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:3.4.23.15 (renin)
35,795 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The effect of enalapril on the intracellular resistance (ri) and conduction velocity was investigated in isolated rat trabeculae. The results indicated a decline in the internal resistance of 35.5% (SE +/- 3.3) and an increase in conduction velocity of 58.7% (SE +/- 6.6). The action potential duration was not altered, but the resting potential was increased by 10.5 mV (SE +/- 4.4). Enalaprilat had no effect on ri probably because the molecule is a diacid and does not cross the cell membrane. These findings indicate that the renin-angiotensin system is involved in the modulation of cell communication in cardiac muscle and that the beneficial effect of the drug in patients with congestive heart failure is, in part, related to an improvement of electrical synchronization of heart cells.
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PMID:Effect of enalapril on intracellular resistance and conduction velocity in rat ventricular muscle. 769 67

This study was designed to quantitate cardiac mRNA levels encoding components of the local renin-angiotensin system during the development of volume overload-induced cardiac hypertrophy. Changes in cardiac renin mRNA levels were measured in relation to renin activity in the left ventricle (LV) and in plasma after acute passive stretch of the heart caused by an aortovenocaval shunt in the rat. A quantitative reverse-transcriptase polymerase chain reaction method with competitive internal standards was used to measure mRNA levels in total RNA derived from cardiac tissues after shunt. Seven days after shunt surgery, LV weight was increased by 23%. Renin activities were elevated four- and twofold in plasma and LV, respectively. LV angiotensinogen mRNAs were not significantly increased by shunt surgery; they were twofold higher than phosphoglycerate kinase mRNA from the housekeeping gene PGK-1. By day 7, LV levels for renin mRNA were significantly increased from well below 0.25% to approximately 1% of PGK-1 mRNA. Identity between renin polymerase chain reaction products from kidney and heart cDNAs and absence of "reninlike" amplification products were supported by Southern blotting. Volume overload caused increased expression of the renin gene in the stretched myocardium. This finding is consistent with the concept of a myocardial renin-angiotensin system that can be activated by locally produced renin and contributes to the hypertrophy of cardiac muscle.
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PMID:Stretch-mediated activation of cardiac renin gene. 794 10

Hypertrophy is a fundamental adaptive process employed by postmitotic cardiac and skeletal muscle in response to mechanical load. How muscle cells convert mechanical stimuli into growth signals has been a long-standing question. Using an in vitro model of load (stretch)-induced cardiac hypertrophy, we demonstrate that mechanical stretch causes release of angiotensin II (Ang II) from cardiac myocytes and that Ang II acts as an initial mediator of the stretch-induced hypertrophic response. The results not only provide direct evidence for the autocrine mechanism in load-induced growth of cardiac muscle cells, but also define the pathophysiological role of the local (cardiac) renin-angiotensin system.
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PMID:Autocrine release of angiotensin II mediates stretch-induced hypertrophy of cardiac myocytes in vitro. 825 33

Although various factors, such as myocardial infarction, pressure overload and volume overload, result in the development of congestive heart failure (CHF), the pathogenesis of contractile dysfunction in this situation is poorly understood. Loss of cardiac muscle due to myocardial infarction appears to activate several humoral and hormonal pathways, including the renin-angiotensin and sympathetic systems which serve as adaptive mechanisms to maintain cardiovascular performance at early stages of failure. However, under chronic conditions, an altered hormonal profile produces deleterious effects and permits transition from the compensated heart to the failing heart. Since several risk factors--such as hypertension, hypercholesteremia, stress, diabetes, smoking, ageing, obesity and lack of exercise--precipitate ischemic heart disease, it is possible that development of CHF due to myocardial infarction may vary according to the nature of these pathogenetic entities. While a great deal of research work remains in this area of investigation, it is becoming evident that cardiac dysfunction is intimately associated with calcium handling abnormalities of cardiac cells. In view of the role of sarcolemma, sarcoplasmic reticulum and mitochondria in regulating the intracellular concentration of Ca2+ and the importance of myofibrillar interaction with Ca2+, it appears that Ca2+ handling and Ca2+ interaction abnormalities in the failing heart are due to remodelling of different subcellular organelles. Such a remodelling of the subcellular organelles may be due to changes in gene expression for different protein components or the interactions of proteins with phospholipids. Accordingly, it is proposed that new interventions, which could prevent the remodelling of subcellular organelles, be developed for improving the therapy of CHF.
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PMID:Pathophysiology of cardiac dysfunction in congestive heart failure. 828 76

