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

---

Query: EC:4.6.1.2 (guanylate cyclase)
8,497 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Dark voltage and light responses of isolated retinal rods of Rana esculenta were investigated by employing the whole-cell patch-clamp technique. When the recording pipette was filled with a medium devoid of nucleotides, a spontaneous hyperpolarization of the dark voltage partly due to a diffusional loss of cGMP and its precursor GTP and a retardation in the recovery of the light responses was observed. The larger part of the retardation of the light responses was prevented by 1 mM ATP. Addition of GTP attenuated the hyperpolarization, but did not abolish it completely. When the nitric-oxide-releasing substance sodium nitroprusside plus GTP was applied, the tendency of hyperpolarization disappeared and a stable dark voltage or even a slight depolarization was measured during the whole-cell recording period. Similar results were also obtained when GTP was given in combination with either EGTA or IBMX which are both known to interfere with the cGMP regulating enzymes in retinal rods. In addition to its effects on the dark voltage, an acceleration of the recovery phase of the light responses by sodium nitroprusside was also observed. Our observations strongly suggest that sodium nitroprusside activates guanylate cyclase in photoreceptors, as it does in other tissues, but we cannot exclude with certainty an effect on the phosphodiesterase.
...
PMID:Sodium nitroprusside alters dark voltage and light responses in isolated retinal rods during whole-cell recording. 135 84

Various parameters of the rat pineal gland display a 24-h rhythm. However, nothing is known about possible 24-h variations in cyclic GMP (cGMP) metabolism. In the present study, 24-h variations in pineal gland cGMP accumulation were investigated by determining the increase in cGMP level with and without inhibitors of phosphodiesterase at different time points over a light/dark cycle (12/12 h). Furthermore, the activity of guanylate cyclase (GC) was determined under substrate-saturated conditions regarding the cytosolic and particulate forms of the enzyme. It has been found that cGMP accumulation and GC activity display biphasic 24-h variations with two peaks--one approximately 7 h after lights "on" and the other approximately 7 h after lights "off." The activity of cytosolic GC remains unchanged in the presence of the nitric oxide (NO) synthesis inhibitor N-monomethyl-L-arginine, indicating that 24-h variations in the activity do not reflect changes in the synthesis of the GC stimulator NO.
...
PMID:Biphasic 24-hour variations in cyclic GMP accumulation in the rat pineal gland are due to corresponding changes in the activity of cytosolic and particulate guanylate cyclase. 135 14

We attempted to identify and establish the role of cyclic nucleotide phosphodiesterase (PDE) isozymes in human basophils by using standard biochemical techniques as well as describing the effects of isozyme-selective and nonselective inhibitors of PDE. The nonselective PDE inhibitors, theophylline and 3-isobutyl-1-methylxanthine, inhibited anti-IgE-induced release of histamine and leukotriene C4 (LTC4) from basophils. This inhibition was accompanied by elevations in cAMP levels. Rolipram, an inhibitor of the low Km cAMP-specific PDE (PDE IV), inhibited the release of both histamine and LTC4 from activated basophils and increased cAMP levels in these cells. In contrast, mediator release from basophils was not inhibited by either siguazodan or SK&F 95654, inhibitors of the cGMP-inhibited PDE (PDE III) or zaprinast, an inhibitor of the cGMP-specific PDE (PDE V). SK&F 95654 failed to elevate basophil cAMP in these experiments whereas zaprinast induced significant increases in cAMP content. The inhibitory effect of rolipram on mediator release was potentiated by siguazodan or SK&F 95654, but not by zaprinast. SK&F 95654 also enhanced the ability of rolipram to increase cAMP content. Forskolin, a direct activator of adenylate cyclase, inhibited IgE-dependent release of mediators from basophils and increased cAMP levels in these cells. These effects were enhanced by rolipram, but not by SK&F 95654 or zaprinast. The cell permeant analog of cAMP, dibutyryl cAMP, inhibited mediator release from these cells, a property not shared by either dibutyryl-cGMP or sodium nitroprusside, an activator of soluble guanylate cyclase. The presence of both PDE III and PDE IV was confirmed by partially purifying and characterizing PDE activity in broken cell preparations. Overall, these data lend support to the hypothesis that cAMP inhibits mediator release from basophils and suggest that the major PDE isozyme responsible for regulating cyclic AMP content in these cells is PDE IV, with a minor contribution from PDE III. However, the finding that zaprinast caused increases in cAMP without inhibiting mediator release indicates that cAMP accumulation is not invariably linked to an inhibition of basophil activation.
...
PMID:Preliminary identification and role of phosphodiesterase isozymes in human basophils. 137 72

