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:4.6.1.2 (guanylate cyclase)
8,497 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We evaluated the role of receptor desensitization, activation of AT(2) receptors, and enzymatic degradation of angiotensin II (Ang II) by amino/neutral endopeptidases in rat anococcygeus smooth muscle (ASM) relaxation. Ang II (0.3 nM to 10 microM) produced contractions (E(max) = 21.50 +/- 5.73%) followed by passive relaxations (E(max) reduced to 9.08 +/- 2.55%). Contractions were inhibited (E(max) = 13.67 +/- 2.03%) by losartan (0.1 microM; AT(1) antagonist) but not by PD123,319 [S-(+)-1-([4-(dimethylamino)-3-methylphenyl]methyl)-5-(diphenylacetyl)-4,5,6,7-tetrahydro-1H-imidazo(4,5-c)pyridine-6-carboxylic acid] (0.1 microM; AT(2) antagonist). Conversely, the passive relaxation was inhibited (E(max) = 18.00 +/- 3.45%) by PD123,319 but not by losartan. Ang II (0.3 microM to 100 microM) produced initial contractions (E(max) = 11.49 +/- 9.39%) followed by active relaxations [I(max) (maximum inhibition elicited by the agonist) = 47.85 +/- 4.23%] on strips precontracted by bethanechol (100 microM). A second administration of Ang II on the background of bethanechol (1 h later) resulted in stronger relaxations (I(max) = 64.03 +/- 5.47%) without the initial contractions. N(G)-Nitro-l-arginine methyl ester [nitric-oxide synthase (NOS) inhibitor], ODQ (1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one; guanylate cyclase inhibitor), PD123,319, and tetrodotoxin (neurotoxin) inhibited the relaxations. The presence of AT(1) and AT(2) receptors was confirmed by Western blot. Experiments with amastatin (1 microM) and thiorphan (1 microM), aminopeptidase, and neutral endopeptidase inhibitors, respectively, excluded the involvement of enzymatic degradation in Ang II-induced relaxation of ASM. In conclusion, the rat ASM relaxation by Ang II is the result of active and passive relaxations. The passive relaxation depends on desensitization of excitatory AT(1) receptors, and the active relaxation is mediated by stimulation of AT(2) receptors and activation of the neuronal NOS/soluble guanylate cyclase pathway.
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PMID:Angiotensin II-induced relaxation of anococcygeus smooth muscle via desensitization of AT1 receptor, and activation of AT2 receptor associated with nitric-oxide synthase pathway. 1517 97

Nitric oxide (NO) is involved in adipose tissue biology by influencing adipogenesis, insulin-stimulated glucose uptake, and lipolysis. The enzymes responsible for NO formation in adipose cells are endothelial NO synthase (eNOS) and inducible NO synthase (iNOS), whereas neuronal NO synthase (bNOS) is not expressed in adipocytes. We characterized the expression pattern and the influence of adipogenesis, obesity, and weight loss on genes belonging to the NO system in human subcutaneous adipose cells by combining in vivo and in vitro studies. Expression of most of the genes known to belong to the NO system (eNOS, iNOS, subunits of the soluble guanylate cyclase, and both genes encoding cGMP-dependent protein kinases) in human adipose tissue and isolated human adipocytes was detected. In vitro adipogenic differentiation increased the expression level of iNOS significantly, whereas eNOS expression levels were not influenced. The genes encoding eNOS, iNOS, and cGMP-dependent protein kinase 1 were expressed at higher levels in obese women. Expression of these genes, however, was not influenced by 5% weight loss. Insulin and angiotensin II (Ang II) increased NO production by human preadipocytes in vitro. Increased eNOS and iNOS expression in adipocytes and local effects of insulin and Ang II may increase adipose tissue production of NO in obesity.
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PMID:Regulation of the nitric oxide system in human adipose tissue. 1523 49

