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 present study investigates whether or not chronic feeding of rats with a diet enriched in fish oil affects the reactivity of balloon-injured carotid arteries. The left carotid arteries were injured in vivo by the repeated passage of a balloon catheter. Both the right (control artery) and the left carotid arteries were excised 24 h after the injury, and suspended in organ chambers for the measurement of changes in isometric tension in the presence of indomethacin. 2. Phenylephrine evoked similar concentration-contraction curves in the right (control) carotid arteries without endothelium from control and fish oil-fed rats. Balloon injury decreased the contractility of carotid arteries to phenylephrine in both types of rats and the pEC50 for phenylephrine was significantly decreased in balloon-injured arteries from control rats compared to those obtained in arteries from fish oil-fed rats (pEC50 7.59 +/- 0.1 and 7.28 +/- 0.06, respectively) while maximal contractions were similar (1.93 +/- 0.15 g and 1.79 +/- 0.12 g, respectively). 3. The treatment of control right carotid arteries without endothelium with either NG-nitro-L-arginine (an inhibitor of nitric oxide synthase) or superoxide dismutase (which protects nitric oxide from degradation) did not affect significantly the contractions to phenylephrine in either group. In these preparations, methylene blue (an inhibitor of soluble guanylate cyclase) decreased slightly but significantly maximal contractions to phenylephrine in both groups. The treatment of balloon-injured carotid arteries with NG-nitro-L-arginine or methylene blue partly restored contractions to phenylephrine in arteries from both types of rat. Superoxide dismutase further depressed the contractility to the alpha l-adrenoceptor agonist in balloon-injured arteries from control diet-fed rats but had no effect in balloon-injured preparations from fish oil-fed rats.4. 3-Morpholino-sydnonimine (SIN-1, a donor of nitric oxide) evoked similar concentration-dependent relaxations in control and balloon-injured carotid arteries from both types of rat.5. Balloon injury caused an increase in the tissue content of cyclic GMP in carotid arteries from control diet-fed rats. This production of cyclic GMP was abolished by N0-nitro-L-arginine. Superoxide dismutase potentiated significantly the production of cyclic GMP caused by balloon injury in control but not in fish oil-fed rats.6 These observations confirm that in vivo balloon injury causes the production of nitric oxide in the injured blood vessel wall. This production of nitric oxide from L-arginine accounts for the decreased contractility to phenylephrine and the accumulation of cyclic GMP in balloon-injured arteries. They further indicate that chronic feeding of rats with fish oil potentiates the L-arginine-nitric oxide pathway in the injured vessel leading to an enhanced hyporeactivity to phenylephrine.
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PMID:Potentiation of the hyporeactivity induced by in vivo endothelial injury in the rat carotid artery by chronic treatment with fish oil. 767 Jul 27

1. The effects of hydrogen peroxide (H2O2, 0.1-1 mM) on the tone of the rings of rabbit aorta precontracted with phenylephrine (0.2-0.3 microM) were studied. 2. H2O2 induced a concentration-dependent relaxation of both the intact and endothelium-denuded rings. However, in the presence of intact endothelium, H2O2-induced responses were 2-3 fold larger than in its absence, demonstrating the existence of endothelium-independent and endothelium-dependent components of the vasorelaxant action of H2O2. 3. The endothelium-dependent component of H2O2-induced relaxation was prevented by NG-nitro-L-arginine methyl ester (L-NAME, 30 microM) or NG-monomethyl-L-arginine (300 microM), inhibitors of nitric oxide synthase (NOS), in a manner that was reversible by L-, but not by D-arginine (2mM). The inhibitors of NOS did not affect the responses of denuded rings. 4. Methylene blue (10 microM), an inhibitor of soluble guanylate cyclase, blocked H2O2-induced relaxation of both the intact and denuded rings. 5. H2O2 (1 mM) enhanced the efflux of cyclic GMP from both the endothelium-intact and denuded rings. The effect of H2O2 was 4 fold greater in the presence of intact endothelium and this endothelium-dependent component was abolished after the inhibition of NOS by L-NAME (30 microM). 6. In contrast to the effects of H2O2, the vasorelaxant action of stable organic peroxides, tert-butyl hydroperoxide or cumene hydroperoxide, did not have an endothelium-dependent component. Moreover, they did not potentiate the efflux of cyclic GMP from the rings of rabbit aorta. 7. Exogenous donors of NO, specifically, 3-morpholinosydnonimine (SIN-1), glyceryl trinitrate or sodium nitroprusside were used to decrease the tone of denuded rings to the level induced by endogenous NO released from intact endothelium. This procedure did not influence the vasorelaxant activity of H202, showing that H202 does not potentiate the vasorelaxant action of NO within the smooth muscle.8. Thus, H202-induced relaxation in the rabbit aorta has both endothelium-dependent and independent components. The endothelium-dependent component of the relaxant action of H202 is due to enhanced endothelial synthesis of NO.
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PMID:Involvement of nitric oxide in the endothelium-dependent relaxation induced by hydrogen peroxide in the rabbit aorta. 769 74

