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)

Myocardial pump deficiency is regarded to be the hemodynamic hallmark of congestive heart failure. A decline of arterial pressure in the systemic circulation is counter-regulated by vasoconstriction in the arteriolar vascular bed; the compensatory vasoconstriction, however, results in an increased afterload that in turn aggravates myocardial pump deficiency. As part of the counterregulatory systems the sympathetic nervous system is activated (increase of neuronal activity, increased plasma norepinephrine) and the renin-angiotensin-aldosterone system is stimulated as well (increased plasma renin activity, elevated angiotensin II serum levels, hyperaldosteronism). In parallel, serum levels of antidiuretic hormone (ADH) is despite a serum hypoosmolarity increased and only poorly compensated by release of the atrial natriuretic peptide. On the cellular level, congestive heart failure leads to a shift of the expression of contractile proteins towards to fetal forms (for instance myosin-isoenzymes). Although the counterregulatory activation of the neuroendocrine systems vasoconstricts the peripheral arteries thereby maintaining perfusion of vital organs, the rise in afterload ultimately leads to a progression of congestive heart failure. Consequently, vasodilators (such as ACE-inhibitors) that not only induce vasodilation in the peripheral arteries, but also inhibit progressive neuroendocrine stimulation evolved as excellent compounds for treating congestive heart failure.
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PMID:[Pathophysiology of left heart failure with reference to hemodynamic and neurohumoral changes]. 135 6

Experimental myocardial infarction is a model of cardiac overload due to amputation of part of the cardiac muscle. The development of cardiac failure depends on the size of the infarct and the time factor. This model of overload is associated with changes of the phenotype of the remaining healthy muscle and with peripheral vascular modifications partially dependent of the activation of pressor and/or deactivation of dilator systems. These changes are proportional to the size of the infarction at a given time after induction of the model. The degree of right ventricular hypertrophy and the decrease in blood pressure reflect the severity of infarction and the deterioration of the remaining myocardial function, affecting the haemodynamics both before and after the left ventricle. The increases in the 1/3 forms of isomyosins, the amount of subendocardial collagen, the biosynthesis, stocking and secretion of ANF are related to the infarct size and degree of overload. Similarly, the concentration of cyclic GMP is proportional to the infarct size. These parameters reflect ventricular overload, the increase of stress and energy deprivation of the remaining healthy muscle. The activation of peripheral pressor systems is also dependent on the infarct size reflects the effect of cardiac pump dysfunction on the kidney, liver, brain and endothelium. Large infarcts are associated with increased circulating renin and renal concentrations, with a decrease in angiotensinogen levels related to its consumption by the renin and to reduced hepatic synthesis and also with increased secretion and biosynthesis of vasopressin by the hypothalamus. In this model, Perindopril is beneficial by decreasing the cardiac load. It reduces the blood pressure, causes regression of bi-auricular and right ventricular hypertrophy. Changes in myosin isoenzyme configuration regress and subendocardial fibrosis and ANF concentrations are normalised. The effects of ACE inhibitors in this context, though very beneficial, are limited by the impossibility of normalising cardiac load and stress when the initial amputation of cardiac contractile mass exceeds 40%.
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PMID:[Experimental myocardial infarction in the rat. Effect of perindopril]. 166 27

Attempts at treating idiopathic cardiomyopathy have been made both clinically and experimentally using the cardiomyopathic Syrian hamster. In recent years, the angiotensin converting enzyme (ACE) inhibitor has attracted considerable attention as an agent to treat heart failure. We administered the ACE inhibitor captopril to the cardiomyopathic hamster. In this study, 15 mg/kg body weight of captopril was administered to the cardiomyopathic hamster J2N at 5 weeks of age for 10 weeks; age matched J2N hamsters were used as non-treated control animals. At the end of captopril administration, blood was collected from the ventral aorta. Serum malondialdehyde (MDA), serum CPK, aldolase and LDH were determined, and myosin isoenzyme patterns of the extirpated myocardium were compared. Additionally, ECGs were compared and the fibrotic ratio of both ventricles determined. Serum MDA, CPK, and aldolase increased significantly in the cardiomyopathic hamster, whereas these indices were significantly inhibited in the hamster treated with captopril. The pathological ECG findings and the ventricular V3 predominant myosin isoenzyme patterns of the J2N were also much improved in the captopril group. However, the improvement in these parameters by enalapril administration was less than that seen with captopril. These results suggested that the effect of captopril is not only due to decrease of the angiotensin II level, but also due to increase in tissue kinin and vasodilatory prostaglandin which play an important role in the beneficial effect of captopril.
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PMID:Protective effect of ACE- and kininase-inhibitor on the onset of cardiomyopathy. 178 64

