Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

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

There is increasing evidence suggesting angiotensin II (AII) may inhibit memory formation in a range of conditioned avoidance and habituation learning tasks in rodents. We were interested to determine if AII might also play an inhibitory role in spatial learning. Angiotensin-converting enzyme (ACE) inhibitors, which block the formation of AII from AI, improve acquisition and/or retention of basal performance inhibited by the muscarinic receptor antagonist, scopolamine, in conditioned avoidance and habituation tasks. In hooded Wistar rats, over 5 days of training in a water maze neither the ACE inhibitor, ceranapril 5 and 50 micrograms/kg/day, nor the ACE inhibitor, ramipril 2 and 10 mg/kg/day, altered the increase in path length produced by administration of scopolamine 0.75 mg/kg/day. In probe trails (without platform), on the last day of training, ceranapril 50 micrograms/kg produced a 35% further deterioration in performance in the scopolamine-treated rats (P < 0.02). Administration of the substrate, renin, that leads to AII formation, did not alter water maze performance over 5 days of training. The angiotensin receptor antagonist, losartan, has been shown to improve basal and scopolamine-impaired performance in a habituation task and reverse the inhibition in long-term potentiation produced by diazepam. However, neither losartan 10 and 30 mg/kg/day nor ramipril 2 and 10 mg/kg/day reversed diazepam-impaired (3 mg/kg/day) acquisition of the spatial memory task over 5 days of training. These studies suggest AII does not inhibit spatial learning in rats in the constant platform position water maze task nor does it mediate the inhibitory effects of scopolamine or diazepam in this task.
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PMID:No evidence for involvement of angiotensin II in spatial learning in water maze in rats. 895 17

Angiotensin II (Ang II) may regulate the release of components of the renin-angiotensin system in a tissue-specific manner. In order to study: (1) the effect of Ang II on gene expression and tissue levels of angiotensin-converting enzyme (ACE), and (2) the mechanism of the possible Ang II effect, we treated normal rats with Ang II and Losartan, an angiotensin AT1-receptor antagonist. Forty normal rats received Ang II (n = 20) at a rate of 200 ng kg-1 min-1 or 0.9% NaCl (n = 20) subcutaneously for 3 days using osmotic Alzet minipumps. Ten rats in both groups received Losartan (15 mg kg-1 day-1) in their drinking water, while the rest received tap water. ACE activity and mRNA levels were measured from pulmonary, cardiac, and renal tissue. Ang II treatment resulted in significant increases in blood pressure and heart weight as well as an increase in plasma Ang II concentration and a decrease in plasma renin activity. Simultaneous treatment with Losartan reduced the Ang II-induced effects on blood pressure and heart weight, and attenuated the Ang II-induced decrease in plasma renin activity. Pulmonary ACE activity and mRNA levels decreased during Ang II treatment, and these effects were not modified by simultaneous treatment with Losartan. Cardiac and kidney ACE activities and mRNA levels did not change significantly during Ang II treatment, but Losartan increased cardiac ACE activity (and decreased pulmonary ACE activity). The data indicate that Ang II regulates gene expression and activity of ACE in a tissue-specific manner in the rat, an effect probably involving angiotensin receptor subtype(s) different from the AT1-receptor.
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PMID:Tissue-specific regulation of angiotensin-converting enzyme by angiotensin II and losartan in the rat. 897 55

This review article looks at the emerging concepts about the renin angiotensin system. The specific aspects it covers include angiotensin II receptors, angiotensin receptor antagonists and alternative enzymatic pathways for the conversion of angiotensin I to angiotensin II other than angiotensin converting enzyme. The review, additionally, looks at the current and future clinical applications of the above concepts.
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PMID:Emerging concepts about the renin angiotensin system: present and future clinical applications. 899 Dec 44

