Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.23.15 (renin)
 35,795 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The benefit effects of nitric oxide (NO) donors in acute heart failure have led to the development of vasodilators as treatment of chronic heart failure. However, the mechanisms involved in the effects of NO are complex and still discussed. In chronic heart failure, the eNOS downregulation in vascular endothelium explains the alteration of endothelial function. In addition, in the myocardium, cytokines induce the expression of inducible nitric oxide synthase (iNOS) which increase NO production by myocytes and surrounding cells. This excess of NO production, associated with anion superoxide synthesis, limits the inotropic properties of catecholamines and exert proapoptotic effects. The role of NO donors in heart failure treatment is still controversial but by reducing preload they improve patient's symptoms. Beside blockade of the renin-angiotensin system, the angiotensin converting enzyme inhibitors act via the inhibition of bradykinin degradation which increase NO levels. Finally, vascular endothelial NO expression is improved by exercise training and participates in the improvement of exercise capacity in patients with chronic heart failure involved in cardiac readaptation program.
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PMID:[Role of nitric oxide in heart failure]. 1132 16

In nephrology, intensive research has focused in recent years on the interplay between NO produced by the different isoforms of NO synthase (NOS) and complex renal functions. In this regard, the juxtaglomerular apparatus is of particular interest. First, it is the main site for control of renal blood flow by autoregulation and of glomerular filtration rate by tubuloglomerular feedback, as well as of renin secretion. Second, two constitutive NOS, nNOS and eNOS, are expressed, respectively, in the macula densa cells and in the endothelium of the afferent and efferent arteriole. It was thus not unexpected that NO could interact with the physiological variables. Indeed, NO attenuates rapidly the autoregulatory efficacy of renal blood flow as well as the sensitivity of the tubuloglomerular feedback by inhibiting Ca++ influx mainly in the afferent arteriole. On the other hand, renin secretion may be stimulated as well as inhibited by NO. These opposing effects, although as yet unexplained, could be related to the source of NO. If so, the hypothetical dual effect of NO could be secondary to a difference in modulation of each NOS isoform by their specific stimuli and results in secretion or not of renin. This hypothesis seems to be applicable to changes in extracellular volume.
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PMID:[Paracrine kidney activity and homeostasis: the emergence of nitric oxide. A conceptual perspective]. 1147 97

Blood pressure is frequently elevated, blood volume is usually normal or increased and plasma renin and aldosterone are usually low in nephrotic syndrome (NS). These observations challenge the conventional view attributing sodium retention in NS to a hypoalbuminemia-induced intravascular volume contraction. Given the pivotal role of nitric oxide (NO) in regulation of renal sodium (Na) handling, vascular resistance and sympathetic activity, we considered that Na retention and hypertension in NS may be associated with impaired NO system. Urinary excretion of Na and NO metabolites (NOx), as well as immunodetectable endothelial (eNOS), inducible (iNOS) and neuronal (nNOS) NO synthases were determined in rats with puromycin aminonucleoside (PAN)-induced NS, rats with protein overload proteinuria, Nagase rats (NAR) with inherited analbuminemia, iNOS inhibitor (aminoguanidine)-treated rats, prenephrotic PAN-treated and placebo-treated control rats. The NS group showed marked proteinuria, hypoalbuminemia, decreased fractional excretion of Na (FENa), reduced urinary NOx excretion, and severe reduction of iNOS and nNOS protein abundance in the kidney. Similar results were found in rats with protein overload proteinuria in which proteinuria was present without hypoalbuminemia. In contrast, despite extreme hypoalbuminemia, NAR showed normal FENa, increased urinary NOx excretion and upregulations of iNOS and nNOS protein abundance in the kidney. Administration of aminoguanidine for 3 weeks lowered FENa in normal rats to levels approximating those found in the NS group. Animals studied 2 days after PAN administration (wherein proteinuria was absent) showed no abnormality. Thus, chronic PAN-induced NS results in downregulation of kidney iNOS and nNOS, which can contribute to the reduction of FENa by augmenting renal tubular Na reabsorption, and preglomerular vasoconstriction. Findings in the NAR, which had profound hypoalbuminemia without proteinuria, and in rats with protein overload proteinuria, which had proteinuria without hypoalbuminemia, point to proteinuria as the primary mediator of kidney iNOS and nNOS deficiency and impaired Na excretion in PAN-induced NS.
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PMID:Downregulation of nitric oxide synthase in nephrotic syndrome: role of proteinuria. 1285 18

