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)

Systemic vasoconstriction due to stimulation of the sympathetic and renin-angiotensin-aldosterone systems is a hallmark of heart failure and this is accompanied by impaired endothelium-dependent relaxations at the level of large arteries. This study investigated, in a rat model of heart failure, whether such an endothelial dysfunction also exists at the level of the resistance artery, and whether this is associated with morphologic changes, as well as the effects of chronic treatment with the angiotensin-converting enzyme inhibitor perindopril (2 mg/kg/day). After 12 months, arterial pressure, left ventricular (LV) end diastolic pressure (LVEDP), and LV dP/dt were measured in anesthetized rats. Responses to acetylcholine and nitroprusside were determined in isolated and perfused mesenteric artery segments (diameter: 280 +/- 15 microns). After fixation, vessel diameter, media cross-sectional area, and media collagen and elastin densities were measured by image analysis. After 12 months, untreated rats showed signs of heart failure, i.e., reduced LV dP/dt, and increased LVEDP, heart weight/body weight, LV cavity circumference, and myocardial collagen density. In mesenteric vessels the endothelium-dependent vasodilator response to acetylcholine was impaired, whereas the response to the nitric oxide donor nitroprusside was unaffected. Heart failure did not affect vascular morphological parameters. Perindopril decreased blood pressure and LVEDP without any modification of LV dP/dt, and prevented cardiac remodeling. At the vascular level, perindopril improved the response to acetylcholine and reduced media cross-sectional area and collagen density without affecting internal vessel diameter or elastin density. Thus, heart failure decreases endothelium-dependent vasodilator response to acetylcholine without modification of vessel structure.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Vascular and myocardial protective effects of converting enzyme inhibition in experimental heart failure. 748 84

Evidence from in vivo, in vitro, and genetic studies suggests that the reversal as well as the development of left ventricular hypertrophy do not depend solely on hemodynamic load; other factors are involved. Several humoral agents that may affect mitogenesis of cardiac myocytes and nonmyocitic elements have been identified, including the local renin-angiotensin system, norepinephrine, endothelins, transforming growth factor beta, insulin-like growth factor, bradykinin, prostaglandins, and nitric oxide. Animal studies using various models of left ventricular hypertrophy are beginning to suggest that reversal of hypertrophy may decrease mortality, improve coronary flow reserve, and maintain cardiac performance. Studies in humans are less supportive, and more are needed before it may be concluded that reduction of left ventricular mass decreases the cardiovascular morbidity and mortality associated with cardiac hypertrophy.
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PMID:Reversal of hypertrophy: an active biologic process. 749 54

We conducted the present study to investigate whether the vasodilator nitric oxide plays a role in plasma volume homeostasis during pregnancy. Pregnant Sprague-Dawley rats were randomly assigned to a control group (n = 18) or to groups receiving 0.69 mmol/L (n = 11) or 1.7 mmol/L (n = 14) N omega-nitro-L-arginine, a competitive inhibitor of nitric oxide synthetase, from gestational days 7 through 21. On day 20 systolic pressure was measured. On day 21 blood samples were taken for plasma volume, hematocrit, and hormonal measurements. Fetal and placental weights also were determined. Systolic pressure was significantly higher in experimental rats (101 +/- 6 and 115 +/- 6 mm Hg in the 0.69 and 1.7 mmol/L groups, respectively) than in controls (79.7 +/- 7.5 mm Hg), and plasma volume was lower (18.4 +/- 1.1 and 17.1 +/- 0.5 mL) than in controls (21.5 +/- 0.8 mL). Both experimental groups had increased hematocrit levels. Plasma renin activity was significantly lower in the experimental groups (11.5 +/- 3 and 7.2 +/- 1.5 ng angiotensin I/mL per hour) than in controls (21.9 +/- 2.7 ng angiotensin I/mL per hour); however, no changes were observed in aldosterone levels. Experimental groups had lower fetal weight (4.6 +/- 0.1 and 5.1 +/- 0.1 g) than controls (5.5 +/- 0.1 g). In addition, fetal hindlimb hypoplasia was observed in the experimental groups. In conclusion, the present data indicate that long-term N omega-nitro-L-arginine administration to pregnant rats leads to increased blood pressure, reduced plasma volume expansion, lower plasma renin activity, and fetal growth retardation.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Effects of long-term nitric oxide synthesis inhibition on plasma volume expansion and fetal growth in the pregnant rat. 749 60