The study shows that endothelial cells from human umbilical veins have a soluble guanylate cyclase which can be activated by sodium nitroprusside (SNP), SIN-1 (3-morpholinosydnonimine) and S35b (4-methyl-3-phenylsulfonylfuroxan). Cells which were pretreated with these compounds showed an inhibition of thrombin-induced arachidonic acid release, PGI2 formation, PAF synthesis and PMNL adhesion. Endothelial guanylate cyclase can also be activated by nitric oxide (NO) which is generated in endothelial cells upon stimulation with thrombin or ionomycin. It is suggested that endogenously produced NO might control cell activation and endothelial function through a cGMP-dependent mechanism.
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PMID:Activation of endothelial guanylate cyclase inhibits cellular reactivity. 771 76

The effects of the nitric oxide (NO) donor 3-morpholino-sydnonimine (SIN-1) on the L-type Ca2+ current (ICa) were examined in frog ventricular myocytes under basal and phosphorylated conditions. SIN-1 was found to exert insignificant effects on basal ICa but to induce a biphasic action on stimulated ICa. Indeed, in the nanomolar range of concentrations (0.1-10 nM), SIN-1 induced a pronounced (approximately 40%) stimulation of ICa elevated by a non-maximal concentration of forskolin (0.3 microM). However, the stimulatory effects of SIN-1 on ICa were not additive with those of maximal concentrations (10 microM) of forskolin or intracellular cAMP. In contrast, at higher concentrations (100 nM to 1 mM), SIN-1 strongly reduced ICa (by up to 85%) which had been previously stimulated by cAMP, forskolin, or isoprenaline. All the effects of SIN-1 appeared to be mediated by the liberation of NO since they were suppressed by methylene blue and LY83583 and were not mimicked by SIN-1C, a metabolite of SIN-1. The stimulatory or inhibitory effects of SIN-1 were absent, respectively, in the presence of milrinone (10 microM) or when the hydrolysis-resistant cAMP analog 8-bromo-cAMP was used instead of cAMP to stimulate ICa. In addition to its effects on ICa, SIN-1 induced a dose-dependent stimulation of guanylyl cyclase activity in the cytosolic and membrane fractions of frog ventricle. The membrane form of guanylyl cyclase displayed a higher sensitivity to SIN-1 than the cytosolic form, which correlated with SIN-1 sensitivity of ICa. Our data suggest that the activatory and inhibitory effects of NO donors on ICa result from an inhibition of the cGMP-inhibited cAMP-phosphodiesterase and an activation of the cGMP-stimulated cAMP-phosphodiesterase, respectively, both linked to the activation of guanylyl cyclase, possibly a membrane form of the enzyme.
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PMID:Nitric oxide regulates cardiac Ca2+ current. Involvement of cGMP-inhibited and cGMP-stimulated phosphodiesterases through guanylyl cyclase activation. 790 37

This study was designed to determine if nitric oxide (NO) has direct effects on heart rate or if it is involved in the chronotropic actions of adrenergic or cholinergic stimulation. Right atria were isolated from hearts of adult male rats, bathed in Krebs-Henseleit buffer (37 degrees C), and used to monitor spontaneous rate. For comparison, ring segments of thoracic aorta were also suspended in the Krebs-Henseleit solution and used to examine vascular actions of various agents. The dose-dependent chronotropic effects of acetylcholine (10(-7)-10(-3) M) and norepinephrine (10(-8)-3 x 10(-4) M) in right atria were not affected by pretreatment with 10(-4) M N-nitro-L-arginine or 10(-3) M N-nitro-L-arginine-methyl ester, inhibitors of L-arginine-derived NO production. SIN-1 (3-morpholino-sydnonimine), an agent which releases NO in aqueous solution, elicited a dose-dependent (0.3-100 microM) vasorelaxation in aortic preparations constricted with 60 mM KCl; the ED50 value for this effect was increased by pretreatment with methylene blue (10 microM) and LY-83,583 (6-(phenylamino)-5,8- quinolinedione; 1 and 3 microM), compounds which inhibit NO-induced stimulation of guanylate cyclase. SIN-1 produced a negative chronotropic effect in right atria; however, this action was not observed at concentrations less than 300 microM and was not antagonized by methylene blue or LY-83,583. 8-Bromo cyclic GMP produced a dose-dependent (10-3000 microM) decrease in KCl-induced tension in aortic rings. In right atria, 8-bromo cyclic GMP elicited a positive chronotropic effect.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Nitric oxide has no chronotropic effect in right atria isolated from rat heart. 791 42

