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:3.4.15.1 (ACE)
18,300 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Neurohormonal activation is one of the major determining factors in the process of transition from asymptomatic ventricular dysfunction to end-stage heart failure, in the prognosis of heart failure, and in the efficacy and, hence, choice and timing of pharmacological therapy. Although various counteracting hormonal systems are involved, emphasis in terms of functionality is on vasopressor and growth-promoting systems. In contrast, ANF and N-terminal proANF probably have a significant prognostic value, even at an early stage. The focus of heart failure therapy is moving from measures aimed at improving cardiac function to ones that concentrate on modulating neuroendocrine changes during failure and their effects on intrinsic peripheral and cardiac alterations. Although ACE inhibition undoubtedly constitutes a major step forward in this approach, alternative ways to modulate neurohormonal activation pharmacologically are needed. Several such novel approaches are being developed, including angiotensin receptor antagonists, dopaminergic stimulation, neutral endopeptidase inhibition, aldosterone antagonism and beta blockade. In addition to their positive inotropic properties digitalis glycosides may act as neurohormonal modulators. Finally, the realization that several well-established forms of heart failure therapy may aggravate neuroendocrine stimulation demands careful consideration as to whether such agents are really necessary, and underlines the desirability of co-administering neurohormonal modulating therapy.
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PMID:Therapeutic strategies and neurohormonal control in heart failure. 771 2

There is a large body of anatomical and functional evidence supporting an interaction between brain angiotensin and central catecholamine systems. Angiotensin II AT1 receptors have been identified on dopamine containing cells in the substantia nigra and striatum of human brain using receptor autoradiography. Using in vivo microdialysis we have demonstrated that locally administered angiotensin II stimulates dopamine release from the striatum of conscious rats. Since some angiotensin receptor antagonists and angiotensin converting enzyme inhibitors can cross the blood brain barrier it is possible that they interact with the brain catecholaminergic systems.
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PMID:Interactions of angiotensin II with central catecholamines. 773 74

1. The blood pressure-lowering and cardioprotective actions of angiotensin converting enzyme (ACE) inhibitors are thought to be based primarily on a reduction in vascular angiotensin II (Ang-II) formation. However, since ACE also degrades the potent endothelium-dependent vasodilator bradykinin, it has been proposed that the local accumulation of this peptide represents an additional mechanism by which ACE inhibitors exert their cardiovascular effects. 2. Incubation of endothelial cells with ACE inhibitors indeed causes an enhanced formation of nitric oxide (NO) and prostacyclin (PGI2) which can be completely blocked by the B2-kinin receptor antagonist Hoe 140, suggesting that the vascular endothelium is capable of generating vasoactive kinins from an endogenous source. 3. Moreover, ACE inhibitors not only prevent the breakdown of bradykinin but, by virtue of an as yet unidentified mechanism, also enhance the potency of bradykinin at the receptor level and reverse the desensitization of the B2-kinin receptor following continuous exposure to bradykinin. Both of these effects may enhance or sustain the bradykinin-induced formation of NO and PGI2 by the endothelium. 4. Furthermore, ACE inhibition leads to the accumulation of Ang-I which can be metabolised to Ang-(1-7) by another endothelial enzyme, neutral endopeptidase 24.11. By activating an as yet unidentified angiotensin receptor, Ang-(1-7), but not other known angiotensin peptides, stimulates endothelial NO release in porcine coronary arteries as well as in the isolated perfused rat heart. This effect is, albeit to a different degree, dependent on the release of vasoactive kinins from the endothelium. The shift in Ang-I metabolism towards an enhanced formation of Ang-(1-7) in the presence of an ACE inhibitor may thus contribute to the hypotensive action of this class of compounds as well.
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PMID:Mechanisms involved in the angiotensin II-independent hypotensive action of ACE inhibitors. 774 81

