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 cyclic nucleotides cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) are second messengers involved in the regulation of contractility in various smooth muscle organs including detrusor smooth muscle. They are synthesized by activation of adenylate and guanylate cyclases, respectively, and inactivated by phosphodiesterases (PDEs). In order to delineate the intracellular regulation of porcine detrusor contractility by cyclic nucleotides and phosphodiesterases, functional organ bath studies and determinations of intracellular cyclic nucleotide contents were performed after incubation of porcine detrusor strips with forskolin (adenylate cyclase activator), sodium nitroprusside (guanylate cyclase activator), and various phosphodiesterase-inhibitors. Significant relaxant responses were achieved only by forskolin, the nonspecific phosphodiesterase-inhibitor papaverine, and the phosphodiesterase 1-inhibitor vinpocetine (62.4 +/- 5.6%, 73 +/- 4.3%, and 53 +/- 7.9%, respectively). Sodium nitroprusside and the selective PDE-inhibitors milrinone, rolipram, zaprinast, and dipyridamole were significantly less efficacious (26.9 +/- 3.9%, 15.5 +/- 3.8%, 15.3 +/- 3.0%, 13 +/- 4.0%, and 13.2 +/- 2.1%, respectively). Forskolin, papaverine, and vinpocetine elevated intracellular cAMP concentrations (7.3-, 1.9-, and 1.7-fold increase at 100 microM, respectively), whereas the other substances failed to enhance cAMP levels. cGMP levels were only increased by sodium nitroprusside (7.8-fold). The adenylate cyclase-cAMP system seems to be the more important signal transduction system involved in the relaxation of carbachol induced smooth muscle tone of the porcine detrusor. The role of the guanylate cyclase-cGMP system is less clear. In addition, the calcium/calmodulin-stimulated PDE I seems to be of major functional importance in regulating cAMP hydrolysis in the porcine detrusor smooth muscle in vitro.
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PMID:Effects of various phosphodiesterase-inhibitors, forskolin, and sodium nitroprusside on porcine detrusor smooth muscle tonic responses to muscarinergic stimulation and cyclic nucleotide levels in vitro. 869 57

1. In rat aortic rings precontracted by phenylephrine, H7 (10(-5)M) and staurosporine (10(-7)M), which inhibit PKA, PKG and PKC, and H-89 (10(-6)M), which inhibits PKA and PKG, potentiated relaxations induced by nitroglycerin. Forskolin-induced relaxations were not affected by H7 (10(-5)M). 2. Nitroglycerin-induced relaxations were not affected by calphostin-C (10(-7)M), which inhibits PKC, H-89 (10(-7)M), which inhibits PKA, and staurosporine (2 x 10(-9)M), which inhibits PKC. 3. Iberiotoxin (3 x 10(-8)M), an inhibitor of large conductance Kca channels, partly inhibited the relaxation induced by nitroglycerin and completely inhibited the potentiating effect of H7 on nitroglycerin-induced relaxations. 4. The potentiating effect of zaprinast (10(-5)M), an inhibitor of cGMP-phosphodiesterase, on nitroglycerin-induced relaxation was not affected by iberiotoxin. In the presence of methylene blue (10(-5)M), an inhibitor of guanylate cyclase, the residual relaxing response to nitroglycerin was not affected by H7, but it was inhibited by iberiotoxin. 5. These results suggest that the potentiation of nitroglycerin-induced relaxation by H7, staurosporine and H-89 may be due to inhibition of PKG.
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PMID:The potentiation of nitroglycerin-induced relaxation by PKG inhibition in rat aortic rings. 885 8