1. The availability of orally active specific angiotensin receptor antagonists (AT1 antagonists) has opened new therapeutic choices and provided probes to test the specific role of the renin-angiotensin system in the pathogenesis of cardiovascular disease. 2. The data available so far suggest that the antihypertensive efficacy of angiotensin receptor antagonists is comparable to that of angiotensin-converting enzyme (ACE) inhibitors. This provides further evidence that this latter class of drugs exerts its effect mainly through blockade of the renin-angiotensin enzymatic cascade. As expected, the association of a diuretic exerts an equally strong additive effect to the antihypertensive efficacy of both classes of drugs. 3. The most common side effect of ACE inhibitors, dry cough, does not occur with AT1 antagonists, which confirms the long-held view that this untoward effect of the ACE inhibitors is due to renin-angiotensin-independent mechanisms. 4. Long-term studies with morbidity/mortality outcome results are needed, before a definite position can be assigned to this newcomer in the orchestra of modern antihypertensive drugs. Notwithstanding, this new class of agents already represents an exciting new addition to our therapeutic armamentarium.
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PMID:Experience with angiotensin II antagonists in hypertensive patients. 899 54

Angiotensin-(1-7) is a novel peptide of the renin-angiotensin system that counteracts the pressor and proliferative responses to angiotensin II. We now report that cultured bovine aortic endothelial cells contain a saturable, high-affinity [125I]angiotensin-(1-7) binding site with an affinity of 19.3 +/- 10.7 nmol/L and a density of 1351 +/- 710 fmol/mg protein. Angiotensin-(1-7) competed at a second lower-affinity site, with an IC50 of 2.9 mumol/L. The high-affinity angiotensin II receptor antagonist sarcosine1-isoleucine8-angiotensin II blocked [125I]angiotensin-(1-7) binding to bovine aortic endothelial cells at both a high- (IC50 = 1.3 nmol/L) and a low-affinity (IC50 = 6.2 mumol/L) binding site. In contrast, D-alanine7-angiotensin-(1-7) completely blocked [125I]angiotensin-(1-7) binding, with an IC50 of 19.8 nmol/L, suggesting that D-alanine7-angiotensin-(1-7) may selectively block responses to angiotensin-(1-7) in endothelial cells. Neither the AT1 antagonist losartan nor the AT2 antagonist PD 123319 exhibited significant competition for [125I]angiotensin-(1-7) binding to endothelial cells isolated from bovine aorta, in agreement with the absence of detectable mRNAs encoding typical angiotensin receptor subtypes 1 or 2 (AT1 or AT2). Angiotensin II also competed for [125I]angiotensin-(1-7) binding to bovine aortic endothelial cells; however, the relative affinity was 13-fold lower than angiotensin-(1-7), suggesting a preference for angiotensin-(1-7) over angiotensin II. These results demonstrate that bovine aortic endothelial cells contain a unique non-AT1, non-AT2 angiotensin receptor that preferentially binds angiotensin-(1-7).
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PMID:Bovine aortic endothelial cells contain an angiotensin-(1-7) receptor. 903 32

Single drug therapy for the treatment of hypertension has traditionally been a standard of practice. More recently combination therapy as first-line treatment has gained acceptance both by the medical practice community and the US Food and Drug Administration. The advantages of combinations may be a synergistic or additive antihypertensive effect, metabolic improvement, or both. The combination of a thiazide-type diuretic and a potassium-sparing diuretic has been quite useful in the past to prevent the need for potassium supplementation. The combination of beta-adrenoceptor blockade and a thiazide diuretic results in an additive antihypertensive effect that permits the effective use of very low thiazide doses. The mechanism of antihypertensive effects of each member of the combination are complimentary with increased sympathetic outflow and renin-angiotensin axis activation induced by the diuretic being blunted by beta1-adrenergic blockade. Combinations not used as first-line therapy, such as angiotensin converting enzyme inhibitors or angiotensin receptor blockade and a thiazide diuretic, have complimentary antihypertensive mechanisms and have been useful in treating patient groups who do not respond well to converting enzyme inhibitor monotherapy. The combination of a calcium antagonist with diuretic therapy has an additive hypertensive effect as well; however, the complimentary mechanisms are less obvious. Finally, the combination of angiotensin converting enzyme inhibition and calcium antagonist therapy has been useful in selected patients, but again the complimentary mechanisms are less obvious. As first-line therapy, combinations for diuretics and beta1-receptor blockers have been useful for achieving increased antihypertensive effect with decreased adverse drug effect.
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PMID:Pharmacological properties of combination therapies for hypertension. 905 2

