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)

Relaxation of the lower esophageal sphincter (LES) results from activation of its intrinsic innervation. This relaxation is associated temporally with an increase in the guanosine 3',5'-cyclic monophosphate (cGMP) content of the muscle. This study tests the hypothesis that variations in the production of cGMP mediate resting LES tone and nerve-induced relaxation. We examined the effects of guanylate cyclase inhibitors, such as cystamine and methylene blue (MB), on the resting tone, resting membrane potential, electrical field stimulation (EFS)-induced relaxation, and cGMP content of circular smooth muscle from the LES of the opossum. Strips of sphincter muscle were placed in a tissue bath and stretched to 125% resting length. Both cystamine and MB increased the resting tone of LES muscle in a concentration-dependent manner (EC50 = 1.1 +/- 0.2, n = 12, and 1.6 +/- 0.4 mM, n = 10, respectively). The increase in tone by cystamine was not blocked by tetrodotoxin, atropine, or propranolol. Cystamine (1 mM) did not alter the resting membrane potential of circular muscle cells of the LES. The removal of extracellular Ca2+ by the addition of ethylene glycol-bis(beta-aminoethyl ether)-N,N,N',N'-tetraacetic acid (EGTA, 4 mM) and nifedipine (1 microM) shortened the duration but not the amplitude of the response to cystamine. Pretreatment with caffeine (5 mM) in the presence of EGTA and nifedipine to deplete intracellular Ca2+ stores blocked the increase in tone by cystamine. Cystamine (1 mM) failed to inhibit LES relaxation induced by EFS. Carbachol, at a concentration that induced a similar increase in base-line tone, attenuated the nerve-mediated relaxation. Cystamine did not alter basal cGMP levels, but inhibited the rise in cGMP induced by EFS. The data indicate that cystamine increases LES tone but does not inhibit EFS-induced relaxation, even though it inhibits EFS-induced increases in cGMP content. The increase in tone is dependent on the presence of intracellular Ca2+ stores.
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PMID:Guanylate cyclase inhibitors: effect on tone, relaxation, and cGMP content of lower esophageal sphincter. 135 4

1. The inhibitory effects of the K+ channel activator, cromakalim, upon contractions to noradrenaline, histamine and caffeine were examined in rabbit isolated renal artery. For comparison, the effects of pinacidil, dazodipine and sodium nitroprusside were also studied in some experiments. 2. In normal Krebs solution, cromakalim (1 microM) produced a 39.1% reduction in area under the curve (AUC) of the noradrenaline concentration-response, and a 61.8% reduction in the histamine AUC. Ca2+ removal (with EGTA 0.1 mM) gave an 80.0% reduction in the noradrenaline AUC and a 74.5% reduction in the histamine AUC. The combination of Ca2+ removal and cromakalim (1 microM) had no further effect on the noradrenaline responses (a reduction of 78.4% in AUC), but produced a significantly greater reduction in the histamine AUC (86.2%). 3. LaCl3 (1 mM) reduced the noradrenaline AUC by 74.8% and gave an 81.8% reduction in the response to a single (EC90) histamine concentration. LaCl3 (1 mM) plus cromakalim (1 microM) produced no further reduction in the noradrenaline AUC (71.9%) but gave a significant further reduction of the histamine response (94.6%). 4. Pinacidil (3 microM) reduced the noradrenaline AUC by 35.5%. Pinacidil (3 microM) plus LaCl3 (1 mM) produced the same reduction in the noradrenaline AUC (80.9%) as LaCl3 alone (80.9%). 5. In both normal and Ca2+-free Krebs solution, cromakalim (0.1, 1.0 and 10 microM) produced concentration-related inhibition of the contraction to caffeine (10 mM). This inhibition was antagonised by the K+ channel blocker, glibenclamide (3 microM). Similarly, pinacidil (0.3, 3.0 and 30 microM) produced a glibenclamide-sensitive inhibition of the caffeine contraction. At equi-vasorelaxant concentrations, dazodipine (0.01, 0.1 and 1.O microM) and sodium nitroprusside (0.03, 0.3 and 3.0 microM) had no significant effect on caffeine contractions. 6. The data show that the K+ channel activators, cromakalim and pinacidil, unlike the Ca2+ channel blocker, dazodipine, or the guanylate cyclase activator, sodium nitroprusside, can inhibit the contraction which results from caffeine-induced Ca2+ release. Cromakalim and pinacidil, however, inhibit only the component of the noradrenaline response resulting from Ca2+ influx (tonic component) and not that resulting from Ca2 + release (phasic component). Cromakalim may affect both components of the histamine contraction.
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PMID:Effect of cromakalim on contractions in rabbit isolated renal artery in the presence and absence of extracellular Ca2+. 257 15

