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

Protease nexin-1 (PN-1) is a potent inhibitor of serine proteases, such as thrombin and plasminogen activators, which is secreted into the extracellular space. Since PN-1 is induced following lesion of the sciatic nerve, the effect of substances known to accumulate at the site of injury was examined in primary cultures of Schwann cells. Among the cytokines, growth factors, mitogens, neurotrophins, and neuroactive peptides analyzed, only angiotensin II (Ang II), calcitonin gene-related peptide (CGRP), and vasoactive intestinal peptide (VIP) were found to regulate the expression of PN-1 on Schwann cells. While Ang II and CGRP caused downregulation, VIP acted as a positive modulator of PN-1. Displacement of Ang II binding using the selective ligands losartan and CGP 42112 led to a severalfold increase of PN-1 protein and mRNA over basal levels, indicating that the observed effect was mediated by specific binding sites. Indeed, the presence of AT1 and AT2 angiotensin receptor subtypes was demonstrated in cultured Schwann cells as well as in the rat sciatic nerve. Moreover, the detection of angiotensinogen- and renin-mRNA in these cultures suggested an endogenous production of Ang II. This data identified one of the mechanisms regulating PN-1 synthesis. Altogether our results indicate that neuropeptides can differentially control the proteolytic activity of the microenvironment, providing new aspects of neuron-glia interactions in the intact tissue and following nerve injury.
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PMID:Regulation of protease nexin-1 expression in cultured Schwann cells is mediated by angiotensin II receptors. 782 77

It is now clear that specific angiotensin-dependent mechanisms contribute importantly to the pathophysiology of hypertension (HT) and altered renal function in models of two-kidney, one-clip (2-K, 1-C) HT in rats. The discovery of specific antagonists for angiotensin-converting enzyme and the newer angiotensin receptor and kinin receptor antagonists have allowed delineation of the contributions of these hormones to altered renal function in these models. The focus of interest in most of these studies has been the nonclipped kidney, which would be expected to ameliorate elevated blood pressure by exhibiting a pressure diuresis and natriuresis in the environment of systemic HT. Antagonism of the renin-angiotensin system in rat models of renal vascular HT indicates that the effects of angiotensin attenuate renal hemodynamic and excretory behavior, particularly in the nonclipped kidney. Furthermore, angiotensin attenuates the efficiency of autoregulation of renal hemodynamics in the nonclipped kidney. Function of the clipped kidney appears to be both angiotensin and perfusion pressure dependent. Evidence that inhibition of angiotensin reverses or improves these altered hemodynamic and excretory functions indicates that angiotensin may contribute importantly to the pathophysiology of HT in these models by altering or impairing the ability of the nonclipped or "normal" kidney to excrete sodium and volume. The precise roles of altered activity of vasodilator hormones to contribute to these alterations of renal function remains to be defined.
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PMID:Pathophysiology of altered renal function in renal vascular hypertension. 794 24

Clinical observations demonstrate an enhanced risk for myocardial infarction in patients with sustained activation of the local and/or systemic renin-angiotensin system, such as a high renin-sodium profile or a heritably enhanced expression of angiotensin converting enzyme. Chronic renin-angiotensin system blockade by angiotensin converting enzyme inhibition in patients with moderate heart failure reduces the rate of myocardial infarction and reinfarction. Preliminary experimental evidence suggests that these clinical observations may be partially explained by a proatherogenic effect of an activated renin-angiotensin system, which can downregulate the endothelial releasability of nitric oxide. Nitric oxide exerts many potentially antiatherogenic effects on endothelium, platelets and low density lipoproteins and indirectly on monocytes and leukocytes. Hypertension-induced chronic distension of elastic arteries upregulates the local renin-angiotensin system in these arteries and thereby downregulates nitric oxide releasability. Enhanced local synthesis of the trophic factor angiotensin-II and reduced releasability of the antitrophic factor nitric oxide appear to cooperate in the trophic adaptation of the distended vessel wall to the enhanced load, but with the disadvantage of enhanced susceptibility for atheroma development due to reduced releasability of nitric oxide. Chronic blockade of the renin angiotensin system by angiotensin converting enzyme inhibitors or by angiotensin receptor type-1 antagonists normalizes a reduced endothelial releasability of nitric oxide in several models, partially by a bradykinin-dependent mechanism. This endothelial protection proved to attenuate the progression of atherosclerosis in experimental models. The antiatherogenic potential of renin angiotensin system blockade in humans is presently under study.
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PMID:Vascular renin-angiotensin-system, endothelial function and atherosclerosis? 794 78

