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)

We have previously shown that in rat renal cortex, cyclooxygenase-2 (COX-2) expression is localized to cTALH cells in the region of the macula densa, and that dietary salt restriction increases COX-2 expression. Administration of the angiotensin converting inhibitor, captopril, further increased COX-2 mRNA and renal cortical COX-2 immunoreactivity, with the most pronounced expression in the macula densa. Administration of an AT1 receptor antagonist, losartan, also significantly increased cortical COX-2 mRNA expression and COX-2 immunoreactivity. Mutant mice homozygous for both Agtr1a and Agtr1b null mutations (Agtr1a-/-,Agtr1b-/-) demonstrated large increases in immunoreactive COX-2 expression inthe cTALH/macula densa. To determine whether increased COX-2expression in response to ACE inhibition mediated increases in renin production, rats were treated with captopril for one week with or without the specific COX-2 inhibitor, SC58236. Plasma renin activity increased significantly in the captropril group, and this increase was significantly inhibited by simultaneous treatment with SC58236. Thus, these studies indicated that angiotensin II inhibitors augment upregulation of renal cortical COX-2 in states of volume depletion, suggesting that negative feedback by the renin-angiotensin system modulates renal cortical COX-2 expression and that COX-2 is a mediator of increased renin production in response to inhibition of angiotension II production.
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PMID:Angiotensin II attenuates renal cortical cyclooxygenase-2 expression. 1019 67

(1) Case reports and epidemiological studies show that nonsteroidal antiinflammatory drugs (NSAIDs) can cause or worsen heart failure, though this is reversible when the drug is withdrawn. (2) Heart failure can occur or worsen when an NSAID (including aspirin) is combined with a diuretic or angiotensin-converting-enzyme inhibitor (ACE inhibitor). (3) In patients with heart failure, the use of NSAIDs, including "specific" COX 2 inhibitors, should be avoided. If such treatment is unavoidable, patients must be watched closely for clinical worsening.
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PMID:NSAIDs and heart failure. 1182 43

Healthy vascular endothelium is a powerful generator of nitric oxide (NO), prostacyclin (PGI2), prostaglandin E2 (PGE2), and plasminogen activator (t-PA). These endothelial products protect vascular wall against aggression from activated blood platelets and leukocytes. In particular they protect against thrombosis, promote thrombolysis, maintain tissue perfusion, and inhibit remodeling of vascular and cardiac walls. Endothelial dysfunction appears on one hand as suppression in the release of the above mediators, and on the other as deleterious discharge of prostaglandin endoperoxides (PGH2, PGG2), superoxide anion O2-, peroxynitrite (ONOO-), and plasminogen activator inhibitor (PAI-1). Our data point to endothelial bradykinin (Bk) as a trigger for protective endothelial mechanisms. In cultured endothelial cells (CEC) Bk through kinin B2 receptors raised in a concentration-dependent manner (1pM-10 nM) free cytoplasmic calcium ions [Ca2+]i. This rise was accompanied by the release of NO as quantified by a porphyrinic sensor. Other endothelial agonists were weaker-stimulators of [Ca2+]i than Bk. In vivo we analyed the effects of exogenous Bk and of amplifiers of endogenous Bk, such as perindopril and quinapril ("tissue type" angiotensin converting enzyme inhibitors, ACE-I) on endothelial function using our original thrombolytic bioassay and EIA assays for 6-keto-PGF1alpha and t-PA antigen. A major difference found between exogenuous Bk and endogenous Bk (that rendered by "tissue ACE-I") was a) prolonged thrombolytic action (> 4h) of quinapril or perindopril. Moreover, only exogenous Bk evoked an immediate and profound hypotensive action. In vivo, Bk-induced thrombolysis was B2 kinin receptor-dependent, PGI2-mediated. The unexpected action of Bk came to light in CEC. Then appeared incubated for 4 h increased expression of mRNAs for haemoxygenase (HO-1), cyclooxygenase 2 (COX-2), prostaglandin E synthase (PGE-S), but hardly for nitric oxide synthase 2(NOS-2). We hypothesize that a network of interactions of Bk-induced enzymes may constitute a delayed phase of Bk effects in the endothelium, whereas the primary phase would be activation by BK of [Ca2+]i-dependent constitutive endothelial enzymes. In blood-perfused rat endotoxemic lungs, NO is the most eminent cytoprotective mediator. Summing up, in peripheral circulation endogenous Bk is the most efficient activator of protective endothelial function. Thrombolytic action of "tissue-type" ACE-Is relies on receptor B-2-mediated, [Ca2+]i-dependent release of PGI2. Bk also may act as a "microcytokine" by inducing mRNAs for HO-1, COX-2, or PGE-S. Activation of HO-1 may lead to a deficiency in intracellular heme required as a cofactor for both COX and NOS. This network of interactions triggered by Bk call for further studies.
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PMID:Bradykinin as a major endogenous regulator of endothelial function. 1205 3

