Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:4.6.1.2 (guanylate cyclase)
 8,497 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Short-term infusion of carperitide (atrial natriuretic peptide) has beneficial effects on neurohumoral factors; however, it remains unclear whether the effects are sustained for long-term infusion. To evaluate the effects of long-term infusion of carperitide on neurohumoral factors in patients with chronic congestive heart failure (CHF), we measured neurohumoral factors before and 1 hour after stopping carperitide infusion in 42 CHF patients. Carperitide infusion was continued for more than 2 days until there was symptomatic improvement of CHF. Patients were divided into 2 groups by the median value of infusion duration: group 1 (less than 7 days, n=21) and group 2 (more than 7 days, n=21). In group 1, aldosterone (ALD) and endothelin-1 (ET-1) were significantly increased after stopping carperitide. In contrast, ALD and ET-1 did not change after stopping carperitide in group 2. The molar ratio of cyclic guanosine monophosphate/atrial natriuretic peptide before stopping carperitide was significantly lower in group 2 than in group 1. Suppression of ALD and ET-1 was maintained for 7 days of carperitide infusion, but the beneficial effect on neurohumoral factors was attenuated after more than 7 days, probably through down-regulation of biologic receptors coupled with guanylate cyclase in CHF patients.
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PMID:Inhibition of aldosterone and endothelin-1 by carperitide was attenuated with more than 1 week of infusion in patients with congestive heart failure. 1616 Jun 6

Lead exposure induces dysfunction of the cyclic guanosine monophosphate-dependent vasodilator system through downregulation of soluble guanylate cyclase (sGC) expression. The endothelium not only releases vasodilators but also vasoconstrictors such as endothelin-1 (ET-1). Our aim was to explore the role of the vascular endothelium and ET-1 as possible mediators of lead-induced downregulation of sGC. Isolated aortic segments from Wistar Kyoto rats were incubated in the presence or absence of lead (1 parts per million) for 24 h. Endothelium was mechanically removed in some of the aorta segments. As reported previously, lead exposure induced downregulation of sGC protein expression in the intact aortic segments. However, lead exposure failed to significantly modify sGC-beta1 subunit expression in the endothelium-denuded aortic segments. Incubation with a selective ETA-type receptor inhibitor, BQ-123 (10(-6) mol/l), restored sGC protein expression in lead-exposed intact aortic segments. As it has also been previously observed, incubation in lead-containing medium resulted in the upregulation of cyclooxygenase-2 (COX-2) in the intact aortic segments. Denudation of endothelium partially abrogated this effect of lead. Incubation with BQ-123 prevented the lead-induced upregulation COX-2 in the intact aortic segments. However, neither ET-1 content nor ETA-type receptor expression were modified by lead exposure of the aortic segments. As conclusion, the endothelium through the activation of ETA-type receptors mediates the downregulation of sGC expression by lead in the vascular wall.
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PMID:Involvement of endothelium and endothelin-1 in lead-induced smooth muscle cell dysfunction in rats. 1639 54

Results from experimental studies suggested a significance of the nitric oxide (NO)-cGMP- and cAMP-pathways in the control of the function of the smooth musculature of the human prostate. In addition, it has also been assumed that the vasoconstrictory peptide endothelin-1(ET-1) may play a role in the dynamic component of benign prostatic hyperplasia (BPH) and the so-called lower urinary tract symptomatology (LUTS). Nevertheless, up till now, little is known as to potential interactions between the contraction of prostatic smooth muscle mediated by ET-1 and the relaxation induced by NO and cGMP. Thus, it was the aim of the study to elucidate the effects of drugs interfering with the cGMP-pathway on the tension induced by ET-1 of isolated human prostate tissue, as well as contractile responses of isolated strip preparations to ET-1 and angiotensin-II (AT-II). Macroscopically normal human prostate tissue from the transition zone was obtained from male patients who had undergone surgery for localized cancer of the prostate or urinary bladder. Using the organ bath technique, the ability of ET-1 and AT-II to contract isolated prostate strips was evaluated. In another set-up, the effects of the NO-donor S-nitrosogluthatione (GSNO) and C-type natriuretic peptide(CNP), known as an endogenous ligand of the membrane bound guanylyl cyclase, (1 nM-1/10 microM) on the tension induced by 0.1 microM ET-1 of human prostate strips were investigated. The adenylyl cyclase stimulating agents forskolin and NO-donor natrium nitroprusside (NNP) were used as reference compounds. While AT-II failed to contract the prostate tissue, ET-1 induced stable and reproducible contractions of the tissue strips. The tension induced by 0.1 microM ET-1 was dose-dependently reversed by the drugs. The rank order of efficacy was forskolin >NNP>CNP(1 microM)>GSNO. R(max) values ranged from 55% (forskolin) to 35% (GSNO). Forskolin was the only compound which reached an EC50 value. Our results demonstrate that drugs in terfering with the cGMP- and cAMP-pathways can reverse the tension induced by ET-1. These findings are in support of the hypothesis that both cGMP and cAMP contribute to the control of the prostate smooth muscle tension and may provide new strategies for the future pharmacotherapy of LUTS und BPH.
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PMID:[In vitro effects of cAMP- and cGMP-stimulating drugs on the relaxation of the prostate smooth muscle tissue contraction induced by endothelin-1]. 1657 20

