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 molecular basis for the inhibitory action of the antiatopic drug, N-(3',4'-dimethoxycinnamoyl)anthranilic acid (Tranilast), on the thrombin-induced release of a lysosomal enzyme, beta-N-acetylglucosaminidase, from washed rabbit platelets was investigated. Tranilast dose dependently increased cyclic AMP and cyclic GMP levels in thrombin-stimulated platelets, parallel with the inhibition of beta-N-acetylglucosaminidase release. There was no significant effect of Tranilast on adenylate or guanylate cyclase activity. Tranilast inhibited the activity of cyclic AMP and cyclic GMP phosphodiesterases in a cell-free system. The data suggest that the inhibitory action of Tranilast on the release reaction in platelets was due at least in part to inhibition of cyclic nucleotide phosphodiesterases followed by an elevation of cyclic AMP and cyclic GMP levels.
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PMID:The mechanism for the inhibitory action of N-(3',4'-dimethoxycinnamoyl)anthranilic acid (tranilast) on the release reaction in platelets. 246 71

Bradykinin, which activates polymodal nociceptors, increased cyclic GMP (cGMP) in a capsaicin-sensitive population of cultured sensory neurones from rat dorsal root ganglia (DRG) by stimulating guanylate cyclase, but had no effect on cyclic AMP (cAMP). In nonneuronal cells from DRG, bradykinin increased cAMP, but not cGMP. The bradykinin-induced increase in cGMP in the neurones was completely blocked by removal of extracellular Ca2+, or by incubation of the cells with the calcium channel blockers nifedipine and verapamil. Pretreatment of the neurones with either dibutyryl cGMP or sodium nitroprusside (which elevates cGMP) inhibited bradykinin-induced formation of inositol phosphates. It is possible that cGMP could be involved in the regulation of polyphosphoinositide turnover in DRG neurones.
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PMID:Activation of guanylate cyclase by bradykinin in rat sensory neurones is mediated by calcium influx: possible role of the increase in cyclic GMP. 247 84

We studied the influence of endothelium-derived relaxing factor (EDRF) on sydnonimine (SIN-1)-induced vasodilatation and the accumulation of cyclic GMP in the rabbit femoral artery. The potency of SIN-1 to elicit vasodilatation in norepinephrine-contracted femoral arteries was significantly enhanced in the absence of the endothelium or following impairment of the synthesis of EDRF with gossypol or NG-nitro-L-arginine, whether the application of SIN-1 was intra- or extraluminal. The increase in cyclic GMP in the femoral segments by a combination of SIN-1 and endothelium-derived relaxant factor (released by the endothelium of either the rabbit thoracic aorta or the femoral artery) was significantly less than the sum of the increases in cyclic GMP induced by each agent alone. In contrast, stimulation of purified soluble guanylate cyclase by submaximal concentrations of SIN-1 was additive with the effect of EDRF, released from acetylcholine-stimulated rabbit aortas. This indicates the absence of a direct interaction between the factor and SIN-1 at the level of soluble guanylate cyclase. The interaction seems to be specific for cyclic GMP-mediated responses, since cyclic AMP-induced dilatations elicited by isoproterenol were not affected by the presence of the endothelium. The results indicate that the endothelium can modulate the vascular reactivity to SIN-1. This modulation may be mediated either by EDRF or by another endothelial substance that alters the metabolism or the action of cyclic GMP in vascular smooth muscle.
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PMID:Modulation of the vasodilator action of SIN-1 by the endothelium. 248 6

The purpose of the present investigations was to determine whether or not SIN-1, a metabolite of molsidomine that spontaneously releases nitric oxide, stimulates the production of adenosine-3',5'-cyclic monophosphate (cyclic AMP) and of guanosine-3',5'-cyclic monophosphate (cyclic GMP) in endothelial cells. All experiments were performed on first or second passage cultured porcine aortic endothelial cells. SIN-1 induced a time- and concentration-dependent accumulation of cyclic GMP but not of cyclic AMP. The production of cyclic GMP evoked by SIN-1 but not evoked by human alpha-natriuretic polypeptide was inhibited by treatment of the cells with either methylene blue (an inhibitor of soluble guanylate cyclase) and hemoglobin (a scavenger of nitric oxide). These data suggest that SIN-1 enhances the activity of soluble guanylate cyclase, which in turn induces the accumulation of cyclic GMP in endothelial cells. This response is probably due to the spontaneous release of nitric oxide, which is a potent activator of soluble guanylate cyclase.
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PMID:SIN-1 stimulates the production of cyclic GMP but not cyclic AMP in porcine aortic endothelial cells. 248 8