Nonsteroidal anti-inflammatory drugs (NSAIDs) are a frequently prescribed group of highly effective drugs of which the most well-known side effect is gastrointestinal peptic ulcer. However, NSAIDs have additional renal, cardiovascular, hematological, dermatological, and neurological side effects. Although the spectrum of side effects is slightly different between the conventional NSAIDs and the recently developed cyclooxygenase 2 (COX-2) inhibitors, their overall spectrum is quite similar. Aim of this review is to summarize the current knowledge about NSAIDs and their effects on patients with cardio- or cerebrovascular disorders. NSAIDs interact with many drugs which are used in patients with cardio- or cerebrovascular disorders: They attenuate the effects of diuretics, betablockers, ACE inhibitors and AT-2 blockers, thus leading to uncontrolled hypertension or aggravation of heart failure. They increase digoxin levels, potentiate the effect of oral anticoagulants and interact with platelet inhibitors, thus leading to a higher bleeding risk. There are indications that NSAIDs may induce hypertension in normotensives and that COX-2 inhibitors may lead to an increased rate of myocardial infarction and strokes. Based on these data it is recommended that NSAIDs should be avoided in patients with cardio- or cerebrovascular disorders and alternative pharmaceutical, physical or surgical therapy should be applied. If NSAIDs are inevitable, their side effects should be well monitored; they should be prescribed with caution when given in combination with diuretics, betablockers, ACE inhibitors, AT-2 blockers, digitalis, oral anticoagulants and platelet inhibitors. COX- 2 inhibitors should be avoided in patients with known coronary or cerebrovascular disorders. In patients with uncontrolled hypertension or worsening of heart failure, unreported NSAID-use should be considered. Generally, there is a need to develop further analgetic drugs without the described side effects for patients with cardio- and cerebrovascular disorders.
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PMID:Nonsteroidal anti-inflammatory drugs in patients with cardio- or cerebrovascular disorders. 1450 88

Our in vivo assay for thrombolysis consisted of recording the weight of platelet-rich thrombi adhering to a collagen strip that was superfused with arterial blood in extracorporal circulation of anaesthetised Wistar rats. Immediate thrombolysis occurred in response to intravenously administrated angiotensin-converting enzyme inhibitor (ACE-I) at non-hypotensive doses of 3-30 microg kg(-1) (captopril<perindopril<quinapril). The thrombolytic response lasted up to 3 h with maximum reduction of the weight of thrombus by 75%. Pretreatment with COX-1 and COX-3 inhibitors (aspirin at a low dose of 1 mg kg(-1), SC 560 and acetaminophen, 0.3-3 mg kg(-1)) slightly augmented thrombolysis by ACE-I, while COX-2 inhibitors (nimesulide and coxibs at doses <1 mg kg(-1) and aspirin at a high dose of 50 mg kg(-1)) or a kinin B2 receptor antagonist (icatibant) abolished it. NOS inhibition by L-NAME blunted and delayed thrombolysis by ACE-I. In parallel to maximum thrombolysis by quinapril (30 microg kg(-1)), plasma levels of 6-keto-PGF1alpha rose significantly from 40 +/- 7 to 554 +/- 91 pg ml(-1) (n=5, mean +/- S.D.), while basal levels of PGE2 (12 +/- 3 pg ml(-1)) and TXB2 (47 +/- 11 pg ml(-1)) remained essentially unchanged. Pretreatment with celecoxib (0.1-1.0 mg kg(-1)) abolished not only thrombolysis by quinapril but also the quinapril-induced rise in plasma 6-keto-PGF1alpha. In cultured bovine aortic endothelial cells, perindoprilate (30 microM) increased cytosolic free calcium [Ca2+]i, but this effect was by three to four orders of magnitude weaker than that of bradykinin (Bk). In aortas of Wistar rats, the transcripts of COX-2 and PGI-S were overexpressed as compared to COX-1. Thus, in blood vessels of Wistar rats, the preferable route of the PGI2 generation might lead through the COX-2 pathway. We conclude that in Wistar rats, ACE-I induces thrombolysis via accumulation of endogenous kinins over the endothelium and a subsequent activation of B2 receptors followed by the release of prostacyclin and nitric oxide. Thrombolysis by ACE-I seems to be mediated mainly through prostacyclin that is made by COX-2. It may well be that an increase in endothelial [Ca2+]i by ACE-I activates phospholipase A2, which supplies COX-2 with the substrate for making thrombolytic prostacyclin.
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PMID:Mechanisms of angiotensin-converting enzyme inhibitor induced thrombolysis in Wistar rats. 1459 56

