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 purpose of this study was to elucidate the mechanisms by which arachidonic acid activates guanylate cyclase from guinea pig lung. Guanylate cyclase activities in both homogenate and soluble fractions of lung were examined. Guanylate cyclase activity was determined by measuring formtion of [32-P] cyclic GMP from alpha-[32-P] GTP in the presence of Mn2+, a phosphodiesterase inhibitor and a suitable GTP regenerating system. Arachidonic acid, and to a slight extent dihomo-gamma-linolenic acid, activated guanylate cyclase in homogenate but not soluble fractions. Similarly, phospholipase A2 activated homogenate but not soluble guanylate cyclase. Methyl arachidonate, linolenic, linoleic and oleic acids did not activate guanylate cyclase in either fraction. High concentrations of indomethacin, meclofenamate and aspirin inhibited activation of homogenate guanylate cyclase by arachidonic acid and phospholipase A2, without altering basal enzyme activity. These data suggested that a product of cyclooxygenase activity, present in the microsomal fraction, may have accounted for the capacity of arachidonic acid to activate homogenate guanylate cyclase. This view was supported by the findings that addition of the microsomal fraction to be soluble fraction enabled arachidonic acid to activate soluble guanylate cyclase, an effect which was reduced with cycloooxygenase inhibitors. Lipoxygenase activated guanylate cyclase in homogenate and soluble fractions. Arachidonic acid potentiated the activation of soluble guanylate cyclase by lipoxygenase, and this effect was inhibited with nordihydroguairetic acid, 1-phenyl-3-pyrazolidone and hydroquinone, but not with high concentrations of indomethacin, meclofenamate or aspirin. These data suggest that arachidonic acid activates guinea pig lung guanylate cyclase indirectly, via two independent mechanisms, one involving the microsomal fraction and the other involving lipoxygenase.
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PMID:Arachidonic acid activation of guinea pig lung guanylate cyclase by two independent mechanisms. 4 57

Pharmacological probes were used to assess the possible roles of guanosine 3',5'-cyclic monophosphate (cGMP)-associated endothelium-derived relaxing factor (EDRF) in mediating microvascular responses to endogenous and exogenous agents in vivo. Pentobarbital-anesthetized rats (Wistar, 6 wk old) were prepared for in vivo microscopic observation and quantification of changes in diameter of third-order arterioles (15-25 microns) in the cremaster muscle to topical application of all agents. In indomethacin-pretreated preparations, cremasteric arteriolar dilator responses to acetylcholine, bradykinin, or ATP, but not to adenosine, histamine, or prostaglandin E2, were inhibited by hydroquinone (50 microM). Vasodilation to acetylcholine was also inhibited by methylene blue (5 microM), a blocker of guanylate cyclase activation. Constrictor responses to norepinephrine were not affected by hydroquinone or methylene blue. The inhibition of acetylcholine-induced vasodilation by hydroquinone and methylene blue was reversed by superoxide dismutase, suggesting that superoxide anion antagonized the response. On the other hand, basal arteriolar diameters or responses to acetylcholine were not affected by oxygen metabolite scavengers. Unlike in isolated arteries, vasodilator responses to the calcium ionophore A23187 or arachidonic acid were completely antagonized by cyclooxygenase inhibition. These data suggest that EDRF could be involved in the control of microvascular tone; however, significant differences exist in the stimuli that elicit dilation through this mediator in small and large blood vessels.
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PMID:Endothelium-associated vasodilators in rat skeletal muscle microcirculation. 249 47

Since there is evidence suggesting that nicorandil (SG-75) relaxes coronary arterial smooth muscle by increasing cGMP levels, the effects of this vasodilator on soluble guanylate cyclase from bovine coronary arteries were studied more closely. It was found that nicorandil stimulated guanylate cyclase dose-dependently (3-30 mM) up to 100-fold the control value. Similar to nitroglycerin but in contrast to sodium nitroprusside, cysteine (0.5-20 mM) was required to obtain this stimulation. All other investigated thiols, except thiosalicylic acid which was partially able to mimic the cysteine effect, were ineffective. As evident from time course studies, nicorandil induced stimulation of guanylate cyclase was characterized by a lag-phase which could be avoided by preincubating the enzyme with nicorandil. The stimulatory effect of nicorandil was diminished in the presence of methylene blue, ferricyanide or hydroquinone. These results give further evidence that a) nicorandil exerts its vasodilating effect via stimulation of guanylate cyclase and b) nitrate esters, such as nitroglycerin or nicorandil, stimulate the enzyme, at least in vitro, only in the presence of cysteine or, to a lesser extent, thiosalicylic acid.
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PMID:Stimulation of coronary guanylate cyclase by nicorandil (SG-75) as a mechanism of its vasodilating action. 285 1