The mechanisms by which two nitrogen monoxide (NO) generators, hydroxylamine and S-nitroso-L-cysteine (NO-CYS), induce hippocampal [3H]norepinephrine ([3H]NE) release was investigated. Neither hydroxylamine- nor NO-CYS-induced release was affected by the guanylate cyclase inhibitors, methylene blue or LY 83,583. The effect of hydroxylamine was completely dependent on extracellular Ca++ and reduced by 40% in the presence of omega-conotoxin GVIA, an N-type Ca(++)-channel antagonist; however it was unaffected by Ni++, nifedipine, caffeine or thapsigargin. The stimulatory effect of hydroxylamine on hippocampal cyclic GMP formation was not significantly affected by removal of extracellular Ca++, indicating that Ca(++)-dependent release is not due to inhibition of NO formation from hydroxylamine. However, the response to NO-CYS was reduced by 35 to 50% in either nominally Ca(++)-free or 10 mM MgSO4-containing buffer. Interestingly, buffer containing ethylene glycol bis(beta-aminoethyl ether)-N,N'-tetraacetic acid dramatically enhanced the formation of NO from NO-CYS and potentiated the NO-CYS response. Both NO-CYS- and hydroxylamine-induced [3H]NE release was inhibited by NE transport blockers, indicating a prominent role for reverse transport. NO-CYS completely inhibited synaptosomal uptake of [3H]NE (IC50 approximately, 300 microM). NO generator-induced [3H]NE release has a glutamate-dependent component (see accompanying article). Inhibition of glutamate-evoked [3H]NE release by mazindol, an inhibitor of NE transport, suggests that the glutamate-dependent component also involves reversal of the NE transporter. These data suggest that NO produced from hydroxylamine or NO-CYS evoke both vesicular and nonvesicular release of hippocampal [3H]NE. Putative NO target molecules and the role of extracellular Ca++ are discussed.
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PMID:Characterization of nitric oxide generator-induced hippocampal [3H]norepinephrine release. II. The role of calcium, reverse norepinephrine transport and cyclic 3',5'-guanosine monophosphate. 756 42

Previous studies have demonstrated low percentage of HL-60 cell differentiation with theophylline. The present study demonstrate that millimolar concentrations of the non-selective phosphodiesterase inhibitors theophylline, caffeine and isobutyl-methylxanthine all inhibit growth, induce substantial differentiation and elevation of both cAMP and cGMP in HL-60 cells. Selective inhibition of cAMP hydrolysis by Ro20-1724 was without effect. The guanylate cyclase stimulator sodium nitroprusside, which increased cGMP only poorly and also increased cAMP, produced growth inhibition but no differentiation. We put forward the hypothesis that elevation of both cAMP and cGMP above a critical level is necessary for significant cyclic nucleotide induced HL-60 cell differentiation.
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PMID:Effects of cAMP and cGMP elevating agents on HL-60 cell differentiation. 797 38

The role of intracellular signal transduction mechanisms in regulating the motility and metabolism of rat spermatozoa in undiluted caudal epididymal fluid (CEF) was examined. Samples of CEF containing immotile spermatozoa were exposed to drugs and other agents that either stimulate signal transduction pathways or mimic the action of their second messengers. Under these conditions, sperm motility in 25-30 nl of CEF was stimulated by calcium ions (Ca2+), N2,2'-O-dibutyrylguanosine 3':5'-cyclic monophosphate (dibutyryl cGMP), cyclic adenosine 3':5'-monophosphate (cAMP), N6,2'-O-dibutyryladenosine 3':5'-cyclic monophosphate (dibutyryl cAMP), 8-bromoadenosine 3':5'-cyclic monophosphate (8-bromo cAMP), caffeine, theophylline and bicarbonate ions (HCO3-). Other agents such as magnesium ions (Mg2+), veratridine, phospholipase C (PLC), ionophore A23187, 1,2-dioctenoyl-sn-glycerol (DAG), phorbol 12-myristate 13-acetate, phospholipase A2 (PLA2), arachidonic acid, and melittin did not significantly influence motility. In the presence of radiolabelled energy substrates, untreated (immotile) spermatozoa in samples of CEF utilised D-[U-14C]glucose and [1-14C]acetate as exogenous energy sources for oxidative metabolism. No detectable 14C-lactate was produced, and none of the drugs altered the rate of glycolytic or oxidative metabolism. The findings suggest that the motility of rat caudal epididymal spermatozoa is regulated by Ca2+ and the guanylate cyclase and adenylate cyclase pathways, but not through the PLC and PLA2 pathways. Also, their metabolism of exogenous substrate was uncoupled from the induction of motility, and their oxidative capacity exceeded the rate of flux of glucose-carbon through the glycolytic pathway.
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PMID:Intracellular signal transduction mechanisms of rat epididymal spermatozoa and their relationship to motility and metabolism. 804 68

