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)

To ascertain the pathophysiological roles of the renin-angiotensin system and endothelin in heart failure and cardiac hypertrophy, we assessed changes in cardiac angiotensin converting enzyme (ACE) and endothelin-1 (ET-1) receptor using rats in which myocardial infarction was induced by left coronary ligation. The animals were decapitated 1 or 8 months after the operation. Cardiac ACE and ET-1 receptor were quantified by computerized in vitro autoradiography using 125I-MK351A (a lisinopril derivative) and 125I-ET-1. One month after myocardial infarction, cardiac weight and plasma atrial natriuretic peptide had increased in rats with infarction, compared to sham-operated controls, indicating the presence of chronic left ventricular dysfunction, although exchangeable body sodium and plasma renin activity were unchanged. Cardiac ACE increased markedly in the infarcted area and moderately in hypertrophied myocardium without any change in affinity compared to sham-operated rats. On the other hand, there was no change in cardiac ET-1 receptors in infarcted rats. The same results were found even at 8 months after myocardial infarction. The present study indicates that cardiac ACE may participate in tissue repair at the site of myocardial infarction and may also play a role in the pathophysiology of cardiac hypertrophy in rats with chronic heart failure. However, the present results do not reveal whether ET-1 receptor participates in the pathophysiology of cardiac hypertrophy in this model.
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PMID:Cardiac angiotensin converting enzyme and endothelin receptor in rats with chronic myocardial infarction. 899 88

1. Chronic treatment with a combined ETA/ETB endothelin receptor antagonist has been shown to reduce blood pressure in experimental rat models of hypertension in which endothelin-1 gene overexpression occurs in the walls of blood vessels, particularly small, resistance-sized arteries, but not in those genetic or experimental models of hypertension in which there is no overexpression of vascular endothelin-1. Failure of some experimental models of hypertension to respond to treatment with the combined ETA/ETB endothelin antagonist may be due in part to blockade of vasorelaxant endothelial ETB receptors which could in theory reduce the efficacy of endothelin antagonism. 2. In this study the orally active ETA-selective endothelin antagonists A-127722.5 and LU 135252 were used in chronic experiments on deoxycorticosterone acetate (DOCA)-salt hypertensive rats (which overexpress vascular endothelin-1 and respond with blood pressure lowering to combined ETA/ETB endothelin receptor antagonism), on spontaneously hypertensive rats (SHR) (which do not overexpress vascular endothelin-1 and do not respond with blood pressure lowering to the combined ETA/ETB receptor antagonist), and in 1-kidney 1 clip Goldblatt (1-K IC) hypertensive rats (which present mild overexpression of vascular endothelin-1 but do not respond with blood pressure lowering to the combined ETA/ETB receptor antagonist). Additionally, it has been suggested that interruption of the renin-angiotensin system may sensitize responses to endothelin antagonism. Accordingly, SHR were treated with an angiotensin converting enzyme inhibitor, cilazapril, in addition to the ETA receptor antagonist. 3. Blood pressure of DOCA-salt hypertensive rats was lowered by a mean of 24 and of 27 mmHg (P < 0.01) by A-127722.5 after 4 weeks of treatment, when given orally at two different doses (10 and 30 mg kg-1 day-1), and by 18 mmHg by LU 135252 50 mg kg-1 day-1. 4. SHR treated with A-127722.5 for 8 weeks starting at 12 weeks of age exhibited the same progressive rise in blood pressure as untreated SHR. Addition of cilazapril resulted in similar reduction of blood pressure in A-127722.5-treated and untreated SHR. 5. Treatment of 1-K IC hypertensive rats with the dose of LU 135252 which lowered blood pressure in DOCA-salt hypertensive rats did not cause any reduction in blood pressure relative to untreated rats. 6. These results demonstrate that treatment with either dose of the selective ETA receptor antagonists A-127722.5 or LU 135252 caused reductions in blood pressure similar to those obtained for a combined ETA/ETB endothelin antagonist. Blood pressure was lowered only in hypertensive rats known to overexpress vascular endothelin-1 (DOCA-salt hypertensive rats) but not in those which do not (SHR) or only have mild vascular overexpression of endothelin-1 gene (1-K 1C hypertensive rats). Reduction in activity of the renin-angiotensin system in SHR did not sensitize blood pressure to potential hypotensive effects of an ETA-selective receptor antagonist.
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PMID:Effect of chronic ETA-selective endothelin receptor antagonism on blood pressure in experimental and genetic hypertension in rats. 922 50

