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)

Although atrial and brain natriuretic peptides are well known to be involved in the regulation of cardiovascular and endocrine functions as circulating hormones, the roles of the C-type natriuretic peptide (CNP) remain unknown. We examined the effects of CNP on the secretion of aldosterone and cyclic nucleotides from bovine adrenal zona glomerulosa cells in culture. CNP produced a dose-dependent increase in the basal secretion of cGMP, with an EC50 of 3.8 x 10(-10)M. CNP significantly inhibited the ACTH-induced increase in aldosterone and cAMP in a dose-related manner, with an IC50 of 3.6 x 10(-10)M. Although ACTH itself did not increase cGMP secretion, the addition of CNP elicited a significant increase in cGMP secretion. The effects of CNP on the basal secretion of cGMP and the ACTH-induced secretion of aldosterone were significantly reversed by a nonpeptide natriuretic peptide receptor antagonist, HS-142-1. CNP immunoreactivity was localized in the zona glomerulosa by immunohistochemical staining. In addition, expression of CNP messenger RNA and natriuretic peptide B receptor messenger RNA was demonstrated by RT-PCR in the zona glomerulosa tissue and cells in culture. These findings suggest that CNP is a local factor regulating ACTH-induced aldosterone secretion through a guanylyl cyclase-cGMP pathway.
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PMID:C-type natriuretic peptide as a possible local modulator of aldosterone secretion in bovine adrenal zona glomerulosa. 853 40

Hamsters with cardiomyopathy (CMO), an experimental model of congestive heart failure, display stimulated renin-angiotensin-aldosterone and enhanced sympathetic nervous activity, all factors that lead to sodium retention, volume expansion and subsequent elevation of plasma atrial natriuretic factor (ANF) by the cardiac atria. However, sodium and water retention persist in CMO, indicating hyporesponsiveness to endogenous ANF. These studies were undertaken to fully characterize renal ANF receptor subtypes in normal hamsters and to evaluate whether alterations in renal ANF receptors may contribute to renal resistance to ANF in cardiomyopathy. Transcripts of the guanylyl cyclase-A (GC-A) and guanylyl cyclase B (GC-B) receptors were detected by quantitative polymerase chain reaction (PCR) in renal cortex, and outer and inner medullas. Compared to normal controls, the cardiomyopathic hamster's GC-A mRNA was similar in cortex but significantly increased in outer and inner medulla. Levels of GC-B mRNA were not altered by the disease. On the other hand, competitive binding studies, autoradiography, and affinity cross-linking demonstrated the absence of functional GC-B receptors in the kidney glomeruli and inner medulla. Also, C-type natriuretic peptide (CNP), the natural ligand for the GC-B receptors, failed to stimulate glomerular production of its second messenger cGMP. In CMO, sodium and water excretion were significantly reduced despite elevated plasma ANF (50.5 +/- 11.1 vs. 309.4 +/- 32.6 pg/ml, P < 0.001). Competitive binding studies of renal glomerular ANF receptors revealed no change in total receptor density, Bmax (369.6 +/- 27.4 vs. 282.8 +/- 26.2 fmol/mg protein), nor in dissociation constant, Kd (647.4 +/- 79.4 vs. 648.5 +/- 22.9 pM). Also, ANF-C receptor density (254.3 +/- 24.8 vs. 233.8 +/- 23.5 fmol/mg protein), nor affinity were affected by heart failure. Inner medullary receptors were exclusively of the GC-A subtype with Bmax (153.2 +/- 26.4 vs. 134.5 +/- 21.2 fmol/mg protein) and Kd (395.7 +/- 148.0 vs. 285.8 +/- 45.0 pM) not altered by cardiomyopathy. The increase in ANF-stimulated glomerular cGMP production was similar in normal and CMO hamsters (94- vs. 75-fold). These results demonstrate that renal ANF receptors do not contribute to the attenuated renal responses to ANF in hamster cardiomyopathy.
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PMID:Renal atrial natriuretic factor receptors in hamster cardiomyopathy. 858 47