The release of somatostatin-like immunoreactivity was studied in isolated synaptosomes. A significant release of somatostatin-like immunoreactivity was observed in the presence of vasoactive intestinal polypeptide (VIP) (10(-6) M: 53.0 +/- 12.4 pg/mg, basal: 14.3 +/- 1.7 pg/mg, n = 5, P < 0.05), secretin (10(-6) M: 56.1 +/- 3.8 pg/mg, basal: 25.8 +/- 1.6 pg/mg, n = 6, P < 0.01) and isoproterenol (10(-5) M: 54.0 +/- 13.4 pg/mg, basal: 20.0 +/- 3.4 pg/mg, n = 8, P < 0.05). Forskolin, an unspecified activator of the adenylate cyclase, caused a significant release of somatostatin-like immunoreactivity (10(-6) M: 57.3 +/- 13.2 pg/mg, basal: 30.0 +/- 5.8 pg/mg, n = 13, P < 0.01) which was further augmented in the presence of the phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine (IBMX 10(-4) M) (77.0 +/- 17.8 pg/mg, n = 13, P < 0.01). 3-Isobutyl-l-methylxanthine and N6, 2'-O-dibutyryladenosine-3',5'-cyclic monophosphate mimicked at effect of forskolin and VIP. The release of somatostatin was paralleled by an increase of cAMP immunoreactivity in the presence of VIP (10(-6) M: 37.1 +/- 9.4 pmol/mg, basal: 19.8 +/- 4.2 pmol/mg, n = 10, P < 0.05), isoproterenol (10(-5) M: 42.4 +/- 9.8 pmol/mg basal: 16.7 +/- 2.4 pmol/mg, n = 12, P < 0.01) and forskolin (10(-6) M: 47.1 +/- 12.4 pmol/mg, basal: 19.8 +/- 4.2 pmol/mg, n = 10, P < 0.01). The effect of nitric oxide (NO) which acts as an inhibitory neurotransmitter in the enteric nervous system was studied. NO is known to activate guanylate cyclase to induce transmitter release. The NO-generating compound sodium nitroprusside and bromoguanosine-3',5'-cyclic monophosphate (8-Br-cGMP) had no effect on the release of somatostatin-like immunoreactivity. These data demonstrate the stimulatory effect of VIP, secretin and isoproterenol on release of somatostatin-like immunoreactivity from enteric synaptosomes, which is presumably mediated by cAMP-dependent mechanisms. cGMP-dependent mechanisms seem to be of minor relevance.
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PMID:Presynaptic modulation by VIP, secretin and isoproterenol of somatostatin release from enriched enteric synaptosomes: role of cAMP. 895 33

1. Forskolin, an activator of adenylate cyclase, potentiated the relaxing response to isoproterenol in rabbit aortic rings precontracted by phenylephrine (PE). 2. The potentiating effect of forskolin was inhibited by propranolol, a beta-adrenoceptor inhibitor, but not by methylene blue, a guanylate cyclase inhibitor. 3. The relaxing response to terbutaline, a beta 2-adrenoceptor agonist, but not lower concentrations of dobutamine, a beta 1-adrenoceptor agonist, also was potentiated by forskolin. Forskolin, however, potentiated the relaxing response to high concentrations of dobutamine, which activates both beta 1- and beta 2-adrenoceptors. 4. Yohimbine, an alpha 2-adrenoceptor inhibitor, glyburide, an ATP-sensitive K+ channel inhibitor, iberiotoxin, a Ca(2+)-activated K+ channel inhibitor, or endothelium-removal failed to affect the potentiating effect of forskolin. 5. Dibutyryl cyclic AMP (cAmp) also potentiated the relaxing response to terbutaline. 6. These results suggest that in rabbit aortic rings forskolin causes the apparent potentiation of isoproterenol-induced relaxation by mainly affecting the relaxing response due to the activation of beta 2-adrenoceptors by the forskolin-induced increase in the level of cAMP.
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PMID:Potentiation of the relaxing action of isoproterenol by forskolin in rabbit aortic rings: the involvement of beta 2-adrenoceptors. 918 14