The endothelium is involved in cardiac and vascular dysfunction characteristic of heart failure. Vascular dysfunction has been related either to an impaired endothelium dependent vasodilation of both capacitance and resistance vessels, or to an increase in the plasmatic levels of endothelium derived contracting factors, such as endothelin-1. While the former seems to respond favourably to ACE-inhibitors, physical training and L-arginine; the latter will soon be treatable with endothelin-1 A e B receptor antagonists or with inhibitors of its converting enzyme. Cardiac dysfunction may be explained not only by the loss of the positive inotropic effect induced by low concentrations of nitric oxide (produced by the constitutive NO-synthase in the normal endothelium), but also by the negative inotropic effect induced by the high concentrations of nitric oxide, produced as a consequence of the stimulation of the inducible NO-synthase. It is therefore conceivable that cardiac dysfunction would also improve with the administration of drugs presently used to correct endothelium dependent vasodilatation disturbances.
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PMID:[The importance of the endothelium in heart failure]. 925 29

Several randomised studies have demonstrated that various nonsteroidal anti-inflammatory drugs (NSAIDs) elevate blood pressure in normotensive and hypertensive individuals; however, these data have been contradicted by numerous negative studies. Two meta-analyses have demonstrated that, after pooling data drawn from published reports of randomised trials of younger adults, NSAID use produces a clinically significant increment in mean blood pressure of 5 mm Hg, most marked in patients with controlled hypertension. Stratification by NSAID type revealed that piroxicam, naproxen and indomethacin had the greatest, and sulindac the smallest, pressor effect. These data were supported by 2 large community studies involving elderly patients. Recent NSAID users had a 1.7-fold higher risk of requiring the initiation of antihypertensive therapy compared with nonusers; NSAID users also had a 40% increased risk of receiving a diagnosis of hypertension compared with nonusers. It is vital to determine the nature of the association in the elderly, 12 to 15% of whom are concurrently receiving an NSAID and an antihypertensive agent. Importantly, a 5 to 6 mm Hg increase in diastolic blood pressure maintained over a few years may be associated with a 67% increase in total stroke risk and a 15% increase in coronary heart disease events. While the mechanism(s) remain speculative, salt and water retention through several factors operating in parallel, coupled with increased total peripheral vascular resistance, via increased renal endothelin-1 synthesis, are potentially important. Clinicians should strive to avoid excessive use of NSAID treatment and consider well-tolerated therapeutic alternatives, including simple analgesics and physical therapy. For patients who require concomitant NSAID and antihypertensive treatment, physicians should be aware that indomethacin, naproxen and piroxicam may be associated with a greater pressor effect than many other NSAIDs, and that antagonism of beta-blockers may be greater than that of vasodilators (including ACE inhibitors and calcium antagonists) and diuretics. Finally, the progress of each patient should be monitored by careful blood pressure measurement, particularly during the period of initiation of NSAID therapy.
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PMID:NSAIDs and increased blood pressure. What is the clinical significance? 939 72

Recently, we have reported that endothelin-1 (ET-1) production is increased in blood vessels and glomeruli of rats with chronic renal failure. This study was design to investigate the role of angiotensin II (Ang II) in endogenous ET-1 production in rats with reduced renal mass. One week after subtotal (5/6) nephrectomy, uremic rats were divided into three groups, and received either no treatment, the Ang II subtype 1 receptor (AT1) antagonist losartan (10 mg/kg/day), or the angiotensin-converting enzyme inhibitor (ACE-I) captopril (30 mg/kg/day) for 6 weeks. Sham-operated rats were used as controls and received no treatment. The levels of immunoreactive ET-1 (ir-ET-1) in plasma and urine, as well as in vascular and renal tissues, were determined by radioimmunoassay (RIA) after extraction. In uremic rats, losartan and captopril completely prevented the increase in systolic blood pressure. At week 6, plasma ir-ET-1 was similar in the different groups of uremic rats and in the controls. However, ir-ET-1 concentration in the mesenteric arterial bed, the thoracic aorta, preglomerular arteries, and glomeruli, as well as urinary ir-ET-1 excretion were significantly greater in uremic-untreated rats compared to controls (P < .01). Treatment of uremic rats with losartan or captopril reduced irET-1 concentration in the thoracic aorta and preglomerular arteries (P < .05), but ir-ET-1 concentration in the mesenteric arterial bed was unchanged. Although both drugs completely prevented the increase in proteinuria, losartan but not captopril significantly reduced ir-ET-1 concentration in glomeruli (P < .05) and normalized urinary ir-ET-1 excretion. This indicates that increased ET-1 production in blood vessels and glomeruli of uremic rats is modulated, at least in part, by Ang II through the AT1 receptor. The beneficial effects of the AT1 antagonist losartan could be attributable to the attenuation of Ang II-induced ET-1 production in this rat remnant kidney model of chronic renal failure, whereas those of the ACE-I captopril are not related to changes in ET-1 production in glomeruli.
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PMID:Effects of losartan and captopril on endothelin-1 production in blood vessels and glomeruli of rats with reduced renal mass. 971 93