Plasminogen activator-inhibitor C-1 (PAI-1) plays a critical role in the regulation of fibrinolysis, serving as the primary inhibitor of tissue-type plasminogen activator. Elevated levels of PAI-1 are a risk factor for recurrent myocardial infarction, and locally increased PAI-1 expression has been described in atherosclerotic human arteries. Recent studies have shown that the administration of angiotensin converting enzyme inhibitors reduces the risk of recurrent myocardial infarction in selected patients. Since angiotensin II (Ang II) has been reported to induce PAI-1 production in cultured astrocytes, we have hypothesized that one mechanism that may contribute to the beneficial effect of angiotensin converting enzyme inhibitors is an effect on fibrinolytic balance. In the present study, we examined the interaction of Ang II with cultured bovine aortic endothelial cells (BAECs) and the effects of this peptide on the production of PAI-1. 125I-Ang II was found to bind to BAECs in a saturable and specific manner, with an apparent Kd of 1.4 nM and Bmax of 74 fmol per mg of protein. Exposure of BAECs to Ang II induced dose-dependent increases in PAI-1 antigen in the media and in PAI-1 mRNA levels. Induction of PAI-1 mRNA expression by Ang II was not inhibited by pretreating BAECs with either Dup 753 or [Sar1, Ile8]-Ang II, agents that are known to compete effectively for binding to the two major angiotensin receptor subtypes. These data indicate that Ang II regulates the expression of PAI-1 in cultured endothelial cells and that this response is mediated via a pharmacologically distinct form of the angiotensin receptor.
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PMID:Angiotensin II regulates the expression of plasminogen activator inhibitor-1 in cultured endothelial cells. A potential link between the renin-angiotensin system and thrombosis. 788 1

It is well documented that angiotensin converting enzyme inhibitors decrease blood pressure, which is associated with natriuresis in humans and certain animal models of hypertension. However, it is not clear whether these beneficial effects are due solely to blockade of angiotensin-II production and/or also involves any contribution by kinins. The present study was performed in Inactin (5-ethyl-5-(1-methylpropyl)-2-thio-barbiturate sodium)-anesthetized spontaneously hypertensive rats aged 10-13 wks to examine the relative influence of the angiotensin receptor antagonist losartan (2-n-butyl-4-chloro-5-hydroxymethyl-1- [(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl] imidazole potassium salt) and the bradykinin receptor 2 antagonist HOE 140 (D-Arg-[Hyp3, Thi5, D-Tic7, Oic8] bradykinin) on renal and hemodynamic responses to the angiotensin converting enzyme inhibitor ramiprilat. We found that ramiprilat (1 mg/kg, i.v.) caused sustained reduction in mean blood pressure, marked increases in urine output and urinary sodium excretion without alteration in glomerular filtration rate. In a separate group of animals, it was found that losartan (1 mg/kg, i.v.) decreased blood pressure to a similar degree as ramiprilat and the magnitude of blood pressure fall seen following the combined administration of ramiprilat and losartan was similar to that caused by either compound alone. However, the increase in urinary sodium excretion seen following losartan administration was significantly smaller than that following ramiprilat or ramiprilat plus losartan.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Contribution by bradykinin to the natriuretic response to the angiotensin converting enzyme inhibitor ramiprilat in spontaneously hypertensive rats. 793 59

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

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. Angiotensin II (AII) reduces blood flow, modulates vascular remodelling and is a growth factor. Human inflammatory arthritides are characterized by synovial hypoperfusion, hypoxia and proliferation. We aimed to localize and characterize receptors for AII in human synovium. 2. We used quantitative in vitro receptor autoradiography with [125I]-(Sar1, Ile8)AII and [125I]-AII on human synovium from patients with chondromalacia patellae, osteoarthritis and rheumatoid arthritis. 3. [125I]-(Sar1, Ile8)AII and [125I]-AII bound to similar sites on synovial blood vessels, lining cells and stroma. Binding to microvessels (< 100 microns diameter) was more dense than to arteriolar media, and vascular binding was more dense than that to lining cells and stroma. 4. Microvessels and arterioles which displayed angiotensin converting enzyme-like immunoreactivity also displayed specific binding of [125I]-(Sar1, Ile8)AII. 5. Specific binding of [125I]-(Sar1, Ile8)AII to each structure was completely inhibited by 10 microM dithiothreitol and was inhibited by unlabelled ligands with the rank order of potency (Sar1, Ile8)AII > AII > losartan = SKF108566 > PD123319 indicating an AT1 subclass of angiotensin receptor. 6. GTP gamma S (1 microM) abolished specific binding of [125I]-AII and abolished the high affinity component of the binding inhibition curve for AII against [125I]-(Sar1, Ile8)AII, indicating G protein coupling. 7. The distribution of [125I]-(Sar1, Ile8)AII binding sites was similar in all disease groups and no significant differences in binding densities, affinities or specificities were observed between disease groups. 8. Locally generated AII may act on synovial AT1 receptors to modulate synovial perfusion and growth. Specific AT1 receptor antagonists should help elucidate the role of angiotensins in human arthritis.
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PMID:AT1 receptor characteristics of angiotensin analogue binding in human synovium. 807 62

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

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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