The effects of copper deficiency on smooth muscle relaxation were studied in the cremaster muscle microcirculation. Male Sprague-Dawley rats were fed either a copper-adequate diet (CuA, 5 micrograms copper/g diet) or copper-deficient diet (CuD, no added copper) for 17-27 d before experimentation. In vivo television microscopy was used to quantify agonist-induced diameter changes in third-order arterioles. Endothelium-dependent relaxation, which is hypothesized to be mediated by nitric oxide, was attenuated by copper deficiency. Both receptor (acetylcholine, 10(-7) to 10(-4) mol/L) and nonreceptor (calcium ionophore A23187, 10(-8) to 10(-7) mol/L) relaxation was decreased. Nitric oxide-mediated dilation, which was endothelium-independent (10(-7) to 10(-5) mol/L sodium nitroprusside), was also attenuated by copper deficiency. Maximal responses were as follows: for acetylcholine, 136 +/- 16% CuA vs. 45 +/- 15% CuD; for A23187, 104 +/- 16% CuA vs. 21 +/- 11% CuD; and for nitroprusside, 125 +/- 12% CuA vs. 46 +/- 13% CuD. There was no difference in microvascular dilation between groups treated with 10(-6) to 10(-4) mol/L of the phosphodiesterase inhibitor papaverine (e.g., CuA 109 +/- 11% vs. CuD 133 +/- 21% with 10(-4) mol/L). These results suggest that copper deficiency inhibits the nitric oxide-mediated mechanism of vascular smooth muscle relaxation without altering the capacity of the smooth muscle to relax. We suggest that copper deficiency either decreases nitric oxide radical availability or disrupts the nitric oxide-guanylate cyclase interaction.
...
PMID:Copper deficiency alters vasodilation in the rat cremaster muscle microcirculation. 161 79

There is increasing evidence that resting pulmonary vascular tone is mediated in part by the release of endothelium-derived relaxing factors (EDRF). Because L-arginine may be a precursor for EDRF synthesis, we studied the pulmonary vasodilating effects of L-arginine at rest and during pulmonary hypertension in 16 intact newborn lambs. At rest, the intravenous infusions of L-arginine (150 mg/kg) had no hemodynamic effects. However, during pulmonary hypertension induced by hypoxia or the infusion of U-46619 (a thromboxane A2 mimic), L-arginine decreased pulmonary arterial pressure by 22 and 27%, respectively (P less than 0.05). The decrease in pulmonary arterial pressure produced by L-arginine was blocked by methylene blue, a guanylate cyclase inhibitor, and augmented by Zapranast, a guanosine 3',5'-cyclic monophosphate (cGMP) phosphodiesterase inhibitor (-17.9 vs. -31.2%, P less than 0.05). In addition, L-arginine partially reversed the pulmonary hypertension induced by N omega-nitro-L-arginine, a competitive EDRF synthesis inhibitor, but D-arginine had no hemodynamic effects. This study suggests that L-arginine produces pulmonary vasodilation by increasing cGMP concentrations, supporting the in vitro hypothesis that L-arginine is a precursor for EDRF synthesis, whose availability may become rate limiting during pulmonary hypertension.
...
PMID:L-Arginine, a precursor of EDRF in vitro, produces pulmonary vasodilation in lambs. 165 28