1. The cellular mechanism(s) of action of endothelium-derived vasodilator substances in the rabbit middle cerebral artery (RMCA) were investigated. Specifically, the subtypes of potassium channels involved in the effects of endothelium-derived relaxing factors (EDRFs) in acetylcholine (ACh)-induced endothelium-dependent vasorelaxation in this vessel were systematically compared. 2. In the endothelium-intact RMCA precontracted with histamine (3 microM), ACh induced a concentration-dependent vasorelaxation, which was sensitive to indomethacin (10 microM) or N(G)-nitro-L-arginine (L-NOARG; 100 microM); pD2 values 8.36 vs 7.40 and 6.38, P < 0.01 for both, n = 6 and abolished by a combination of both agents. ACh caused relaxation in the presence of high K+ PSS (40 mM KCl), which was not affected by indomethacin, but abolished by L-NOARG and a combination of indomethacin and L-NOARG. 3. In the presence of indomethacin, relaxation to ACh in the endothelium-intact RMCA precontracted with histamine was unaffected by either glibenclamide (10 microM), an ATP-sensitive K+ channel (K[ATP]) blocker, 4-aminopyridine (4-AP, 1 mM) or dendrotoxin (DTX, 0.1 microM), delayed rectifier K channel (Kv) blockers. However, relaxation responses to ACh were significantly inhibited by either LY83583 (10 microM) and 1H-[1,2,4]oxadiazolo[4,3,-a]quinoxalin-1-one (ODQ, 10 microM), guanylyl cyclase inhibitors, or charybdotoxin (CTX; 0.1 microM), iberiotoxin (ITX, 0.1 microM) and apamin (APA, 0.1 microM), large conductance Ca2+-activated K+ channels (BK[Ca]) blocker and small conductance Ca2+-activated K+ channel (SK[Ca]) blocker, respectively. 4. In the presence of L-NOARG, relaxation to ACh was unaffected by glibenclamide or the cytochrome P450 mono-oxygenase inhibitor, clotrimazole (1 microM), but was significantly inhibited by either 9-(tetrahydro-2-furanyl)-9H-purin-6-amine (SQ 22,536, 10 microM) and 2',3'-dideoxyadenosine (2',3'-DDA, 30 microM), adenylyl cyclase inhibitors, or 4-AP, DTX, CTX, ITX and APA. 5. In the endothelium-denuded RMCA precontracted with histamine, authentic NO-induced relaxation was unaffected by glibenclamide, 4-AP and DTX, but significantly reduced by ODQ, ITX and APA. Authentic prostaglandin I2 (PGI2)-induced relaxation was unaffected by glibenclamide, but significantly reduced by 2',3'-DDA, 4-AP, DTX, ITX and APA. Forskolin-induced relaxation was significantly inhibited by high K+, CTX and 4-AP. 6. These results indicate that: (1) in the RMCA the EDRFs released by ACh are NO and a prostanoid (presumably PGI2), and there is no evidence for the release of a non-NO/PGI2 endothelium-derived hyperpolarizing factor (EDHF), (2) K(Ca) channels are involved in NO-mediated relaxation of the RMCA but both K(Ca) and Kv channels are involved in PGI2-mediated relaxation.
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PMID:Roles of calcium-activated and voltage-gated delayed rectifier potassium channels in endothelium-dependent vasorelaxation of the rabbit middle cerebral artery. 953 9

Atrial natriuretic peptide receptor (ANP) subtypes and their signal transduction response were characterized in choroid plexus of spontaneously hypertensive (SHR) and normotensive (WKY) rats. We found two ANP receptor subtypes, guanylate cyclase coupled and uncoupled, in both rat strains. Binding of ANP was lower in SHR choroid plexus when compared to WKY. The lower ANP binding in SHR was the result of a decrease of binding to the guanylate cyclase-coupled receptor subtype A, a decrease that correlated well with the decreased ANP-induced cGMP formation in SHR. Forskolin stimulated cGMP production to the same extent in both strains. In WKY rats, ANP increased basal and forskolin-stimulated cAMP production; conversely, in SHR, ANP did not affect the basal level of cAMP and inhibited the forskolin-stimulated cAMP production. These results demonstrate differences in ANP receptor subtype expression, and ANP signal transduction in choroid plexus of hypertensive and normotensive rats, which is of possible significance to the central mechanisms of blood pressure control.
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PMID:Decreased expression of natriuretic peptide A receptors and decreased cGMP production in the choroid plexus of spontaneously hypertensive rats. 964 74

