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 most potent known agonist for the natriuretic peptide receptor-B (NPR-B)/guanylyl cyclase-B is C-type natriuretic peptide (CNP). A homologous ligand-receptor system consists of atrial natriuretic peptide (ANP) and NPR-A/guanylyl cyclase-A. A third member of this family is NPR-C, a non-guanylyl cyclase receptor. Monoclonal antibodies were raised against NPR-B by immunizing mice with a purified receptor-IgG fusion protein consisting of the extracellular domain of NPR-B and the Fc portion of human IgG-gamma 1. One monoclonal antibody, 3G12, did not recognize NPR-A or NPR-C and bound to human and rat NPR-B. CNP binding to NPR-B and stimulation of cGMP synthesis were inhibited by 3G12. With cells isolated from either the media or adventitia layers of rat thoracic aorta, 3G12 did not interfere with ANP-stimulated cGMP synthesis, but it inhibited CNP-stimulated cGMP levels in cells from both layers. CNP (IC50 = 10 nM) and ANP (IC50 = 1 nM) caused relaxation of phenylephrine-contracted rat aortic rings. 3G12 caused a marked increase in the IC50 for CNP, from 10 nM to 140 nM, but failed to affect ANP-mediated relaxation. Therefore, our results for the first time demonstrate that CNP relaxes vascular smooth muscle by virtue of its binding to NPR-B.
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PMID:Natriuretic peptide receptor-B (guanylyl cyclase-B) mediates C-type natriuretic peptide relaxation of precontracted rat aorta. 787 38

The ultracytochemical localization of particulate guanylate cyclase has been studied in lamb olfactory mucosa after activation with rat atrial natriuretic factor (rANF), porcine brain natriuretic peptide (pBNP), porcine C-type natriuretic peptide (pCNP) or rat brain natriuretic peptide (rBNP). Particulate guanylate cyclase is the receptor for these peptides and recently two subtypes of the cyclase have been identified. These isoforms are stimulated differently by ANF, BNP and CNP. Under our experimental conditions, rANF, pCNP and pBNP were strong activators of particulate guanylate cyclase in lamb olfactory mucosa, as demonstrated by the presence of reaction product. Samples incubated in basal conditions without rANF, pCNP or pBNP, or samples incubated in presence of rBNP did not reveal any cyclase activity. The rANF-stimulated cyclase activity was localized in the apical portion of olfactory epithelium. pCNP-stimulated guanylate cyclase was detected to the lamina propria in association with secretory cells of Bowman's glands and with cells in close relation with Bowman's glands (elongated cells and myoepithelial cells). The cyclase activity stimulated by pBNP was limited to cells of Bowman's glands. The present data indicate that ANF and CNP are recognized by different receptors and that BNP and CNP bind to the same receptor.
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PMID:Ultracytochemical localization of particulate guanylate cyclase after stimulation with natriuretic peptides in lamb olfactory mucosa. 788 88

Asymptomatic or early left ventricular dysfunction in humans is characterized by increases in circulating atrial natriuretic peptide (ANP) without activation of the renin-angiotensin-aldosterone system (RAAS). We previously reported a canine model of early left ventricular dysfunction (ELVD) produced by rapid ventricular pacing and characterized by an identical neurohumoral profile and maintenance of the natriuretic response to volume expansion (VE). To test the hypothesis that elevated endogenous ANP suppresses the RAAS and maintains sodium excretion in ELVD, we assessed the effects of antagonism of ANP on cardiorenal and neurohumoral function in ELVD. Chronic ANP suppression was produced by bilateral atrial appendectomies before the production of ELVD by rapid ventricular pacing (ELVD-APPX, n = 5). This group was compared with a separate group with ELVD and intact atrial appendages (ELVD-INTACT, n = 8). ELVD-APPX was characterized by lower circulating ANP (50 +/- 11 vs. 158 +/- 37 pg/ml, P < 0.05), activation of plasma renin activity (PRA) (9.4 +/- 2.4 vs. 0.6 +/- 0.4 ng/ml per h, P < 0.05) and aldosterone (36.4 +/- 12.5 vs. 2.5 +/- 0.0 ng/dl, P < 0.05) when compared to ELVD-INTACT. In comparison to the ELVD-INTACT group, sodium excretion was decreased before and during VE in the ELVD-APPX group. Acute ANP antagonism was produced by administration of the particulate guanylate cyclase coupled natriuretic peptide receptor antagonist, HS-142-1, to seven conscious dogs with ELVD and intact atrial appendages (ELVD-INTACT). HS-142-1 decreased plasma concentrations and renal generation of the ANP second messenger, cGMP, and was associated with activation of PRA and sodium retention with enhanced tubular sodium reabsorption. These data support a significant role for elevated endogenous ANP in the maintenance of sodium excretion and regulation of the RAAS in experimental ELVD.
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PMID:A functional role for endogenous atrial natriuretic peptide in a canine model of early left ventricular dysfunction. 788 58