The present study investigates the mechanism of endothelium-dependent relaxation of vascular smooth muscle. Melittin, a polypeptide found in honeybee venom and a known activator of phospholipase A2, induced transient, endothelium-dependent relaxations of rat thoracic aortae contracted with norepinephrine. Higher concentrations of melittin induced relaxations followed by contractions. Prior incubation of melittin with trypsin abolished the changes in relaxation and contraction due to melittin. Melittin (10 micrograms/ml)-induced relaxations were associated with transiently elevated levels of cyclic GMP with a peak increase of 30-fold, which occurred 30 seconds after melittin exposure. Melittin (10 micrograms/ml) elevated cyclic AMP levels less than twofold and this effect was variable. A lower concentration of melittin (1 microgram/ml) elevated cyclic GMP levels approximately twofold, while exposure to 1 microgram/ml melittin in the presence of the cyclic GMP phosphodiesterase inhibitor, M&B 22948 (1 mM), increased cyclic GMP levels fivefold. Removal of the endothelium prevented the increased levels of cyclic GMP and cyclic AMP due to melittin. Exposure to the guanylate cyclase inhibitor, methylene blue, prevented the increased levels of cyclic GMP. Methylene blue, nordihydroguaiaretic acid, and the phospholipase A2 inhibitor, parabromophenacyl bromide, inhibited melittin-induced relaxations, while the cyclo-oxygenase inhibitor, indomethacin, was without effect. Arachidonic acid increased cyclic AMP levels but had no effect on cyclic GMP levels in the presence or absence of indomethacin. Relaxations to melittin, and to the endothelium-dependent vasodilators acetylcholine, trypsin, histamine, and the Ca2+ ionophore A23187, and/or the associated increased cyclic GMP levels, were reduced following exposure to melittin. Prior exposure to polyarginine (10 micrograms/ml), which induced endothelium-dependent relaxations that were prevented by methylene blue, also inhibited relaxations to the endothelium-dependent vasodilators. In contrast, relaxations to sodium nitroprusside were potentiated in tissues previously exposed to melittin. Removal of the endothelium by rubbing the intimal surface also potentiated relaxations to sodium nitroprusside. Scanning electron micrographs of the intimal surface demonstrated that melittin and polyarginine greatly damaged the endothelial cells. The present results suggest that polycation containing peptides induce endothelium-dependent relaxation through elevation of cyclic GMP levels within the smooth muscle.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Effects of melittin on endothelium-dependent relaxation and cyclic GMP levels in rat aorta. 253 55

These studies were performed in vitro to investigate the nature of the second messenger for lower esophageal sphincter (LES) smooth muscle relaxation in response to electrical field stimulation (EFS) and vasoactive intestinal polypeptide (VIP). It was seen that VIP, permeant derivatives of the cyclic nucleotide 8-bromo cyclic GMP (BrcGMP) and 8-bromo cyclic AMP (8-BrcAMP), the guanylate cyclase stimulant sodium nitroprusside (SNP), the adenylate cyclase stimulant forskolin, M&B 22,948 (cGMP phosphodiesterase inhibitor) and SK&F 94,120 (cAMP phosphodiesterase inhibitor) caused dose-dependent and tetrocotoxin resistant fall in LES tension. Guanylate cyclase inhibitor methylene blue (MB) (3 x 10(-5) M), caused significant antagonism of fall in LES tension by SNP without modifying the inhibitory response of forskolin. The possible adenylate cyclase inhibitor N-ethylmaleimide (NEM) (1 x 10(-4) M), on the other hand, caused significant antagonism of fall in LES tension by forskolin without any effect on that caused by SNP. The inhibitory responses of 8-BrcGMP and 8-BrcAMP were not modified by MB or NEM. NEM (1 x 10(-4) M) and MB (3 x 10(-5) M) caused significant inhibition of the fall in LES tension with EFS. NEM also caused inhibition of fall in LES tension by VIP. Furthermore, SK&F 94,120 and not M&B 22,948 caused significant potentiation of fall in LES tension by EFS. From these results we conclude that: 1) cAMP and cGMP may act as second messengers for LES relaxation with EFS and VIP, and 2) VIP may act primarily via cAMP system and remains a strong possibility for one of the inhibitory neurotransmitters in the LES.
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PMID:Influence of stimulators and inhibitors of cyclic nucleotides on lower esophageal sphincter. 253 11