Hypoxic pulmonary hypertension is characterized by profound remodeling of the walls of small pulmonary arteries: endothelial swelling and proliferation of media and adventitia to a degree that may narrow the lumen. The molecular mechanism responsible for these changes is unknown. Recent studies have demonstrated the existence of a vascular and cardiac renin-angiotensin system. This system can induce hypertrophy and proliferation of aortic smooth muscle cells and cardiac muscle cells in animal models of systemic hypertension. In the present experiments, Northern blot analysis and a receptor binding assay specific to angiotensin II (Ang II) receptors was used to study the pulmonary renin angiotensin system in a rat model of hypobaric hypoxic pulmonary hypertension. mRNA transcripts for the Ang II receptor AT(1A) were constitutively expressed, and specific binding of Ang II to the receptors occurred in lung tissue of control rats that breathed ambient air. After 3 days of hypobaric hypoxia (380 Torr), the AT(1A) mRNA level and the index of Ang II receptors had increased, but right ventricular hypertrophy was not still evident. Ang II receptors were significantly increased after 14 days of hypoxia, when histological evidence of pulmonary hypertension was observed. In addition, the Ang II level in pulmonary tissue was higher after 14 days of hypoxia than in normal controls. These findings suggest that the renin-angiotensin system in pulmonary tissue was activated in these rats, and that it contributes to the morphological changes observed in hypoxic pulmonary hypertension.
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PMID:[Angiotensin II receptors in a rat model of hypobaric hypoxic pulmonary hypertension]. 862 75

Experimental myocardial infarction is a model of cardiac overload in which part of the cardiac muscle is removed. The resulting left ventricle insufficiency depends on the size of the infarct and time. The infarcted area remodels, due to proteolytic activity of inflammatory cells and collagenogenesis from fibroblast activity. The phenotype of the residual healthy cardiac muscle undergoes modification, and there are peripheral vascular changes which are partly dependent on the activation of pressor systems and/or inactivation of dilator systems. The changes are proportional to the infarct size at any given time after induction of the model. The degree of right ventricular hypertrophy and the drop in arterial pressure are upstream and downstream markers of the loss of left ventricular function and therefore indicate the extent of the remodelling. The increase of type V3isomyosin, the amount of subendocardial collagen, and the biosynthesis, storage and secretion of atrial natriuretic factor (ANF) are all proportional to the infarct size and the degree of cardiac overload. The level of urinary cGMP is also correlated with infarct size. These indices show ventricular remodelling, increased stress and energy restriction of the residual healthy cardiac muscle. The activation of peripheral pressor systems also depends on infarct size. They reflect the influence of defective cardiac pumping on the kidney, liver, brain and endothelium. Massive infarcts are accompanied by an increase in circulating renin and in renal renin content, by a decrease in angiotensinogen due to its consumption by renin, and to its insufficient hepatic synthesis, and by an increase in vasopressin secretion and biosynthesis in the hypothalamus. Converting enzyme inhibition has beneficial effect in this model by lowering cardiac load. It reduces arterial pressure, reverses bi-atrial and right ventricular hypertrophy, reduces the changes in the myosin isoenzyme patterns, and normalizes subendocardial fibrosis and the level of ANF. Although the effects of converting enzyme inhibition are beneficial in this model, they are restricted by their inability to normalize the load and stress when the initial loss of cardiac contractile material exceeds 40%.
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PMID:Left ventricular remodelling following experimental myocardial infarction. 882 57