The calcium-dependent modulation of type A K+ current (IA) has been investigated using a two-electrode voltage clamp on larval muscle cells of Drosophila. It was found that the amplitude of IA increases when [Ca2+]o is changed from 0.2 mM to 2 mM. The increase in IA amplitude is not due to overlap with the Ca(2+)-dependent fast K+ current, ICF, since it is observed also in slo1 mutants, which are deficient for this current. This effect is not due to Ca(2+)-dependent shifts in the steady-state activation/inactivation kinetics. The phenomenon is probably due to elevations in internal calcium since it is abolished by Ca2+ channel blockers and promoted by caffeine (5 mM) if added in the absence of external calcium. This calcium effect was dose-dependent since it was not observed in the presence caffeine plus 2 mM calcium in the bath nor for values of [Ca2+]o above 4 mM. The Ca(2+)-dependent modulation of IA is absent in V7, a mutation that causes overexpression of frequenin, a recoverin-like Ca(2+)-binding protein which stimulates guanylyl cyclase [31]. One possible explanation for the loss of IA modulation in the V7 mutation is that the excess of frequenin alters intracellular cGMP-dependent metabolic pathways responsible for the internal calcium homeostasis.
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PMID:Modulation of type A K+ current in Drosophila larval muscle by internal Ca2+; effects of the overexpression of frequenin. 805 77

Stimulation of portal vein myocytes with noradrenaline (NA) in the presence of a voltage-dependent Ca2+ channel blocker, evoked a transient increase in the concentration of free cytosolic Ca2+, due to inositol 1,4,5-trisphosphate mediated Ca2+ release, followed by activation of a Ca2+ entry pathway. Combining patch-clamp and indo-1 measurements we have tested the effects of various pharmacological agents on this Ca2+ entry following NA-induced Ca2+ release in order to determine the mechanism involved. Only the guanylate cyclase inhibitor LY-83583 specifically inhibited the maintained Ca2+ entry during NA stimulation. This inhibition was reversed by dibutyryl cGMP (DB-cGMP) or 8-bromo cGMP. Under control conditions, addition of DB-cGMP to the external solution was without effect. Thapsigargin and caffeine each depleted the intracellular Ca2+ store but did not evoke Ca2+ entry in venous myocytes under control conditions. However, application of DB-cGMP or NA after Ca2+ store depletion induced by caffeine or thapsigargin caused a rise in [Ca2+]i by activation of a Ca2+ entry pathway. The effect of cGMP seems to involve phosphorylation since cGMP-activated protein kinase inhibitors KT-5823 and H-8 blocked the NA-induced Ca2+ entry. Our results thus suggest that the activation of the voltage-independent Ca2+ entry by NA involves an increase in cellular cGMP.
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PMID:Activation of voltage-independent Ca2+ entry by noradrenaline involves cGMP in vascular myocytes. 874 49

We investigated the vasorelaxant effects of MCI-154, a cardiotonic agent designed to target thin filaments in cardiac muscles in intact and skinned vessels from guinea pigs. In normal Krebs-Henseleit solution, MCI-154 (10(-7)-10(-4) M) inhibited the contractions induced by angiotensin II, (Ang II), endothelin-1 (ET-1), phenylephrine, and phorbol 12-myristate 13-acetate (PMA) in a concentration-dependent manner in guinea pig aorta. In Ca(2+)-free solutions, ET-1 and PMA caused slowly developing and sustained contractions in guinea pig aorta, whereas phenylephrine and caffeine induced transient contractions due to Ca2+ release from the sarcoplasmic reticulum (SR). MCI-154 (10(-7)-10(-4) M) inhibited the contractile responses to ET-1 and PMA. MCI-154 also reduced the contraction induced by Ca2+ release from phenylehrine- and caffeine-sensitive Ca2+ store sites. On the other hand, the relaxation response to MCI-154 was not affected by the presence of methylene blue, a guanylate cyclase inhibitor or by the removal of endothelial cells. MCI-154 decreased the Ca(2+)-activated tension development in saponin-treated skinned fibers from guinea pig femoral arteries. The effects of MCI-154 were not potentiated in the presence of protein kinase A (PKA), whereas those of cyclic AMP were potentiated, possibly because of lack of protein kinase A. The present experiments demonstrate that MCI-154 inhibits vascular contraction when the contractions are produced by any of three mechanisms: protein kinase C (PKC) activation, Ca2+ mobilization from store sites, or sensitization of contractile elements by Ca2+.
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PMID:MCI-154-induced relaxation in vascular smooth muscles of guinea pig. 884 68