Angiotensin-converting enzyme (ACE) inhibitors were designed to prevent the vasoconstrictor influence of the activated renin-angiotensin system. However, it has long been suspected that the vasodilator actions of these compounds are not entirely related to inhibition of the generation of angiotensin II. Bradykinin, which is rapidly degraded by ACE, stimulates the release of endothelium-derived vasodilator mediators, including nitric oxide, endothelium-derived hyperpolarizing factor, and prostacyclin. These mediators do not contribute to the vasodilator effect of bradykinin in every arterial bed. However, the prevention by ACE inhibitors of the degradation of bradykinin-induces an augmentation of the production of these substances and thus potentiates the dilatation evoked by the peptide. The existence of a local kallikrein-kinin system in the vascular wall has been demonstrated, and locally generated kinins contribute to the acute vasodilator actions of ACE inhibitors. ACE inhibitors can potentiate endothelium-dependent dilatations evoked by neurohumoral mediators that are not substrates for ACE. Thus, the vasodilator properties of ACE inhibitors not only reflect inhibition of the renin-angiotensin system but also depend on the enhanced production of endothelium-derived mediators.
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PMID:Endothelium-dependent effects of converting-enzyme inhibitors. 750 46

The influence of dietary sodium restriction and angiotensin II blockade on hypertension induced by a 25-day period of administration of the inhibitor of nitric oxide synthesis NG-nitro-L-arginine methyl ester (L-NAME: 10 mg/kg twice daily by gavage) was assessed in Wistar rats fed a normal or low sodium diet. In addition, the angiotension II receptor blocker, losartan (30 mg/kg once daily by gavage) was administered prior to and during L-NAME in rats fed the normal sodium diet. Results expressed as mean +/- ESM are presented in the following table: [table: see text] At the end of studies, conscious systolic arterial pressure increased similarly in L-NAME-treated groups maintained on NS or LS intake. Moreover, a 25% reduction in cardiac output due to a decrease in stroke volume was observed in both groups. A slight but significant cardiac hypertrophic response was observed in hypertensive rats irrespective of sodium intake. Losartan totally prevented the development of hypertension as well as the decrease in cardiac output and the cardiac hypertrophy associated with L-NAME treatment in rats on normal sodium intake. In conclusion, hypertension resulting from chronic blockade of nitric oxide synthesis was not affected by dietary sodium restriction. A crucial role for the renin-angiotensin system was demonstrated in this new model of hypertension.
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PMID:[Sodium intake and angiotensin in hypertension induced by chronic NO synthase inhibition in the rat]. 751 Apr 68

From pharmacologic investigations and clinical studies it is known that angiotensin-converting enzyme (ACE) inhibitors exhibit additional local actions, which are not related to hemodynamic changes and which cannot be explained simply by interference with the renin-angiotensin system with subsequent inhibition of angiotensin II formation. Because ACE is identical to kininase II, which inactivates the nonapeptide bradykinin (BK), potentiation of BK might be responsible for these additional effects of ACE inhibitors. To prove the specificity of BK-mediated effects by ACE inhibition, we used the specific B2 kinin receptor antagonist HOE 140 in different models: endothelial cell cultures; atherosclerosis in high-cholesterol-fed rabbits; neointima formation with smooth cell proliferation and migration after endothelial denudation in rats; myocardial ischemia in rats, rabbits, and dogs; and left ventricular hypertrophy in rats. The beneficial effects of ramipril or BK given in non-blood pressure-lowering doses in these models were abolished by HOE 140 (icatibant). Ramipril exerts cardioprotective effects in different experimental models. The formation of the endothelial autacoids nitric oxide and prostacyclin, enhanced when BK degradation is inhibited by ACE inhibition, may contribute to the observed beneficial effects.
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PMID:Contribution of bradykinin to the cardiovascular effects of ramipril. 751 34