Several experimental models involving the development of cardiac hypertrophy in adult rats are characterized by the reexpression of the fetal isoform of myosin heavy chain (V3). To determine whether a similar adult-to-fetal shift in the expression of the thin-filament proteins occurs during cardiac hypertrophy, we have examined the expression of the isoforms of myosin, tropomyosin, and troponin T in the left ventricle of young spontaneously hypertensive rats (SHR) with and without treatment using enalapril, an angiotensin converting enzyme inhibitor. Phosphorylation of tropomyosin, which is predominant in the fetal state, was also analyzed. Twelve-week-old SHR were treated with enalapril for 2, 5, 8, and 9 weeks followed by withdrawal of treatment for 9 weeks. Control SHR, without drug treatment, were weight- and age-matched. After 9 weeks of enalapril treatment, mean arterial blood pressure was reduced (from 166 +/- 11 to 89 +/- 5 mm Hg), and left ventricular weight/body weight ratio was regressed (from 2.53 +/- 0.14 to 1.96 +/- 0.05 g/kg) to normotensive levels. During the 9-week treatment period, the percent V3 decreased in SHR substantially from 35 +/- 3% to 13 +/- 1%. There was a significant correlation between the left ventricular hypertrophy and the percent V3 myosin expression in the SHR during regression (r = 0.697, p less than 0.001). However, only the adult isoforms of tropomyosin and troponin T were detected in the SHR with or without enalapril treatment, and the level of tropomyosin phosphorylation remained constant irrespective of the degree of left ventricular hypertrophy.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Regression of cardiac hypertrophy in spontaneously hypertensive rats by enalapril and the expression of contractile proteins. 214 74

Cathepsin B was purified about 11,000-fold from monkey skeletal muscle by ammonium sulfate fractionation and sequential column chromatographies monitored by assaying of Z-Phe-Arg-MCA hydrolase activity. The purified enzyme gave a single protein band on SDS-polyacrylamide gel electrophoresis, and its molecular weight was estimated to be 24,000 by gel filtration. It had a pH optimum of 6.5, required a thiol reducing agent for activation, and was inhibited by various thiol protease inhibitors. These properties were similar to those reported for cathepsins B from other sources. Although the enzyme scarcely hydrolyzed ordinary proteins, such as casein, hemoglobin, and bovine serum albumin, it degraded myosin and actin among various myofibrillar proteins. These results strongly suggested that skeletal muscle cathepsin B may participate in the degradation of muscle proteins in vivo. In addition, cathepsin B was shown to hydrolyze various neuropeptides such as Leu-enkephalin, beta-neoendorphin, alpha-neoendorphin, dynorphin(1-13), and substance P. It appeared to act on these peptides mainly as a dipeptidyl carboxypeptidase, although not so rigorously, presumably due to its endopeptidase activity.
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PMID:Purification and characterization of cathepsin B from monkey skeletal muscle. 672 39

