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)

The diverse biological actions of endothelins (ET) appear to be mediated by specific cell-surface receptors. Autoradiography and membrane binding studies have shown abundant ET binding sites in the kidney. However, their expression in specific types of renal cells is unclear. We studied the binding of 125I-labelled endothelin-1 in freshly isolated cell suspensions from canine inner medullary collecting duct. Competition binding experiments revealed the presence of specific high-affinity binding sites: unlabelled ET-1 and ET-2 compared with the radioligand with an IC50 of 135 and 83 pM, respectively, while the IC50 of ET-3 and big ET-1 were 2 and 4 orders of magnitude higher, indicating the presence of ETA-type receptor. Angiotensin II, vasopressin, and atrial natriuretic peptide (ANP) did not compete for ET binding even at a concentration of 10(-6) M. Saturation binding experiments showed a single class of binding sites of high density (Bmax = 56.7 +/- 10.3 fmol/10(6) cells) and high affinity (Kd = 69.8 +/- 10 pM). In contrast, ANP receptors in the same cell preparations appeared as two classes of binding sites with widely different affinity and density. The high-affinity ANP site (Kd = 311 +/- 48 pM) was compatible with ANP-B (guanylate cyclase-coupled) receptor. ET-1 did not compete for this receptor. ET-1 (10(-7) M) did not alter ANP-induced cGMP generation in these cells (3.8-fold increase at 10(-7) M ANP), nor basal levels of cGMP.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Specific endothelin binding sites in renal medullary collecting duct cells: lack of interaction with ANP binding and cGMP signalling. 128 83

To elucidate the ligand-receptor relationship of the natriuretic peptide system, which comprises at least three endogenous ligands, atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), and C-type natriuretic peptide (CNP), and three receptors, the ANP-A receptor or guanylate cyclase-A (GC-A), the ANP-B receptor or guanylate cyclase-B (GC-B), and the clearance receptor (C-receptor), we characterized the receptor preparations from human, bovine, and rat tissues and cultured cells with the aid of the binding assay, Northern blot technique, and the cGMP production method. Using these receptor preparations, we examined the binding affinities of ANP, BNP, and CNP for the C-receptor and their potencies for cGMP production via the ANP-A receptor (GC-A) and the ANP-B receptor (GC-B). These analyses revealed the presence of a marked species difference in the receptor selectivity of the natriuretic peptide family, especially among BNPs. Therefore, we investigated the receptor selectivity of the natriuretic peptide family using the homologous assay system with endogenous ligands and receptors of the same species. The rank order of binding affinity for the C-receptor was ANP greater than CNP greater than BNP in both humans and rats. The rank order of potency for cGMP production via the ANP-A receptor (GC-A) was ANP greater than or equal to BNP much greater than CNP, but that via the ANP-B receptor (GC-B) was CNP greater than ANP greater than or equal to BNP. These findings on the receptor selectivity of the natriuretic peptide family provide a new insight into the understanding of the physiological and clinical implications of the natriuretic peptide system.
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PMID:Receptor selectivity of natriuretic peptide family, atrial natriuretic peptide, brain natriuretic peptide, and C-type natriuretic peptide. 130 30

This study was undertaken to examine the alterations in vascular relaxation responsiveness to endothelium-dependent or -independent vasodilators, including atrial natriuretic peptide (ANP) and acetylcholine, in aortas of Watanabe heritable hyperlipidemic (WHHL) rabbits during the progression of the atherosclerotic plaque. WHHL rabbits were divided into two groups according to age: group 1, 6-11 months, and group 2, 12-18 months. The isolated thoracic aortas obtained from both normal (control) and WHHL rabbits were suspended in a bath containing oxygenated Krebs' buffer for recording of isometric force. The endothelium-dependent relaxation evoked by acetylcholine was reduced in group 1 WHHL rabbits and decreased progressively in proportion to the degree of atherosclerosis progression when compared with age-matched control rabbits. ANP-induced relaxation was not significantly decreased in group 1 WHHL rabbits. However, ANP-induced relaxation was markedly impaired in group 2 WHHL rabbits. Thoracic aortas with severe atherosclerosis were less sensitive to ANP, with a significant increase in the median effective dose, although maximum relaxation induced by ANP was not reduced. Accumulation of cyclic GMP induced by ANP and acetylcholine was markedly reduced in atherosclerotic arteries obtained from group 2 WHHL rabbits compared with control rabbits. Vascular relaxation elicited by nitroglycerin or isoproterenol was not significantly impaired in atherosclerotic arteries from either group 1 or group 2 WHHL rabbits. From these results, we suggest that ANP-induced cyclic GMP formation and vascular relaxation via particulate guanylate cyclase in vascular smooth muscle cells are impaired in severely atherosclerotic arteries.
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PMID:Impaired vasodilatory response to atrial natriuretic peptide during atherosclerosis progression. 131 25