Chronic hypoxia has been shown to increase plasma endothelin levels. The current study was undertaken to examine the effect of exercise-induced tissue hypoxia on plasma levels of endothelin-1 (ET-1) and its precursor big endothelin-1 (Big-ET-1). After approval by the local ethical committee an incremental dynamic exercise test was performed in 12 physically trained volunteers (aged 20 to 40 years), using an electrically braked bicycle ergometer. The protocol included a step-wise increase of the workload until a heart rate of 130/min was reached, followed by a maintenance period of 25 min, and a further step-wise increase until exhaustion. Blood was drawn before, at several time points during, and 5 min after termination of the study for determination of ET-1, Big-ET-1, plasma renin activity (PRA), angiotensin converting enzyme (ACE), norepinephrine, epinephrine, and lactate. Lactate levels at baseline were 14.5 +/- 1.6 mg/dL (mean +/- SEM), which increased to 76.5 +/- 4.8 mg/dL at the time of exhaustion (P < .01). Baseline values for ET-1 and Big-ET-1 were 0.264 +/- 0.061 and 0.637 +/- 0.130 fmol/ml, respectively, which remained essentially unaltered throughout the exercise test. PRA was 1.46 +/- 0.45 ng/mL/h before exercise and increased to 3.55 +/- 0.96 ng/mL/h at exhaustion (P < .001). Norepinephrine and epinephrine were also increased at exhaustion. The study demonstrates that exhaustive physical exercise with acute development of pronounced tissue hypoxia--in contrast to chronic hypoxia--does not influence the release of ET-1 or Big-ET-1 or the conversion of the precursor to the active compound. Unlike endothelin, circulating renin and the catecholamines were markedly stimulated by this maneuver.
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PMID:Exhaustive exercise-induced tissue hypoxia does not change endothelin and big endothelin plasma levels in normal volunteers. 971 98

Circulating endothelin-1, a very strong peptide vasoconstrictor first discovered in 1988, is raised in cardiac failure. This increase contributes to the deleterious effects of cardiac failure. Although specific anti-endothelin drugs are under development in this condition, the effects of more commonly used drugs on circulating endothelin-1 levels are not well known. The aim of this study was to evaluate the effects of ACE inhibitor therapy on plasma endothelin-1 levels in cardiac failure. The plasma endothelin-1 levels were measured in 24 patients (stages III and IV of the NYHA classification), before and after treatment with angiotensin converting enzyme inhibitor (Captopril: test doses, then 75 mg/day). A control group of 10 paired patients was used to shake off the effects of bed rest and hospital salt-free diet. The initial endothelin-1 levels were high but equivalent in the control and study groups: 9.13 +/- 1.87 fmol/mL vs 8.98 +/- 1.92 fmol/mL. Plasma endothelin-1 decreased significantly in the study group 72 hours after beginning ACE inhibitor therapy (7.44 +/- 1.95, p < 0.02) but remained higher than normal (p < 0.01), whereas the values in the control group remained the same. This study demonstrates a decreases in plasma endothelin-1 levels 72 hours after onset of ACE inhibitor therapy in patients with stable severe cardiac failure. This results, already suggested by many experimental studies and certain ancillary clinical trials, could explain some of the beneficial effects of ACE inhibitors in this condition.
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PMID:[Rapid decrease of serum endothelin-1 levels after treatment with ACE inhibitors in chronic cardiac failure]. 974 64