Changes of ischemic myocardium following coronary occlusion, including active and passive functions, and adaptive changes of non-ischemic surviving myocardium have been summarized under the term "left ventricular remodeling" post myocardial infarction. An increase in left ventricular volume may be a consequence, and associated with an adverse prognosis. Although left ventricular dilatation may increase stroke volume and, thus, be compensatory at first, in about one-fifth of patients it ultimately results in progressive dysfunction and heart failure. Major determinants of this process are time, infarct size, infarct location, global left ventricular function assessed 4 days after infarction by radionuclide ejection fraction and right heart catheter (stroke volume), and morphology of the infarct-associated coronary artery. The surviving myocardium hypertrophies and may also dilate structurally. Depression of left ventricular ejection fraction chronically after the infarct is due to deterioration of wall motion of chamber segments initially classified normal by radionuclide analysis. Biochemical changes may also occur, including reduction of phosphocreatine, prolongation of time to peak Cai2+, and changes in myosin isoforms. Systemic or local humoral factors may be involved in these changes, however, clear evidence is still lacking. Perfusion of surviving myocardium may be altered under various conditions due to morphologic and functional changes of coronary vasculature. Successful prevention of heart failure and death by angiotensin converting enzyme inhibitors in asymptomatic patients with left ventricular dysfunction post-myocardial infarction has supported the pathophysiologic concepts of remodeling.
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PMID:Ventricular remodeling after myocardial infarction. Experimental and clinical studies. 835 28

As a consequence of persistently raised blood pressure, left ventricular hypertrophy (LVH) develops as a compensatory mechanism for wall stress induced by the increase in afterload. Recent advances in the fields of molecular biology and genetics are now clarifying the mechanisms involved in the development of LVH. It has been reported that messenger RNA of oncogenes, such as c-fos and c-myc, increases by stretching; these oncogenes contribute to the progression of LVH, the messenger RNA expression of myosin and contractile protein synthesis in the cardiomyocytes. Vasoactive hormones and vascular contracting factors are also reported to have a progressive effect on LVH. In contrast, some antihypertensive agents have been shown to have pharmacological effects on regression of LVH in animals and man. The mechanisms responsible for LVH progression have been extensively studied. In contrast, the mechanisms of LVH regression have not been defined and require elucidation. This paper outlines the basic recognition of the mechanisms of LVH progression and discusses the varied pharmacological actions of calcium antagonists and angiotensin converting enzyme inhibitors on the regression of LVH in man and rats. Although the role of antihypertensive therapy in regression of LVH remains controversial, the calcium antagonist nicardipine appears to have an important role to play in the treatment of LVH in hypertension and in congestive heart failure.
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PMID:Therapeutic advances in the treatment of left ventricular hypertrophy. 837 Mar 75

Factors that influence the development of the normal pulmonary vasculature are poorly understood. Since increased local production of angiotensin II (AII) by angiotensin converting enzyme (ACE) has been implicated in the medial hypertrophy of systemic and pulmonary hypertension, we questioned whether ACE and angiotensin receptor expression may influence the muscularization of the normal pulmonary vasculature during development. The approach employed measurement of lung ACE activity, assessment of local ACE expression by immunohistochemistry, and angiotensin type 1 receptor (AT1) expression by in situ hybridization in rat lungs ranging from 15 days of intrauterine life (term = 21 d) to adulthood. The temporal and spatial pattern of ACE expression was compared with that of the endothelial marker, von Willebrand factor (vWF), and the smooth muscle cell markers, alpha smooth muscle actin and smooth muscle myosin. ACE activity was first detected in lung homogenates on day 17 of gestation (1 +/- 0.2 mU/mg) and increased progressively to term (27.7 +/- 3.2 mU/mg). However, the greatest increase in lung ACE activity to adult levels (379 +/- 25.2 mU/mg) occurred between 2 and 4 wk of postnatal life. Immunohistochemistry demonstrated vWF expression by vascular endothelium throughout the lung as early as day 15 of gestation. In contrast, ACE expression was observed in the endothelium of only hilar pulmonary arteries on day 15 of gestation, and thereafter was noted to be expressed in endothelial cells of progressively more distal arteries, such that by term, endothelial cells of all muscularized arteries expressed ACE. Alveolar capillary ACE expression was not detected until day 20 of gestation, and increased dramatically after birth. Smooth muscle actin expression in lung arteries closely paralleled the expression of endothelial ACE. AT1 receptor mRNA was first expressed in the peripheral lung on day 17 of gestation by non-epithelial undifferentiated mesenchyme. In contrast, AT1 mRNA signal was much reduced in differentiated smooth muscle. We speculate that ACE expression in the fetal lung circulation may influence the muscularization of fetal pulmonary arteries by the interaction of locally produced angiotensin II with the AT1 receptor.
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PMID:Developmental regulation of angiotensin converting enzyme and angiotensin type 1 receptor in the rat pulmonary circulation. 865 81