The influence of estrogen on the regulation of cardiovascular function remains a controversial and complex area of investigation. We assessed the effects of estrogen depletion in the congenic mRen(2). Lewis rat, established from the back-cross of the original (mRen2)-27 transgenic onto the Lewis inbred strain. Ovariectomy of heterozygous mRen(2). Lewis at 4 to 5 weeks resulted in a progressive increase in blood pressure compared with the sham surgery congenics at weeks 6 to 11. At 11 weeks, the ovariectomized mRen(2). Lewis (OVX) systolic blood pressure averaged 195+/-3.7 mm Hg versus 141+/-4.0 mm Hg for sham. Plasma Angiotensin (Ang) II, serum ACE activity, plasma renin concentration, as well as urinary excretion of Ang II, 8-isoprostane F2alpha, and endothelin-1 were elevated; however, renal mRNA levels of eNOS were suppressed after ovariectomy. Estrogen replacement reduced blood pressure below both the sham and OVX by 11 weeks (125+/-2.9 mm Hg, n=7, P<0.01 versus OVX and sham). Moreover, the AT1 receptor antagonist olmesartan (CS866; week 12 to 16) essentially normalized blood pressure to 113+/-5.4 mm Hg (n=6, P<0.01 versus OVX and sham). The attenuation of the hypertension was still evident 7 weeks after complete withdrawal of treatment (124+/-4.1 mm Hg at week 23). In summary, the OVX mRen.2. Lewis exhibited a rapid and sustained increase in blood pressure. Estrogen or olmesartan lowered pressure by a similar extent. We conclude that the ovary exerts considerable influence on the regulation of the blood pressure in the mRen2. Lewis strain, possibly by limiting activation of the renin-angiotensin system.
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PMID:Estrogen or the AT1 antagonist olmesartan reverses the development of profound hypertension in the congenic mRen2. Lewis rat. 1287 87

High-altitude pulmonary oedema (HAPE) is a potentially fatal condition affecting fit and previously well individuals at altitudes in excess of 3000 m. This article discusses the mechanisms of HAPE, considers the contribution of hypoxic pulmonary vasoconstriction and alterations in sodium transport to the pathological process. It discusses the various biochemical mediators such as nitric oxide (NO), endothelin-1 (ET-1), and the renin-angiotensin-aldosterone system (RAS) that may be involved and considers possible oxygen-sensing mechanisms involved in hypoxic adaptation such as hypoxia-inducible factor-1 (HIF-1). Those who have had HAPE once run an unpredictable but significant risk of recurrence; therefore, there may be a constitutional or genetic component in its aetiology. This paper considers the possible involvement of genes that may be involved in physiological adaptation to hypoxia (e.g., angiotensin-1 [AT(1)]-converting enzyme [ACE], tyrosine hydroxylase, serotonin transporter [5-HTT], and endothelial NO synthase [eNOS] genes). As yet, no formal association has been identified between an identified genetic polymorphism and HAPE, but genetic variation provides a possible mechanism to explain interindividual variation in response to hypoxia and enhanced or reduced performance at altitude.
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PMID:The genetic basis of high-altitude pulmonary oedema. 1476 4