The characterization and cloning of constitutive and inducible nitric oxide (NO)-synthesizing enzymes and the development of specific inhibitors of the L-arginine NO pathway have provided powerful tools to define the role of NO in renal physiology and pathophysiology. There is increasing evidence that endothelium-derived NO is tonically synthesized within the kidney and that NO plays a crucial role in the regulation of renal hemodynamics and excretory function. Bradykinin and acetylcholine induce renal vasodilation by increasing NO synthesis, which in turn leads to enhancement of diuresis and natriuresis. The blockade of basal NO synthesis has been shown to result in decreases of renal blood flow and sodium excretion. These effects are partly mediated by an interaction between NO and the renin angiotensin system. Intrarenal inhibition of NO synthesis leads to reduction of sodium excretory responses to changes in renal arterial pressure without an effect on renal autoregulation, suggesting that NO exerts a permissive or a mediatory role in pressure natriuresis. Nitric oxide released from the macula densa may modulate tubuloglomerular feedback response by affecting afferent arteriolar constriction. Nitric oxide produced in the proximal tubule possibly mediates the effects of angiotensin on tubular reabsorption. In the collecting duct, an NO-dependent inhibition of solute transport is suggested. The L-arginine NO pathway is also active in the glomerulus. Under pathologic conditions such as glomerulonephritis, NO generation is markedly enhanced due to the induction of NO synthase, which is mainly derived from infiltrating macrophages. An implication of NO in the mechanism of proteinuria, thrombosis mesangial proliferation, and leukocyte infiltration is considered. In summary, the data presented on NO and renal function have an obvious clinical implication. A role for NO in glomerular pathology has been established. Nitric oxide is the only vasodilator that closely corresponds to the characteristics of essential hypertension. Using chronic NO blockade, models of systemic hypertension will provide new insights into mechanisms of the development of high blood pressure.
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PMID:Nitric oxide in the kidney: synthesis, localization, and function. 751 25

Nitric oxide (NO) has effects on renal blood flow, glomerular filtration rate, renin secretion, and renal sodium excretion. Four isoforms of nitric oxide synthase (NOS) have been cloned to date. However, the molecular identity of NOS present in the renal vasculature is unknown. Endothelial NOS (NOS-III) is regulated both acutely by cell calcium and chronically by shear stress. To determine if renal blood vessels and the glomerulus express NOS-III mRNA, we used degenerate polymerase chain reaction (PCR) to clone a portion of rat NOS-III. We then assayed NOS-III mRNA in microdissected renal structures by reverse transcriptase-PCR. NOS-III mRNA was expressed at high levels in glomeruli, arcuate vessels, and interlobular artery/afferent arterioles. NOS-III mRNA was detected inconsistently in proximal tubules, thick ascending limbs, and cortical and inner medullary collecting ducts. Previous studies have shown that chronic oral treatment with the NOS inhibitor N omega-nitro-L-arginine methyl ester (L-NAME) decreases NO synthesis and causes hypertension. To determine if the systemic blockade occurs only by competitive inhibition, we determined the effect of L-NAME on glomerular NOS-III mRNA. L-NAME administration (5 days) decreased NOS-III mRNA in the glomerulus to 25 +/- 12% of control levels. We conclude that endothelial NOS-III mRNA is preferentially expressed in the glomerulus and renal vasculature, where it can modulate renal blood flow and glomerular filtration rate. Furthermore, glomerular NOS-III may be modulated at the level of mRNA abundance in vivo by systemic L-NAME.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Localization and regulation of endothelial NO synthase mRNA expression in rat kidney. 752 Jun 68

