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)

The effect of enoximone was assessed by a randomised double blind trial versus placebo. The clinical status of the patients was evaluated by the NYHA classification and quality of life score. Inotropic state was estimated from the maximum acceleration of aortic and pulmonary blood flow recorded by Doppler echocardiography. Thirty patients with severe cardiac failure, aged 66.4 +/- 14 years, symptomatic despite maximal therapy associating diuretics, digitalis, nitrate derivatives and angiotensin converting enzyme inhibitors, were included. Fifteen patients were given enoximone 100 mg three times a day orally (Group E) and the other 15 were given a placebo (Group P). The NYHA class and quality of life scores were assessed at D0, D4 and D31. Doppler echocardiography and Holter recordings were performed on D0 and D31. The two groups were comparable at D0. Ten patients abandoned the trial, 3 from Group E (including 1 death) and 7 from Group P (including 3 deaths). At D4, 13 patients from Group E and 8 from Group P were clinically improved (p < 0.05). At D31, the clinical state was stable or improved in 10 of the 12 patients in Group E and 6 of the 8 patients in Group P (NS). No secondary effects were severe enough to warrant the withdrawal of treatment: the frequency of ventricular extrasystoles was comparable in the two groups at D0 and D31. At D31 the maximal aortic acceleration had increased by 20% compared with D0 (p < 0.05) and the maximal pulmonary acceleration by 31% (p < 0.05) in Group E. The same parameters showed no significant change in Group P (-6% and +5% respectively).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[Double-blind clinical and echocardiographic study of oral enoximone versus placebo in severe cardiac insufficiency]. 144 35

Nitrate derivatives are venous vasodilators which are effective in reducing the symptoms of pulmonary congestion. The beneficial action on exercise capacity was recently demonstrated in the Veterans II Study in association with Hydralazine and has also been suggested by other trials. The reduction in mortality from cardiac failure was demonstrated in the Veterans I Study in association with Hydralazine compared to conventional digitalo-diuretic therapy but seems less important than that obtained by angiotensin converting enzyme inhibitors. The phenomenon of tolerance seems to be related to the use of high doses in continuous therapy and may be countered by discontinuous use of the drug during the 24 hour period. Tolerance seems to be related to neuro-hormonal factors and perhaps to depletion of SH groups. Simultaneous use of nitrates and ACE inhibitors seems to be an interesting therapeutic concept.
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PMID:[Nitrate derivatives and cardiac insufficiency]. 153 Apr 25

The synthesis of adenosine triphosphate (ATP) depends on the coordinated interaction of oxygen delivery and glucose breakdown in the Krebs cycle. Cellular oxygen depots are non-existent, therefore the peripheral cells are totally dependent on the circulation for sufficient oxygen delivery. Shock is the clinical manifestation of cellular oxygen craving. The commonly measured variables--blood pressure, heart rate, urinary output, cardiac output and systemic vascular resistance--are not sensitive or accurate enough to warn of impending death in acutely ill patients nor are they appropriate for monitoring therapy. Calculated oxygen transport and oxygen consumption parameters provide the best available measures of functional adequacy of both circulation and metabolism. In order to optimise oxygen delivery (DO2), 4 interacting factors must be taken into account: cardiac output, blood haemoglobin content, haemoglobin oxygen saturation and avidity of oxygen binding to haemoglobin. For viscosity reasons, the optimal haemoglobin concentration is in the vicinity of 90 to 100 g/L, but for optimising the oxygen transport 100 to 115 g/L or a haematocrit of 30 to 35% seems better. The p50 (the pO2 at which haemoglobin is 50% saturated) describes the oxygen-haemoglobin dissociation curve; normally its value is +/- 27 mm Hg. It can be influenced by attaining normal body temperature, pH, pCO2 and serum phosphorous levels. In order to obtain an arterial blood saturation (SaO2) of more than 90% with acceptable haemodynamics, the ventilation mode and inspired oxygen fraction (FiO2) must be adapted; care must be taken not to stress the labile circulation with haemodynamic compromising ventilation techniques [e.g. high positive end expiratory pressure (PEEP) levels, inverse-ratio ventilation, etc.]. The factor most amenable to manipulation is the cardiac output, with its 4 determinants--preload, afterload, contractility and heart rate. In daily clinical practice, heart rate should be between 80 and 120 beats/min; small variations are acceptable. Important deviations must be treated by chemically [isoprenaline (isoproterenol)] or electrically (pacing techniques) accelerating the heart, or with the different antiarrhythmic drugs. A wide variety of agents is available to decrease the preload: diuretics [especially furosemide (frusemide)], venodilators like nitroglycerin (glyceryl trinitrate), isosorbide dinitrate (sorbide nitrate) and sodium nitroprusside, ACE inhibitors, phlebotomy, and haemofiltration techniques (peritoneal or haemodialysis, continuous arteriovenous haemofiltration). To increase the preload, volume loading using a rigid protocol ('rule of 7 and 3'), preferably with colloids, or vasopressor agents [norepinephrine (noradrenaline), epinephrine (adrenaline), dopamine] are useful. Arterial vasopressors are needed to improve perfusion pressure of 'critical' (coronary and cerebral) arteries. Afterload can be decreased by arterial vasodilators. Predominantly arterial dilators are hydralazine and clonidine, while sodium nitroprusside, nitroglycerin and isosorbide dinitrate have combined arterial and venous dilating actions.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Haemodynamic monitoring. Problems, pitfalls and practical solutions. 171 63