Adrenomedullin (ADM), a ubiquitous vasoactive peptide, has been the target of a multitude of studies concerning its effect on the vascular tone. The present work aims at clarifying a series of its interactions with the renin-angiotensin system. The study uses the rat aorta ring as a model of conductance vessels, with or without vascular endothelium, and the second order branch of rat mesenteric arteries as a model of resistance arteries. Interactions between various concentrations of ADM and angiotensin II (Ang II) were studied, in the presence of L-NAME (a nitric oxide [NO] synthase inhibitor) and methylene blue (MB; a soluble guanylate cyclase inhibitor). Results point out differences in the mechanism of the inhibitory action of ADM upon Ang II effects in the two vessel types studied. Inhibition of Ang II contraction by ADM involves guanylate cyclase in both cases. However, NO is involved in ADM-induced inhibition of angiotensinergic vasoconstriction only in the conductance arteries, not in the resistance ones.
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PMID:Comparative study of the inhibitory effects of adrenomedullin on angiotensin II contraction in rat conductance and resistance arteries. 1529 19

Angiotensin II AT2 receptors act as a functional antagonist for the AT1 receptors in various tissues. We previously reported that activation of the renal AT2 receptors promotes natriuresis and diuresis; however, the mechanism is not known. The present study was designed to investigate whether activation of AT2 receptors affects the activity of Na+-K+-ATPase (NKA), an active tubular sodium transporter, in the proximal tubules isolated from Sprague-Dawley rats. The AT2 receptor agonist CGP-42112 (10(-10)-10(-7) M) produced a dose-dependent inhibition of NKA activity (9-38%); the inhibition was attenuated by the presence of the AT2 receptor antagonist PD-123319 (1 microM), suggesting the involvement of the AT2 receptors. The AT1 receptor antagonist losartan (1 microM) did not affect the CGP-42112 (100 nM)-induced inhibition of NKA activity. The presence of guanylyl cyclase inhibitor ODQ (10 microM) and the nitric oxide (NO) synthase inhibitor N(omega)-nitro-L-arginine methyl ester (L-NAME; 100 microM) abolished the CGP-42112 (100 nM)-induced NKA inhibition. ANG II (100 nM), in the presence of losartan, significantly inhibited NKA activity; the inhibition was attenuated by PD-123319. CGP-42112 also, in a dose-dependent manner, stimulated NO production (approximately 0-230%) and cGMP accumulation (approximately 25-100%). The CGP-42112 (100 nM)-induced NO and cGMP increases were abolished by the AT2 receptor antagonist PD-123319, ODQ, and L-NAME. The data suggest that the activation of the AT2 receptor via stimulation of the NO/cGMP pathway causes inhibition of NKA activity in the proximal tubules. This phenomenon provides a plausible mechanism responsible for the AT2 receptor-mediated natriuresis-diuresis in rodents.
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PMID:Angiotensin II AT2 receptors inhibit proximal tubular Na+-K+-ATPase activity via a NO/cGMP-dependent pathway. 1638 Apr 64

The objective of this study was to investigate the role of protein kinase C (PKC) in the angiotensin II (Ang II)-dependent repression of Npr1 (coding for natriuretic peptide receptor-A, NPRA) gene transcription. Mouse mesangial cells (MMCs) were transfected with Npr1 gene promoter-luciferase construct and treated with Ang II and PKC agonist or antagonist. The results showed that the treatment of MMCs with 10 nM Ang II produced a 60% reduction in the promoter activity of Npr1 gene. MMCs treated with 10nM Ang II exhibited 55% reduction in NPRA mRNA levels, and subsequent stimulation with 100 nM ANP resulted in 50% reduction in guanylyl cyclase (GC) activity. Furthermore, the treatment of MMCs with Ang II in the presence of PKC agonist phorbol ester (100 nM) produced an almost 75% reduction in NPRA mRNA and 70% reduction in the intracellular accumulation of cGMP levels. PKC antagonist staurosporine completely reversed the effect of Ang II and phorbol ester. This is the first report to demonstrate that ANG II-dependent transcriptional repression of Npr1 gene promoter activity and down-regulation of GC activity of translated protein, NPRA is regulated by PKC pathways.
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PMID:Inhibition and down-regulation of gene transcription and guanylyl cyclase activity of NPRA by angiotensin II involving protein kinase C. 1693 May 45

