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)

1. The effects of forskolin, a direct activator of adenylate cyclase and sodium nitroprusside, a direct activator of guanylate cyclase, were studied on rabbit isolated ear arteries preconstricted with 80 mM potassium. 2. Bolus injection of these two compounds resulted in vasodilatation. They had similar potencies in this tissue but forskolin had a significantly longer duration of action than sodium nitroprusside. 3. In the same tissue, perfusion with isobutylmethylxanthine (IBMX), a non-selective phosphodiesterase (PDE) inhibitor, or zaprinast, selective for the PDE primarily responsible for the metabolism of guanosine 3':5'-cyclic monophosphate (cyclic GMP), resulted in vasodilatation. However, SK&F 94120 selective for cyclic AMP-PDE (PDE III), primarily responsible for the metabolism of adenosine 3':5'-cyclic monophosphate (cyclic AMP), resulted in vasodilatation only at very high concentrations. The rank order of potency for the compounds was IBMX greater than zaprinast greater than SK&F 94120. 4. The effects of these three PDE inhibitors were studied on the vasoconstriction produced by perivascular sympathetic nerve stimulation in the absence of raised potassium. IBMX and zaprinast, caused a reduction in the response at 50 Hz stimulation frequency and a shift in the frequency-response curve to the right. SK&F 94120 did not displace the frequency-response curve but did reduce the response at 50 Hz. The same order of potency for the inhibition of the vasoconstrictor responses to perivascular sympathetic nerve stimulation was found as for vasodilatation i.e. IBMX greater than zaprinast greater than SK&F 94120. 5. These results indicate that in the same tissue direct activation of adenylate and guanylate cyclase results in vasodilatation. Non-specific PDE and cyclic GMP-PDE inhibition also resulted in vasodilatation and inhibition of vasoconstrictor responses to sympathetic nerve stimulation. However a selective cyclic AMP-PDE (PDE III) inhibitor did not result in vasodilatation, except at very high concentrations, or inhibit sympathetic vasoconstrictor responses except to reduce the response at 50Hz stimulation. These findings provide further support for the ability of PDE inhibitors to be tissue selective.
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PMID:A comparison of vasodilator activity of agents activating cyclic nucleotides with those inhibiting their metabolism in rabbit isolated ear artery. 254 50

Electrical field stimulation (EFS) of isolated strips of opossum lower esophageal sphincter (LES) produced a relaxation that was accompanied by an elevation of intracellular cyclic GMP content. In order to compare the time dependence of the EFS-induced relaxation with that of the elevation of cyclic GMP, the ability of EFS to produce relaxation and increase cyclic GMP was measured. The results of these experiments showed that cyclic GMP content increased before the onset of relaxation. Cumulative addition of atriopeptin II, an activator of particulate guanylate cyclase, produced a concentration-dependent relaxation of this tissue and increased cyclic GMP content. In other experiments, zaprinast, an inhibitor of a cyclic GMP selective-phosphodiesterase, produced a concentration-related relaxation of opossum LES and increased cyclic GMP content. However, pretreatment with zaprinast (3 microM) did not potentiate the EFS-induced relaxation or the increase in cyclic GMP content. At this concentration, however, zaprinast increased the basal content of cyclic GMP. Finally, 8-Br-cyclic GMP, a membrane-permeable analog of cyclic GMP, produced a concentration-dependent relaxation of isolated strips of opossum LES. In conclusion, these data extend the initial findings that an elevation in cyclic GMP content is associated with relaxation and suggest that cyclic GMP is a potential intracellular messenger of neurally- and drug-induced relaxation of opossum LES.
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PMID:Cyclic GMP: a potential mediator of neurally- and drug-induced relaxation of opossum lower esophageal sphincter. 254 33