Non steroidal anti-inflammatory drugs (NSAIDs) are one of the categories of drugs most frequently used by elderly people, and maybe the most self-prescribed drugs. Both coronary events, and stroke, can be prevented by daily aspirin assumption. Other NSAIDs, except selective COX-2 inhibitors (coxibs), seem to reduce the incidence of cardiovascular events, but a definitive judgement is yet impossible. Moreover, these drugs cause more than 100,000 serious gastric adverse events each year in the US, and the risk increases exponentially in the elderly. Coxibs cause less gastric damage, but their cost is very high. Moreover, NSAIDs inhibit renal function and reduce the efficacy of diuretics and angiotensin converting enzyme (ACE) inhibitors, often used by elderly patients. Recent studies show that even COX-2 is important in the renal physiology, so that even coxibs appear not to be avoided of renal toxicity. Both gastric and renal toxicity induced by traditional NSAIDs and coxibs seem to be related to the fact that these drugs inhibit the synthesis of prostaglandins (PGs), but not those of leukotrienes (LTs), important mediators of inflammation and of many other physiopatological events. Newly developed anti-inflammatory drugs block both COX and the 5-LOX metabolic pathways, inhibiting the formation of PGs, thromboxanes (TXs) and LTs. The inhibition of the LT synthesis increases the anti-inflammatory efficacy (especially in pneumological and rheumatological diseases), reducing the risk of gastric damage. Even if preliminary data seem to be very interesting, further clinical safety data on these drugs obtained from elderly oriented trials need to be available before to give a final evaluation.
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PMID:Clinical perspectives of anti-inflammatory therapy in the elderly: the lipoxigenase (LOX)/cycloxigenase (COX) inhibition concept. 1506 7

Here we studied the mechanism of thrombolytic response (THR) induced by angiotensin converting enzyme (ACE-I) in vivo in anaesthetised Wistar rats with extracorporeal circulation. Intravenous injections of ACE-Is, i.e. perindopril or quinapril at non-hypotensive doses of 3-30 microg kg(-1) produced a dose-dependent thrombolysis that was associated with a parallel rise in arterial blood levels of 6-keto-PGF(1 alpha), but not those of TXB(2) or PGE(2). L-NAME at a dose of 5 mg kg(-1) affected significantly neither ACE-I-induced thrombolysis nor prostacyclinemia; however, the pre-treatment with icatibant (0.1-0.5 mg kg(-1)) abolished both effects. The selective COX-1 inhibitor, SC 560 (100-300 microg kg(-1) i.v.), or a would be selective COX-3 inhibitor--paracetamol (acetaminophen, 1-3 mg kg(-1)), both agents induced a transient thrombolysis and slightly potentiated thrombolysis by ACE-Is. In contrast, selective COX-2 inhibitors (rofecoxib>>celecoxib>nimesulide>NS 398) were thrombogenic, and abolished THR and rise in 6-keto-PGF(1 alpha) induced by ACE-Is. Summing up, in our in vivo bioassay system ACE-Is such as quinapril, perindopril or captopril at non-hypotensive doses evoke THR that is mediated by endogenous bradykinin and prostacyclin derived from endothelial COX-2.
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PMID:In vivo endothelial interaction between ACE and COX inhibitors. 1562 95