C-type natriuretic peptide (CNP) is a member of the natriuretic peptide family which is produced in vascular endothelial cells and may play an important paracrine role in the vasaculature. We sought to determine the regulation of CNP production by other vasoactive peptides from cultured aortic endothelial cells. The vasoconstrictors endothelin-1 and angiotensin II had little effect on the basal secretion of CNP. In contrast, atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) strongly stimulated the secretion of CNP. BNP caused as much as a 400-fold enhancement above the basal accumulated secretion of CNP over 24 h at a concentration of 1 microM; this was 20 times greater than the stimulatory effect of ANP, BNP and ANP also significantly enhanced the production of new CNP protein (translation) and mRNA expressed in the BAEC. In contrast, C-ANP-4-23, a truncated form of ANP which selectively binds to the natriuretic peptide clearance receptor, did not stimulate CNP secretion. The enhanced production and secretion of CNP, caused by either ANP or BNP, was significantly prevented by LY 83583, an inhibitor of cGMP generation, and was also attenuated by KT 5823, an inhibitor of cGMP-dependent protein kinase. Our results indicate that ANP and BNP can stimulate CNP production through a guanylate cyclase receptor on endothelial cells. BNP is a much more potent stimulator of CNP secretion, compared to ANP. Our findings suggest that the vasodilatory, and anti-mitogenic effects of ANP and BNP in the vasculature could occur in part through CNP production and subsequent action if these interactions occur in vivo.
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PMID:Atrial and brain natriuretic peptides stimulate the production and secretion of C-type natriuretic peptide from bovine aortic endothelial cells. 788 64

Binding studies, affinity cross-linking and guanylate cyclase assays allowed a comparison of receptors with which the rat forms of atrial/A-type natriuretic peptide (rANP), brain/B-type natriuretic peptide (rBNP) and C-type natriuretic peptide (rCNP) interact in rat kidney cortex and lung. This work represents the first study in which the rat form of BNP (= rBNP-45/iso-rANP(1-45)) has been used as a radiolabelled tracer to further characterize its receptors in these tissues. In addition, these studies stress the use of the same species of natriuretic peptide and assay system, an important experimental des ign given that BNPs show species-specific differences in structure. rBNP-45 bound with lower affinity to rANP (99-126) receptors, namely guanylate cyclase-linked receptor(s) and C-receptor. No receptor which interacted with only rBNP-45 was detectable in lung and kidney cortex. Since rBNP-45 interacted preferentially with the C-receptor and was less potent than rANP(99-126) in stimulating glomerular guanylate cyclase, rBNP-45 may signal through another second messenger in addition to cyclic GMP. Work with truncated analogues of this hormone pinpointed regions of this peptide which may contribute to receptor binding affinity and guanylate cyclase activation. CNP-22 bound to only a subset of ANP receptors and was least effective in stimulating glomerular guanylate cyclase, suggesting a differential mode of action from ANP.
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PMID:Characterization of binding sites in rat for A, B and C-type natriuretic peptides. 790 75