This study was designed to investigate the role of arginase in regulating myometrial contractions during gestation in the rat. Arginase activity in the myometrium was significantly decreased during the 7th-21st day of gestation, with the lowest value on the 14th day. However, the enzyme activity became significantly higher at term gestation (22nd day) than that in the non-pregnant myometrium. Arginase I protein was undetectable in the non-pregnant myometrium, at 7th and 14th day of gestation and after delivery. A slight positive signal for arginase I was detectable at 21st day of gestation. However, the protein was clearly up-regulated at term gestation (22nd day), although arginase II protein was down-regulated during gestation, with the lowest value on the 14th day. Gestational changes in arginase activity negatively correlated with those in cyclic GMP production, whereas the changes positively correlated with those in endogenous nitric oxide synthase (NOS) inhibitors and endothelin-1 (ET-1) contents. Myometrial arginase activity was inhibited by N(G)-hydroxy-L-arginine as an intermediate of NO production from L-arginine in a concentration-dependent manner. Both basal and stimulated guanylyl cyclase activities were enhanced at mid- and reduced at term gestation and after delivery, thereby partly increasing cyclic GMP production at mid- and partly decreasing the nucleotide production at term gestation and after delivery. These results suggest that the decreased arginase activity at mid-gestation possibly results from the down-regulation of arginase II protein. Whereas, the enhanced overall arginase activity at term gestation seems to be because of the induced functional arginase I in concert with the attenuated arginase II expression. The enhanced arginase activity at term gestation would be implicated in increasing myometrial contractions mediated by the increased ET-1. The increased peptide production at term gestation is possibly because of the reduced cyclic GMP production resulting from enhanced arginase activity, accumulated endogenous NOS inhibitors and attenuated guanylyl cyclase activity.
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PMID:Involvement of arginase in regulating myometrial contractions during gestation in the rat. 1673 58

The vascular endothelium synthesizes and releases a spectrum of vasoactive substances and therefore plays a fundamental role in the basal and dynamic regulation of the circulation. Nitric oxide (NO)-originally described as endothelium-derived relaxing factor-is released from endothelial cells in response to shear stress produced by blood flow, and in response to activation of a variety of receptors. After diffusion from endothelial to vascular smooth muscle cells, NO increases intracellular cyclic guanosine-monophosphate concentrations by activation of the enzyme guanylate cyclase leading to relaxation of the smooth muscle cells. NO has also antithrombogenic, antiproliferative, leukocyte-adhesion inhibiting effects, and influences myocardial contractility. Endothelium-derived NO-mediated vascular relaxation is impaired in spontaneously hypertensive animals. NO decomposition by free oxygen radicals is a major mechanism of impaired NO bioavailability. The resulting imbalance of endothelium-derived relaxing and contracting substances disturbs the normal function of the vascular endothelium. Endothelin acts as the natural counterpart to endothelium-derived NO. Besides its arterial blood pressure rising effect in humans, endothelin-1 induces vascular and myocardial hypertrophy, which are independent risk factors for cardiovascular morbidity and mortality. Current therapeutic strategies concentrate mainly on lowering low-density lipoprotein cholesterol and an impressive reduction in the risk for cardiovascular morbidity and mortality has been achieved. Inflammatory mechanisms play an important role in vascular disease and inflammatory plasma markers correlate with prognosis. The production of reactive oxygen species under pathological conditions may represent an important inflammatory trigger. Novel therapeutic strategies specifically targeting inflammation thus bear great potential for the prevention and treatment of atherosclerotic vascular disease. In this context, the vascular actions of flavanol-rich cocoa, particularly with regard to enhanced NO synthesis and endothelial function observed in humans following consumption, warrants further attention. This review discusses pharmacological and dietary intervention.
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PMID:Protection of endothelial function: targets for nutritional and pharmacological interventions. 1679 51

