Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.23.15 (renin)
 35,795 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The actions of angiotensin II in the cardiovascular system are transmitted by two known and possibly some unknown angiotensin receptor types. AT1 and AT2 both correspond to G-protein-coupled receptors with seven hydrophobic transmembrane domains, several N-glycosylation sites and a potential G-protein binding site. Cloning of coding regions and promoter sequences contributed to the understanding of receptor protein function and regulation. Angiotensin receptors with atypical binding properties for the known AT1- and AT2-specific ligands are expressed on human cardiac fibroblasts and in the human ulcrus. In several animal models, receptors with high affinity for angiotensin (1-7) have been described. AT1 stimulation is mediated by the generation of phospholipid-derived second messengers, activation of protein kinase C, the MAPkinase pathway and of immediate early genes. Recently, phosphorylation and dephosphorylation of tyrosine kinases have been associated with AT1- and AT2-mediated signal transduction. ATR are regulated by phosphorylation, internalization, modification of transcription rate and mRNA stability. Regulation is highly cell and organ specific and includes upregulation of ATR in some pathophysiological situations where the renin angiotensin system is activated. Whereas the function of AT1 in the cardiovascular system is relatively well established, there is little information regarding the role of AT2. Recent hypotheses suggest an antagonism between AT1 and AT2 at the signal transduction and the functional level. Transgenic animal models, particularly with targeted disruption of the AT1 and AT2 genes, suggest the contribution of both genes to blood pressure regulation. Genetic polymorphisms have been described in the AT1 and AT2 gene or neighbored regions and are used to analyze the association between gene defects and cardiovascular diseases. AT1 antagonists are now being introduced into the treatment of hypertension and potentially heart failure, and more interesting pharmacological developments are expected from the ongoing basic studies.
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PMID:Molecular biology of angiotensin receptors and their role in human cardiovascular disease. 877 61

Angiotensin II exerts its action via at least two distinct receptor subtypes designated AT1 and AT2. AT1 receptors seem to be responsible for most of the known angiotensin II effects while the role of AT2 receptors is not yet clear. Adipocytes of adult rats express exclusively the AT1 subtype. Angiotensin II stimulates prostacyclin release in adult rat adipocytes and in mouse preadipocytes. In the latter prostacyclin release is completely blocked by an AT2 receptor antagonist. Adipocyte angiotensin II receptors seem to be regulated by age and fat mass. Blockade of these receptors by an AT1 antagonist seems to prevent adipose tissue hypertrophy. Moreover, adipose tissue contains all the main components of the renin-angiotensin system such as angiotensinogen, angiotensin converting enzyme, angiotensin II and angiotensin II receptors. Angiotensinogen expression in adipocytes is stimulated by a high fat diet concurrent with enlargement of fat mass, associated with insulin resistance. Angiotensin converting enzyme inhibitors improve insulin sensitivity. Taken together, there is evidence of interaction between insulin and angiotensin II in regulation of adipose tissue metabolism and cellularity. Clarification of these interactions could lead to significant progress in pharmacological treatment of obesity and its comorbidity.
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PMID:The role of angiotensin II and its receptors in regulation of adipose tissue metabolism and cellularity. 878 38

Paralleling the classic circulating system, recent evidence has demonstrated the presence of a cardiac renin-angiotensin system, as well as the synthesis of angiotensin II in the heart. Two receptors for angiotensin II have been identified and classified as AT1 and AT2. The proportions of these receptor subtypes vary with the tissues, species and stage of development. From the results of other studies, it might be generalized that the expression of angiotensin II receptors and the proportion of AT2 receptor subtype are much higher in fetal and neonatal tissues than in the same tissues from an adult. The aim of this study was to specifically evaluate the AT1/AT2 ratio in the neonatal and adult conduction systems of rat hearts by means of quantitative autoradiogrphy. In the neonatal hearts, angiotensin II binding sites were highly concentrated in the vasculature, arterial duct, and conduction system, whereas their concentrations were barely detectable in the myocardium. Incubation with selective angiotensin II receptor ligands (losartan and CGP 42112) revealed that AT2 was the major subtype in vasculature (86 +/- 3%) and conduction system (73 +/- 4%). In the adult conduction system, the total expression of angiotensin II receptors was greatly reduced meanwhile the AT1 receptors represented the major proportion of the binding sites (80 +/- 3%). Our results demonstrated that the pattern of angiotensin II receptor expression in the conduction system of the rat heart is developmentally regulated. We suggest, as others have already, that the renin-angiotensin system plays a role during the early stage of cardiac development.
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PMID:Angiotensin II receptor expression in the conduction system and arterial duct of neonatal and adult rat hearts. 879 83