The major long-term benefits of angiotensin-converting enzyme (ACE) inhibitors have now clearly been demonstrated in patients with arterial hypertension, cardiac insufficiency, coronary artery disease and several renal diseases. Such long-term treatment markedly alters the cardiovascular response to anaesthesia and surgery, whereas preliminary data suggest that short-term renin angiotensin system blockade might provide perioperative organ protection and improved circulatory conditions. Besides the classic view that the conversion of angiotensin I to angiotensin II is mainly due to ACE, alternative pathways have recently been identified, including cathepsin G as well as chymostatin- and aprotinin-sensitive serine proteases that are released from mastocytes and endothelial cells and which are insensitive to the effects of ACE inhibitors. These proteases are thought to contribute to tissue perfusion under hypoxic conditions and to structural remodelling. In clinical practice, ACE inhibitors may be preferred to angiotensin II receptor antagonists since the former, besides reducing angiotensin II synthesis, also lead to an accumulation of kinins (e.g. bradykinin), which have important cardio- and renal protective effects through liberation of prostacyclin and nitric oxide in endothelial cells and through stimulation of guanylate cyclase to form cyclic GMP.
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PMID:Inhibitors of the renin angiotensin system: implications for the anaesthesiologist. 1701 40

Natriuretic peptides play an important role in sodium regulation and blood pressure (BP) control. We examined the effects of atrial natriuetic peptide (ANP), brain natriuretic peptide (BNP) and C-type natriuretic peptide (CNP) on human isolated resistance arteries and the mechanisms involved in vasorelaxation. Human subcutaneous resistance arteries were mounted in an isometric myograph and contracted with phenylephrine. CNP, but not ANP or BNP, relaxed arteries in a concentration dependent manner. The action of CNP was unaffected by removal of the endothelium, inhibition of nitric oxide synthase by NG-monomethyl-Larginine or inhibition of soluble guanylate cyclase by 1H-[1,2,4] oxadiazolo [4,3-alpha] quinoxalin-1-one. Blockade of cyclic GMPdependent kinase by 8- bromoguanosine- 3, 5- cyclic monophosphorothioate, Rp-isomer (Rp-8-Br-cGMPS) inhibited CNP relaxation. CNP relaxation was also inhibited by high potassium or iberiotoxin, indicating that it was due to opening of BKCa channels. Omapatrilat, a vasopeptidase inhibitor of neutral endopeptidase and angiotensin-converting enzyme, enhanced the effect of CNP and inhibited responses to Ang I. In summary, CNP, but not ANP or BNP, relaxes human resistance arteries by activating cyclic GMP-dependent kinase and BKCa. The effects of CNP are enhanced by vasopeptidase inhibition and this may contribute to the vasodilator effects of these agents in vivo. Since CNP is widely present in endothelium it may play a role in the regulation of peripheral resistance in man in physiological and pathological circumstances.
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PMID:CNP, but not ANP or BNP, relax human isolated subcutaneous resistance arteries by an action involving cyclic GMP and BKCa channels. 1708 62

In this study, we demonstrate that B-type natriuretic peptide (BNP) opposed angiotensin II (Ang II)-stimulated de novo cholesterol biosynthesis, cellular cholesterol uptake, cholesterol transfer to the inner mitochondrial membrane, and steroidogenesis, which are required for biosynthesis of steroid hormones such as aldosterone and cortisol in primary human adrenocortical cells. BNP dose-dependently stimulated intracellular cGMP production with an EC(50) of 11 nm, implying that human adrenocortical cells express the guanylyl cyclase A receptor. cDNA microarray and real-time RT-PCR analyses revealed that BNP inhibited Ang II-stimulated genes related to cholesterol biosynthesis (acetoacetyl coenzyme A thiolase, HMG coenzyme A synthase 1, HMG coenzyme A reductase, isopentenyl-diphosphate Delta-isomerase, lanosterol synthase, sterol-4C-methyl oxidase, and emopamil binding protein/sterol isomerase), cholesterol uptake from circulating lipoproteins (scavenger receptor class B type I and low-density lipoprotein receptor), cholesterol transfer to the inner mitochondrial membrane (steroidogenic acute regulatory protein), and steroidogenesis (ferredoxin 1,3beta-hydroxysteroid dehydrogenase, glutathione transferase A3, CYP19A1, CYP11B1, and CYP11B2). Consistent with the microarray and real-time PCR results, BNP also blocked Ang II-induced binding of (125)I-labeled low-density lipoprotein and (125)I-labeled high-density lipoprotein to human adrenocortical cells. Furthermore, BNP markedly inhibited Ang II-stimulated release of estradiol, aldosterone, and cortisol from cultured primary human adrenocortical cells. These findings demonstrate that BNP opposes Ang II-induced steroidogenesis via multiple steps from cholesterol supply and transfer to the final formation of steroid hormones. This study provides new insights into the cellular mechanisms by which BNP modulates Ang II-induced steroidogenesis in the adrenal gland.
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PMID:B-Type natriuretic peptide inhibited angiotensin II-stimulated cholesterol biosynthesis, cholesterol transfer, and steroidogenesis in primary human adrenocortical cells. 1747 52