In this study we used HS-142-1, a novel non-peptide antagonist for the atrial natriuretic peptide (ANP) receptor, to clarify the possible physiological significance of ANP in acute hypervolemia. Substantial volume expansion in anesthetized rats induced a strong diuresis and natriuresis. These renal responses were significantly blocked by HS-142-1 at a dose of 3.0 mgkg-1 i.v. This observation suggests that ANP and its guanylyl cyclase-coupled receptor are, under the present conditions, physiologically involved that appears to be responsible for the renal responses in the volume homeostasis.
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PMID:Effects of HS-142-1, a novel non-peptide ANP antagonist, on diuresis and natriuresis induced by acute volume expansion in anesthetized rats. 131 Mar 97

Studies with Escherichia coli-induced heat-stable enterotoxin (STa), an activator of intestinal particulate guanylate cyclase, have established an independent role for cyclic guanosine monophosphate (cGMP) as an intracellular mediator of intestinal salt and water secretion. The present study addressed whether atriopeptins (APs), known activators of particulate guanylate cyclase in other tissues, function as physiological agonists for cGMP-linked Cl- secretion in intestine. APs, in contrast to STa, caused no or only minor changes in cGMP levels in freshly isolated rat intestinal villus and crypt cells and in cultured human colon carcinoma cell lines (HT29glc-, CaCo-2, and T84). Conversely, APs, but not STa, induced a large increase in intracellular cGMP levels in the undifferentiated small intestinal cell lines IEC-6, IEC-18, and INT407. Addition of AP II (atrial natriuretic peptide fragment 5-27) to stripped mucosa of rat proximal colon in Ussing chambers caused a transient increase in the transepithelial potential difference (PD), which most likely represents an increase in Cl- secretion. In contrast, a sustained increase in PD was observed in response to STa or 8Br-cGMP. The AP II-provoked increase in PD was blocked by the neurotoxin tetrodotoxin. Immunohistochemical detection of cGMP in this tissue provided evidence for a different localization pattern of cells responding with an increase in cGMP levels to STa (colonocytes and goblet cells) or AP (specific cells in the submucosa) in rat proximal colon. This indicates that APs, unlike STa, do not directly stimulate the colonic epithelial cells but possibly provoke Cl- secretion by release of a neurotransmitter in the submucosa.
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PMID:Atriopeptins and Escherichia coli enterotoxin STa have different sites of action in mammalian intestine. 131 72

To determine the ontogeny of intrarenal distribution of guanosine 3',5'-cyclic monophosphate (cGMP) formation in response to atrial natriuretic peptide (ANP) or sodium nitroprusside (SNP), adult and neonatal Sprague-Dawley rats were anesthetized and infused for 60 s with rat ANP (5-2,500 micrograms/kg) or SNP (0.1-10.0 mg/kg). cGMP was identified by the immunoperoxidase technique using a specific antibody. In adult rats, infusion of ANP localized cGMP primarily to the glomerular podocytes, whereas stimulation by SNP increased cGMP in the mesangium only (P less than 0.01). In neonatal rats, although overall renal cGMP immunostaining was greater than in adults, specific localization to podocytes (ANP) or mesangium (SNP) resulted only with higher doses of agonists. Although basal generation of cGMP by isolated glomeruli was greater in neonatal rats, the threshold for stimulation by ANP was lower in glomeruli from adult rats. We conclude that in vivo ANP stimulates glomerular particulate guanylate cyclase primarily in the podocytes, whereas SNP stimulates soluble guanylate cyclase localized to the mesangial cells. There is a maturational increase in the sensitivity for activation of glomerular particulate and soluble guanylate cyclase.
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PMID:Localization of cGMP after infusion of ANP or nitroprusside in the maturing rat. 131 44

We have compared the levels and subtypes of atrial natriuretic peptide (ANP) receptors in astrocyte glial and neuronal cultures prepared from the hypothalamus and brain stem of 1-day-old rats. Astrocyte glial cultures contain approximately twice the number of ANP receptors, as measured by 125I-ANP specific binding, compared with neuronal cultures. Rat ANP-(99-126), rat brain natriuretic peptide (BNP32), C-type natriuretic peptide (CNP-22), atriopeptin I, and [des-Gln18,Ser19,Gly20,Leu21, Gly22]atrial natriuretic factor-(4-23)-NH2[C-ANF-(4-23)] all competed strongly for 125I-ANP binding in both culture types, with inhibitory constant values ranging from 0.47 to 8.07 nM. The presence of ANP-C receptors (clearance type) in both cell types is indicated from the strong competition of 125I-ANP specific binding by C-ANF-(4-23). The potency profiles for stimulation of guanosine 3',5'-cyclic monophosphate levels by these peptides were ANP = BNP much greater than CNP-22 greater than atriopeptin I in astrocyte glia and CNP-22 much greater than BNP32 greater than ANP greater than atriopeptin I in neuronal cultures. These results indicate that both types of culture contain guanylate cyclase-coupled ANP receptors, with astrocytes containing predominantly the ANP-A subtype and neurons predominantly the ANP-B subtype.
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PMID:Atrial natriuretic peptide receptor subtypes in rat neuronal and astrocyte glial cultures. 131 98