1. We hypothesized that acetylcholine would attenuate the metabolic effect of increasing cAMP and decreasing cGMP on cardiac myocyte O2 consumption (VO2) in dog, and this effect would be altered in left ventricular hypertrophy (LVH) produced by aortic valve placation. 2. Steady-state VO2 of a suspension of ventricular myocytes from control (n = 7) and LVH (n = 6) dogs was measured by Clark O2 electrodes during electrical stimulation (5 ms, 1 Hz, in 2 mm Ca2+). Cyclic AMP and cyclic GMP were determined by radioimmunoassay. Cellular cAMP was increased by forskolin (adenylate cyclase stimulator) and cGMP was decreased by LY83583 (guanylate cyclase inhibitor) both at 10(-7,-6,-5,-4) M with and without 10(-6) M acetylcholine. 3. Baseline cGMP level in LVH (62 +/- 10 fmol 10(-5) myocytes) was significantly greater than that in control (20 +/- 3), although the myocyte VO2 (356 +/- 39 nL O2 min(-1) 10(-5) myocytes) and cAMP levels (3.9 +/- 0.6 nmol 10(5-1) myocytes) were similar to control (312 +/- 23 and 6.9 +/- 3.1). 4. Forskolin increased myocyte cAMP in both control and LVH myocytes and increased VO2 by 51 +/- 13 in control and 91 +/- 65 in LVH myocytes. LY83583 decreased myocyte cGMP levels in control and LVH myocytes and increased VO2 by 128 +/- 57 in control and 43 +/- 26 in LVH myocytes. 5. Acetylcholine altered the cAMP, cGMP, and VO2 levels in control to 2.4 +/- 0.4, 30 +/- 3 and 213 +/- 27 and LVH to 2.5 +/- 0.3, 85 +/- 9 and 261 +/- 32. Acetylcholine attenuated the maximal effects of forskolin on VO2 to 32 +/- 27 in control and 66 +/- 56 in LVH myocytes. Acetylcholine also decreased the maximal effects of LY83583 to 82 +/- 50 in control and 19 +/- 19 in LVH myocytes. 6. The positive metabolic effects of both increases in myocyte cAMP and decreases in cGMP were blunted by acetylcholine. There was a significant increase in myocyte cGMP with forskolin in LVH myocytes. Acetylcholine decreased the increased myocyte VO2 caused by elevated cAMP or decreased cGMP in both control and LVH myocytes, although the absolute decrease in cAMP was reduced and the absolute values of cGMP were higher in LVH myocytes.
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PMID:Altered effects of acetylcholine on cyclic AMP and GMP induced changes in O2 consumption of hypertrophic dog cardiac myocytes. 1038 66

1. The sensitivity of the soluble guanylate cyclase (sGC)-cyclic guanosine-3',5'-monophosphate (cyclic GMP) system to nitric oxide (NO) was investigated in mouse aorta from wild type (WT) and NO synthase (NOS) knockout (KO) animals. 2. The NO donor, spermine-NONOate (SPER-NO) was more potent in aortas from eNOS KO mice compared to WT (pEC50 7.30+/-0.06 and 6.56+/-0.04, respectively; n=6; P<0.05). In contrast, the non-NO based sGC activator, YC-1 was equipotent in vessels from eNOS WT and KO mice. The sensitivity of aortas from nNOS and iNOS KO animals to SPER-NO was unchanged. Forskolin (an adenylate cyclase activator), was equipotent in vessels from eNOS WT and KO animals. 3. The cyclic GMP analogue, 8-Br-cGMP was equipotent in eNOS WT and KO mice (pEC50 4. 38+/-0.04 and 4.40+/-0.05, respectively; n=5; P>0.05). Zaprinast (10-5 M) a phosphodiesterase type V (PDE V) inhibitor, had no effect on the response to SPER-NO in vessels from eNOS WT or KO mice. 4. The NOS inhibitor NG-nitro-L-arginine methyl ester (L-NAME; 3x10-4 M) increased the potency of SPER-NO in aortas from WT mice (pEC50 6. 64+/-0.02 and 7.37+/-0.02 in the absence and presence of L-NAME, respectively; n=4; P<0.05). 5. In summary, there is increased sensitivity of vessels from eNOS KO animals to NO. Cyclic AMP-mediated dilatation is unchanged, consistent with a specific up-regulation of sGC - cyclic GMP signalling. The functional activity of cyclic GMP-dependent protein kinase (G-kinase) and PDE V was also unchanged, suggesting that sGC is the site of up-regulation. These alterations in the sensitivity of the sGC - cyclic GMP pathway might represent a mechanism for the dynamic regulation of NO bioactivity.
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PMID:Autoregulation of nitric oxide-soluble guanylate cyclase-cyclic GMP signalling in mouse thoracic aorta. 1055 46