We report the production of a novel human natriuretic peptide receptor/guanylyl cyclase A (hNPR-A)-selective agonist ANP [G9T, R11S, G16R] (sANP). This agonist has similar affinity to ANP for hNPR-A and 1,000-10,000-fold reduced affinity for the human natriuretic peptide clearance receptor (hNPR-C). sANP was used to directly test the hypothesis that hNPR-A mediates the inhibitory effect of natriuretic peptides on aldosterone generation in a human zona glomerulosa cell line, H295R. Human type A natriuretic peptide and sANP (10(-11) to 10(-6) M) resulted in concentration-dependent increases in cGMP levels and decreases in forskolin (100 nM)- and angiotensin II (5 nM)-induced aldosterone and pregnenolone production. These results revealed an inhibitory effect of both peptides on the agonist-stimulated conversion of cholesterol to pregnenolone (i.e., cytochrome P-450 cholesterol monooxygenase side-chain cleaving enzyme, EC 1.14.15.6). H295R cells also exhibited angiotensin II- and forskolin-evoked conversion of [3H]cortico-sterone to [3H]aldosterone (i.e., cytochrome P-450 steroid 11 beta-monooxygenase/aldosterone synthase, EC 1.14.15.4). Human type A natriuretic peptide and sANP (10(-7) M) inhibited the angiotensin II-stimulated late pathway but did not affect forskolin-facilitated conversion of corticosterone to aldosterone. Our results directly demonstrate inhibitory effects of hNPR-A-mediated signal transduction on cytochrome P-450 cholesterol monooxygenase side-chain cleaving enzyme and steroid 11 beta-monooxygenase/aldosterone synthase complex depending on the steroidogenic agonist used.
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PMID:Novel natriuretic peptide receptor/guanylyl cyclase A-selective agonist inhibits angiotensin II- and forskolin-evoked aldosterone synthesis in a human zona glomerulosa cell line. 870 Jan 53

Brain natriuretic peptide (BNP) is a cardiac hormone with a spectrum of activities quite similar to those of atrial natriuretic peptide (ANP), including diuretic, natriuretic, hypotensive and smooth muscle relaxant activities. These effects are due to the stimulation of guanylate cyclase-linked natriuretic peptide receptors, leading to an increase in cyclic GMP concentration in target cells. BNP has a lower affinity than ANP for C (clearance) receptors, and is less susceptible to degradation by neutral endopeptidase-24.11, resulting in a longer half-life. In the kidney, BNP increases the glomerular filtration rate and inhibits sodium reabsorption in the distal tubule. It also inhibits the release of renin and aldosterone. Unlike ANP, produced by the atria, BNP is mainly synthesized and released into circulation by the left ventricle and is therefore influenced by stimuli involving this cardiac chamber, such as an increase in arterial pressure, left ventricular hypertrophy and dilation. Plasma BNP levels are very low in healthy subjects, and respond modestly, although significantly to physiological stimuli such as changes in posture or sodium intake. In contrast, plasma BNP concentrations increase in disease states such as cirrhosis with ascites, hypertension, chronic renal failure, acute myocardial infarction and congestive heart failure. In the latter condition, plasma BNP concentration is a reliable prognostic index. Evidence obtained by administering BNP to healthy subjects and hypertensive patients suggests that BNP, at physiological and pathophysiological plasma concentrations, markedly influences cardiovascular homeostasis, mainly due to its effects on sodium excretion and the renin-aldosterone axis.
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PMID:[Brain natriuretic peptide]. 871 58

The inhibitory effect of atrial natriuretic peptide (ANP) on angiotensin II (AII)-stimulated aldosterone secretion has been previously studied in rat and bovine adrenal zona glomerulosa cells in primary culture. However the understanding of the mode of action of ANP at the molecular level has been hampered by limitations of those primary cell culture systems and by the lack of cell lines from human adrenal cortex. Here we demonstrate the presence of fully functional ANP receptors in the recently characterized AII-responsive adrenocortical carcinoma cell line H295R. Specific saturable binding of 125I-rANP to H295R cell membrane preparations revealed a single class of high affinity binding sites with a density of 20 fmol/mg of protein. The pharmacological profile of this ANP receptor was documented by competitive binding of 125I-rANP with naturally occurring natriuretic peptides. rANP was the most potent with a Kd of 42 pM. pBNP32 was less potent with a Kd of 174 pM. 125I-rANP binding was not competed by pCNP (NPRB-specific ligand) nor by C-ANF (NPRC-specific ligand). Photoaffinity labeling of membrane preparations with 125I-BPA-ANP revealed a single specific protein of molecular weight around 130 kDa. This protein was further identified by immunodetection with a specific antibody directed to the human ANP-specific receptor NPRA. Natriuretic peptides stimulated cGMP production by the receptor-coupled guanylate cyclase with the same specificity. Aldosterone production by AII-stimulated H295R cells was dose-dependently inhibited by rANP with an ED50 of 1.5 nM. In addition, we used this model to test two chimeric analogs of ANP and BNP. pBNP1 and pBNP3 were, respectively, 4- and 2-fold more potent than rANP in competing for 125I-rANP binding with Kd of 10 and 20 pM. pBNP1 was 24-fold more potent in inhibiting AII-stimulated aldosterone production with ED50 of 63 pM. pBNP1 is therefore the most potent natriuretic peptide analog tested. In summary, the human H295R cell line contains NPRA receptors positively coupled to the particulate guanylate cyclase and that antagonize angiotensin II stimulation of aldosterone secretion.
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PMID:The H295R human adrenocortical cell line contains functional atrial natriuretic peptide receptors that inhibit aldosterone biosynthesis. 873 99