The kidney of vertebrates plays a key role in excretion of endogenous waste products and xenobiotics. Active secretion in the proximal nephron is at the basis of this excretion, mediated by carrier proteins including multidrug resistance protein 2 (Mrp2). We previously showed that Mrp2 function is reduced by endothelin-1 (ET-1) through a basolateral B-type receptor, nitric oxide (NO), cGMP, and PKC (Notenboom S, Miller DS, Smits P, Russel FGM, Masereeuw R. Am J Physiol Renal Physiol 282: F458-F464, 2002; Notenboom S, Miller DS, Smits P, Russel FG, Masereeuw R. Am J Physiol Renal Physiol 287: F33-F38, 2004). This pathway was rapidly activated by several nephrotoxicants and appeared to be calcium dependent. In the present study, we studied the effect of the calciotropic hormones parathyroid hormone (PTH), PTH-related protein (PTHrP), and stanniocalcin (STC) to interfere with ET-regulated Mrp2 transport. Like ET-1, PTH reduces Mrp2-mediated transport by 40% in killifish renal proximal tubules. When given in combination, an additive effect was seen, which is partially reversed by the PKC inhibitor calphostin C. Recombinant PTHrP shows a comparable inhibitory effect, which is concentration dependent and additive to the inhibition by ET. STC fully reverses PTHrP-inhibited transport as does a guanylyl cyclase inhibitor. Finally, to confirm PTHrP bioactivity in a homologous assay, we performed immunolocalization and transport studies in sea bream kidney tubules. Mrp2 immunoreactivity was observed in approximately 40% of the tubules and is associated with the brush-border and apical plasma membrane of cells. Both proximal tubules and distal (collecting) tubules express the antigen. A highly significant 40% inhibition of Mrp2-mediated transport was observed with PTHrP in sea bream tubules. In conclusion, ET-regulated Mrp2 transport is influenced by calciotropic hormones and involves PKC and cGMP signaling.
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PMID:Endothelin and calciotropic hormones share regulatory pathways in multidrug resistance protein 2-mediated transport. 1691 62

Endothelial dysfunction is an early pathophysiological feature and independent predictor of poor prognosis in most forms of cardiovascular diseases. Epidemiological studies report an inverse association between dietary flavonoid consumption and mortality from cardiovascular diseases. In the present paper, we review the effects of flavonoids, especially quercetin and wine polyphenols, on endothelial function and dysfunction and its potential protective role in hypertension, ischemic heart disease and stroke. In vitro studies show that flavonoids may exert multiple actions on the NO-guanylyl cyclase pathway, endothelium-derived hyperpolarizing factor(s) and endothelin-1 and protect endothelial cells against apoptosis. In vivo, flavonoids prevent endothelial dysfunction and reduce blood pressure, oxidative stress and end-organ damage in hypertensive animals. Moreover, some clinical studies have shown that flavonoid-rich foods can improve endothelial function in patients with hypertension and ischemic heart disease. Altogether, the available evidence indicates that quercetin and wine polyphenols might be of therapeutic benefit in cardiovascular diseases even though prospective controlled clinical studies are still lacking.
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PMID:Endothelial function and cardiovascular disease: effects of quercetin and wine polyphenols. 1701 50