Homogeneous or partially purified soluble guanylate cyclase (GTP pyrophosphate-lyase (cyclizing), EC 4.6.1.2) from rat liver exhibited variable sensitivity to assay pH that was dependent upon buffer composition and the cation cofactor. Enzyme activity with 3 mM Mn2+ in excess of Mn2+-GTP was considerably less in Tris buffers above pH 8.0 than in glycine buffer. In the pH range of 6.0-7.6, however, manganese-supported activity was greater in Tris buffers than in imidazole or cacodylate buffers of corresponding pH. The differences in activity seen with various buffers were not apparent when Mg2+ was the sole cation cofactor but were dependent upon Mn2+ concentrations in excess of Mn2+-GTP. The effects of excess Mn2+ on guanylate cyclase varied with assay pH and buffer composition. At pH 7.6 in Tris-HCl buffer, excess Mn2+ increased guanylate cyclase activity with an apparent Ka of 0.25 mM and concentrations above 3 mM were slightly inhibitory. At pH 9.0 in Tris-HCl buffer, however, concentrations of excess Mn2+ above 0.1 mM were strongly inhibitory. By comparison, in cacodylate (pH 7.6) or glycine (pH 9.0) buffers, high concentrations of excess Mn2+ were considerably less inhibitory and the apparent Ka values for excess Mn2+ were greater than in Tris-HCl buffer at equivalent pH. The variable effects of Mn2+ on enzyme activity as a function of buffer pH and composition were qualitatively similar to its effects on catecholamine oxidation. Furthermore, the inhibition of guanylate cyclase by excess Mn2+ was partially prevented by dithiothreitol and the stimulation of enzyme activity by excess cation was completely blocked by the antioxidant hydroquinone. The studies suggest that the apparent requirement and preference of soluble guanylate cyclase for excess Mn2+ as cation cofactor, as well as the inhibition of enzyme activity by excess Mn2+ may be mediated by oxidative events associated with changes in the oxidation state of the free cation.
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PMID:Oxidative modulation of soluble guanylate cyclase by manganese. 610 32

Isolated perfused rat kidney was used to examine the possible mechanisms involved in the hypotensive/vasodilator actions of cryptolepine. In kidneys preconstricted by phenylephrine (PE 5-7.5 x 10(-7) M), cryptolepine at bolus doses of 2.5, 5, and 10 micrograms elicited dose-dependent reductions in perfusion pressure by 29.8 +/- 4.1, 43.3 +/- 3.9, and 54.3 +/- 4.9 mm Hg, respectively. In the presence of indomethacin, cryptolepine-induced reduction in perfusion pressure was not significantly changed, suggesting a lack of a cyclooxygenase-mediated component in its renal vasodilator response. Removal of the endothelium with p-bromophenacyl bromide (p-BPB 10 microM) inhibited the vasodilator response to cryptolepine 2.5, 5, and 10 micrograms to 10.2 +/- 1.8, 15.9 +/- 1.5, and 20.2 +/- 2.0 mm Hg, respectively (p < 0.01). The vasodilator response to acetylcholine (ACh 50 ng) was also reduced from a control value of 56.7 +/- 4.5 to 15.3 +/- 1.9 mm Hg (p < 0.01); responses to sodium nitroprusside (SNP 5 micrograms) and isoprenaline (1 microgram) were not affected. In kidneys treated with hydroquinone (10(-5) and 10(-4) M), a specific inhibitor of endothelium-dependent vasodilation, cryptolepine- and ACh-induced vasodilation were inhibited dose dependently (p < 0.01). N omega-nitro-L-arginine (L-NNA 10(-5)-10(-4) M), a specific inhibitor of the synthesis/release of endothelium-derived relaxing factor/nitric oxide (EDRF/NO), attenuated the vasodilator response to cryptolepine and ACh (50 ng) dose dependently. At 10(-4) M L-NNA, cryptolepine-induced vasodilation was reduced to 6.6 +/- 2.2 (2.5 micrograms), 10.9 +/- 2.2 (5 micrograms), and 13.3 +/- 1.4 mm Hg (10 micrograms). L-Arginine (10(-4) and 3 x 10(-4) M) but not D-arginine (10(-4) M) inhibited the effects of L-NNA, with vasodilatory effects of cryptolepine returning to control values, suggesting that the vasodilator material released by cryptolepine is EDRF, possibly NO. Methylene blue (MB 10(-4) M), the inhibitor of soluble guanylate cyclase which inhibited 50 ng ACh and 5 micrograms SNP-induced vasodilation also reduced the vasodilatory responses to cryptolepine to 0.8 +/- 0.8 (2.5 micrograms), 4.2 +/- 4.2 (5 micrograms), and 10.8 +/- 6.2 mm Hg (10 micrograms) suggesting that the effector pathway for cryptolepine-induced vasodilation is soluble guanylate cyclase-linked increase in cyclic GMP of vascular smooth muscle.
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PMID:Role of the endothelium and cyclic GMP in renal vasodilator responses to cryptolepine in rats. 751 10