The heart expresses the three natriuretic peptide receptors (NPR), namely NPR-A, NPR-B, and NPR-C. We have examined the temporal relationship between the expression of mRNA transcripts for atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) and their receptors in the heart during the development of cardiac hypertrophy in the aortovenocaval fistula rat. Messenger RNAs were measured by cDNA amplification. Progressive cardiac hypertrophy was accompanied by increased ANP mRNA prevalence throughout the heart and increased BNP mRNA in the left atrium. The most striking observation was the gradual disappearance of NPR-C transcripts (the putative "clearance" receptor) in all chambers; this was in marked contrast to the increase in mRNA levels for NPR-A and NPR-B (the guanylyl cyclase-linked receptors). Our observations have important therapeutic implications if the transcript changes are mirrored at the receptor protein level because (a) the apparent down-regulation of NPR-C may enhance the local action of natriuretic peptides on the heart, and (b) the loss of NPR-C, particularly if it is widespread, may reduce the rate of elimination of the natriuretic peptides, restricting the therapeutic potential of specific NPR-C ligands designed to reduce peptide clearance.
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PMID:Differential regulation of natriuretic peptide receptor messenger RNAs during the development of cardiac hypertrophy in the rat. 790 46

Of the four endogenous members of the natriuretic peptide family, only atrial natriuretic peptide has been demonstrated to have neuromodulatory effects. This study compares the neuromodulatory effects of atrial natriuretic peptide and a recently identified natriuretic peptide, C-type natriuretic peptide, in the rabbit isolated vas deferens. The ability of these peptides to alter cyclic nucleotide concentrations was assessed to determine the potential contribution of either cyclic AMP or cyclic GMP to the observed responses. The central hypothesis tested was that C-type natriuretic peptide modulates neurotransmission via an interaction with a guanylyl cyclase. C-type natriuretic peptide inhibited both purinergic and adrenergic neurotransmission in a concentration-dependent manner but failed to alter either cyclic GMP or cyclic AMP concentrations. Maximal inhibitory effects of C-type natriuretic peptide averaged 35 +/- 4% for purinergic and 49 +/- 7% for adrenergic neurotransmission. Atrial natriuretic peptide not only attenuated both purinergic and adrenergic neurotransmission but also increased cyclic GMP concentrations. C-type natriuretic peptide probably inhibited the release of the neurotransmitters because it failed to alter contractions to exogenously administered norepinephrine or ATP, the two putative neurotransmitters. These results suggest that the C-type natriuretic peptide receptor, guanylyl cyclase B, is not present in rabbit vas deferens and that C-type natriuretic peptide suppresses peripheral sympathetic neurotransmission independently of guanylyl cyclase activation.
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PMID:C-type natriuretic peptide neuromodulates independently of guanylyl cyclase activation. 790 55

We examined the effects of C-type natriuretic peptide (CNP) on cyclic GMP production and catecholamine synthesis in cultured bovine adrenal medullary cells. 1) CNP increased intracellular cyclic GMP content in a concentration-dependent manner (10-1000 nM). 2) The cyclic GMP production induced by 1 microM CNP reached a 200-fold increase, and the effect of CNP was most potent among the natriuretic peptide family. 3) The CNP-induced cyclic GMP production was attenuated by endothelin (1 microM) and angiotensin II (0.1-1 microM). 4) When the cells were cultured with hypertonic NaCl medium, the CNP-induced cyclic GMP production was potentiated in a time (1-4 days)- and concentration (25-100 mM)-dependent manner. 5) CNP stimulated the synthesis of 14C-labeled catecholamines from [14C] tyrosine but not from [14C] dopa. The stimulatory effect of CNP on the 14C-labeled catecholamine synthesis was observed at the concentrations of 100 to 100 nM. 6) 8-Bromo cyclic GMP, a membrane-permeable cyclic GMP analog, and sodium nitroprusside, an activator of soluble guanylate cyclase, also stimulated the synthesis of 14C-labeled catecholamines from [14C]tyrosine, whereas C-ANF, a specific ligand for the ANP-C (clearance) receptor that does not increase cyclic GMP content, failed to stimulate the synthesis of 14C-labeled catecholamines. 7) CNP (1 microM) as well as 8-bromo cyclic GMP and sodium nitroprusside increased the activity of tyrosine hydroxylase in the cells. These results suggest that in the adrenal medulla, CNP is a potent agonist for cyclic GMP production, which is modulated by endothelin, angiotensin II and the hypertonic NaCl condition.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:C-type natriuretic peptide stimulates catecholamine synthesis through the accumulation of cyclic GMP in cultured bovine adrenal medullary cells. 790 32