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

1. Retinas from channel catfish were dissociated and the cells maintained in culture. Horizontal cells that normally receive input from cone photoreceptors were identified. The conductance of the electrical junction formed between a pair of 'cone' horizontal cells was measured by controlling the membrane voltage of each cell with a voltage clamp maintained through either a micropipette or a patch pipette. The two techniques yielded similar results. 2. Transjunctional current was measured while transjunctional voltage was stepped to values between +/- 60 mV. The current (measured 5 ms after a step) was proportional to voltage over the range tested. For steps to voltages greater than +/- 45 mV, the current exhibited a slight time-dependent decline. 3. Dopamine decreased junctional conductance in a dose-dependent fashion. A 50% reduction was obtained with 10 nM-dopamine. The D1 agonist fenoldopam (100 nM) also decreased junctional conductance. The uncoupling produced by either agent was rapid and reversible. 4. The introduction of 100 microM-cyclic AMP into one cell of a pair decreased junctional conductance by, on average, 40%. Forskolin (1-10 microM), an activator of adenylate cyclase, decreased junctional conductance 50-90%. 5. The introduction of 80 microM-cyclic GMP into one cell of a pair decreased junctional conductance by, on average, 40%. Nitroprusside (1-10 microM), an activator of guanylate cyclase, reduced junctional conductance 40-65%. 6. The introduction of a peptide inhibitor specific for the cyclic AMP-dependent protein kinase reversed a decrease in junctional conductance produced by superfusion with either dopamine (1 microM), fenoldopam (100 nM) or forskolin (5-10 microM). 7. Intracellular Ca2+ concentration was measured with the fluorescent indicator Fura-2. The intracellular Ca2+ concentration was increased by activation of a Ca2+ current. Junctional conductance remained constant as the internal Ca2+ concentration changed from 100 to 700 nM. 8. Intracellular pH was measured with the fluorescent indicator bis-carboxyethylcarboxyfluorescein. The application of acetate (2.5 mM) reduced intracellular pH by 0.2-0.3 units and decreased junctional conductance by approximately 50%. A subsequent application of fenoldopam did not alter intracellular pH, but decreased junctional conductance by more than 50%. 9. The sensitivity of the junctional conductance between isolated horizontal cells to dopamine is consistent with dopamine having a direct effect on coupling in intact retina. Dopamine regulates the activity of a cyclic AMP-dependent protein kinase which in turn modulates junctional conductance. Changes in intracellular pH and Ca2+ concentration are not involved in mediating the effect of dopamine on coupling. Cyclic GMP and intracellular pH may participate in regulatory pathways independent of that used by cyclic AMP.
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PMID:Modulation of an electrical synapse between solitary pairs of catfish horizontal cells by dopamine and second messengers. 255 70

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

Guanylate cyclase appears to represent a central member of a diverse family of proteins involved in cell signaling mechanisms including the protein kinases, a low Mr ANP receptor, and possibly adenylate cyclase (based on limited sequence identity with the yeast enzyme). A membrane form of guanylate cyclase represents a new model for cell surface receptors, although such a model was once envisioned for adenylate cyclase (79). In original models for adenylate cyclase, hormone was thought to bind with either the enzyme or with an unknown protein to enhance cyclic AMP production (79). Guanylate cyclase appears to fall into the first adenylate cyclase model where binding of a ligand to an extracellular site on the enzyme transmits a signal to an intracellular catalytic site. The production of cyclic GMP, a second messenger, and of pyrophosphate are then increased. The protein tyrosine kinase family of receptors (80) and possibly another forthcoming family of cell surface receptors containing protein tyrosine phosphatase activity (81-83) contain a single transmembrane domain like guanylate cyclase. Furthermore, the protein tyrosine kinases are activated by ligand binding to the extracellular domain. However, the activation of guanylate cyclase, unlike these cell surface receptors, results in the formation of a low molecular weight second messenger.
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PMID:Guanylate cyclase, a cell surface receptor. 256 11


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