We compared the consequences of chronic angiotensin-converting enzyme (ACE) inhibition with quinapril and of specific AT1 blockade with losartan in a renin-dependent model of hypertension, the (mRen2)27 transgenic rats (TG). Animals were orally treated with 10 mg/kg/24 h of either quinapril (TGQ, n = 13) or losartan (TGL, n = 12) from age 4 to age 9 weeks. Indirect systolic blood pressure (SBP), and sodium and water balances were measured for 3 consecutive weeks. Nine-week-old rats were instrumented to record aortic BP in the conscious state. In addition, they received an infusion of glucose and saline to increase their diuresis and thus allow accurate assessment of their renal excretion during short time periods. These rats were studied for three one-h periods: (a) baseline, (b) after the administration of a bradykinin (BK) antagonist, and (c) after a cross-treatment; i.e., TGQ rats receiving losartan (10 mg/kg intravenously, i.v.) and TGL rats receiving quinapril (10 mg/kg i.v.). TGL rats differed from TGQ rats by an unconsistently lower indirect SBP associated with significantly lower urinary volume and sodium excretion, whereas the sodium balance did not differ between the two groups. In conditions of fixed sodium intake the aortic BP of TGQ rats was still nonsignificantly different from that of TGL rats, and TGQ rats also exhibited two-fold higher natriuresis. The BK antagonist had no effect in either group, whereas losartan decreased the BP of TGQ rats. We conclude that in TG rats ACE inhibition is associated with an increased natriuresis as compared with specific AT1 blockade, an effect that is independent of the sodium intake. Because a BK antagonist had no effect, such a difference might be due to an antinatriuretic effect of AT2 receptors in chronic conditions.
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PMID:Comparison between chronic converting enzyme inhibition and AT1 blockade in mRen2 transgenic rats. 884 62

We analyzed the components of the renin-angiotensin system (RAS) in ocular tissues of normal rabbit eyes and compared the results with those measured in rabbit eyes with proliferative vitreoretinopathy and ocular hypertension. Proliferative vitreoretinopathy was induced by injection of human platelets into the vitreous humor, and ocular hypertension was induced by injection of alpha-chymotrypsin into the posterior chamber. Angiotensinogen, renin, angiotensin converting enzyme (ACE), angiotensin II (Ang II), and Ang II receptors were assessed using conventional biochemical techniques. The vascularized tissues of normal eyes contained high renin and ACE activities concomitant with low concentration of angiotensinogen and Ang II. In general, in the ocular humors, the opposite was found. The Ang II receptor density was highest in the uveal tract [range 35-190 fmol/mg protein]. The AT1 receptor subtype predominated [> 80%]. The RAS was only minimally different in the two pathological models except that, in ocular hypertension, the renin activity in the uveal tract was reduced [-50%]. Also, the ratio of AT1 to AT2 receptors changed as compared to control, although the total receptor density remained unaltered. In conclusion, we present evidence for the presence of a complete local RAS in the rabbit eye, which is only marginally affected by the two pathological models studied.
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PMID:The renin-angiotensin system in the rabbit eye. 887 36

Angiotensin II (A II), the active component of the renin-angiotensin system, plays a major role in the regulation of blood pressure and renal function. A II actions are mediated by the interaction of this peptide with specific receptors that have been classified into two major types. AT1 and AT2. AT1 receptors have been associated with all of the known cardiovascular and renal effects of A II. Losartan, the first nonpeptide A II-receptor antagonist, exerts its antihypertensive action through the inhibition of A II binding to AT1 receptors. However, additional mechanisms seem to be involved in the actions of losartan in the rat. Administration of the nitric oxide (NO)-synthase inhibitor, NG-nitro-L-arginine methyl ester (LNAME), prevented the hypotensive effect induced by losartan in spontaneously hypertensive rats (SHR). Similarly, pretreatment with LNAME reduced the increases in renal plasma flow and glomerular filtration rate produced by this AT1-receptor antagonist in SHR. Furthermore, concurrent administration of the prostaglandin (PG)-synthesis inhibitor indomethacin attenuated vasodepressor, diuretic, and natriuretic effects of losartan in SHR. Finally, it should be mentioned that losartan was able to reduce the "ex vivo" vasoconstriction induced by phenylephrine in aortic rings from SHR. This effect was not observed in endothelium-denuded rings, suggesting a mediatory role of an endothelium-derived factor in this effect of losartan. Consequently, these data suggest a contributory role of NO and PGs in the vasodepressor and renal actions of AT1-receptor antagonists in SHR.
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PMID:The potential role of nitric oxide in angiotensin II-receptor blockade. 891 37