Renin synthesis and secretion from human chorion and decidua have previously been shown to be stimulated by agents which increase cellular cyclic adenosine monophosphate (cAMP). We have now used organ culture of villous placenta, incubated for periods up to 72 h, to investigate the cellular regulation of renin in this tissue. The placental tissues release renin (92-96% in the form of prorenin) and human chorionic gonadotrophin (hCG), but not prolactin. We found that cholera toxin and forskolin markedly stimulate the synthesis and release of renin in a time-dependent manner. This stimulation was potentiated by phosphodiesterase inhibitors and inhibited by an angiotensin II agonist, sar-1-angiotensin II. The inhibitory action of the angiotensin agonist on renin release was blocked by sar-1-leu-8-angiotensin II, a selective angiotensin receptor antagonist. The potential for stimulation of renin expression by cyclic AMP-regulated elements is supported by the dramatic (two-orders of magnitude) increase in renin release observed with cholera and forskolin at 72 h. There are several possible candidates for primary signals for adenylyl cyclase-coupled renin secretion from the placenta, including relaxin and epinephrine. The extremely low concentration of renin in term villous placenta may be related to activation of negative regulatory elements on the renin gene. We propose that angiotensin II is one negative regulator of this system.
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PMID:Prorenin secretion from villous placenta: regulation by cyclic AMP and angiotensin. 799 49

Renal artery stenosis, particularly related to advancing atherosclerotic disease, is a common concern to internists seeing patients with worsening hypertension and deteriorating renal function. Understanding the hormonal and hemodynamic consequences of critical vascular lesions allows better selection of antihypertensive therapy. With the application of potent antihypertensive agents--especially those that block the renin-angiotensin system, such as ACE inhibitors or the soon-to-be-released angiotensin receptor antagonists--blood pressure control often is not the primary reason to consider renal revascularization. Instead, protection of renal function beyond a critical level of arterial stenosis is becoming the main indication for both percutaneous angioplasty and surgical revascularization. Both procedures pose hazards, so optimal management of the patient with renovascular hypertension depends on achieving a balance between the risks and benefits to the individual patient. It remains incumbent upon the internist to weigh the cardiovascular and cerebrovascular risks against both the gains in blood pressure control and the likely progression of renal compromise during the patient's lifetime. Improved understanding of the outcomes of medical therapy versus revascularization depends on future prospective studies.
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PMID:Renovascular hypertension. 807 Apr 20

1. In this article we review the physiological actions of the heptapeptide angiotensin-(1-7) [Ang-(1-7)] at the periphery and on central pathways involved in the control of arterial pressure. Peripherally Ang-(1-7) has been shown to present a potent antidiuretic effect on water-loaded rats. Microinjection of pmol amounts of Ang-(1-7) into the dorsomedial or ventrolateral medulla (VLM) of anesthetized rats produces cardiovascular effects comparable to Ang II. In addition, in vitro experiments have shown that Ang-(1-7) has a potent vasopressin and prostaglandin releasing activity and excites neuronal activity in the hypothalamus and medulla. 2. Evidence for the existence of a new angiotensin receptor subtype that mediates the central cardiovascular actions of this active peptide of the renin-angiotensin system (RAS) is also provided. Neither the AT1 receptor antagonist DUP 753 or the AT2 receptor antagonist CGP 42112A blocked the pressor response produced by microinjection of Ang-(1-7) into the rostral VLM. However, the effect of Ang-(1-7) on VLM was completely abolished by the non-specific angiotensin receptor antagonist, Sar1-Thr8-Ang II. 3. The data presented here reinforce the hypothesis of the existence of complex site-specific interactions between multiple angiotensins and multiple receptors in the mediation of important central and peripheral effects of the RAS.
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PMID:Central and peripheral actions of angiotensin-(1-7). 808 84

The past decade has been considerable advances in basic knowledge of the renin-angiotensin system. Perhaps the most important new development has been the appreciation of a tissue-based renin-angiotensin system that can be independently regulated from the circulation. Greater insight into the mechanism by which the renin-angiotensin system exerts its actions has been achieved through the study of molecular biology and pharmacologic characterization of multiple angiotensin receptor subtypes. Ang II is now considered a growth promoter in cardiovascular tissues, and the resultant vascular hypertrophy is an important contributor to the maintenance of hypertension. Ang II also plays a role in the kidney, not only as a regulator of hemodynamics, but in the development of structural changes (hypertrophy, sclerosis), which are important in the pathogenesis of a variety of renal disorders. Finally, a central role for the renin-angiotensin system in experimental renovascular hypertension has been reaffirmed. In the future, basic knowledge and techniques of investigation gained from experimental models will be used to investigate clinical disorders such as hypertension and various renal disorders characterized by abnormal function of the renin-angiotensin system.
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PMID:The renin-angiotensin system. New concepts in regulation of blood pressure and renal function. 817 86