Natriuretic peptide receptor-B (NPR-B) was identified in rat chondrocytes, and its physiological functions were investigated. Rat tissues, including the xiphoid cartilage, brain, lung, liver, adrenal gland, and kidney, were screened for NPR-B activity, which we assayed by receptor guanylate cyclase activity specifically stimulated by C-type natriuretic peptide (CNP), a known selective activator of NPR-B. Cartilage showed distinctly higher NPR-B activity. Furthermore, exposure of cultured rat chondrocytes to CNP (10(-6) M) resulted in a large increase in intracellular cGMP production (376 +/- 38 pmol/well), with threshold responses occurring between 10(-10) and 10(-9) M CNP. Atrial natriuretic peptide and brain natriuretic peptide also stimulated cGMP production in rat chondrocytes but with a potency that was at least 10 times less than that of CNP. Polymerase chain reaction analysis also demonstrated NPR-B gene expression in adult rat xiphisternum and cultured chondrocytes. These findings indicate that NPR-B is present in rat chondrocytes. In rat chondrocytes exposed to CNP, [3H]thymidine incorporation was inhibited in a dose-dependent manner (half-maximal response, 10(-11)M). However, much higher concentrations of atrial natriuretic peptide were required to induce the inhibition of thymidine incorporation. Interestingly, CNP-like immunoreactivity was detected in the conditioned medium from chondrocyte cultures. In addition, TGF-beta 1, a multifunctional cytokine, induced a marked increase in CNP secretion and CNP mRNA levels in chondrocytes. These results indicate that autocrine CNP inhibits mitogenesis in chondrocytes via NPR-B under the control of TGF-beta 1.
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PMID:Autocrine regulation of rat chondrocyte proliferation by natriuretic peptide C and its receptor, natriuretic peptide receptor-B. 790 95

We have compared the effects of atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), and C-type natriuretic peptide (CNP) on the accumulation of cyclic GMP (cGMP) in secondary cultures of rat astrocytes. The order of potency of these peptides was CNP > ANP > BNP, which would be compatible with a predominance of guanylate cyclase B (GC-B)- versus guanylate cyclase A (GC-A)-type receptors in these cells. Accordingly, we found by northern blot analysis that the mRNA transcripts of GC-B were much more abundant in astrocytes than the transcripts of GC-A. In addition, astrocytes from diencephalon accumulated two times more cGMP in response to CNP than astrocytes from cortex. Binding experiments with 125I-labeled ANP or [Tyro]-CNP established that these ligands recognized only clearance-type receptors on astrocytes. However, the number of binding sites was approximately 100 times higher in astrocytes from cortex than in astrocytes from diencephalon and thus was inversely correlated to the amplitude of the cGMP response in the same cells. We found no further evidence for differences in the levels of GC-B receptors in astrocytes from the two regions because (a) the abundance of GC-B mRNA was similar and (b) there was no difference in particulate guanylate cyclase activity in astrocytes from each region. In addition, occupancy of clearance receptors with C-ANP4-23 did not affect the accumulation of cGMP in response to CNP; this makes it unlikely that the differences in cGMP responsiveness can be accounted for by binding and sequestration of CNP to the clearance receptors.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Effects of C-type natriuretic peptide on rat astrocytes: regional differences and characterization of receptors. 790 48


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