Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:4.6.1.2 (guanylate cyclase)
 8,497 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Recently, it was shown that in LLC-PK1 kidney epithelial cells hormones such as vasopressin or oxytocin increase cyclic GMP in a receptor-mediated and L-arginine-dependent manner. In the present study, the possible existence of cross-tolerance to vasopressin and oxytocin was investigated in nitrate-tolerant LLC-PK1 cells. Pretreatment with 1 mM glyceryl trinitrate for 3 h decreased cyclic GMP stimulation by 1 microM vasopressin and 1 microM oxytocin by 49% and 54%, respectively. Under the same conditions, cyclic GMP stimulation at 1 microM sodium nitroprusside was diminished by 56% whereas the cyclic GMP response to 100 microM glyceryl trinitrate was virtually abolished. Our results demonstrate that a substantial degree of cross-tolerance to L-arginine-dependent guanylate cyclase activators occurs in nitrate-pretreated nonvascular cells which may be due to glyceryl trinitrate-induced desensitization of soluble guanylate cyclase.
Pol J Pharmacol Pharm
PMID:Cross-tolerance to L-arginine-dependent guanylate cyclase activators in nitrate-tolerant LLC-PK1 kidney epithelial cells. 197 70

Protein kinase activities are regulated by endogenous thermostable protein inhibitors. Type I inhibitor is a protein of MW 22,000-24,000 which inhibits specifically cyclic AMP-(cAMP) dependent protein kinase (APK) as a competitive inhibitor of catalytic subunits of the enzyme. Type I inhibitor activity changes inversely according to the activation of adenylate cyclase and the changes in cAMP content in tissues. It seems that type I inhibitor serves as a factor preventing spontaneous cAMP-dependent phosphorylation in unstimulated cell. The other thermostable protein which inhibits APK activity has been found in Sertoli cell-enriched testis (testis inhibitor). Physiological role of the testis inhibitor is unknown. Type II inhibitor is a protein of MW 15,000 which blocks phosphorylation mediated by cAMP and cyclic GMP (cGMP) dependent (APK and GPK) and cyclic nucleotide independent protein kinases as a competitive inhibitor of substrate proteins. Activity of this inhibitor specifically changes in reciprocal manner to the changes in cGMP content. It seems that type II inhibitor serves as a factor preventing the phosphorylation catalyzed by GPK when cGMP content is low. Stimulation of guanylate cyclase and activation of GPK is followed by a decrease of type II inhibitor activity. This change in relationship between activities of GPK and type II inhibitor allows for effective phosphorylation catalyzed by this enzyme when cGMP content is increased.
Pol J Pharmacol Pharm
PMID:Regulation of the activity of protein kinases by endogenous heat stable protein inhibitors. 299 38

Mesoionic oxatriazole derivatives were synthetized by GEA LTD1. The GEA compounds (GEAC) constitute a new class of NO-donors, some of which stimulate selectively guanylate cyclase abiding either platelets or leukocytes or lung tissues. In consequence, some of GEAC are potent anti-platelet, fibrinolytic, thrombolytic or broncholytic agents, both in vitro and in vivo. GEAC synergize with prostacyclin in their thrombolytic actions. They also suppress the release of histamine and leukotriene B4, and prevent degranulation of granulocytes. Methylene blue reduces, and zaprinast augments their pharmacological effects. It is suggested that within a series of the newly synthetized GEA compounds there are likely to be found potential candidates for treating either thrombotic or asthmatic disorders.
Pol J Pharmacol
PMID:Pharmacology of mesoionic oxatriazole derivatives in blood, cardiovascular and respiratory systems. 754 20