In this study, the effect of bradykinin on coronary flow in the isolated rat heart was significantly potentiated when cysteine or the sulfhydryl-containing converting enzyme inhibitors captopril and zofenoprilat were administered simultaneously. In contrast, the effect of concomitant administration of enalaprilat only slightly increased the effect of bradykinin on coronary flow. In nitrate-tolerant hearts of rats pretreated with isosorbide dinitrate (15 mg daily), the increase in coronary flow by nitroglycerin and bradykinin was significantly less when compared to control hearts. The effect of captopril was not affected by pretreatment. The involvement of endothelium-derived relaxing factor (EDRF) in the effect of captopril was apparent from experiments with L-arginine, the precursor of EDRF, and L-NMMA, the "false" precursor of EDRF. L-Arginine increased the effect of captopril, whereas L-NMMA showed a competitive antagonism for the effect of captopril on coronary flow in the isolated rat heart. Clinically, the effect of captopril was studied in 10 patients with stable, exercise-induced angina pectoris that had been treated for 3 weeks with slow-release isosorbide dinitrate (20 mg four times daily). At day 7, a baseline exercise test was obtained. Subsequently, patients with chest pain and at least 1-mm ST-segment depression on the ECG during exercise were included. They received on day 14 and 21 either captopril (25 mg) or placebo 1 h before exercise testing in a randomized, double-blind, crossover design. Captopril significantly improved the combined score of maximal ST-segment depression, maximal workload, and time to angina when compared to placebo. No differences in the pressure-rate index at rest and during exercise were seen. These results indicate that the sulfhydryl group of certain angiotensin converting enzyme inhibitors can potentiate their effect on the endogenous nitrovasodilator EDRF. In the clinical situation, this may lead to an improved exercise performance in patients with stable angina pectoris during chronic nitrate treatment, independent of its systemic vascular effects.
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PMID:Converting enzyme inhibitors and the role of the sulfhydryl group in the potentiation of exo- and endogenous nitrovasodilators. 172 Aug 43

Tolerance to the organic nitrates is a vexing problem. Tolerance is clearly avoidable with the employment of appropriate and well-designed dosing regimes, utilizing fewer doses and/or a nitrate-free interval. The emerging story of thiol donors and ACE inhibition to prevent tolerance is as yet incomplete. Hopefully, future research will provide the clinician with additional modalities to eliminate the threat of nitrate attenuation. The organic nitrates are superb drugs whose potential usefulness in cardiovascular medicine is clearly limited by nitrate tolerance. While the mechanisms involved in producing vascular smooth muscle attenuation are complex and multiple, it appears that we will be able to resolve this problem in the future, increasing the remarkable benefits of these drugs for patients around the world.
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PMID:Clinical aspects of nitrate tolerance. 179 Jul 83