Hydrogen peroxide (H2O2), but not tertbutyl hydroperoxide, produces a concentration-dependent vasodilation of the pulmonary circulation in isolated saline perfused rabbit lungs when pulmonary arterial pressures (PAP) are raised with the thromboxane analogue U-46619. This vasodilation was enhanced in the presence of indomethacin, suggesting that H2O2 possesses both a prostaglandin-mediated constrictor and an additional dilator mechanism. In isolated rabbit intrapulmonary arteries the endothelium did not alter the dose-dependent relaxation of arterial rings to H2O2, and indomethacin enhanced the relaxant response of the peroxide. The decrease in PAP and relaxation of isolated pulmonary arteries observed with H2O2 was attenuated with 10 microM methylene blue, an inhibitor of soluble guanylate cyclase activation. M & B 22948, a guanosine 3',5'-cyclic monophosphate (cGMP)-selective phosphodiesterase inhibitor, enhanced the vasodilation or relaxation to the peroxide in both preparations. These changes were not endothelium dependent. Inhibition of the cGMP-associated endothelium-derived relaxant factor (EDRF) with nitro-L-arginine, did not alter relaxation of arterial rings to peroxide. Thus H2O2 appears to produce pulmonary vasodilation through the activation of guanylate cyclase and accumulation of cGMP. Both H2O2 and EDRF may function as tonic stimulators of guanylate cyclase in the pulmonary circulation and contribute to the maintenance of low basal pressures.
...
PMID:Hydrogen peroxide-induced pulmonary vasodilation: role of guanosine 3',5'-cyclic monophosphate. 166 18

The effect of aging on the ATP-induced relaxation of rat thoracic aorta was examined. Haemoglobin, methylene blue and NG-nitro L-arginine, and removal of the endothelium inhibited or reversed the relaxation induced by ATP. The relaxant response of the aorta to ATP was greatest in the preparations from 4-week-old rats. As the age of rats increased to 45 and 105 weeks, the concentration-response curve for ATP was shifted to the right with reduction of maximal relaxation. ATP elevated cyclic GMP levels. This action was endothelium-dependent and inhibited by methylene blue, haemoglobin and NG-nitro L-arginine. With an increase in age of the rats from 4 weeks to 45 weeks, ATP-stimulated cyclic GMP production was attenuated, and in the aorta from 105-week-old rats cyclic GMP level was no longer elevated by ATP. In contrast to the age-associated marked change in cyclic GMP levels, cyclic AMP production was not affected by aging. It is suggested that age-related changes in ATP-induced relaxation and cyclic GMP formation occur mainly at the level of the vascular smooth muscle. Alterations in soluble guanylate cyclase, at step(s) distal to the guanylate cyclase, or in cyclic GMP-phosphodiesterase might contribute.
...
PMID:Possible association of decrease of ATP-induced vascular relaxation with reduction of cyclic GMP during aging. 166 32

Nitric oxide (NO) formation from L-arginine and subsequent activation of a soluble guanylate cyclase accounts for the effect of the endothelium derived relaxing factor (EDRF). Cyclic GMP produced in smooth muscle cells induces relaxation through a mechanism which involves cyclic GMP kinase, but has not yet been entirely elucidated. Experiments with specific inhibitors of the different cyclic nucleotide phosphodiesterases (PDEs) suggest that a cyclic GMP-inhibited PDE which selectively hydrolyzes cyclic AMP, called PDE III, might also be involved in the relaxing mechanism of cyclic GMP. In arteries removed from endotoxemic rats or exposed to E. coli endotoxin, an extra-endothelial production of NO or a NO-like relaxing factor is induced in smooth muscle cells. Evidence that this phenomenon may be important in endotoxin shock is provided by experiments in which vascular reactivity is restored to control level by inhibitors of NO production in endotoxemic rats. These findings show that the L-arginine-NO pathway and cyclic GMP play a major role in regulating vascular contractility in physiological and pathological conditions.
...
PMID:The L-arginine-NO pathway and cyclic GMP in the vessel wall. 166 67