The survival of metazoan organisms is dependent upon the utilization of O2 as a substrate for COX (cytochrome c oxidase), which constitutes Complex IV of the mitochondrial respiratory chain. Premature transfer of electrons, either at Complex I or at Complex III, results in the increased generation of ROS (reactive oxygen species). Recent studies have identified two critical adaptations that may function to prevent excessive ROS production in hypoxic cells. First, expression of PDK1 [PDH (pyruvate dehydrogenase) kinase 1] is induced. PDK1 phosphorylates and inactivates PDH, the mitochondrial enzyme that converts pyruvate into acetyl-CoA. In combination with the hypoxia-induced expression of LDHA (lactate dehydrogenase A), which converts pyruvate into lactate, PDK1 reduces the delivery of acetyl-CoA to the tricarboxylic acid cycle, thus reducing the levels of NADH and FADH2 delivered to the electron-transport chain. Secondly, the subunit composition of COX is altered in hypoxic cells by increased expression of the COX4-2 subunit, which optimizes COX activity under hypoxic conditions, and increased degradation of the COX4-1 subunit, which optimizes COX activity under aerobic conditions. Hypoxia-inducible factor 1 controls the metabolic adaptation of mammalian cells to hypoxia by activating transcription of the genes encoding PDK1, LDHA, COX4-2 and LON, a mitochondrial protease that is required for the degradation of COX4-1. COX subunit switching occurs in yeast, but by a completely different regulatory mechanism, suggesting that selection for O2-dependent homoeostatic regulation of mitochondrial respiration is ancient and likely to be shared by all eukaryotic organisms.
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PMID:Oxygen-dependent regulation of mitochondrial respiration by hypoxia-inducible factor 1. 1755 2

We first aimed to test the effect of anti-inflammatory drugs, etanercept and dexamethasone sodium phosphate (DSP), on the expression of inducible inflammatory signaling molecules (the bradykinin [BK] B(1) receptor [B(1)R], cyclooxygenase [COX]-2) in lipopolysaccharide (LPS)-treated rabbits. Preliminary experiments mostly based on a novel cellular model, rabbit dermis fibroblasts, showed that etanercept inhibited TNF-alpha-induced B(1)R expression ([(3)H]Lys-des-Arg(9)-BK binding), but that DSP also inhibited cytokine-induced B(1)R upregulation with less selectivity. LPS (100 microg/kg i.v.) induced the expression of the B(1)R (aortic contractility ex vivo, mRNA in hearts) and COX2 (immunoblots, heart extracts). However, the function of the BK B(2) receptor was unchanged (jugular vein contractility ex vivo). DSP pre-treatment profoundly reduced the induction of the B(1)R and COX2 whereas etanercept significantly inhibited only COX2 expression. The second aim was to verify whether chronic angiotensin converting enzyme (ACE) blockade in rabbits would induce B(1)R expression, as reported in other species. 14-Day enalapril oral dosing, but not treatment with the angiotensin receptor antagonist losartan, significantly increased aortic contractions mediated by B(1)Rs, however much less than LPS. Enalapril treatment did not increase COX2 expression but increased the ex vivo relaxation of the mesenteric artery mediated by endogenous prostaglandins. Chronic ACE inhibition recruits inflammatory signaling systems.
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PMID:Cardiovascular expression of inflammatory signaling molecules, the kinin B1 receptor and COX2, in the rabbit: effects of LPS, anti-inflammatory and anti-hypertensive drugs. 1793 16

We have previously demonstrated that chronic exposure to low-dose of mercury induced endothelial dysfunction and increased vasoconstrictor responses. The aim of this work was to investigate if mercury exposure alters contractile prostanoids production from cyclooxygenase-2 (COX-2) and its contribution to phenylephrine responses. For this, aortic segments from 3-month old Wistar rats daily treated with HgCl(2) (1(st) dose 4.6 microg/kg, subsequent dose 0.07 microg/kg/day, i.m.) or vehicle for 30 days were used. Mercury treatment did not affect systolic blood pressure but increased phenylephrine-induced vasoconstriction. The non selective COX inhibitor, indomethacin (10 micromol/l) reduced the response to phenylephrine more in aortic segments from mercury-treated than control rats. The selective COX-2 inhibitor NS 398 (1 micromol/l), the thromboxane A(2)/prostaglandin H(2) receptor (TP) antagonist SQ 29,548 (1 micromol/l), the TXA(2) synthase inhibitor furegrelate (1 micromol/l), the EP(1) receptor antagonist SC 19220 (1 micromol/l) and the AT(1) receptor antagonist losartan (10 micromol/l) reduced phenylephrine response only in vessels from mercury-treated rats. TXA(2) and PGE(2) levels were greater in the incubation medium of vessels from treated than untreated rats; NS 398 decreased these levels only in the mercury group. COX-2 protein was localized in adventitial and endothelial cells. Aortic COX-2 mRNA expression and plasma angiotensin converting enzyme activity were greater in mercury-treated rats. These results suggest that treatment with low doses of mercury increases the release of COX-2-derived vasoconstrictor prostanoids and its participation in phenylephrine responses. The increased activation of the renin-angiotensin system after mercury treatment might be associated to this increased COX-2 activity.
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PMID:The role of cyclooxygenase (COX)-2 derived prostanoids on vasoconstrictor responses to phenylephrine is increased by exposure to low mercury concentration. 2022 12


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