In this study, we show that particulate guanylate cyclase (GC) is present in rat pancreatic acinar cells and is located both on plasma membrane and membranes of endoplasmic reticulum (ER). Western blot analysis indicates that the enzyme isoform GC-A is present in the acinar cell membranes. The specific inhibitors of ER Ca(2+)-ATPase thapsigargin, 2,5-di-(t-butyl)-1,4-hydroquinone (BHQ), and cyclopiazonic acid all activated particulate GC in pancreatic acini, both in membrane fractions and intact cells. These inhibitors also induced dephosphorylation of GC. Dose dependencies of Ca(2+)-ATPase inhibition and GC activation by BHQ are very similar, and those for thapsigargin partially overlap. ER Ca(2+)-ATPase and GC are coimmunoprecipitated both by antisera against membrane GC and by antisera against ER Ca(2+)-ATPase, suggesting a physical association between the two enzymes. The results suggest that thapsigargin and the other inhibitors act through ER Ca(2+)-ATPase to activate membrane GC in pancreatic acinar cells, although their direct effect on GC cannot be excluded.
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PMID:Endoplasmic reticulum Ca(2+)-ATPase inhibitors stimulate membrane guanylate cyclase in pancreatic acinar cells. 1066 32

Nitric oxide (NO) and NO donors exhibit actions that are not entirely mediated by soluble guanylate cyclase (sGC). The site of NO release may influence the involvement of sGC-independent effects. Here we use spermine NONOate (SPER/NO) to release NO extracellularly, compared with other NO donors. Isolated rat femoral arteries were perfused luminally and perfusion pressure monitored. Vessels were contracted with phenylephrine (2-14 microM) in the presence of an NO synthase inhibitor (N(omega)-nitro-L-arginine methyl ester; 20 microM). Vasodilator responses to NO donors were assessed before and after perfusion of an sGC inhibitor (1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one; ODQ; 20 microM), NO scavengers (hemoglobin; Hb & hydroquinone; HQ), and a superoxide generator (duroquinone; DQ). ODQ (20 microM) abolished the vasodilator responses to glyceryl trinitrate (10(-8) - 10(-3) M), and sodium nitroprusside (10(-8) - 10(-4) M), which release NO intracellularly. ODQ (20 microM) attenuated, but failed to abolish, the vasodilator responses to SPER/NO (10(-6) - 10(-3) M). ODQ abolished responses to S-nitrosoglutathione and S-nitroso-N-valeryl-D-penicillamine (10(-8) - 10(-4) M), but a small residual vasodilatation remained in response to 10(-3) M. In the presence of ODQ, the remaining vasodilatation to SPER/NO was all but abolished by scavengers of extracellular NO (Hb; 10 microM, HQ; 100 microM). Superoxide generation (DQ; 100 microM) also attenuated ODQ-resistant vasodilatation. The data suggest that, in rat femoral arteries, NO donors that are capable of releasing extracellular NO cause vasodilatation that is only partially mediated by sGC. Lack of augmentation of sGC-independent effects by superoxide suggests that they are not mediated by peroxynitrite.
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PMID:Extracellular nitric oxide release mediates soluble guanylate cyclase-independent vasodilator action of spermine NONOate: comparison with other nitric oxide donors in isolated rat femoral arteries. 1507 29

In septic shock, systemic vasodilation and myocardial depression contribute to the systemic hypotension observed. Both components can be attributed to the effects of mediators that are released as part of the inflammatory response. We previously found that lysozyme (Lzm-S), released from leukocytes, contributed to the myocardial depression that develops in a canine model of septic shock. Lzm-S binds to the endocardial endothelium, resulting in the production of nitric oxide (NO), which, in turn, activates the myocardial soluble guanylate cyclase (sGC) pathway. In the present study, we determined whether Lzm-S might also play a role in the systemic vasodilation that occurs in septic shock. In a phenylephrine-contracted canine carotid artery ring preparation, we found that both canine and human Lzm-S, at concentrations similar to those found in sepsis, produced vasorelaxation. This decrease in force could not be prevented by inhibitors of NO synthase, prostaglandin synthesis, or potassium channel inhibitors and was not dependent on the presence of the vascular endothelium. However, inhibitors of the sGC pathway prevented the vasodilatory activity of Lzm-S. In addition, Aspergillus niger catalase, which breaks down H(2)O(2), as well as hydroxyl radical scavengers, which included hydroquinone and mannitol, prevented the effect of Lzm-S. Electrochemical sensors corroborated that Lzm-S caused H(2)O(2) release from the carotid artery preparation. In conclusion, these results support the notion that when Lzm-S interacts with the arterial vasculature, this interaction results in the formation of H(2)O(2), which, in turn, activates the sGC pathway to cause relaxation. Lzm-S may contribute to the vasodilation that occurs in septic shock.
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PMID:Lysozyme, a mediator of sepsis that produces vasodilation by hydrogen peroxide signaling in an arterial preparation. 1826 14

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