The effects of 2-nitratopropyl 3-nitratopropyl 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate (CD-349) and sodium nitroprusside (NP) on cyclic GMP (cGMP) metabolism in bovine intrapulmonary artery (BPA) and vein (BPV) were examined. CD-349 inhibited cGMP phosphodiesterase (PDE) activity in BPA and BPV. In the latter, about 40% of the cGMP PDE activity was Ca2+ dependent. The inhibition of cGMP PDE activity by CD-349 also depended on Ca2+. The inhibitory effect of CD-349 was more potent than that of nicardipine or nifedipine. The conversion of cGMP from GTP in the homogenates of BPA and BPV was stimulated by NP in a concentration-dependent manner. The NP-induced cGMP formation was stimulated further by CD-349. This effect of CD-349 depended on Ca2+ in the BPV but not in the BPA. The NP-induced elevation of cGMP levels in the tissue preparations of BPA and BPV was also potentiated by CD-349. These results suggest that CD-349 inhibited Ca2+-dependent cGMP PDE activity and that the levels of cGMP were elevated in vascular smooth muscle, particularly when guanylate cyclase was activated.
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PMID:Alteration of cyclic GMP metabolism by CD-349, a novel calcium antagonist, and by sodium nitroprusside in bovine intrapulmonary artery and vein. 254 8

Glucose transport in isolated rat cardiomyocytes is stimulated by insulin, catecholamines, and anoxia approximately 2- to 3-fold over basal rates. The molecular mechanisms controlling these responses are unknown. In our search for possible cellular mediators of glucose transport stimulation, we examined the effects of a number of nucleotides on 3-O-methylglucose transport in heart cells. The nucleotides and/or permeable analogs (monosuccinyl, 8-bromo, and dibutyryl derivatives) included cUMP, cIMP, cCMP, cAMP, and cGMP at concentrations ranging from 10 nM to 1 mM. Of all the nucleotides tested only cGMP analogs induced a significant stimulation of transport at concentrations as low as 100 nM. This effect was observed in both the 8-bromo- and dibutyryl derivatives and with 1 mM cGMP itself. The effect was concentration dependent for both analogs and produced a maximal response equivalent to that of 100 nM insulin. This insulinomimetic effect of cGMP was examined in more detail in order to evaluate its role as a potential mediator of this response. Agents that are known to stimulate guanylate cyclase in the heart produced a clear stimulation of transport when added to cardiomyocytes. These include insulin, aminophylline, histamine, beta-estradiol, and biotin-nitrophenyl ester. Methylene blue, an inhibitor of guanylate cyclase, blocked the insulin response when added to cells before insulin, but was ineffective when added after insulin. In addition, agents that raise intracellular cGMP levels by inhibiting cyclic nucleotide phosphodiesterases were also examined for effects on glucose transport. Out of several phosphodiesterase inhibitors tested, only Zaprinast (which selectively increases cGMP in heart) stimulated transport in a concentration-dependent manner to within 80% of the maximal insulin effect. These results are consistent with the notion that cGMP may be involved in glucose transport stimulation.
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PMID:Stimulation of glucose transport in rat cardiac myocytes by guanosine 3',5'-monophosphate. 254 35

We have investigated the role of Ca2+ and calmodulin in the stimulation of cGMP formation by mouse Leydig cells in response to rat atriopeptin-II (rAP-II). Removal of extracellular Ca2+ had no influence on the levels of cGMP accumulated by the cells stimulated with rAP-II. The amounts of testosterone produced by unstimulated and rAP-II-stimulated cells were, however, reduced by 50% in the absence of Ca2+ from the incubation medium. Addition of ionomycin to the Leydig cells led to a dose-related inhibition of rAP-II-stimulated cGMP formation, but the basal cGMP level was not affected. These experiments were carried out in the presence of a phosphodiesterase inhibitor. The inhibitory effect of ionomycin was absolutely dependent upon the presence of Ca2+ in the medium. The guanylate cyclase activity required the presence of a cation, and Mn2+, Mg2+, or Ca2+ could function as the required cation. There was no direct inhibition of the cyclase activity by Ca2+ up to as high a concentration as 8 mM. Furthermore, three structurally unrelated calmodulin antagonists, W7, trifluoperazine, and calmidazolium, but not W5, caused a dose-related inhibition of rAP-II-stimulated cGMP accumulation by the cells. The inhibitory effect of calmodulin antagonists was not exerted directly at the level of guanylate cyclase activity, since the particulate enzyme was not inhibited by any of these drugs. We conclude, therefore, that extracellular Ca2+ is not essential for rAP-II-mediated stimulation of cGMP formation by mouse Leydig cells, at least under the short term incubation conditions used. An excessive ionophoretic influx of Ca2+ into the cells impairs the ability of rAP-II to stimulate cGMP formation. Therefore, it appears that a finely regulated level of intracellular Ca2+ is required for optimal activation of atrial natriuretic peptide-responsive guanylate cyclase in mouse Leydig cells, and calmodulin plays an important role in this process.
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PMID:The role of Ca2+ and calmodulin in the regulation of atrial natriuretic peptide-stimulated guanosine 3',5'-cyclic monophosphate accumulation by isolated mouse Leydig cells. 254 43