1. Transgenic(TG) (mRen-2) rats overexpressing the mouse renin gene develop fulminant hypertension and cardiac hypertrophy. Since the activation of AT1 receptor by angiotensin II is involved in blood pressure regulation, cardiac performance and myocardial growth, we investigated the biological effects of angiotensin II and the regulation of the AT1 receptor in the heart and aorta of TGR (mRen-2)27 rats in comparison to control animals. 2. Contraction studies on isolated cardiac muscle strips reveal that angiotensin II exerts no positive inotropic effect on the left ventricular myocardium of both, transgenic and control rats. In contrast, angiotensin II leads via AT1 receptor activation in the left atrium of control rats to a significant contraction (130 +/- 5% of basal contraction) which is not detectable in left atrium preparations of the transgenic animals. Furthermore, AT1 receptor activation causes a profound contraction of aortic rings isolated from control rats amounting to 1.39 +/- 0.2 mN mg-1 wet weight, whereas aortic rings from TGR (mRen-2)27 rats contract only minimally upon angiotensin II stimulation (0.2 +/- 0.02 mN mg-1 wet weight). 3. These altered physiological responses of angiotensin II in the transgenic rats are in part due to a marked down-regulation of the AT1 receptor in atrial, ventricular and aortic tissue of these transgenic animals in comparison to control Sprague-Dawley rats, as shown by radioligand binding assays and quantitative polymerase chain reaction (PCR) experiments. The AT1 receptor density Bmax in the left atrium was 1.3 +/- 0.08 fmol mg-1 protein in control rats (KD 1.1 +/- 0.18 nmol l-1) and 0.94 +/- 0.15 fmol mg-1 protein (KD 2.1 +/- 0.3 nmol l-1. In the aorta Bmax values were 15.1 +/- 0.5 fmol mg-1 protein (KD 1.9 +/- 0.27 nmol l-1) for control rats and 11.3 +/- 0.76 fmol mg-1 protein (KD 1.9 +/- 0.27 nmol l-1) for the TGR(mRen-2)27 rats AT1 receptor mRNA was reduced in the transgenic animals to 46 +/- 3% in the left atrium, 50 +/- 11% in the left ventricle and 40 +/- 3% in the aorta, respectively. 4. Together, the AT1 receptor is down-regulated in TGR (mRen-2)27 rats in comparison to wildtype Sprague Dawley rats leading to a profoundly decreased response of cardiac and aortic tissue upon stimulation with angiotensin II.
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PMID:Down-regulation of aortic and cardiac AT1 receptor gene expression in transgenic (mRen-2) 27 rats. 914 97

Heart failure is defined as a malfunction of the cardiac muscle. The ongoing interaction between pump failure and the vasculature, however, results in symptoms due to malperfusion of the pulmonary and systemic circuit. As a consequence, biologic systems of pressure and volume control are activated. In the neurohumoral heart failure model the sympathetic nervous system, the renin system and endothelin all develop their own pathologic contribution to the disease process. Thereby the role of endothelin seems to be special since its production is particularly increased in advanced disease. Like angiotensin, endothelin has major proliferative properties to promote adverse vascular and myocardial growth. The finding of increasing neurohumoral activation as heart failure progresses and the role of plasma levels of neurohormones as predictors of mortality has rearranged the primary goal of therapy to suppress these deleterious neurohumoral systems as completely as possible. Though angiotensin converting enzyme inhibitors are currently first line therapy of heart failure, uncertainties remain concerning their mechanisms of action and - associated to that - optimal dosing.
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PMID:[Significance of neuroendocrine parameters in heart failure]. 965 97