The cardiac hormones atrial and brain natriuretic peptides (NPs) counteract the systemic, hypertensive, and hypervolemic actions of angiotensin II (Ang II) via their guanylyl cyclase-A (GC-A) receptor. In the present study, we took advantage of genetically modified mice with conditional, cardiomyocyte (CM)-restricted disruption of GC-A (CM GC-A knockout mice) to study whether NPs can moderate not only the endocrine but also the cardiac actions of Ang II in vivo. Fluorometric measurements of [Ca(2+)](i) transients in isolated, electrically paced adult CMs showed that atrial NP inhibits the stimulatory effects of Ang II on free cytosolic Ca(2+) transients via GC-A. Remarkably, GC-A-deficient CMs exhibited greatly enhanced [Ca(2+)](i) responses to Ang II, which was partly related to increased activation of the Na(+)/H(+)-exchanger NHE-1. Chronic administration of Ang II to control and CM GC-A knockout mice (300 ng/kg body weight per minute via osmotic minipumps during 2 wk) provoked significant cardiac hypertrophy, which was markedly exacerbated in the later genotype. This was concomitant to increased cardiac expression of NHE-1 and enhanced activation of the Ca(2+)/calmodulin-dependent prohypertrophic signal transducers Ca(2+)/calmodulin-dependent kinase II and calcineurin. On the basis of these results, we conclude that NPs exert direct local, GC-A-mediated myocardial effects to antagonize the [Ca(2+)](i)-dependent hypertrophic growth response to Ang II.
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PMID:Local actions of atrial natriuretic peptide counteract angiotensin II stimulated cardiac remodeling. 1751 Feb 45

Angiotensin II (Ang II) has been reported to induce migration in neuronal cell types. Using time-lapse microscopy, we show here that Ang II induces acceleration in NG108-15 cell migration. This effect was antagonized by PD123319, a selective AT2 receptor antagonist, but not by DUP753, a selective AT1 receptor antagonist, and was mimicked by the specific AT2 receptor agonist CGP42112. This Ang II-induced acceleration was not sensitive to the inhibition of previously described signaling pathways of the AT2 receptor, guanylyl cyclase/cyclic GMP or p42/p44 mapk cascades, but was abolished by pertussis toxin treatment and involved PP2A activation. Immunofluorescence studies indicate that Ang II or CGP42112 decreased the amount of filamentous actin at the leading edge of the cells. This decrease was accompanied by a concomitant increase in globular actin levels. Regulation of actin turnover in actin-based motile systems is known to be mainly under the control of the actin depolymerizing factor and cofilin. Basal migration speed decreased by 77.2% in cofilin-1 small interfering RNA-transfected NG108-15 cells, along with suppression of the effect of Ang II. In addition, the Ang II-induced increase in cell velocity was abrogated in serum-free medium as well as by genistein or okadaic acid treatment in a serum-containing medium. Such results indicate that the AT2 receptor increases the migration speed of NG108-15 cells and involves a tyrosine kinase activity, followed by phosphatase activation, which may be of the PP2A type. Therefore, the present study identifies actin depolymerization and cofilin as new targets of AT2 receptor action, in the context of cellular migration.
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PMID:Angiotensin II type 2 receptor stimulation increases the rate of NG108-15 cell migration via actin depolymerization. 1832 1


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