The role of genetic susceptibility to coronary artery disease (CAD) seems to be quite important in young patients. In the last years the attention has been focused on polymorphisms influencing some biological functions (coagulation and fibrinolysis, platelets, vascular function, lipid metabolism, inflammation). The study of prothrombotic polymorphisms has kindled a deep interest. The role of atherosclerosis and thrombosis is different in the different ages. In all the studies we examined, the polymorphism G20210A in the prothrombin gene was associated with an increased risk of acute myocardial infarction (AMI) in young people, especially when other risk factors were present. Contradictory results have been found in the studies on Factor V Leiden: according to many authors the activated protein C resistance (APCR) is associated with an increased risk of AMI only in smokers, above all if women. On the other hand, some polymorphisms of the Factor VII gene seem to be protective. Young AMI could be also caused by a reduction of the fibrinolytic activity, as it was found when the allele 4G in the promoter of plasminogen activator inhibitor (PAI) gene is present. The attention has also been focused on the effects of variations in genes that influence platelet functions. According to a metanalysis of studies published up to 1999, there is no association between the polymorphism PlA1/A2 of the GP IIIa gene and young AMI, whereas there is doubt about the role of the polymorphism in the GP IIb e GP Ib genes. Moreover, it seems to be present an association with the polymorphisms in the thrombopoietin gene (C4830A and A5713G). Also the role of some genes coding for proteins influencing the vascular functions has been valued. Few studies were performed on genetics of the renin-angiotensin-aldosterone system and the results are insufficient and contradictory, such as those about the association between the polymorphism G894T in the eNOS gene or the polymorphism C677T in the MTHFR gene and young AMI. Genes coding for proteins involved in the lipid metabolism have been closely examined. Many polymorphisms were discovered in the Apo B gene: the variant C-516T was found to be associated with increased LDL levels, whereas the results about the association between this and other polymorphisms in the same gene (I/D of LAL sequence, PvuII, MspI, Asp4311Ser) and young AMI are discordant. On the other hand, the variant e4 of the ApoE gene was associated with an increased risk of AMI at young age in many works. In the last years, a particular interest has kindled the study of the relationship between inflammation, atherosclerosis and CAD. Even if the studies performed are few, it was found an association between young AMI and polymorphism C-260T in the CD14 gene, between coronarics atherosclerosis and polymorphism A516C in the E Selectin gene or polymorphisms Leu125Val and Ser563Asn in the PECAM1 gene.
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PMID:Genetic risk factors in myocardial infarction at young age. 1528 79

In congestive heart failure, angiotensin-converting enzyme inhibitors (ACEIs) may prevent cardiac fibrosis via interaction with both angiotensin II and endothelin-1, which enhance myocardial collagen synthesis. However, whether endogenous bradykinin with an ACEI modifies the cardiac collagen architecture, affecting the endothelin system, has not yet been fully elucidated. We evaluated the changes in circulating hormonal factors, myocardial fibrosis and cardiac gene expression closely linked with heart failure, using an orally active specific bradykinin type 2 receptor antagonist, FR173657 (0.3 mg/kg/day, n = 6), with an ACEI, enalapril (1 mg/kg/day), in dogs with tachycardia-induced congestive heart failure (270 p.p.m., 22 days) and compared the effects with enalapril alone (n = 6). Although there were no differences observed in blood pressure, plasma renin activity, aldosterone and endothelin-1 levels, combined FR173657 significantly increased the cardiac expression of preproendothelin- 1 mRNA (P < 0.05) and collagen type I and type III mRNA (P < 0.05), and cardiac collagen deposits (P < 0.05), and decreased eNOS gene expression (P < 0.05) in the left ventricle compared with the ACEI-treated group. Furthermore, there was a significant negative correlation between the expression of preproendothelin- 1 and eNOS mRNA levels (r = -0.708, P < 0.001). In conclusion, bradykinin may prevent cardiac fibrosis in part via suppression of the local endothelin system in the failing heart through the enhancement of nitric oxide production under chronic angiotensin-converting enzyme inhibition.
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PMID:Endogenous bradykinin suppresses myocardial fibrosis through the cardiac-generated endothelin system under chronic angiotensin-converting enzyme inhibition in heart failure. 1583 17