The hypothesis that the relaxant action of many drugs on vascular and other smooth muscle is mediated by increases in intracellular cGMP, the "cGMP hypothesis," is gaining wide acceptance. While much information supporting this idea can be found in the literature, there is also a significant amount of information indicating that an elevation in the tissue content of cGMP is by itself insufficient to cause smooth muscle relaxation. The literature is reviewed with reference to the criteria that need to be fulfilled to consider cGMP as the second messenger mediating relaxation of smooth muscle by a drug; i.e., activation of guanylate cyclase, elevation of tissue content of cGMP, potentiation by phosphodiesterase inhibitors, antagonism by inhibitors of cGMP synthesis, and production of relaxation by cGMP analogues. For each criterion, key observations supporting the hypothesis are considered, followed by examples of important observations not consistent with the hypothesis. It is concluded that in some smooth muscles, for example, rat myometrium and vas deferens, cGMP is not a mediator of drug-induced relaxation. In other smooth muscles, including vascular smooth muscle, cGMP appears to play an important role in the relaxation process; but current evidence suggests that other factors are also important and that the cGMP hypothesis may need to be modified.
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PMID:Role of cGMP in relaxation of vascular and other smooth muscle. 254 2

cGMP is a second messenger that mediates numerous metabolic events; in the present work a role in myeloid cell differentiation was demonstrated. Nitroprusside and NaNO2, which activate cytosolic guanylate cyclase and increase the intracellular cGMP concentration, induced granulocytic differentiation of the human promyelocytic cell line HL-60; differentiation was measured by acquisition of the OKM1 antigen, morphological changes, and nitroblue tetrazolium reduction. When theophylline, a phosphodiesterase inhibitor, which by itself induced modest differentiation, was added to nitroprusside or NaNO2, differentiation increased in an additive fashion. The degree of differentiation correlated with the increase in the intracellular cGMP concentration. 8-Bromoguanosine 3',5'-cyclic monophosphate, a membrane-permeable cGMP analogue, also induced differentiation of HL-60 cells but was much more effective in the presence of theophylline, with the two agents interacting synergistically. The effect of theophylline in these studies could not be attributed to increasing the intracellular cAMP concentration. Dimethyl sulfoxide, and established inducer of differentiation of HL-60 cells, markedly enhanced the differentiation induced by nitroprusside and NaNO2.
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PMID:cGMP-induced differentiation of the promyelocytic cell line HL-60. 255 Sep 30

The distribution of cyclic guanosine 3',5' monophosphate (cGMP) producing cells in various organs of the rat were studied immunocytochemically using antibodies raised against formaldehyde-fixed cGMP. Sodium nitroprusside (SNP), a direct activator of guanylate cyclase and vasodilator, was used to enhance cGMP levels. In order to reach all organs optimally, whole body perfusion was performed using a modified Krebs-Ringer buffer at 37 degrees C, aerated with 5% CO2/95% O2, also containing isobutyl methyl xanthine (IBMX); a phosphodiesterase inhibitor. After 15-min pre-perfusion, SNP was added to the perfusate, followed by fast fixation with ice-cold 4% paraformaldehyde-phosphate buffer. After vehicle perfusion, only the retina showed cGMP immunoreactivity in the photoreceptor and ganglion layer, while other organs lacked cGMP immunoreactivity. After 15-min perfusion with SNP (10 microM), enhanced cGMP immunostaining was seen in smooth muscles of the aorta, amacrine-like cells in the retina, glomeruli of the kidney cortex, blood vessels in the dura mater, as well as cells in the pineal and in the median eminence. The results indicate that the distribution and the reactivity of cGMP producing cells, situated outside the blood brain barrier, can be studied by immunocytochemistry after pharmacological manipulations of the intact tissue with a nitrovasodilator using whole body perfusion.
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PMID:cGMP immunocytochemistry in aorta, kidney, retina and brain tissues of the rat after perfusion with nitroprusside. 255 68