Studies were performed to examine the regulation of atrial natriuretic peptide- (ANP) stimulated guanylate cyclase in the the inner medulla. Primary cultures of rat inner medullary collecting tubular cells exposed to 10(-7) M ANP increased cGMP formation to 31.2 +/- 1.8 compared to the basal production of 2.1 +/- 0.6 fm/micrograms protein. This response did not appear to be transduced via a Gi protein, as preincubation with pertussis toxin did not alter the response to 10(-7) M ANP, and saponized cells exposed to 10 microM GTP gamma S did not enhance the response to ANP (77.3 +/- 5.9 vs. 86.7 +/- 6.3 g/micrograms). Likewise, changes in extracellular Ca2+ from 0.5 to 3.0 mM, decrements in intracellular Ca2+ with EGTA or increments in intracellular Ca2+ with ionomycin (5 microM) did not significantly alter the response to ANP. Neither activation of protein kinase A with forskolin (36.5 +/- 5.1) nor of protein kinase C with s,n-1,2-dioctanoylglycerol (33.2 +/- 2.5) altered the response to 10(-7) M ANP (32.2 +/- 3.3, NS). As the inner medullary environment was hypertonic, the effect of altering tonicity was studied. Cells grown for 48 hours in hypertonic media (600 mOsm/kg H2O) displayed enhanced response to 10(-8) and 10(-7) M ANP when osmolality was raised by either Na+ alone or in combination with urea, but not by urea alone. Our studies demonstrate that ANP-stimulated guanylate cyclase is insensitive to alterations in either intra- or extracellular Ca2+, is not subject to inhibition by protein kinase, and does not involve a pertussis-sensitive G protein.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Regulation of atrial natriuretic peptide-stimulated cGMP production in the inner medulla. 131 78

To evaluate the role of endogenous atrial natriuretic peptide (ANP) in patients with congestive heart failure (CHF), the relationship between plasma ANP and cyclic guanosine monophosphate (cGMP) levels and the prognosis of patients with CHF was examined. In patients with chronic mild to moderate CHF, there was a positive correlation between plasma ANP and cGMP levels (r = 0.81, p less than 0.001). However, there was no significant correlation between these plasma levels in patients with chronic severe CHF, in whom the cGMP concentration reached a plateau in spite of high levels of ANP. The ANP extraction level and the cGMP production level in the pulmonary and systemic circulation correlated significantly in patients with mild CHF. In contrast, there was no significant correlation between the 2 parameters in patients with severe CHF, and the molar ratios of cGMP production to ANP extraction in the pulmonary and systemic circulation were significantly lower than those in patients with mild CHF. In 44 patients with chronic severe CHF who were followed up over 2 years, plasma ANP levels provided more sensitive and specific prognostic information than any other parameters. These results indicate that ANP receptors coupled to guanylate cyclase may be down-regulated in patients with chronic severe CHF, suggesting that high plasma ANP levels as a prognostic predictor may be associated with limitations of compensation by endogenous ANP.
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PMID:Limitations of compensation by endogenous atrial natriuretic peptide in heart failure. 131 29

We have prepared an atrial natriuretic peptide analog, ANP[13-27][1-12], in which the connectivity of the disulfide-linked ring has been reversed by formally cleaving the ring and cyclizing the N- and C-terminal tails. This analog, which retains many of the spatial relationships of the native molecule, binds to both ANP-A and ANP-C receptor subtypes, and triggers the production of cyclic-GMP by ANP-A. ANP-C binding of ANP[13-27][1- 12] is roughly equipotent to that of ANP itself, although the ring cleavage falls within the putative ANP-C binding domain. ANP[13-27][1-8], a truncated analog in which much of this binding domain has been removed, surprisingly maintains a high affinity for ANP-C; however, this peptide has lost the ability to activate the ANP-A-linked guanylate cyclase.
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PMID:A ring-reversed analog of atrial natriuretic peptide retains receptor binding, guanylate cyclase stimulation. 131 47


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