1. Frequency-domain spectral analysis of stationary ECG R-R intervals was made by fast Fourier transformation (FFT) in conditions of monitored arterial blood pressure and respiratory activity in diethyl-ether-anaesthetized and pithed adult rats. This technique yields a number of parameters which allow quantitative evaluation of the non-random distribution of the mean values obtained in time-domain studies. The frequency-analysis method enables the overall heart rate variability to be broken down into its various constituents, which are differently affected by physiological loading and capable of selective reactivity to pharmacological agents. 2. The low-frequency spectral component obtained by breaking down the total spectral density power, i.e. the appropriate variability signal (band width < 0.15 Hz) and a higher-frequency band corresponding to spontaneous (0.80-1.60 Hz) or artificially imposed (0.75 Hz) respiratory activity were estimated and their integrated areas evaluated as absolute powers or normalized fractional values. 3. The power of the high-frequency spectral component increased in all animal preparations under treatment with prazosin, dl-propranolol, endothelin-1 and the angiotensin converting enzyme (ACE) inhibitors captopril, lisinopril, quinapril and ramipril. The power of the low-frequency band increased under alpha-r atriopeptin and ACE inhibitors in the pithed preparations only, and decreased in the anaesthetized animals. 4. The new power spectrum features and trends detected indicate that these time-independent, model-dependent cardiovascular and respiratory markers are subject to some form of complex peptidergic control. 5. The relative roles of the various factors operating in the genesis of these short-term changes in spectral power in the low- and high-frequency bands cannot be interpreted as indicating a reciprocal push-pull relationship between sympathetic and parasympathetic control. 6. The study findings, however, can be interpreted as providing evidence of a different and to some extent alternative form of integrative cardiovascular control persisting in the pithed rats (i.e. in the 'peripheral', CNS-destroyed preparations). 7. New areas of theoretical and applied research are being developed in the (auto)classification of (iso)receptors and drug analogues through exploration of multiple physiological and pharmacokinetic parameters in the frequency-domain. Furthermore, model-independent frequency-domain methods not requiring stationary data will afford scope for even more significant developments by separating the overlapping dynamic processes from a whole series of correlated effects.
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PMID:Spectral analysis of intercycle heart fluctuations in the diethyl-ether-anaesthetized or pithed rat treated with prazosin, dl-propranolol, endothelin-1, alpha-r atriopeptin and ACE-inhibitors. 983 Dec 27

Exogenous endothelin-1 (ET-1) is a strong vasoconstrictor in the canine kidney and causes a decrease in renal blood flow (RBF) by stimulating the ETA receptor subtype. The aim of the present study was to investigate the role of endogenously generated ET-1 in renal hemodynamics under physiological conditions. In six conscious foxhounds, the time course of the effects of the selective ETA receptor antagonist LU-135252 (10 mg/kg iv) on mean arterial blood pressure (MAP), heart rate (HR), RBF, and glomerular filtration rate (GFR), as well as its effects on renal autoregulation, were examined. LU-135252 increased RBF by 20% (from 270 +/- 21 to 323 +/- 41 ml/min, P < 0.05) and HR from 76 +/- 5 to 97 +/- 8 beats/min (P < 0. 05), but did not alter MAP, GFR, or autoregulation of RBF and GFR. Since a number of interactions between ET-1 and the renin-angiotensin system have been reported previously, experiments were repeated during angiotensin converting enzyme (ACE) inhibition by trandolaprilat (2 mg/kg iv). When ETA receptor blockade was combined with ACE inhibition, which by itself had no effects on renal hemodynamics, marked changes were observed: MAP decreased from 91 +/- 4 to 80 +/- 5 mmHg (P < 0.05), HR increased from 85 +/- 5 to 102 +/- 11 beats/min (P < 0.05), and RBF increased from 278 +/- 23 to 412 +/- 45 ml/min (P < 0.05). Despite a pronounced decrease in renal vascular resistance over the entire pressure range investigated (40-100 mmHg), the capacity of the kidneys to autoregulate RBF was not impaired. The GFR remained completely unaffected at all pressure levels. These results demonstrate that endogenously generated ET-1 contributes significantly to renal vascular tone but does not interfere with the mechanisms of renal autoregulation. If ETA receptors are blocked, then the vasoconstrictor effects of ET-1 in the kidney are compensated for to a large extent by an augmented influence of ANG II. Thus ET-1 and ANG II appear to constitute a major interrelated vasoconstrictor system in the control of RBF.
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PMID:Contribution of endothelin to renal vascular tone and autoregulation in the conscious dog. 1007 Jan 65

A large proportion of the beneficial effects that oestrogens demonstrate on the vasculature are believed to be mediated via direct effects on the vascular wall. In this study we compared a number of oestrogenic compounds isolated from pregnant mare's urine including 17beta-oestradiol and oestrone, in terms of their abilities to inhibit stimulated endothelin-1 release from normal human coronary artery endothelial cells (CAEC). We also examined their ability to stimulate expression of constitutive endothelial nitric oxide synthase (eNOS) and explored their effects on cellular angiotensin converting enzyme (ACE). All the oestrogens tested were able to inhibit serum-stimulated ET-1 release. Oestrone and 17alpha-dihydroequilenin failed to significantly affect cellular eNOS levels. 17Beta-oestradiol and oestrone significantly increased cellular ACE levels while 17beta,delta(8,9)-dehydroestradiol decreased cellular ACE. We discuss these observations in terms of their potential clinical relevance and use as a means of screening novel oestrogen-like compounds.
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PMID:Effects of equine oestrogens on markers of vasoactive function in human coronary artery endothelial cells. 1041 Dec 97


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