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 characterized in membranes from the human neuroblastoma cell line NB-OK-1, an ANP-R1 receptor (Mr 130 kDa) for the atrial natriuretic peptide (ANP). This receptor recognized biologically active forms of ANP with high affinity but showed no affinity for truncated ANP forms. It was functional in that binding correlated with guanylate cyclase activation (a 2-fold increase in Vmax) with the following rank order of potency: rat ANP-(99-126) greater than human ANP-(99-126) greater than human ANP-(102-126) greater than porcine BNP (brain natriuretic peptide). The enzyme required free Mn2+ in addition to the Mn-GTP substrate (Km of about 0.3 mM for both basal and ANP-stimulated activity). In the presence of dithiothreitol, the dose-response curve of guanylate cyclase activation was shifted rightward by a factor of 30. ANP-R1 receptors were upregulated through protein synthesis in cells exposed to 1 mM carbamylcholine or 1 mM dibutyryl cyclic AMP for 8-24 h (ANP was ineffective).
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PMID:Characterization and regulation of atrial natriuretic peptide (ANP)-R1 receptors in the human neuroblastoma cell line NB-OK-1. 168 Jul 22

Some evidence suggests homologous and heterologous regulation of atrial natriuretic peptide (ANP) receptors. We have examined the effects of exposure to ANP, angiotensin II (ANG II), arginine vasopressin (AVP), and endothelin (ET), on binding of ANP to cultured rat vascular smooth muscle cells (VSMC) and on guanylate cyclase-coupled and -uncoupled ANP receptors. The latter were studied by examining production of guanosine 3',5'-cyclic monophosphate (cGMP) in response to ANP and binding of ANP to Triton X-100-solubilized VSMC membranes, irreversible cross-linking with disuccinimidyl suberate, and sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) in presence of dithiothreitol, followed by radioautography. Exposure to 100 nmol/l ANP for 18 h reduced ANP sites to 43% of control. However, if acid wash of VSMC membranes at pH 5.0 was performed before binding, no decrease in density of ANP binding sites was detected. On SDS-PAGE, a 130-kDa band bound 42 vs. 46% of 125I-labeled ANP in acid-washed membranes from control vs. cells exposed to ANP; the remainder was bound to a 67-kDa band. ANG II (100 nmol/l), AVP (1 mumol/l), or ET-1 or ET-3 (100 nmol/l) did not produce changes in density of ANP sites or in binding to the 130- and 67-kDa bands. cGMP production in response to ANP showed exaggerated response in ANG II but not in AVP- or ET-treated VSMC. Effect of ANG II was abolished by the ANG II antagonist [Sar1-Ile8]ANG II.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Effects of ANP, angiotensin, vasopressin, and endothelin on ANP receptors in cultured rat vascular smooth muscle cells. 184 18

We examined the possibility that, in addition to stimulation of guanylate cyclase (GC), atrial natriuretic peptide (ANP) also activates phospholipase C (PLC) in cultured rat inner medullary collecting tubule (RIMCT) cells. ANP (10(-12)M) causes marked release of inositol trisphosphate (IP3) at a concentration that does not stimulate GC. Concentrations of ANP that stimulate GC (greater than or equal to 10(-10) M) result in attenuated IP3 release. Similarly, exogenous dibutyryl guanosine 3',5'-cyclic monophosphate (10(-6) M) markedly inhibits the response to 10(-10) M ANP. Inhibition of cyclic nucleotide-dependent protein kinase by H 8, but not inhibition of protein kinase C by H 7, restores the response to 10(-8) and 10(-6) M ANP. Therefore, activation of cyclic nucleotide-dependent protein kinase inhibits ANP-stimulated PLC activity. Activation of protein kinase C by phorbol 12-myristate-13-acetate (PMA) decreases ANP-stimulated IP3 production. Pretreatment with H 7, but not H 8, prevents inhibition by PMA. To explore a potential role for G proteins, we examined the effect of guanine nucleotide analogues on ANP-stimulated IP3 production in saponin-permeabilized cells. ANP-stimulated IP3 production is enhanced by GTP gamma S and is inhibited by GDP beta S. Similarly, preincubation with pertussis toxin prevents ANP-stimulated IP3 release. We conclude that ANP stimulates PLC in RIMCT cells via a pertussis toxin-sensitive G protein. Stimulation of PLC is inhibited on activation of either cyclic nucleotide or Ca2+-phospholipid dependent protein kinases.
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PMID:ANP stimulates phospholipase C in cultured RIMCT cells: roles of protein kinases and G protein. 184 66