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

The discovery of orally active nonpeptide angiotensin II (A II)-receptor antagonists has initiated a growing understanding of the physiologic and pathophysiologic roles of A II. Losartan is the first of the new class of antagonists that block all the well-known effects of A II, including vasoconstriction, aldosterone release, renin release (negative feedback), and the stimulation of thirst. A II-receptor subtypes have been described, with losartan antagonism defining the AT1 subtype and with PD123319 antagonism defining the AT2 subtype. The AT1 receptor is G-protein-coupled, involving PLC, PLA2, PLD, or adenylate cyclase and the release of intracellular calcium. The receptor-response coupling of the AT2 site remains elusive but may involve protein tyrosine phosphatase and subserve an antiproliferative role. Losartan as the prototype of an AT1-selective antagonist: i) inhibits A II binding, ii) antagonizes effects of A II in vivo and in vitro, and iii) lowers blood pressure in models of A II-dependent hypertension A II stimulates growth in vitro (DNA and protein synthesis) and in vivo (cardiac and vascular hypertrophy), and these effects are blocked by losartan. Losartan, like angiotensin-converting enzyme inhibitors, has significant renal, cardiac, and cerebral protective effects in models of renal failure, cardiac failure, and stroke, confirming the pathologic role of A II in these models. The pioneering studies in experimental animals are being confirmed by a growing number of other AT1-selective blockers and provide the basis of use of losartan for hypertension and its clinical trial in other disease states.
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PMID:The diversified pharmacology of angiotensin II-receptor blockade. 891 41

Within the past two decades, a great deal has been learnt about the renin-angiotensin system in the brain. The renin-angiotensin system is one of the best-studied enzyme-neuropeptide systems in the brain. The diversity of localization of this peptide throughout the brain has implied a variety of potential functions. Besides its classical role in the regulation of blood pressure and body-fluid homeostasis, it has more subtle functions involving complex mechanisms such as learning and memory. The profound effects on behaviour produced by angiotensin are of broad interest to neuroscientists. The mechanisms of action differ depending on whether angiotensin is locally synthesized and whether regulation is governed by neural or metabolic inputs impinging on the neurones. Its central action is mediated through peptidergic receptors present on neurones. The description of the receptor subtypes AT1 and AT2 for angiotensin II and the development of non-peptidic specific angiotensin receptor subtype antagonists have opened a new area in this field of research. The AT1 site, which preferentially binds to angiotensin II and angiotensin III, appears to mediate the classical angiotensin functions concerned with maintenance of blood pressure and body-fluid control. In addition, most of the behavioural effects described so far are linked with AT1, although so-called psychotropic effects are presumed to be mediated by receptor systems other than the known specific angiotensin receptors. In fact, evidence for the existence of such receptors with high-affinity binding has been reported. The central action of angiotensin II mediated by AT2 is as yet unclear. Most reports concerning this receptor subtype suggest a role in differentiation and development, since the number of binding sites is higher in fetal and young rats than in adults. Furthermore, the neuronal effect of angiotensin II in the inferior olivary nucleus which is blocked specifically by AT2 antagonists suggests an involvement in motor control. Over the next few years we should find answers to many of the questions currently unanswered about angiotensin function and, given the rapid progress in research on this neuropeptide, it may serve as a model for the action of peptides on neuronal function in general.
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PMID:The neuronal role of angiotensin II in thirst, sodium appetite, cognition and memory. 892 99

Increasing evidence suggests that the renin-angiotensin system (RAS) is not only a potent regulator of blood pressure and fluid and electrolyte homeostasis, but that it also plays an important role in growth and differentiation in development as well as in pathological states. We, therefore, investigated the expression of all components of the RAS in the human embryo and fetus by in situ hybridization or immunohistochemistry. This study is the first to demonstrate the presence of all components of the RAS in very early human development (30-35 days of gestation). Angiotensinogen mRNA is expressed in very high amounts in the yolk sac, liver, and kidney, whereas renin mRNA and angiotensin-converting enzyme are expressed in the chorion, kidney, and heart, thus allowing fetal production of angiotensin II. This effector molecule of the RAS mediates its effects through binding to specific receptor types, AT1 and AT2. Both of these receptors are also expressed very early in development (24 days of gestation), suggesting a role for angiotensin II in organogenesis. Based on the expression pattern of these receptors, angiotensin II likely plays a role in the growth and differentiation of the kidney, adrenal gland, heart, and liver, all organs that are of major importance for the regulation of blood pressure later in life.
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PMID:Early expression of all the components of the renin-angiotensin-system in human development. 895 16


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