To investigate the regulation of the angiotensin receptor type 1 (AT1) in different organs in cardiac volume overload, we measured AT1 mRNA content in the atria, left and right ventricle, kidney and liver of rats with an aortocaval shunt, produced by infrarenal aortocaval puncture 4 weeks earlier. For angiotensin receptor mRNA quantitation a novel quantitative PCR procedure based on liquid phase hybridization was used that allowed the determination of absolute AT1 mRNA copy numbers and its comparison in different organs. Glyceraldehydephosphate dehydrogenase (GAPDH) mRNA was measured by RT-PCR to control externally equal mRNA content and quality of RNA extraction in shunt animals and controls. Heart weight was increased in the shunt animals, with the greatest increase in the atria. Blood pressure, plasma renin activity, plasma angiotensin I and II and aldosterone concentrations were not significantly altered. The AT1 mRNA content was significantly increased in the atria (shunt: 1167 +/- 350 copies AT1 mRNA/ng RNA vs controls: 803 +/- 240; p < 0.05). No change was found in the right or left ventricle, in the kidney and liver. The findings document that atrial hypertrophy in cardiac volume overload parallel with a significant increase in atrial AT1 mRNA content.
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PMID:Myocardial angiotensin receptor type 1 gene expression in a rat model of cardiac volume overload. 922 99

In view of the vasodilator potential of angiotensin-converting enzyme (ACE) inhibition via prostaglandins and kinins, we asked why renin inhibition induces a larger renal vasodilator response than ACE inhibitors in healthy humans in earlier studies. One possibility was that there was a more complete blockade of the renin system, which could also be achieved by an angiotensin II antagonist, eprosartan. We measured the hormonal and renal hemodynamic responses to eprosartan doses, from 10 to 400 mg in 9 healthy young men in balance on a 10-mmol/d sodium intake. The threshold eprosartan dose to influence renal perfusion was <10 mg, and the 100-mg dose induced a near-maximal vasodilator response of 135+/-19.7 mL x min(-1) x 1.73 m2. When the dose was increased to 400 mg, there was a modest additional increase of 147+/-57 mL x min(-1) x 1.73 m(-2). A highly significant dose-related fall in arterial blood pressure occurred (r=-.97; P<.001), with no indication of a maximal response at 400 mg. In 6 additional subjects, we compared responses to eprosartan on a high salt and a low salt diet. The renal response to 200 mg eprosartan on a high salt diet, 26.0+/-6.6 mL x min(-1) x 1.73 m(-2), was significantly less than that seen with the low salt diet (P<.001). There was no renal partial agonist angiotensin-like effect of eprosartan. Eprosartan reduced sharply the pressor, renal vascular, and hormonal responses to exogenous angiotensin II. The renal vasodilator response to the angiotensin II antagonist eprosartan closely resembles responses to renin inhibition and exceeds previously reported responses to ACE inhibitors. Thus, eprosartan probably exerted its effect via the angiotensin receptor. More complete blockade of the renin system can be achieved by pharmacological interruption at this level, a finding that could have therapeutic implications.
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PMID:Renal hemodynamic response to an angiotensin II antagonist, eprosartan, in healthy men. 926 Sep 87

We investigated whether chronic deficiency of nitric oxide (NO) in stroke-prone spontaneously hypertensive rats (SHRSP) precipitates stroke and whether exogenous nitrates and other pharmacological agents can prevent stroke. Groups of five-week-old male SHRSP rats chronically received saline, L-nitro-arginine methyl ester (L-NAME) in saline, L-NAME along with pharmacological agents (L-arginine, isosorbide dinitrate, enalapril maleate and L-158,809; angiotensin receptor antagonist; 5,7-dimethyl-2-ethyl-3(-)[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]meth yl]-imidazo[4,5-b]pyridine) in saline to drink. The development of visible neurological deficits following various treatments was considered as an occurrence of stroke. Within hours following onset of stroke, the rats were anesthetized, catheterized and attached to a Cardiomax blood pressure recorder. SHRSP treated with L-NAME (10+/-2 mg/day) developed stroke in 11+/-2 days while no neurological deficit was seen in animals receiving saline till the end of the study period (35 days). Blockade of the renin-angiotensin system with enalapril or L-158,809 significantly delayed the onset of stroke (19+/-2 and 20+/-2 days, respectively), but caused only slight reductions in mean arterial blood pressure. These results suggest that chronic inhibition of NO synthase in SHRSP is associated with the development of stroke and such stroke appears to be renin-angiotensin system-dependent.
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PMID:Angiotensin receptor antagonists delay nitric oxide-deficient stroke in stroke-prone rats. 931 59


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