Selected studies of nitroglycerin tolerance have demonstrated desensitization of the nitric oxide-stimulated guanylyl cyclase. To define the mechanism by which the response to nitric oxide becomes desensitized, we studied the effects of activating both nitric oxide and atrial natriuretic peptide-stimulated guanylyl cyclases in rat medullary interstitial cells. Cells were pretreated with the nitric oxide agonists nitroprusside (SNP) and SIN-1 for 18 hr before measuring SNP- or SIN-1-stimulated cyclic GMP (cGMP) accumulation in the presence of 3-isobutyl-1-methylxanthine. Pretreatment with SNP decreased SNP- and SIN-1-stimulated cGMP accumulation without altering the EC50 for SNP. Pretreatment with SIN-1 also inhibited SNP and SIN-1-stimulated cGMP accumulation. To rule out a nonspecific metabolic effect of SNP, we showed that SNP pretreatment decreased SIN-1-stimulated soluble guanylyl cyclase activity, but had no significant effect on forskolin-stimulated cyclic AMP accumulation. Pretreatment with SNP also decreased the mRNA abundance of the alpha 1- and beta 1-subunits of guanylyl cyclase. Pretreatment with either atrial natriuretic peptide or 8-chlorophenylthio-cGMP inhibited SNP-stimulated cGMP. We conclude that the soluble guanylyl cyclase-linked nitric oxide receptor exhibits homologous and heterologous desensitization in rat medullary interstitial cells. The site of regulation is unknown, but homologous desensitization may involve decreased abundance of soluble guanylyl cyclase.
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PMID:Homologous and heterologous desensitization of a guanylyl cyclase-linked nitric oxide receptor in cultured rat medullary interstitial cells. 791 20

Human bronchial rings were contracted with histamine (3 microM), and inhibitory responses were obtained with electrical field stimulation (EFS) in the presence of propranolol (1 microM), atropine (1 microM), and indomethacin (3 microM). These nonadrenergic noncholinergic (NANC) relaxations were frequency-dependent (1 to 32 Hz) and inhibited by either tetrodotoxin or Nw-nitro-L-arginine (L-NNA, 100 microM). The selective cAMP-specific phosphodiesterase (PDE) type IV inhibitors rolipram (3 microM) and Ro 20-1724 (3 microM) significantly potentiated NANC relaxations at each frequency of stimulation. The selective cGMP-specific PDE type V inhibitor zaprinast (3 microM) failed to significantly alter the maximal NANC response, but it caused a slight potentiation of the response at lower frequencies. The adenylyl cyclase stimulant forskolin, the nitric oxide donor compound 3-morpholinosydnonimine (SIN-1), and the guanylyl cyclase stimulant sodium nitroprusside caused concentration-dependent relaxation of histamine-contracted airway smooth muscle. Rolipram significantly potentiated the relaxation elicited by forskolin. Rolipram also potentiated responses to SIN-1 and sodium nitroprusside. Considered together these data support the hypothesis that cAMP plays a facilitory role in NANC relaxation of the human bronchi.
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PMID:Potentiation of nonadrenergic noncholinergic relaxation of human isolated bronchus by selective inhibitors of phosphodiesterase isozymes. 773 37