1. In the cerebellar cortex, brief, 8 Hz activation of parallel fibres (PFs) induces a cyclic adenosine 3'5'-monophosphate (cAMP) and protein kinase A (PKA)-dependent form of long-term potentiation between PFs and Purkinje cells. 2. With 10 mM BAPTA in the recording pipette, potentiation evoked by raised frequency stimulation (RFS) to one of two, synaptically independent PF inputs to the same Purkinje cell did not remain input specific but consistently spread to synapses that did not receive RFS, up to the maximum distance tested of 168 microm. 3. LTP at activated and non-activated sites was accompanied by a decrease in paired pulse facilitation (PPF). The PKA inhibitor H-89 blocked both of these effects. Inhibition of nitric oxide synthase (NOS), either by 7-nitro-indazole (7-NI) or N (G)-nitro-L-arginine methyl ester (L-NAME), completely prevented heterosynaptic potentiation and associated reduction in PPF. LTP at distant synapses was selectively prevented by the nitric oxide scavenger 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide (cPTIO). Inhibition of soluble guanylate cyclase or protein kinase G had no effect on either pathway. 4. Synaptic potentiation at PF-PC synapses, induced by the adenylate cyclase activator forskolin, was also prevented by inhibition of NOS. Forskolin-induced increases in mEPSC frequency were similarly prevented by NOS inhibition and mimicked by the NO donor spermine NONOate. 5. These results are consistent with the notion that heterosynaptic potentiation is of pre-synaptic origin and dependent upon activation of cAMP/PKA and NO. Moreover, they suggest that cAMP/PKA activation stimulates NO production and this diffusible messenger facilitates pre-synaptic transmitter release at synapses within a radius of upwards of 150 microm, through a mechanism that does not involve cGMP.
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PMID:Nitric oxide is required for the induction and heterosynaptic spread of long-term potentiation in rat cerebellar slices. 1155 78

In the guinea pig gastric antrum, the effects of sodium nitroprusside (SNP), an NO donor, on pacemaker potentials were investigated in the presence of nifedipine. The pacemaker potentials consisted of primary and plateau components; SNP (> 1 microM) increased the frequency of occurrence of these pacemaker potentials, while inhibiting the plateau component. 1H-[1,2,4]-Oxadiazole [4,3-a] quinoxalin-1-one, an inhibitor of guanylate cyclase, had no effect on the excitatory actions of SNP on the frequency of pacemaker potentials. Other types of NO donor, (+/-)-S-nitroso-N-acetylpenicillamine, 3-morpholino-sydnonimine and 8-bromoguanosine 3'5'-cyclic monophosphate had no excitatory effect on pacemaker activity. Forskolin, an activator of adenylate cyclase, or 4,4'-diisothiocyano-stilbene-2,2'-disulphonic acid, an inhibitor of the Ca(2+)-activated Cl(-) channel, strongly attenuated the generation of pacemaker potentials, and SNP added in the presence of these chemicals restored the generation of pacemaker potentials. The pacemaker potentials evoked by SNP were abolished in low-Ca(2+) solution or by membrane depolarization with high-K(+) solution. The SNP-induced generation of pacemaker potentials was not prevented by cyclopiazonic acid, an inhibitor of internal Ca(2+)-ATPase, but was limited to a transient burst by iodoacetic acid, an inhibitor of glycolysis, carbonyl cyanide m-chlorophenyl-hydrazone, a mitochondrial protonophore, or 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid acetoxymethyl ester, an intracellular Ca(2+) chelator. These results suggest that the SNP-induced increase in the frequency of pacemaker potentials is related to the elevated intracellular Ca(2+) concentrations due to release from mitochondria, and these actions may be independent of the activation of guanylate cyclase.
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PMID:Pacemaker frequency is increased by sodium nitroprusside in the guinea pig gastric antrum. 1250 88


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