Type 1 diabetes is an immuno-inflammatory condition which increases the risk of cardiovascular disease, particularly in young adults. This study investigated whether vascular function is altered in mice prone to autoimmune diabetes and whether the nitric oxide (NO)-cyclic GMP axis is involved. Aortic rings suspended in organ chambers and precontracted with phenylephrine were exposed to cumulative concentrations of acetylcholine. To investigate the role of NO, some experiments were performed in the presence of either 1400W (N-(3-aminomethyl)benzyl-acetamidine hydrochloride), a selective inhibitor of the iNOS-isoform, L-NAME (N(G)-nitro-L-arginine methyl ester hydrochloride), an inhibitor of all three NOS-isoforms, or ODQ (1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one), a selective inhibitor of guanylate cyclase. Moreover, contractility to phenylephrine, big endothelin-1, and endothelin-1 was assessed and histological analysis and iNOS immunohistochemistry were performed. Endothelium-dependent relaxation was reduced in prediabetic NOD mice (78+/-4 vs. 88+/-2%, respectively, P<0.05 vs. control) despite normal plasma glucose levels (n.s. vs. control). Preincubation with 1400W further attenuated responses in prediabetic (P<0.05 vs. untreated) but not in diabetic or in control mice. In contrast, basal NO bioactivity remained unaffected until the onset of diabetes in NOD mice. Contractile responses to big endothelin-1 and endothelin-1 were reduced in prediabetic animals (P<0.05 vs. control), whereas in diabetic mice only responses to big endothelin-1 were decreased (P<0.05 vs. control). These data demonstrate that endothelium-dependent and -independent vascular function in NOD mice is abnormal already in prediabetes in the absence of structural injury. Early proinflammatory activation due to iNOS in diabetes-prone NOD mice appears to be one of the mechanisms contributing to impaired vasoreactivity.
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PMID:Impaired vascular function in normoglycemic mice prone to autoimmune diabetes: role of nitric oxide. 1718 32

Endothelium-dependent relaxations are due to the release by the endothelial cells of potent vasodilator substances. The best characterized endothelium-derived relaxing factor (EDRF) is nitric oxide (NO), from 1-arginine by the constitutive endothelial NO synthase. In arterial smooth muscle, NO stimulates soluble guanylate cyclase which leads to the accumulation of cyclic GMP. Endothelial cells also release substances (EDHF) that hyperpolarize vascular smooth muscle. The release of NO from the endothelium can be mediated by both Gi (catecholamines, serotonin, thrombin) and Gq (adenosine diphosphate, bradykinin) G-proteins. In arteries with regenerated endothelium and/or atherosclerosis, there is a selective loss of the Gi mechanism of No-release which favours the occurrence of vasospasm, thrombosis and cellular growth. In addition to relaxing factors, the endothelial cells can produce contracting-substances (EDCF) which include superoxide anions, endoperoxides, thromboxane A2 and endothelin-1. The propensity to release EDCFs is maintained or even augmented in diseased blood vessels. The switch from a normally predominant release of NO to that of EDCF may play a crucial role in vascular disease.
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PMID:[Endothelial dysfunction and vascular pathology]. 1750 29

We investigated whether alpha-lipoic acid (alpha-LA), an antioxidant, attenuates the ischemia-reperfusion (I/R)-induced dysregulation of these transporters. Both renal pedicles of male Sprague-Dawley rats were clamped for 40 min. alpha-LA (80 mg/kg) was administered intraperitoneally before and immediately after induction of ischemia. After 2 days, the expression of aquaporins (AQPs), sodium transporters, and nitric oxide synthases (NOS) was determined in the kidney by immunoblotting and immunohistochemistry. The expression of endothelin-1 (ET-1) mRNA was determined by real-time PCR. Activities of adenylyl cyclase and guanylyl cyclase were measured by stimulated generation of cAMP and cGMP, respectively. The expression of AQP1-3 as well as that of the alpha(1)-subunit of Na-K-ATPase, type 3 Na/H exchanger, Na-K-2Cl cotransporter, and Na-Cl cotransporter was markedly decreased in response to I/R. The expression of type VI adenylyl cyclase was decreased in I/R-injured rats, which was counteracted by the treatment of alpha-LA. AVP-stimulated cAMP generation was blunted in I/R rats and was then ameliorated by alpha-LA treatment. alpha-LA treatment attenuated the downregulation of AQPs and sodium transporters. The expression of endothelial NOS was decreased in I/R rats, which was prevented by alpha-LA. The cGMP generation in response to sodium nitroprusside was blunted in I/R rats, which was also significantly prevented by alpha-LA. The mRNA expression of ET-1 was increased, which was recovered to the control level by alpha-LA treatment. In conclusion, alpha-LA treatment prevents I/R-induced dysregulation of AQPs and sodium transporters in the kidney, possibly through preserving normal activities of local AVP/cAMP, nitric oxide/cGMP, and ET systems.
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PMID:Effects of alpha-lipoic acid on ischemia-reperfusion-induced renal dysfunction in rats. 1803 50


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