In the present studies we sought to determine if cicletanine, which is an antihypertensive agent of unknown mechanism, could alter cGMP metabolism via inhibition of cGMP phosphodiesterases (PDE) in vascular smooth muscle. Cicletanine was determined to be a mixed (competitive, noncompetitive) inhibitor of both calmodulin-regulated and cGMP-specific PDEs from monkey aortic smooth muscle with Ki values of 450 to 700 microM. Cicletanine also potentiated vasorelaxation by the guanylate cyclase activators sodium nitroprusside and atrial natriuretic peptide in isolated rat aortas. Potentiation was not dependent upon the contractile agonists nor was it indomethacin-sensitive. Neither potentiation nor inhibition of cGMP PDEs was stereoselective. Methylene blue attenuated a component of cicletanine-induced vasorelaxation, but did not completely obviate relaxation. Both cicletanine and the cGMP-PDE inhibitor zaprinast potentiated sodium nitroprusside-mediated cGMP formation and relaxation, although the increase in cGMP content was markedly greater with zaprinast compared to cicletanine. In further studies, cicletanine did not potentiate cGMP activation of cGMP-dependent protein kinase, but did inhibit calmodulin-activated myosin light chain kinase and protein kinase C at relatively high concentrations (approximately 1 mM). In summary, these data demonstrate that cicletanine inhibits vascular cGMP PDEs, potentiates vasorelaxation, and to a limited extent, cGMP formation by guanylate cyclase activators in vascular smooth muscle. However, these relationships for cicletanine are dissimilar from the reference cGMP PDE inhibitor, zaprinast. Thus, other mechanisms may also contribute to the vasorelaxant action of cicletanine.
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PMID:Inhibition of low Km cGMP phosphodiesterases and Ca+(+)-regulated protein kinases and relationship to vasorelaxation by cicletanine. 185 Apr 74

Prazosin (25 microM) was found to increase 125I-labeled rat atrial natriuretic peptide ([125I]rANP) receptor binding by 50% (SC50) in bovine adrenal zona glomerulosa membranes. A series of 2,4-disubstituted quinazolines was prepared in order to identify more potent analogues for additional in vitro testing. Compound 7 (N-[3-[[2-(diethyl-amino)-4-quinazolinyl]amino]propyl] guanidine dinitrate) from this series (3 microM) significantly decreased the EC50 for rANP-mediated inhibition of ACTH-stimulated aldosterone synthesis in rat adrenal glomerulosa cells. At a higher concentration (20 microM), compound 7 had no effect on particulate guanylate cyclase from rabbit glomeruli in either the presence or absence of rANP.
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PMID:Atrial natriuretic peptide receptor modulators: effects of disubstituted quinazolines on receptor binding and in vitro biological activity. 196 15

Brain natriuretic peptide (BNP) has recently been found in porcine brain and has been shown to cause diuresis and natriuresis when injected in rats, effects similar to those caused by atrial natriuretic peptide (ANP). BNP is also synthesized in the cardiac atria and circulates in plasma. The amino acid sequence of the peptide resembles that of ANP particularly closely within the ring structure of the peptide. We examined the potential role of BNP in modulating renal function by assessing its ability to mimic the effects of ANP on rat glomeruli and in rabbit inner medullary collecting duct cells (IMCD). BNP bound with high affinity to glomeruli (Kd approximately 900 pM) and IMCD cells (Kd approximately 500 pM). In IMCD cells, BNP stimulated particulate guanylate cyclase (approximately 3-fold at maximum ligand concentration) and inhibited conductive 22Na+ uptake by 50% at concentrations at which ANP is also effective. In rat glomeruli, BNP bound with high affinity to the low-molecular-weight receptors but with lesser affinity to the higher-molecular-weight guanylate cyclase-linked receptors (Kd approximately 50 nM). In addition, the guanosine 3',5'-cyclic monophosphate accumulation response was less impressive in glomeruli than the guanylate cyclase response in IMCD tissue. Thus we conclude that BNP is of only slightly reduced affinity and potency for the ANP receptors in the kidney and probably acts through these receptors to exert its physiological effects.
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PMID:Brain natriuretic peptide: interaction with renal ANP system. 196 35