The stimulation of NMDA receptor activates NO dependent cGMP biosynthesis with dynamic and extent different for hippocampus and brain cortex. The significantly higher NO mediated cGMP level was observed in hippocampus than in brain cortex. NMDA receptor stimulation increases NO mediated cGMP formation about 8 fold in hippocampus and 2.5 fold in brain cortex as compared to basal value (2 mM CaCl2). The activity of NO synthase and the basal level of cGMP in unstimulated slices were only slightly higher in hippocampus then in brain cortex. The CA2+ calmodulin dependent NO synthase was found in brain membrane and cytosol fraction. The enzyme activity was not affected by glucocorticoids, even after 20 days of hydrocortisone treatment in a dose of 40 mg/kg b.w. Brain ischemia induced by ligation of both common carotid arteries in gerbils increases significantly NOS activities as well as the level of cGMP and putrescine but decreases mono-ADP-ribosylation of brain proteins during reperfusion period. The ischemia evoked changes of NOS/cGMP were eliminated by specific inhibitor of neuronal form of NOS, 7-Nitrodazole (7NI) administered in a dose of 25 mg/kg b.w. 5 min. before ischemia. This inhibitor has no effect on the level of putrescine enhanced during ischemia and also biphasically during reperfusion. The inhibitor of guanylate cyclase, LY 83583 administered in a dose of 6 mg/kg b.w. 5 min before ischemia diminishes not only the enhanced level of cGMP but also NOS activity stimulated by ischemia. These results indicate that activation of NMDA receptor stimulates more significantly NO/cGMP production in hippocampus than in brain cortex suggesting the role of NO in neuronal form of NOS and inhibitor of guanylate cyclase protect the brain against excessive production of nitric oxide and cGMP during ischemia-reperfusion. These compounds may offer a new strategy in the therapy of brain ischemia.
Neurol Neurochir Pol 1996
PMID:NMDA receptor mediated nitric oxide dependent cGMP synthesis in brain cortex and hippocampus. Effect of ischemia on NO related biochemical processes during reperfusion. 910 Feb 45

Stimulation of NMDA receptor increases NO-dependent cGMP synthesis. A significantly higher cGMP level was observed in hippocampus (about 8-fold increase) than in cerebral cortex (2.5-fold increase), as compared to basal value. The activity of NO synthase (NOS) and the basal level of cGMP in unstimulated slices were only slightly higher in hippocampus than in the cortex. About 60% of NOS total activity was found in the brain membrane fraction. The enzyme activity was not affected by glucocorticoids, even after 20 days of hydrocortisone treatment in dose of 40 mg/kg b.w. Brain ischemia induced by ligation of the both common carotid arteries in gerbils (Meriones unquiculatus) significantly increased NOS activity as well as cGMP and putrescine concentrations but decreased mono-ADP-ribosolation of proteins. Changes of NOS activity and cGMP concentration evoked by ischemia were decreased by specific inhibitor of the neuronal form of NOS (nNOS), 7-nitrodazole and the inhibitor of guanylate cyclase, LY 83,583 administered respectively in a dose of 25 mg/kg b.w. and 6 mg/kg b.w. 5 min. before ischemia. The inhibitor of nNOS, 7NI, did not change the concentration of putrescine during ischemia and reperfusion. Our results indicated that these inhibitors could protect the brain against excessive production of nitric oxide and biochemical processes dependent on it. In this way they may offer a new strategy in the therapy of brain ischemia.
Neurol Neurochir Pol
PMID:[Influence of NMDA receptor stimulation in brain cortex and hippocampus on NO dependent cGMP synthase. Effect of ischemia on NO related biochemical processes during recirculation]. 977 Jun 92

Involvement of nitric oxide (NO) in nociceptive transmission is well documented. However, there is controversy concerning the exact role of NO in mediation of nociception at different levels of the nervous system. Most studies agree that NO promotes hyperalgesia at the level of the spinal cord. Conversely, at supraspinal sites exogenously applied NO has been found to be both pro- and antinociceptive. In light of this discrepancy, the aim of the present study was to compare the effects of NO donors on nociceptive transmission at spinal and supraspinal sites of the central nervous system using mechanical (paw pressure; PP) and thermal (tail-flick; TF) noxious stimulation. Four NO donors which release NO through different mechanisms were used: S-nitrosoglutathione (SNOG; 3-600 nmol), S-nitroso-N-acetylpenicillamine (SNAP; 0.18-4.5 nmol), hydroxylamine (HYD; 60-1200 nmol) and 3-morpholino-sydnonimine (SIN-1; 490-970 nmol). They were injected intrathecally (i.t.) or intracerebroventricularly (i.c.v.) to male Wistar rats and nociceptive thresholds were evaluated in TF and PP tests. It was found that NO donors administered i.t. or i.c.v. produced a dose-dependent hyperalgesia in the PP test. The hyperalgesia induced by mechanical stimuli was stronger after i.t. than after i.c.v. administration of NO donors. The SIN-1-induced hyperalgesia, as evaluated by teh PP test, was reversed by i.t. pretreatment with haemoglobin (1.5-4 nmol) a NO scavenger, and methylene blue (267-1070 nmol) a guanylate cyclase and NO synthase inhibitor, suggesting that NO exerts its action by facilitating cyclic guanosine 3',5'-monophosphate (GMP) formation. Unlike in the PP test, SNAP and SNOG had no effect on the nociceptive threshold in the TF test, and only SIN-1 administered i.t. produced a weak hyperalgesia in that test, while HYD caused a mild but significant prolongation of the TF reflex. The above data show that NO produces hyperalgesia principally in response to noxious mechanical stimuli. This effect seems to be predominantly mediated in the spinal cord, however, it occurs at both levels of the central nervous system.
Pol J Pharmacol
PMID:Differential effects of intrathecally and intracerebroventricularly administered nitric oxide donors on noxious mechanical and thermal stimulation. 1038 23