Myocardial hypertrophy is one of the basic mechanisms by which the heart compensates for hemodynamic overload. The mechanisms by which hemodynamic overload is transduced by the cardiac muscle cell and translated into cardiac hypertrophy are not completely understood. Candidates include activation of the renin-angiotensin system (RAS) and angiotensin II receptor (AT1) stimulation. In this study, we tested the hypothesis that load, independent of the RAS, is sufficient to stimulate cardiac growth. Four groups of cats were studied: 14 normal controls, 20 pulmonary artery-banded (PAB) cats, 7 PAB cats in whom the AT1 was concomitantly and continuously blocked with losartan, and 8 PAB cats in whom the angiotensin-converting enzyme (ACE) was concomitantly and continuously blocked with captopril. Losartan cats had at least a one-log order increase in the ED50 of the blood pressure response to angiotensin II infusion. Right ventricular (RV) hypertrophy was assessed using the RV mass-to-body weight ratio and ventricular cardiocyte size. RV hemodynamic overload was assessed by measuring RV systolic and diastolic pressures. Neither the extent of RV pressure overload nor RV hypertrophy that resulted from PAB was affected by AT1 blockade with losartan or ACE inhibition with captopril. RV systolic pressure was increased from 21 +/- 3 mmHg in normals to 68 +/- 4 mmHg in PAB, 65 +/- 5 mmHg in PAB plus losartan and 62 +/- 3 mmHg in PAB plus captopril. RV-to-body weight ratio increased from 0.52 +/- 0.04 g/kg in normals to 1.11 +/- 0.06 g/kg in PAB, 1.06 +/- 0.06 g/kg in PAB plus losartan and 1.06 +/- 0.06 g/kg in PAB plus captopril. Thus 1) pharmacological modulation of the RAS with losartan and captopril did not change the extent of the hemodynamic overload or the hypertrophic response induced by PAB; 2) neither RAS activation nor angiotensin II receptor stimulation is an obligatory and necessary component of the signaling pathway that acts as an intermediary coupling load to the hypertrophic response; and 3) load, independent of the RAS, is capable of stimulating cardiac growth.
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PMID:Hypertrophic response to hemodynamic overload: role of load vs. renin-angiotensin system activation. 995 Aug 33

Because of conflicting results in the literature, further studies are needed to confirm an association between the degree of salt consumption and insulin sensitivity. The aim of this study was to measure insulin sensitivity in rats fed from weaning to adulthood with a low (LSD), normal (NSD), or high (HSD) salt diet. Body weight, carcass lipid content, blood glucose, nonesterified fatty acids, plasma insulin, plasma renin activity, and a glucose transporter (GLUT4) were measured. A euglycemic hyperinsulinemic clamp was used in 52 anesthetized rats. Body weight was higher in rats on LSD than in those on NSD (P<0.05) or HSD (P<0.001). Percentage fat carcass content was higher (P<0.05) in rats on LSD than in those on NSD. Basal plasma insulin and glucose levels were not altered (P>0.05) by salt consumption. Nonesterified fatty acids were lower in rats on HSD than in those on LSD (P<0.05) or NSD (P<0.01). Glucose uptake was lower in rats on LSD than in those on NSD (P<0.05) or HSD (P<0. 001). When a euglycemic hyperinsulinemic clamp was used on pair-weight rats, similar results were obtained, which suggests that the effect of LSD on insulin sensitivity was not due to higher body weight. GLUT4 in insulin-sensitive tissues was increased in rats on HSD except in the cardiac muscle. Captopril treatment partially reversed low insulin sensitivity in LSD rats, whereas losartan did not change it, which indicates that the effect of LSD on insulin sensitivity is angiotensin independent. In conclusion, the present results demonstrate that chronic dietary salt restriction induces a decrease in insulin sensitivity not associated with renin-angiotensin system activity or body weight changes.
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PMID:High- or low-salt diet from weaning to adulthood: effect on insulin sensitivity in Wistar rats. 1064 36


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