We prospectively studied 69 consecutive patients hospitalized with a primary diagnosis of acute left ventricular failure so as to assess the impact of vasodilators on incidence and morbidity of acute symptomatic left ventricular failure. The determinants of duration of hospitalization, in-hospital mortality and symptomatic status 2 months after discharge were examined. There were 9 in-hospital deaths (13%), and survival at 60 days was 77%. Median duration of hospitalization was 9 days, and 33% of the surviving patients remained in New York Heart Association functional class III-IV 60 days subsequent to discharge. Of the patients, 49 (76%) had previously received treatment for left ventricular failure: 30 (61%) of these had received vasodilators, most commonly angiotensin converting enzyme inhibitors and nitrates. Ischaemic chest pain was present in 34 (49%) of the patients. Acute utilization of vasodilators (45% of patients) was largely limited to nitrate therapy associated with ischaemic chest pain (P less than 0.01). Multiple logistic regression revealed previous left ventricular failure, advanced age and hypokalaemia as significant correlates of prolonged hospitalization (greater than 9 days). Previous left ventricular failure was also predictive of persistent severe disability two months subsequent to discharge. No factor was a significant predictor of in-hospital death. Although preceding treatment with digoxin and incremental angiotensin converting enzyme inhibitor therapy tended to predict brief hospitalization, the parameter of acute ischaemia, other biochemical anomalies and modes of acute or chronic therapy were not significant correlates of any end point. We conclude that preceding disability, rather than mode of treatment, predicts an adverse outcome in acute left ventricular failure.
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PMID:Acute heart failure: determinants of outcome. 179 Oct 90

Nitroglycerin and the organic nitrates (RONO2) can be considered prodrugs that require conversion to an active intracellular moiety that initiates vascular smooth muscle relaxation. Vasodilation of veins and arteries occurs when the enzyme guanylate cyclase (GC) is activated, initiating the conversion of guanosine triphosphate (GTP) to cyclic guanosine monophosphate (cGMP); this is the final pathway for vascular dilation caused by the nitrovasodilators (organic nitrates, sodium nitroprusside, and molsidomine) as well as endothelium-derived relaxing factor (EDRF). The common denominator appears to be the intracellular production of nitric oxide (NO), which is the activated product of organic nitrate denitration. Nitrate tolerance has been associated with a relative depletion or unavailability of thiol groups that are involved in the initial step of denitration of RONO2. Sulfhydryl groups (SH) are oxidized during this process; with continuous nitrate exposure, decreased nitrate metabolism within the vascular smooth muscle cell occurs as a direct result of the depletion of reduced SH groups. Thus, less NO is formed and cGMP production is diminished, with a subsequent decrease or absence of vasodilation. In addition, SH groups or thiols are required for the production of S-nitrosothiols (RSNO). These short-lived compounds have been identified as an end product of organic nitrate metabolism and as possibly obligatory for the induction of GC. It is unclear, however, as to whether S-nitrosothiols are a necessary by-product of NO production from organic nitrates. It appears that RSNO can be formed outside the cell membrane and may be able to induce vasorelaxation after penetrating the cell and initiating GC activation. Exogenous SH donors, particularly N-acetylcysteine (NAC), have been employed to provide intracellular thiols in efforts to prevent or reverse nitrate tolerance. Nitrate physiologic actions are accentuated following NAC administration in the absence of tolerance. Although controversial, the concept that NAC or other thiols might be able to prevent the development of nitrate tolerance is being actively studied in laboratories around the world. Methionine has also been utilized as an SH donor with some success. Not all data are consistent, however, and the ultimate role of thiol donors for the prevention or reversal of nitrate tolerance remains uncertain. Finally, there has been considerable interest in supplying thiols by use of the SH-containing angiotensin converting enzyme inhibitors, such as captopril. This approach does not seem promising, probably because insufficient thiol can be supplied by therapeutic dosages of these drugs.
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PMID:Interactions between organic nitrates and thiol groups. 192