The Ca(2+)-dependent activation of retina-specific guanylyl cyclase (retGC) is mediated by guanylyl cyclase-activating proteins (GCAPs). Here we report for the first time detection of a 19 kDa protein (p19) with GCAP properties in extracts of rat retina and pineal gland. Both extracts stimulate synthesis of cGMP in rod outer segment (ROS) membranes at low (30 nM) but not at high (1 microM) concentrations of Ca(2+). At low Ca(2+), immunoaffinity purified p19 activates guanylyl cyclase(s) in bovine ROS and rat retinal membranes. Moreover, p19 is recognized by antibodies against bovine GCAP1 and, similarly to other GCAPs, exhibits a Ca(2+)-dependent electrophoretic mobility shift.
Acta Biochim Pol 2002
PMID:p19 detected in the rat retina and pineal gland is a guanylyl cyclase-activating protein (GCAP). 1254 96

Carbon monoxide (CO) is an odorless, tasteless and colorless gas which is generated by heme oxygenase enzymes (HOs). HOs degrade heme releasing equimolar amounts of CO, iron and biliverdin, which is subsequently reduced to bilirubin. CO shares many properties with nitric oxide (NO), an established cellular messenger. Both CO and NO are involved in neural transmission and modulation of blood vessel function, including their relaxation and inhibition of platelet aggregation. CO, like NO, binds to heme proteins, although CO binds only ferrous (FeII) heme, whereas NO binds both ferrous and ferric (FeIII). CO enhances the activity of guanylate cyclase although it is less potent than NO. In contrast, CO inhibits other heme proteins, such as catalase or cytochrome p450. The effects of CO on gene expression can be thus varied, depending on the cellular microenvironment and the metabolic pathway being influenced. In this review the regulation of gene expression by HO/CO in the cardiovascular system is discussed. Recent data, derived also from our studies, indicate that HO/CO are significant modulators of inflammatory reactions, influencing the underlying processes such as cell proliferation and production of cytokines and growth factors.
Acta Biochim Pol 2003
PMID:Carbon monoxide -- a "new" gaseous modulator of gene expression. 1267 45

The influence of nitric oxide (NO) on anticonvulsant activity of diazepam and clonazepam was examined in the pentetrazole- and electroshock-induced seizure models in mice. Protective efficacy of the threshold dose of diazepam against pentetrazole-induced clonic and tonic seizures, and death was significantly increased by NG-nitro-L-arginine methyl ester hydrochloride (L-NAME) while 7-nitroindazole (7-NI) was slightly less effective. The above intensifying effect of L-NAME on antiepileptic activity of diazepam was reversed by L-arginine, a substrate for NO formation, but not by D-arginine. Methylene blue, the guanylate cyclase inhibitor, increased the protective efficacy of diazepam and clonazepam in the pentetrazole-induced seizures. 7-NI was able to potentiate the protective efficacy of diazepam and clonazepam in electroshock-induced tonic hindlimb extension. These findings suggest that the cGMP/NO system may participate in antiepileptic effects of benzodiazepines.
Pol J Pharmacol
PMID:Role of nitric oxide in anticonvulsant effects of benzodiazepines in mice. 1292 45

We report that the classical guanylate cyclase inhibitor methylene blue (MB, 1 microM or 10 microM), but not the selective guanylate cyclase inhibitor 1H-[1,2,4]oxidazolo[4,3-a]quinoxalin-1-one (1 microM) or nitric oxide synthase inhibitor, NG-nitro-L-arginine methyl ester (100 microM), causes a shift to the left in the concentration-response curve for noradrenaline in the isolated rat vas deferens preparations. The main objective of our study was to investigate the pharmacological mechanism by which MB increases the sensitivity of the rat vas deferens to noradrenaline. According to the presented results, MB did not change rat vas deferens sensitivity to methoxamine or noradrenaline in the presence of desipramine (0.1 microM). The pre-contracted rat vas deferens relaxation induced by isoproterenol was also not significantly changed by MB (1 microM). Thus, we suggest that MB increases rat vas deferens sensitivity through neuronal uptake inhibition without interfering in either the nitrergic mechanism or guanylate cyclase activity.
Pol J Pharmacol
PMID:Pharmacological evidence that methylene blue inhibits noradrenaline neuronal uptake in the rat vas deferens. 1458 16


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