Possible involvement of cardiac renin-angiotensin system (RAS) in pressure overload induced left ventricular hypertrophy (LVH) was investigated. Rats were subjected to abdominal aortic constriction (AAC) and examined the effects of 4 weeks treatments with an angiotensin converting enzyme (ACE) inhibitor, captopril and a vasodilator, hydralazine on haemodynamics and ventricular RNA, DNA, protein and myosin isoform pattern in sham and hypertrophied rats. AAC increased the mean arterial pressure (MAP) and systolic blood pressure (SBP), and resulted in increased left ventricle/body weight ratio, LV thickness, RNA and protein content, however total DNA was not changed. The expression of fetal isogene, beta-myosin heavy chain (beta-MHC), was markedly enhanced where as alpha-MHC was reduced. High-dose captopril (100 mg/kg p.o.,) significantly prevented the increase in haemodynamics, development of LVH, LV remodeling, increase in total protein, RNA and antithetical expression of myosin isoforms. Hydralazine (15 mg/kg p.o.,), did not modulate hypertrophic changes and low-dose captopril (1.5 mg/kg p.o.,) which has not produced any marked fall in MAP and SBP also modulated favourably the development of LVH and its biochemical markers. Thus, the prevention of the development of LVH and induction of beta-MHC by non-hypotensive doses of captopril may be related to the blockade of intracardiac production of angiotensin II rather than circulating system. These results suggest that cardiac RAS may play an important role in pressure overload induced LVH.
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PMID:Role of cardiac renin-angiotensin system in the development of pressure-overload left ventricular hypertrophy in rats with abdominal aortic constriction. 871 33

Crossbridge properties of cardiomyopathic Syrian hamster (CSH) diaphragm from the dilated Bio 53-58 strain were analyzed after 5-mo of treatment with the angiotensin converting enzyme (ACE) inhibitor perindopril (1 mg/kg/d by oral gavage). Three groups were studied: control F1B hamsters (C; n = 14); CSH given placebo (PL; n = 11 ); and perindopril-treated CSH (PE; n = 11). Peak isometric tension was lower in PL than in C, in both twitch (21.4 +/- 1.5 versus 46.9 +/- 1.5 mN/mm2; p < 0.001) and tetanus (41.0 +/- 2.7 versus 90.5 +/- 3.3 mN/mm2; p < 0.001). In PE, peak isometric tension was intermediate between C and PL, and was significantly lower than in C and higher than in PL. The single force of one crossbridge (pi), the number (m) of crossbridges, the turnover rate of myosin adenosine triphosphatase (ATPase) (kcat), and peak mechanical efficiency (Effmax) were calculated from A.F. Huxley's equations; m was lower in PL than in C, in both twitch (3.4 +/- 0.2 versus 4.9 +/- 0.2 10(9)/mm2; p < 0.001) and tetanus (4.0 +/- 0.3 versus 8.9 +/- 0.7 10(9)/mm2; p < 0.001); m was higher in PE than in PL, in both twitch 4.3 +/- 0.5 versus 3.4 +/- 0.2 10(9)/mm2; NS) and tetanus (6.2 +/- 0.4 versus 4.0 +/- 0.3 10(9)/mm2; p < 0.01), with no change in pi. In the three groups, Effmax correlated linearly with kcat (r = 0.93; p = 0.001) and showed a negative linear correlation with pi (r = 0.996; p = 0.001). In conclusion, our results show that in experimental cardiomyopathy, ACE inhibitor mainly helps to prevent a decrease in the number of diaphragm muscle crossbridges, resulting in preserved peak isometric tension.
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PMID:Effects of angiotensin converting enzyme inhibition on crossbridge properties of diaphragm in cardiomyopathic hamsters of the dilated bio 53-58 strain. 903 5


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