Over 30 per cent of coronary patients die of cardiac failure excluding the acute phase of myocardial infarction. With the exception of preexisting hypertension, there is no compensatory hypertrophy in ischemic heart disease. However, hypertrophy is a costly adaptation in terms of myocardial oxygen demand and, therefore, coronary flow. Fibrous zones are unresponsive to inotropic drugs and so the treatment of cardiac failure due to ischemic heart disease consists in limiting or preventing episodes of ischemia. Each mechanism of ischemia has an appropriate treatment: the preload is reduced by trinitrin and its derivatives and by molsidomine; the after-load by calcium antagonists and angiotensin converting enzyme inhibitors; tachycardia and hypercontractile states by betablockers. The risk of arrhythmia, aggravated by many inotropic therapies, constitutes the major danger to ischemic heart failure; amiodarone, betablockers and preventive nitrate therapy are the most effective and least dangerous antiarrhythmics. Revascularisation is effective for permanently ischemic segments or for ischemia on effort but does not improve large plaques of fibrosis which sometimes require surgical ablation or plastic procedures. But these measures are incomplete if all aspects of the disease are not taken in consideration: loss of excessive body weight, exercise rehabilitation by modern techniques, limitation of bed rest at the ultimate stage of the disease allowing patients with ischemic cardiac failure a better quality of life without aggravating the prognosis.
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PMID:[Treatment of cardiac insufficiency in ischemic heart disease]. 212 13

Over 70 pesticides have been detected in ground water. Aldicarb and atrazine along with the soil fumigants EDB and DCP and DBCP have been the pesticides most frequently detected in ground water. Atrazine concentrations have been correlated with high nitrate concentrations. The triazine herbicides, simazine and cyanazine, have also been detected in ground water. The annual amount of recharge, soil type, depth of aquifer from the surface, nitrate contamination and soil pH are important field parameters in determining ground-water contamination potential by pesticides. Pesticide leaching is reduced by proper choice of crop rotation, increasing pesticide application efficiency, and integrated pest management.
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PMID:Pesticide contamination of ground water in the United States--a review. 218 18

We have examined the acute renal failure that occurs after uranyl nitrate administration in the rat and the specific effects of pretreatment of rats with angiotensin converting enzyme inhibitor (CEI), plasma volume expansion (PVE) after uranyl nitrate, and a combination of these treatments. We utilized a combination of micropuncture measurements of glomerular hemodynamics, cage studies, and histologic examination of renal tissue to evaluate the degree of acute renal failure in all groups studied. Uranyl nitrate (UN) (25 mg/kg body wt) administration caused a reduction in the nephron filtration rate (SNGFR) (39.4 +/- 1.6 to 24.8 +/- 2.9 nl X min-1 X g kidney wt-1, P less than 0.02) as a result of a major decrease in the glomerular ultrafiltration coefficient (LpA) from control values (greater than or equal to 0.085 +/- 0.008 to 0.035 +/- 0.007 nl X sec-1 X mm Hg-1 X g kidney wt-1, P less than 0.01). Treatments with CEI, PVE, and the combination of CEI and PVE in rats receiving UN restored 0.38 +/- LpA to normal values (greater than 0.061 +/- 0.009, 0.091 +/- 0.020, and 0.138 +/- 0.020 nl X sec-1 X mm Hg-1 X g kidney wt-1, respectively). Cage studies revealed that CEI treatment prevented oliguria and resulted in major volume losses and reduction in weight. However, rats died after a similar period after UN, but probably by different mechanisms. Analysis of renal ultrastructure revealed equivalent tubular damage in all experimental groups. Alterations in LpA after UN are functional in nature and are potentially preventable and reversible by a combination of treatments with CEI and PVE.
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PMID:Functional basis for the glomerular alterations in uranyl nitrate acute renal failure. 300 41


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