myocytes. 928 42

Angiotensin II (ANG II), acting principally at the AT1 receptor, modulates mechanically-induced cardiac growth. The ANG II metabolite Angiotensin IV (ANG IV) has been shown to inhibit ANG II-induced mRNA and protein synthesis in chick cardiomyocytes. This effect did not involve the AT1 receptor, but was likely an action at the AT4 receptor. To determine if ANG IV also modulates a mechanically-induced cardiac growth response, we studied the effects of two AT4 receptor ligands, [Nle1]-ANG IV and [divalinal]-ANG IV, on mechanically-induced immediate-early gene expression (c-fos, egr-1, and c-jun) in the buffer perfused (30 degrees C), ejecting, isolated rabbit heart. Mechanical load alone (high systolic pressure and high end-diastolic volume) induced approximately 23-, 49- and 5-fold increases in c-fos, egr-1 and c-jun mRNA (in comparison to control hearts). Perfusion with [Nle1]-ANG IV (10[-10] mol/l) reduced the mechanically-induced expression of c-/fos and egr-1 by 42% and 48%, respectively (P < 0.05). Mechanically-induced c-jun expression was not significantly reduced. Perfusion with [divalinal]-ANG IV (10[-8] mol/l) had no effect on mechanically-induced immediate-early gene expression. We conclude that AT4 receptor agonism influences mechanical immediate-early gene expression, and propose the hypothesis that AT1 and AT4 receptors initiate opposing effects on mechanically-induced immediate-early gene expression in the isolated rabbit left ventricle.
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PMID:The AT4 receptor agonist [Nle1]-angiotensin IV reduces mechanically induced immediate-early gene expression in the isolated rabbit heart. 935 Sep 76

The renin-angiotensin system seems to play an important role in the pathogenesis of renal interstitial fibrosis. However, the potential direct effects of angiotensin II (Ang II) on cultured renal fibroblasts have been little studied. We have observed that rat renal interstitial fibroblasts (NRK 49F cell line) possess AT1 receptors coupled to intracellular calcium mobilization. Exposure of these cells to Ang II induced several short and long growth-related metabolic events mediated by the AT1 receptor, including c-fos gene expression, changes in cell cycle and cell proliferation. Activation of interstitial fibroblasts by Ang II could also contribute to extracellular matrix accumulation. Stimulation with Ang II increased mRNA expression of TGF-beta 1, fibronectin and type I collagen. In fact, Ang II enhanced fibronectin production via AT1 receptors by a process depending on autocrine TGF-beta secretion. The mechanism of some Ang II actions (calcium mobilization and fibronectin production) depended on protein kinase C and tyrosine kinase activation. We further investigated whether renal fibroblasts could express some components of the renin-angiotensin system. These cells constitutively expressed the angiotensinogen gene that was up-regulated by Ang II. Collectively, these results indicate that in renal interstitial fibroblasts Ang II causes hyperplasia and extracellular matrix production via the AT1 receptor. Ang II may initiate a positive feedback regulation of fibroblasts growth, inducing the expression of TGF-beta 1 and angiotensinogen genes. Ang II, acting directly on interstitial fibroblasts, may be implicated in the pathogenesis of renal fibrosis.
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PMID:Angiotensin II modulates cell growth-related events and synthesis of matrix proteins in renal interstitial fibroblasts. 940 95

Angiotensin II is vasoconstrictor and antinatriuretic; it also stimulates cell growth and proliferation in vascular smooth muscle, resulting in hypertrophy or hyperplasia of conduit and resistance vessels. These actions are mediated through angiotensin II receptors (AT1 subtype), which activate several G-protein-dependent intracellular transduction pathways, such as the phospholipase C, diacylglycerol and inositol trisphosphate the mitogen-activated protein (MAP) kinase pathway, and Janus kinase (JAK)-signal transducers and activators of the transcription (STAT)-mediated pathway. These can all increase the expression of certain proto-oncogenes, particularly c-fos. Angiotensin II also stimulates the activity of certain growth factors, such as platelet-derived growth factor-A-chain and basic fibroblast growth factor. The cellular responses to angiotensin II in vascular smooth muscle have been shown in different hypertensive vessels to be either hypertrophy alone, hypertrophy and DNA synthesis without cell division (polyploidy), or DNA synthesis with cell division (hyperplasia). In genetic hypertension, there is either cellular hyperplasia or remodeling, whereas in renovascular hypertension, there is hypertrophy of vascular smooth muscle cells. Angiotensin-converting enzyme (ACE) inhibitors prevent or reverse vascular hypertrophy in animal models of hypertension. In human hypertension, ACE inhibitors reduce the increased media/lumen ratio of large and small arteries and increase arterial compliance. These properties are also shared by AT1 receptor antagonists. The implications of these findings for morbidity and mortality in hypertension still await rigorous testing in prospective clinical trials.
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PMID:Vascular hypertrophy in hypertension: role of the renin-angiotensin system. 952 May 14


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