1. The effects of selective inhibitors of adenosine 3':5'-cyclic monophosphate (cyclic AMP) and guanosine 3':5'-cyclic monophosphate (cyclic GMP) phosphodiesterases (PDEs) were investigated on PDEs isolated from the rat aorta and on relaxation of noradrenaline (1 microM) precontracted rat aortic rings, with and without functional endothelium. 2. Four PDE forms were isolated by DEAE-sephacel chromatography from endothelium-denuded rat aorta: a calmodulin-activated PDE (PDE I) which hydrolyzed preferentially cyclic GMP, two cyclic AMP PDEs (PDE III and PDE IV) and one cyclic GMP-specific PDE (PDE V). The latter was selectively and potently inhibited by zaprinast. The two cyclic AMP PDEs were discriminated by specific inhibitors: one was inhibited by cyclic GMP (PDE III) and by new cardiotonic agents (milrinone, CI 930, LY 195115 and SK&F 94120); the other was inhibited by denbufylline and rolipram (PDE IV). None of these drugs significantly inhibited PDE I. 3. The PDE III inhibitors caused endothelium-independent relaxations of rat aortic rings with the following EC50 values (microM concentration producing 50% relaxation): LY 195115: 3.4, milrinone: 5.7, CI 930; 7.8, SK&F 94120: 14.7. Neither NG-monomethyl-L-arginine (L-NMMA, 300 microM), an inhibitor of the L-arginine-NO pathway, nor L-arginine (1 mM) modified the effect of PDE III inhibitors. However, methylene blue (10 microM) an inhibitor of soluble guanylate cyclase abolished relaxation induced by PDE III inhibitors except in the case of compound CI 930. 4. The specific PDE IV and PDE V inhibitors both produced endothelium-dependent relaxations which were inhibited by L-NMMA and by methylene blue (10 microM). In the presence of L-NMMA, relaxation was restored by subsequent addition of L-arginine. 5. The relaxant effects of denbufylline and rolipram were studied in the presence of drugs stimulating either adenylate cyclase (forskolin and isoprenaline) or soluble guanylate cyclase (sodium nitroprusside, SNP), or inhibiting PDE III (milrinone). In endothelium-denuded rings, a relaxing effect of both denbufylline and rolipram was found in the presence of milrinone (EC5o values 1.7 and 12 microM, respectively) or SNP (EC50 values 12.3 and 124 microM, respectively), but not in the presence of forskolin or isoprenaline. However in the presence of functional endothelium, relaxations produced by PDE IV inhibitors were significantly potentiated by forskolin, isoprenaline, milrinone and SNP (respective EC50 values for denbufylline: 2, 2, 0.4 and 0.7 microM and for rolipram: 7, 13, 7 and 1.2 microM). 6. These results indicate that the relaxant effects of inhibitors of the cyclic AMP-specific PDE IV are markedly enhanced by cyclic GMP elevating agents and by the PDE III inhibitor milrinone. They support the hypothesis that cyclic GMP enhances cyclic AMP-mediated relaxation, possibly through the inhibition of the cyclic GMP-inhibited PDE III.
...
PMID:Endothelium-dependent and independent relaxation of the rat aorta by cyclic nucleotide phosphodiesterase inhibitors. 166 41

Metabolism of cGMP is critically important for the functioning of phototransduction in the mammalian retina. In rod and cone photoreceptors, two types of antagonistic enzymes, guanylate cyclases and cGMP phosphodiesterases, carefully balance the available amount of the intracellular messenger. Guanylate cyclase produces cGMP and phosphodiesterase rapidly hydrolyzes cGMP upon bleaching of the photopigment. Regulation of their activity in light and dark, influence of Ca++, and feed-back mechanisms are currently under intense investigation. A molecular analysis on both the gene and protein levels will contribute significantly to our understanding of their respective roles in phototransduction. The two types of enzymes have been characterized molecularly to a very different extent. Rod phosphodiesterase was purified to homogeneity almost fifteen years ago, but photoreceptor guanylate cyclase has evaded all attempts for molecular characterization. Characterization of retinal guanylate cyclase cDNA(s), however, will most likely be achieved in the near future. Cone PDE was shown to be a distinct enzyme, different from, but related to, the rod enzyme. Molecular cloning has provided sequence information of two of the three subunits of rod PDE; the small inhibitory subunit has been expressed in bacterial expression vectors, giving us an elegant tool for exploring mechanisms of activation and inhibition. The gene encoding the alpha subunit was shown to be a member of a large gene family of cyclic nucleotide phosphodiesterases, present in many eucaryotes ranging from unicellular organisms (yeast) to mammals. While much has been achieved, many questions remain to be answered. The beta subunit of rod phosphodiesterase has evaded complete molecular characterization, and its origin (one gene and posttranslational modification of the gene product generating alpha and beta, alternative splicing, or two separate genes with distinct gene products) has not been elucidated. Mechanisms of interaction of subunits, activation and inhibition, the active site(s) of the enzyme are undefined. Virtually nothing is known about the molecular organization of the photoreceptor guanylate cyclase(s). Recent cloning of two apparently unrelated mammalian guanylate cyclases, however, containing a common homologous domain signals increasingly rapid progress in this field.
...
PMID:The molecular genetics of retinal photoreceptor proteins involved in cGMP metabolism. 167 36


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>

---