An enhanced risk for myocardial infarction has been observed in humans with sustained activation of the local and/or systemic renin-angiotensin system, such as a high renin-sodium profile or a heritably enhanced expression of angiotensin converting enzyme. Chronic renin-angiotensin system blockade by angiotensin converting enzyme inhibition reduces the rate of myocardial reinfarction in patients with moderate heart failure. Preliminary experimental evidence suggests that these clinical observations may be partially explained by a proatherogenic effect of an activated renin-angiotensin system, which can downregulate the expression of the endothelial nitric oxide synthase III. Nitric oxide exerts many potentially antiatherogenic effects on endothelium, platelets and low density lipoproteins and indirectly on monocytes and leukocytes Hypertension-induced chronic distension of elastic arteries upregulates the local renin-angiotensin system in these arteries and thereby downregulates nitric oxide synthase. Enhanced local synthesis of the trophic factor angiotensin-II and reduced releasability of the antitrophic factor nitric oxide appear to cooperate in the trophic adaptation of the distended vessel wall to the enhanced load, but with the disadvantage of enhanced susceptibility for atheroma development due to reduced availability of nitric oxide. Chronic blockade of the renin-angiotensin system by angiotensin converting enzyme inhibitors or by angiotensin receptor type-1 antagonists normalizes a reduced endothelial nitric oxide availability in several models, partially by a bradykinin-dependent mechanism. This endothelial protection proved to attenuate the progression of atherosclerosis in experimental models. The antiatherogenic potential of renin-angiotensin system blockade in humans is presently under study.
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PMID:The endothelium and the renin-angiotensin system. 818 13

The aim of this study was to determine whether angiotensin receptor subtypes play a role in angiotensin clearance from plasma. Angiotensin metabolic clearance rate was measured in rats by the constant infusion method. Increasing doses of angiotensin II were infused for 15 minutes, and blood was sampled for angiotensin II. The type 1 angiotensin II receptor antagonist losartan decreased the apparent metabolic clearance rate by > 50% at low-dose infusion, suggesting that type 1 angiotensin II receptors are involved in angiotensin II clearance from plasma. At higher angiotensin infusion rates, the-metabolic clearance rate of angiotensin was unaffected. To dissect the contribution of renin-generated angiotensin, additional experiments were performed in nephrectomized rats. In anephric rats, angiotensin clearance was unaffected by type 1 angiotensin II receptor inhibition. In contrast, the type 2 angiotensin II receptor ligand PD123319 in intact rats caused a > 50% increase in metabolic clearance rate of angiotensin at higher infusion rates (P < .05). In anephric rats, the type 2 angiotensin II receptor ligand alone or combined with type 1 receptor inhibition was without effect on the metabolic clearance rate or the T1/2 for angiotensin disappearance. These data argue against a role for type 1 or 2 angiotensin II receptors as clearance receptors. Increased clearance of angiotensin by type 2 receptor blockade in the presence but not the absence of kidneys suggests an alternative renal mechanism by which selective type 2 ligands may alter angiotensin effects.
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PMID:Effects of angiotensin receptor subtype inhibitors on plasma angiotensin clearance. 820 17

1. In pithed rats, preganglionic vagal nerve stimulation (at 5 Hz) elicited a bradycardia. This bradycardia was potentiated by the angiotensin converting enzyme inhibitor, captopril (1 mg kg-1, i.v.) by about 40%. Subsequent angiotensin II infusion (0.03 micrograms kg-1 min-1) reversed this effect. A similar facilitatory effect was also seen with the angiotensin receptor antagonist, losartan (10 mg kg-1, i.v.). These results suggest a tonic inhibitory effect of endogenous angiotensin II on vagal transmission. 2. The effect of captopril in potentiating vagal bradycardia appears to be at the level of vagal neurones, since the bradycardia elicited by the muscarinic agonist, methacholine was unaffected. 3. After the pithed rats were nephrectomized, captopril had no effect on vagally-induced bradycardia, suggesting that the formation of the endogenous angiotensin II responsible for the effect was dependent on renin release from the kidney. 4. When the sympathetic nerves of the pithed rat were electrically stimulated there was a tachycardia, and this was unaffected by captopril. However, when the sympathetic and vagus nerves were activated concurrently, the resulting tachycardia was inhibited by captopril. 5. In pithed guinea-pigs, captopril also potentiated the bradycardia caused by vagal nerve stimulation. This appears to be a tissue-selective effect since the bronchoconstriction due to the vagal stimulation was not affected by captopril. 6. These results suggest that endogenous angiotensin II can have a tonic inhibitory effect on cardiac vagal transmission. Disruption of this mechanism by anti-angiotensin drugs may attenuate the reflex tachycardia associated with the fall in blood pressure in anti-hypertensive therapy.
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PMID:A facilitatory effect of anti-angiotensin drugs on vagal bradycardia in the pithed rat and guinea-pig. 822 Aug 90


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