The novel neuropeptide, brain natriuretic peptide (BNP), causes concentration-dependent relaxations in rat isolated arterial rings. The pD2 value of BNP in rat thoracic aorta is 8.05 +/- 0.06, almost identical to the pD2 value of atrial natriuretic peptide (the 28 amino acid peptide, rat sequence, AP-28, 8.11 +/- 0.08), indicating that BNP and ANP have the same potency in relaxing thoracic aorta. In addition, BNP is equally potent at causing relaxation in abdominal aorta and mesenteric and renal arteries. However, BNP is less potent in causing vasorelaxation in the common iliac and femoral arteries and shows no relaxant effects in caudal arteries. This pharmacological profile of BNP in different rat arteries is very similar to that of ANP. Like ANP, BNP induces a vasorelaxation that is independent of endothelium and is associated with very sustained increases in cyclic GMP, but not cyclic AMP, levels in rat thoracic aorta. The BNP-induced cyclic GMP elevation, like the vasorelaxation, is also independent of endothelium and is not blocked by methylene blue (10 microM), a soluble guanylate cyclase inhibitor. Furthermore, BNP-induced cyclic GMP elevation is independent of extracellular calcium and potentiated by the cyclic GMP-phosphodiesterase inhibitor M & B 22948. Therefore, the pharmacological characteristics of BNP in rat blood vessels are very similar to those of ANP, suggesting that BNP and ANP may act through a common receptor and post-receptor mechanism to cause vasodilation.
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PMID:Brain natriuretic peptide (BNP) causes endothelium-independent relaxation and elevation of cyclic GMP in rat thoracic aorta. 255 55

We have examined the interaction of zaprinast with mediators of guanylate cyclase on the relaxation of aortic smooth muscle. Zaprinast, a selective inhibitor of the low Km-cyclic GMP (cGMP) phosphodiesterase [low Km cGMP phosphodiesterase (PDE)], was equally effective in relaxing phenylephrine-contracted aortas from spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY) with an intact endothelium [EC50 = 7.6 (3.5-16.6) microM vs. 9.3 (4.1-21.3) microM, respectively]. In contrast, the vasorelaxant activity of zaprinast in intact and denuded phenylephrine-contracted guinea pig aortas, as well as denuded (SHR and WKY) aortas was minimal. Sodium nitroprusside and atriopeptin II were significantly (P less than .05) more potent as vasorelaxants in denuded SHR aortas when compared with denuded aortas from WKY. Pretreatment with zaprinast potentiated the vasorelaxant potency of sodium nitroprusside in both SHR and WKY aortas whereas atriopeptin II responses were potentiated only in WKY aortas. In studies with the low Km cGMP PDE, isolated via DEAE column chromatography, the apparent Km for cGMP and potency of zaprinast were approximately 2-fold greater (P less than .05) in WKY when compared with the same PDE isozyme isolated from SHR aortic preparations. However, the Vmax (picomoles per milligram per minute) for cGMP hydrolysis was greater in SHR than in WKY. In conclusion, these data show that, although there are no apparent differences in the influence of spontaneously released endothelium-derived relaxing factor from SHR and WKY aortas, reactivity differences to other agents known to stimulate guanylate cyclase activity exist between SHR and WKY denuded aortas.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Phosphodiesterase isozyme inhibition and the potentiation by zaprinast of endothelium-derived relaxing factor and guanylate cyclase stimulating agents in vascular smooth muscle. 256 75


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