1. Interactions between the synthesis of myo-inositol 1,4,5-trisphosphate (IP3) and guanosine 3':5'-cyclic monophosphate (cyclic GMP) in the smooth muscle cells of the rabbit aorta were investigated. 2. In the presence or absence of vascular endothelium, noradrenaline (NA; 5 microM) consistently reduced the amount of phosphatidylinositol 4,5-bisphosphate (PI-P2) and increased both phosphatidic acid (PA) and IP3. 3. In the presence or absence of endothelium, acetylcholine (ACh; 100 microM but not 5 microM) slightly increased the amount of IP3, but exposure to ACh (100 microM) 4 min after application of NA did not modify NA-induced synthesis of IP3. 4. ACh (100 microM) markedly enhanced the synthesis of cyclic GMP in the presence of endothelium but not in the endothelium-denuded tissues. 5. Prazosin (5 microM) but not dibutyryl cyclic GMP (db-cyclic GMP; 100 microM) blocked the hydrolysis of PI-P2 induced by 5 microM NA. Synthesis of IP3 induced by NA, as estimated with [3H]-inositol was not modified by application of 100 microM db-cyclic AMP or db-cyclic GMP. 6. alpha-Human atrial natriuretic peptide (alpha-hANP; 0.1 microM) increased cyclic GMP in the presence or absence of endothelium. alpha-hANP (0.1 microM) consistently inhibited the hydrolysis of PI-P2 induced by 5 microM NA. 7. The results indicate that synthesis of IP3 is inhibited neither by the synthesis of cyclic GMP in the cytosol nor by cyclic GMP itself. However, synthesis of IP3 through hydrolysis of PI-P2 may be inhibited by an interaction between some steps in the IP3 synthetic process and by the activation of the alpha-hANP-guanylate cyclase process at the sarcolemma.
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PMID:Inhibitory action of alpha-human atrial natriuretic peptide on noradrenaline-induced synthesis of myo-inositol 1,4,5-trisphosphate in the smooth muscle cells of rabbit aorta. 197 Apr 98

The present studies were initiated to determine if cells of intestinal origin possess the molecular components supporting a response to atrial natriuretic peptides. Specific binding in cultured rat ileal cells with 125I-labeled atrial natriuretic peptide was saturable and of high affinity. Scatchard analyses showed a single population of binding sites with a Kd of 2.1 nmol/L and a Bmax of 300 fmol/mg protein. Atrial natriuretic peptide activated particulate guanylate cyclase 5- to 10-fold in a concentration- and time-dependent fashion. The EC50 for activation of enzyme by atrial natriuretic peptide was 6 nmol/L. Accumulation of cyclic guanosine monophosphate stimulated by atrial natriuretic peptide was observed in the intracellular (25-fold) and extracellular (50-fold) compartments and was dependent on concentration and time. Half-maximum intracellular accumulation was observed with 10 nmol/L atrial natriuretic peptide. These data suggest a role for atrial natriuretic peptides in the gastrointestinal tract.
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PMID:Rat intestinal cell atrial natriuretic peptide receptor coupled to guanylate cyclase. 197 6

1. Effects of atrial natriuretic peptide (ANP) on tension development, particulate guanylate cyclase activity and guanosine 3':5'-cyclic monophosphate (cyclic GMP) concentrations of uteri from oestrogen-treated, progesterone-treated, ovariectomized and pregnant rats were determined in vitro. 2. ANP inhibited the tension development by myometrial tissues from oestrogen-treated virgin rats and the sterile horn of 10 to 14 day pregnant rats but not of the uterus from pregnant and progesterone-treated rats. 3. Inhibition of cyclo-oxygenase and lipoxygenase activities did not restore the tocolytic activity of ANP on gravid uterus. ANP exerted a tocolytic effect on nongravid uterus submaximally stimulated by prostaglandin F2 alpha (PGF2 alpha), oxytocin, vasopressin, angiotensin II or 5-hydroxytryptamine (5-HT). 4. Ovariectomy decreased the tocolytic effects of ANP, which could be restored by oestrogen treatment. 5. The refractoriness to the tocolytic effect of ANP in pregnant rats was not accompanied by a decrease in its relaxant effects on isolated aortic strips. 6. Tocolytic effects of isoprenaline, isobutylmethyl xanthine and hydroxylamine were not influenced by pregnancy or progesterone treatment. Up to a concentration of 3 mM, sodium nitroprusside did not affect myometrial tension development. 7. Pregnancy and progesterone treatment markedly inhibited ANP-induced increases in myometrial particulate guanylate cyclase activity and cyclic GMP concentrations but did not influence the effects of ANP on aortic cyclic GMP concentrations. 8. It is concluded that exposure of the myometrium to circulating and placentally-produced progesterone is responsible for the pregnancy-induced decrease in the effects of ANP on myometrial particulate guanylate cyclase activity and cyclic GMP concentrations and in turn on myometrial tension development.
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PMID:Refractoriness of the gravid rat uterus to tocolytic and biochemical effects of atrial natriuretic peptide. 197 61

The effect of porcine brain natriuretic peptide (pBNP) on cyclic guanosine monophosphate (cGMP) production was investigated in localized rat brain areas by radioimmunoassay procedure. Porcine BNP activated particulate guanylate cyclase in the median eminence, subfornical organ, choroid plexus, olfactory bulb, paraventricular nucleus and pineal gland in a concentration-dependent fashion and its action was comparable to that of rat atrial natriuretic peptide (alpha-ANP), with ED50 values ranging from 5 to 7 x 10(-7) M for both peptides. Our results suggest that the activation of a specific receptor coupled to the guanylate cyclase system and the subsequent elevation of cGMP levels constitutes the common mechanism of the central action of BNP and ANP.
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PMID:Brain natriuretic peptide stimulates particulate guanylate cyclase activity in selected areas of the rat brain. 197 38


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