1. The effects of sodium nitroprusside (SNP) on the non-selective cation current activated in response to intracellular calcium store depletion were studied using the whole-cell patch-clamp technique in single smooth muscle cells isolated from the mouse anococcygeus. Voltage-dependent calcium currents were blocked with extracellular nifedipine, and caesium and tetraethylammonium chloride were used to block voltage-dependent potassium currents. Calcium stores were depleted with caffeine (10 mM), carbachol (50 microM) or cyclopiazonic acid (CPA 10 microM; an inhibitor of the sarcoplasmic reticulum [SR] calcium-ATPase). 2. At a holding potential of -40 mV, both CPA and caffeine activated inward currents which consisted of two clearly distinguishable components; an initial transient current followed by a smaller sustained current. In the case of CPA, the amplitudes of the transient and sustained components were 19.7 +/- 2.1 pA and 3.5 +/- 0.3 pA respectively, whilst the equivalent values for caffeine were 188 +/- 21 and 4.8 +/- 0.3 pA. As described previously, the transient current results from activation of a calcium-dependent chloride conductance whilst the sustained current is a non-selective cation current, activated following intracellular calcium store depletion. 3. The muscarinic receptor agonist, carbachol, also activated a transient followed by a sustained current with amplitudes of 238 +/- 55 and 4.7 +/- 0.5 pA respectively. Superimposed on the sustained current were regular, oscillations of calcium-activated chloride current. 4. Both the transient and the sustained currents activated by CPA were absent in cells pretreated with SNP (10 microM). Application of SNP to a cell following activation of the sustained current by CPA inhibited the current by 88.6 +/- 3.8%. SNP (10 microM) did not inhibit the transient current activated by caffeine but abolished the sustained current. 5. SNP (10 microM) had no effect on the initial transient current activated by carbachol (50 microM). However, it did inhibit the oscillations in the inward current. In recordings from cells bathed in extracellular solution containing the chloride channel blocker, anthracene-9-carboxylic acid (A-9-C; 1 mM), carbachol activated only a sustained current. This current was inhibited by 88.1 +/- 6.5% by a concomitant application of SNP (10 microM) and was absent in cells pretreated with the nitrovasodilator. 6. The effects of SNP on the currents activated by caffeine (10 mM) were mimicked by 8-bromo-cyclic GMP (200 microM); thus the nucleotide had no effect on the transient current activated by caffeine but abolished the sustained current. The effects of SNP, but not those of 8-bromo-cyclic GMP, were inhibited by the nitric oxide-sensitive guanylyl cyclase inhibitor, 1H-[1, 2, 4]oxadiazolo[4, 3-a]quinoxaline-1-one (ODQ; 1 microM). ODQ alone produced a significant increase in the size of the sustained current activated by caffeine (7.8 +/- 0.7 pA). 7. These findings suggest that SNP activates guanylyl cyclase to inhibit the non-selective cation current activated as a result of intracellular calcium store depletion in mouse anococcygeus cells. Since the non-selective cation current appears to underlie the calcium entry process responsible for maintaining the sustained contractions to agonists in this tissue, this action of SNP may represent an important mechanism by which nitrates relax non-vascular smooth muscle.
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PMID:Inhibition by sodium nitroprusside of a calcium store depletion-activated non-selective cation current in smooth muscle cells of the mouse anococcygeus. 886 35

The effects of phosphodiesterase inhibitors, an activator and an inhibitor of guanylyl cyclase, and cAMP and cGMP analogs on oxytocin-induced contractions have been studied in the testicular capsule of rats. The nonspecific phosphodiesterase inhibitors, theophylline and caffeine, attenuated the oxytocin-induced contractions via mechanisms that seem to be related to an increase in cAMP levels, since a similar effect was produced by dibutyryl cAMP. Sodium nitroprusside facilitated oxytocin-induced contractions. This effect was mimicked by dibutyryl cGMP. Methylene blue, an inhibitor of soluble guanylyl cyclase, decreased oxytocin-induced contractions, which suggests an involvement of guanylyl cyclase in the oxytocin effect. These results suggest that cAMP modulates the contraction and that cGMP, contrary to what happens in most smooth muscles, could participate in oxytocin-induced contractions in the testicular capsule of rats.
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PMID:Role of cyclic nucleotides in contraction induced by oxytocin in the testicular capsule of the rat in vitro. 899 Apr 88


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