Atrial natriuretic peptide (ANP) and Brain natriuretic peptide (BNP) are cardiac hormones with similar actions and potency in humans yet with distinctly different effects on plasma cyclic guanosine monophosphate (cGMP). Because most biological actions of natriuretic peptides are thought to be mediated by the guanylate cyclase (G-C) receptors via cGMP, we have compared the biological and G-C-stimulating effects of equimolar infusions of ANP and BNP (2 pmol/kg.min), or vehicle control, on renal, hormonal and hemodynamic function in 8 normal subjects. In addition, the modulating effects of ANP and BNP on the biological actions of infused angiotension II (AngII) were studied. During ANP infusions, plasma ANP concentration increased from 8.8 +/- 0.7 pmol/L to 34 +/- 3 pmol/L at 120 min. Similar increments in plasma BNP occurred during BNP infusions (7.3 +/- 0.6 pmol/L preinfusion, 37 +/- 1 pmol/L at 120 min). Increase in plasma cGMP during ANP infusions was 4-fold that observed during BNP infusions yet natriuresis, contraction in plasma volume, and inhibition of plasma aldosterone were comparable. By contrast, ANP (but not BNP) significantly inhibited the plasma aldosterone response to AngII (P < 0.001). The pressor response to AngII was unaltered by ANP or BNP. Thus, at plasma ANP/BNP levels observed in mild heart failure, ANP is more potent than BNP in inhibiting the aldosterone response to AngII. Comparable natriuresis and inhibition of basal aldosterone is seen, despite much less stimulation of plasma cGMP by BNP, suggesting a different mechanism of hormone action-possibly via non-G-C receptor pathways.
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PMID:Differing biological effects of equimolar atrial and brain natriuretic peptide infusions in normal man. 892 31

The data reviewed establish the presence and important role in body fluid homeostasis of brain atrial natriuretic peptide (ANP) in all vertebrate-species examined. The peptide is localized in neurons in hypothalamic and brain stem areas involved in body fluid volume and blood pressure regulation, and its receptors are located in regions that contain the peptide. Most, if not all, of the actions of ANP are mediated by activation of particulate guanylyl cyclase with generation of guanosine 3',5'-cyclic monophosphate, which mediates its actions in brain as in the periphery. Although atrial stretch releases ANP from cardiac myocytes, the experiments indicate that the response to acute blood volume expansion is markedly reduced after elimination of neural control. Volume expansion distends baroreceptors in the right atria, carotid-aortic sinuses, and kidney, altering afferent input to the brain stem and hence the hypothalamus, resulting in stimulation via ANPergic neurons in the hypothalamus of oxytocin release from the neurohypophysis that circulates to the right atrium to stimulate ANP release. The ANP circulates to the kidney and induces natriuresis. Atrial natriuretic peptide also induces vasodilation compensating rapidly for increased blood volume by increased vascular capacity. Atrial natriuretic peptide released into hypophysial portal blood vessels inhibits release of adrenocorticotropic hormone (ACTH), thereby decreasing aldosterone release and enhancing natriuresis. Furthermore, the ANP neurons inhibit AVP release leading to diuresis and decreased ACTH release. Activation of hypothalamic ANPergic neurons via volume expansion also inhibits water and salt intake. These inhibitory actions may be partially mediated via ANP neurons in the olfactory system altering salt taste. Atrial natriuretic peptide neurons probably also alter fluid movement in the choroid plexus and in other brain vascular beds. Therefore, brain ANP neurons play an important role in modulating not only intake of body fluids, but their excretion to maintain body fluid homeostasis.
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PMID:Atrial natriuretic peptide in brain and pituitary gland. 911 21