The relaxing effects of several specific and nonspecific inhibitors of phosphodiesterases (PDE) on rabbit isolated corpus cavernosum (CC) and spongiosum (CS) were investigated. Preparations were mounted in organ baths, and isometric tension was recorded. The results were compared with the effects of direct administration of analogs of the second messenger cyclic nucleotides and the effects of forskolin, a direct stimulator of adenylate cyclase, and the nitric oxide donor 3-morpholinosydnonimine (SIN 1). All drugs relaxed the phenylephrine-induced contractions in CC and CS in a dose-dependent fashion. In CC and CS, type III (SK&F 95654) and type V (zaprinast and dipyramidole) PDE inhibitors, as well as the nonspecific inhibitors papaverine and trequinsin, showed no differences in IC50. The type IV inhibitor rolipram relaxed CC and CS at significantly lower concentrations (p < 0.005) than any other PDE inhibitor, and in CC the type III and IV inhibitor zardaverine was more potent (p < 0.05) than SK&F 95654. SIN 1 stimulates guanylate cyclase and effectively inhibits contractions in CC and CS. Activation of adenylate cyclase by forskolin also was highly effective (p < 0.005). It is concluded that PDE inhibition constitutes an effective relaxing mechanism in rabbit CC and CS. The marked effects of the different types of PDE inhibitors support the importance of cyclic guanosine 3',5'-monophosphate and cyclic adenosine 3',5'-monophosphate in smooth muscle relaxation in erectile tissue.
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PMID:Smooth muscle tone regulation in rabbit cavernosal and spongiosal tissue by cyclic AMP- and cyclic GMP-dependent mechanisms. 796 7

Nitric oxide (NO) released from nonadrenergic-noncholinergic (NANC) nerves seems to be a principal mediator of the relaxation of penile erectile tissue necessary for erection, and drugs acting by release of NO have been shown to produce erection when injected intracorporeally into impotent patients. By producing hyperpolarization, K+ channel openers are effective in relaxing isolated penile erectile tissue from rabbit and man, and can produce tumescence and erection when injected intracorporeally into animals. Nicorandil is classified as a K+ channel opener, but it also acts as a donor of NO. In the present study, the effects of nicorandil on isolated preparations from human corpus cavernosum (CC) and deep cavernous artery (Acc) were compared with those of cromakalim (K+ channel opener) and SIN-1 (NO donor). Nicorandil produced a concentration-dependent relaxation of CC and Acc preparations. The relaxations obtained at the highest nicorandil concentration used (10(-4) M.) were 75 +/- 3% and 66 +/- 4% in CC preparations contracted by noradrenaline and endothelin-1, respectively. The corresponding effects in Acc preparations were 70 +/- 14% and 73 +/- 5%. Glibenclamide (blocking ATP-dependent K+ channels) significantly reduced the nicorandil-induced relaxation in CC, but not in Acc. Methylene blue (believed to block soluble guanylate cyclase) reduced nicorandil's relaxant effect in CC, although statistical significance was not obtained. NG-nitro-L-arginine 10(-4) M. (NO synthase inhibitor) did not significantly influence the effect of nicorandil on precontracted preparations in either tissue. In CC preparations contracted by electrical field stimulation, nicorandil and cromakalim concentration dependently inhibited the responses. This effect was significantly counteracted by glibenclamide. It is concluded that nicorandil is effective in relaxing human CC chiefly by its K+ channel opening action, and to some extent by its ability to release NO. For nicorandil's relaxing effect on Acc, ATP dependent K+ channels seem to be of limited importance. If effective in impotent patients, the drug may represent a new, interesting approach to the treatment of erectile dysfunction.
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PMID:Effects of nicorandil on human isolated corpus cavernosum and cavernous artery. 812 2

This study evaluated the physiological effects of compounds that alter guanosine 3',5'-cyclic monophosphate (cGMP) on the increase in vascular protein clearance induced by nitric oxide (NO) synthesis inhibition in the feline small intestine. A lymphatic vessel draining the small bowel was cannulated; vascular protein clearance and intestinal blood flow were measured. N omega-nitro-L-arginine methyl ester (L-NAME), the NO inhibitor, was infused (0.5 mumol/min) into the superior mesenteric artery. Vascular protein clearance increased approximately 4.6-fold, whereas blood flow decreased to 50% of control. Elevation of cGMP by 1) cytosolic guanylate cyclase activation with a NO donor (SIN 1) or 2) a cGMP analogue, 8-bromoguanosine 3',5'-cyclic monophosphate (8-BrcGMP) completely prevented the rise in microvascular permeability associated with L-NAME. Moreover, these compounds reduced (almost 90%) baseline vascular protein clearance, whereas inhibition of cytosolic guanylate cyclase with methylene blue significantly increased this parameter. Atrial natriuretic factor (ANF) has been reported to increase tissue cGMP levels and microvascular permeability. In this study, ANF did indeed increase intestinal microvascular permeability however this occurred independent of changes in intestinal cGMP levels. These data support a role for cGMP associated with NO-induced microvascular permeability alterations and raise the possibility that ANF has a cGMP-independent effect on microvascular permeability within the intestine.
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PMID:Nitric oxide-induced microvascular permeability alterations: a regulatory role for cGMP. 828 29


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