Vascular endothelial cells produce various biologically active factors regulating blood pressure, coagulation, and possibly cell growth of the vascular wall. Of the factors, nitric oxide (NO) has been the object of attention because of its quite simple molecular structure and variety of biological functions. In the present review, we focused on the physiologic and pathologic aspects of NO in hypertension. In experimental animals, both acute and chronic inhibition of NO synthase (NOS) with arginine derivatives produce a significant rise in blood pressure, indicating that tonic production of NO regulates basal vascular tonus. The chronic hypertension caused by NOS inhibitor is associated with cardiac hypertrophy and renal insufficiency. Sodium retention, though transient, and the plasma and tissue renin/angiotensin system in addition to the reduced production of NO have been implicated in the development of hypertension. Hypertension and the associated target organ failure can be reversed by co-administration of L-arginine or blockades of the renin/angiotensin system. Studies in which L-arginine as the substrate of NO or NOS inhibitor was administered demonstrated an important role of NO in the regulation of tonic vascular tonus also in normal subjects. In hypertensive subjects, however, endothelium-dependent vasorelaxation and production of NO are impaired, possibly due to a deficiency of L-arginine and/or a disorder of its utilization. Recent advances in the methods of detecting NO enabled us to demonstrate its diminished production from endothelial cells of hypertensive rats in vitro, although no definite biochemical evidence has been obtained in hypertensive subjects. The endothelial dysfunction, however, is not a primary cause of hypertension but a secondary result since it is commonly observed in various types of hypertension and can be reversed by correcting the blood pressure. Other common diseases including atherosclerosis and diabetes mellitus are also associated with similar abnormalities of the endothelium. NO has anti-atherogenic actions: inhibition of platelet functions and proliferation of vascular smooth muscle cells. Therefore, potentiation of endogenous NO and/or supplement of exogenous NO donors could be novel therapeutic approaches for the treatment of hypertension and atherosclerosis, while potential adverse effects of NO including cytotoxicity, immunosuppressibility, and hypotensive shock should be taken into account.
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PMID:[Clinical significance of nitric oxide in hypertension]. 752 65

This study was aimed to make a new stable model of chronic hypertension by administration of a nitric oxide synthase inhibitor. L-Nw-nitroarginine methylester (NAME), and using this model, to investigate the roles of nitric oxide for the cardiovascular regulation. Male Wistar rats were implanted of osmotic pumps filled with saline (control group: n = 8), 0.2M NAME (low NAME group: n = 13) or 1M NAME (high NAME group: n = 12) intraperitoneally. After 4-week observation of blood pressure (BP) and heart rate (HR), blood concentrations of cathecholamine, active renin, L-arginine and L-Nw-nitroarginine were measured and histological changes in aorta and heart were examined. Age-matched SHRSP (n = 9) served as positive controls. BP elevated in the low NAME and high NAME group (113.9 +/- 3.1 to 144.0 +/- 4.4 mmHg, and 114.1 +/- 7.3 to 181.4 +/- 9.0 mmHg, respectively; mean +/- S.E.), while BP remained constant in the control group and SHRSP group (116.8 +/- 5.5 to 120.6 +/- 1.9 mmHg, 200.3 +/- 5.1 to 213.8 +/- 7.4 mmHg, respectively). HR in the low NAME and high NAME group rapidly decreased (not equal to 410 to not equal to 340 bpm) and then slowly returned to the control level. HR in the control group and SHRSP group remained constant (not equal to 420 and not equal to 450 bpm, respectively). Noradrenaline increased significantly in the high NAME group (0.21 +/- 0.03 ng/ml), and there were no significant changes in the control, low NAME and SHR group (0.13 +/- 0.02, 0.14 +/- 0.02, 0.15 +/- 0.03 ng/ml, respectively). Adrenaline, dopamine and active renin concentrations did not differ among 4 groups. Aortic wall/lumen area ratio in the high NAME group was similar to that in SHRSP group, in spite of its lower BP and shorter duration of hypertension compared with SHRSP. Left ventricular wall of the high NAME group was significantly thicker than that of SHRSP group. These findings suggest that, in addition to endothelium-derived NO, NO produced in the brain and peripheral neurons may function to regulate cardiovascular system by inhibiting noradrenaline release from sympathetic nerves or by inhibiting cardiac and vascular cell proliferation.
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PMID:[Study on roles of L-arginine to nitric oxide pathway for the cardiovascular control: assessment with a new model of hypertension produced by the chronic administration of nitric oxide synthase inhibitor]. 752 39


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