In this work, we have studied the effects and the possible cellular mechanism of Substance P (SP) on corticosteroid secretion by the adrenal gland of the urodele crested newt, Triturus carnifex. Adrenals were in vitro superfused with SP, prostaglandin E2 (PGE2), nitric oxide (NO) donor, cyclic GMP (cGMP) analogue, and inhibitors of phospholipase A1, phospholipase A2 (PLA2), phospholipase C, adenylate cyclase (AC), cyclooxygenase (COX), NO synthase (NOS), and soluble guanylate cyclase (sGC). PGE2, corticosterone, and aldosterone release and NOS activity were determined. SP, PGE2, NO donor, and cGMP analogue increased corticosterone and aldosterone; SP and PGE2 increased NOS, and SP increased PGE2. PLA2, AC, COX, NOS, and sGC inhibitors counteracted SP and PGE2 effects, except for PLA2, which did not affect PGE2. These results suggest that SP exhibits a stimulatory role on the corticosteroidogenesis of T. carnifex adrenal gland. In particular SP enhances PLA2 activity, increasing PGE2; this prostaglandin affects AC, which, in turn, enhances NO, and the latter therefore affects sGC, with the consequent corticosteroidogenesis increase.
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PMID:Cellular mechanism of substance P in the regulation of corticosteroid secretion by newt adrenal gland. 914 46

The main objective of this study was to find out if the reported changes in the aldosterone-suppressant activity of atrial natriuretic peptide (ANP) during different hormonal states in rats are due to a modulation of ANP receptors. In zona glomerulosa cells, ribonuclease protection assay detected mRNAs for guanylate cyclase (GC)-coupled ANP GC-A and GC-B receptors, and for ANP C receptors, which are not coupled to GC. Western analysis using polyclonal anti-GC-A and anti-GC-B receptor antibodies revealed the presence of GC-A but not GC-B receptor proteins in zona glomerulosa cells. Pregnancy (days 7, 16 and 21), oestradiol-17 beta and progesterone decreased mRNAs for all the three ANP receptors in zona glomerulosa cells. Pregnancy decreased GC-A receptor proteins in zona glomerulosa cells, but these recovered to virgin values on day 2 postpartum. ANP receptor mRNAs in zona glomerulosa cells increased by postpartum day 2, but did not reach the values found in virgin rats. Zona fasciculata mainly contained GC-A receptor mRNA. It is concluded that ANP receptors in rat adrenal zona glomerulosa are modulated by pregnancy, oestrogen and progesterone; a decrease in ANP GC-A receptors during pregnancy might explain the accompanying decrease in the aldosterone-suppressant effects of ANP.
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PMID:Downregulation of adrenal atrial natriuretic peptide receptor mRNAs and proteins by pregnancy in rats. 948 97

To investigate the mechanism of nitric oxide (NO) inhibition of aldosterone release, this study compared the effects of type A natriuretic peptide and heat-stable enterotoxin to a nitric oxide donor, deta nonoate, on cGMP production and angiotensin II-stimulated aldosterone synthesis ill primary cultures of bovine adrenal zona glomerulosa cells. Type A natriuretic peptide (10(-10)-10(-6) M) and deta nonoate (10(-6)-10(-3) M) stimulated concentration-related increases in cGMP production. Heat-stable enterotoxin (10(-6) M) failed to stimulate cGMP synthesis in zona glomerulosa cells. Type A natriuretic peptide and deta nonoate attenuated angiotensin II-stimulated aldosterone production over the same concentration range that stimulated cGMP production. Heat-stable enterotoxin (10(-6) M) was without effect on aldosterone release. To further test the hypothesis that cGMP mediated the inhibition of aldosterone synthesis, the selective inhibitor of soluble guanylyl cyclase, 1H-(1,2,4)oxadiazolo [4,3-a]quinoxalin-1-one (ODQ) was used. ODQ pretreatment (10(-5) M) completely prevented deta nonoate-stimulated cGMP production without altering the inhibitory effect of deta nonoate on angiotensin II-stimulated steroidogenesis. Consistent with its selectivity for inhibiting soluble guanylyl cyclase, ODQ did not block type A natriuretic peptide-stimulated cGMP synthesis or type A natriuretic peptide inhibition of steroidogenesis. Deta nonoate completely blocked 25-hydroxycholesterol- and progesterone-stimulated aldosterone synthesis in zona glomerulosa cells and inhibited the conversion of 25-hydroxycholesterol to pregnenolone in mitochondrial fractions from bovine adrenal cortex. Deta nonoate-derived NO gave an absorbance maximum of the mitochondrial cytochrome P450 of 453 nm and inhibited the absorbance at 450 nm caused by carbon monoxide binding to the enzyme. These results suggest that deta nonoate reduces steroidogenesis independent of guanylyl cyclase activation and that NO has a direct effect to inhibit the activity of cytochrome P450, probably by binding to the heme groups of the cytochrome.
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PMID:Nitric oxide inhibits aldosterone synthesis by a guanylyl cyclase-independent effect. 975 82


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