Oxidative stress and low-grade inflammation are hallmarks of diabetes mellitus. We explored protective, blood pressure-independent effects of the angiotensin II type 1 (AT(1)) receptor antagonist candesartan and the selective beta(1)-adrenoceptor antagonist metoprolol. Diabetes mellitus was induced in 8-week-old Sprague-Dawley rats after injection of streptozotocin. Diabetic rats were randomized to treatment with candesartan or metoprolol in sub-antihypertensive doses or to placebo treatment. In the quadriceps, musculature markers of oxidative stress and inflammation were determined. Function of the inherent vascular bed was measured in vivo in the autoperfused hindlimb. Increases in NAD(P)H activity, expression of its cytosolic subunit p22(phox) and of endothelial NO synthase e(NOS) displayed enhanced oxidative stress. Upregulated intercellular (ICAM)-1 and vascular cell adhesion molecule (VCAM)-1 and of inducible NOS (iNOS) revealed inflammatory processes. Diabetes was associated with severe impairment of endothelium-dependent and -independent vasodilatation. Candesartan, but not metoprolol, reduced NAD(P)H activity, attenuated diabetes-induced over-expression of p22(phox) and eNOS mRNA as well as ICAM-1, VCAM-1, iNOS and eNOS immunoreactivity and led to a substantial improvement of endothelium-dependent vasodilatation (+46.3% vs. placebo treatment; P<0.05). Angiotensin AT(1) receptor antagonism, but not beta(1)-adrenoceptor antagonism, ameliorates diabetes-generated oxidative stress, indicating a pivotal role of the renin-angiotensin system in the development of diabetic complications.
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PMID:Protection against oxidative stress in diabetic rats: role of angiotensin AT(1) receptor and beta 1-adrenoceptor antagonism. 1613 67

We rescued the embryonic lethality of global PPARgamma knockout by breeding Mox2-Cre (MORE) mice with floxed PPARgamma mice to inactivate PPARgamma in the embryo but not in trophoblasts and created a generalized PPARgamma knockout mouse model, MORE-PPARgamma knockout (MORE-PGKO) mice. PPARgamma inactivation caused severe lipodystrophy and insulin resistance; surprisingly, it also caused hypotension. Paradoxically, PPARgamma agonists had the same effect. We showed that another mouse model of lipodystrophy was hypertensive, ruling out the lipodystrophy as a cause. Further, high salt loading did not correct the hypotension in MORE-PGKO mice. In vitro studies showed that the vasculature from MORE-PGKO mice was more sensitive to endothelial-dependent relaxation caused by muscarinic stimulation, but was not associated with changes in eNOS expression or phosphorylation. In addition, vascular smooth muscle had impaired contraction in response to alpha-adrenergic agents. The renin-angiotensin-aldosterone system was mildly activated, consistent with increased vascular capacitance or decreased volume. These effects are likely mechanisms contributing to the hypotension. Our results demonstrated that PPARgamma is required to maintain normal adiposity and insulin sensitivity in adult mice. Surprisingly, genetic loss of PPARgamma function, like activation by agonists, lowered blood pressure, likely through a mechanism involving increased vascular relaxation.
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PMID:Hypotension, lipodystrophy, and insulin resistance in generalized PPARgamma-deficient mice rescued from embryonic lethality. 1730 52

Endothelium-dependent and endothelium-independent reactions of relaxations of vascular smooth muscle (VSM) were examined in the aorta preparations of the two groups (6-8 and 21-22 month). The studies also two NO synthase (NOS) isoform activity--inducible (iNOS) and constitutive (cNOS), activity of arginase and nitrate reductase and the content of high-molecular nitrosothiols (HMNT) and low-molecular nitrosothiols (LMNT) and stable metabolites of NO (NO(-)2, NO(-)3). Aging rats demonstrated only endothelium-dependent responses of VSM to acethylcholine lowering. This endothelial dysfunction depend on high activity of arginase, iNOS and salvage (by nitrate reductase) NO synthesis, both reactive oxigen species (ROS) (by xanthine oxidase) and peroxynitrite generation, as well as low activity of constitutive (eNOS, nNOS) NO synthesis. Angiotensin-converting enzyme inhibitor (enalapril) administration (20 mg/kg, 30 or 55 days) up regalate constitutive NO synthesis by arginase, iNOS, nitrate reductase activity and ROS and peroxynitrite generation inhibition thus restore endothelium-dependent relaxations of VSM in aging rats. The result obtained suggest a new roles for the renin-angiotensin system in vascular tone regulation. Thus enalapril might serve as a novel tool to prevent aging-associated endothelial dysfunction.
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PMID:[Effect of enalapril on nitric oxide synthesis, oxidative metabolism, and vascular tone in aging rats]. 1790 67


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