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)

Previously, we reported an abrupt reduction in chick chorioallantoic membrane (CAM) microvascular permeability to macromolecules between days 4.5 and 5.0 of the 21-day gestation. Further, exogenous activation of the cAMP pathway at day 4.5 served to restrict normal macromolecular extravasation. Here, we evaluated the influence of the cGMP pathway on macromolecular efflux at day 5.0. Zaprinast (10(-4) M), a selective inhibitor of the cGMP-specific phosphodiesterase (PDE V), acutely increased basal levels of FITC-dextran 40 extravasation. Further, the cGMP analogue, 8 br-cGMP (10(-4) and 10(-3) M) and the soluble guanylate cyclase activator, sodium nitroprusside (SNP, 10(-5) and 10(-4) M) increased tracer extravasation in a dose-dependent fashion. The cGMP-mediated increase was not associated with gap formation along the junctional clefts, however, vesiculo-vacuolar structures were characteristic of CAM endothelial ultrastructure. KT 5823 (10(-5) M), the highly selective protein kinase G (PKG) inhibitor, also served to increase basal tracer extravasation. The nonselective PDE inhibitor, IBMX (10(-4) M) had no effect alone, but reduced the permeability effects of both 8 br-cGMP and SNP. Rolipram (10(-4) M), a selective PDE IV inhibitor, on the other hand, potentiated the effect of 8 br-cGMP. These results serve to suggest that cAMP degradation, rather than PKG activation, is a principal component of the cGMP-mediated increase in CAM endothelial permeability in vivo.
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PMID:Cyclic GMP-mediated macromolecular extravasation from angiogenic microvessels in vivo. 1091 13

An isoquinolone derivative, methyl-2-(4-aminophenyl)-1, 2-dihydro-1-oxo-7-(2-pyridinylmethoxy)-4-(3,4, 5-trimethoxyphenyl)-3-isoquinoline carboxylate sulfate (T-1032), was found to be a novel potent inhibitor of cyclic GMP (cGMP)-binding cGMP-specific phosphodiesterase (PDE5). We investigated the inhibitory effects of T-1032 on six PDE isozymes isolated from canine tissues. T-1032 specifically inhibited the hydrolysis of cGMP by PDE5 partially purified from canine lung, at a low concentration (IC(50) = 1.0 nM, K(i) = 1.2 nM), in a competitive manner. In contrast, the IC(50) values of T-1032 for PDE1, PDE2, PDE3, and PDE4 were more than 1 microM. T-1032 also inhibited PDE6 from canine retina with an IC(50) of 28 nM, which is of the same order of magnitude as the IC(50) of sildenafil. cGMP hydrolytic activities of two alternative splice variants of canine PDE5 expressed in COS-7 cells were inhibited by this compound to a similar extent. T-1032 increased the intracellular concentration of cGMP in cultured rat vascular smooth muscle cells in the presence and absence of C-type natriuretic peptide, an activator of membrane-bound guanylate cyclase, whereas the compound did not change cyclic AMP levels. These data indicated that T-1032, which belongs to a new structural class of PDE5 inhibitors, is a potent and selective PDE5 inhibitor. This compound may be useful in pharmacological studies to examine the role of a cGMP/PDE5 pathway in tissues.
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PMID:Characterization and effects of methyl-2- (4-aminophenyl)-1, 2-dihydro-1-oxo-7- (2-pyridinylmethoxy)-4-(3,4, 5-trimethoxyphenyl)-3-isoquinoline carboxylate sulfate (T-1032), a novel potent inhibitor of cGMP-binding cGMP-specific phosphodiesterase (PDE5). 1100 27

Sildenafil (0.1 - 30 microM), a cyclic GMP phosphodiesterase 5 (PDE 5) inhibitor, induced inhibition of electrically evoked contractions of ring segments of human vas deferens from 34 vasectomies. Zaprinast (0.1 - 100 microM), another PDE 5 inhibitor, and the nitric oxide (NO) donor sodium nitroprusside (SNP) (0.1 - 100 microM) had no effect on neurogenic contractions. The inhibition induced by sildenafil was not modified by the inhibitor of guanylate cyclase 1H-[1,2,4]oxadiazolo[4,3-a]quinoxaline-1-one (ODQ) (1 - 30 microM) but it was abolished by the K(+) channel blockers tetraethylammonium (TEA, 1 mM), iberiotoxin (0.1 microM) and charybdotoxin (0.1 microM). Sildenafil, zaprinast and SNP did not affect the contractions induced by noradrenaline. SNP (10 microM) caused elevation of cyclic GMP levels that was potentiated by sildenafil (10 microM) and zaprinast (100 microM). ODQ (10 microM) inhibited the increase in cyclic GMP. Sildenafil inhibits adrenergic neurotransmission in human vas deferens. The inhibition is not related to accumulation of cyclic GMP but is probably due to activation of prejunctional large-conductance Ca(2+)-activated K(+) channels.
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PMID:Inhibition of neuroeffector transmission in human vas deferens by sildenafil. 1105 5

The corpora cavernosa (CC) muscles of the human penis and their structural arrangements are essential for the physiology of erection. Contraction of this muscle causes detumescence, and relaxation, tumescence. The motor excitatory neurotransmission is adrenergic, acting through the alpha adrenoceptors. Continuous adrenergic transmitter (noradrenaline) release is necessary for the maintenance of non-erectile (contractile) state of the penis. The inhibitory neurotransmitter that relaxes CC muscle to produce erection is nitrergic i.e., the chemical messenger being nitric oxide (NO). The latter can also be released from cavernous endothelium. Presence of NO increases intracellular cGMP through activation of the enzyme guanylate cyclase. This causes relaxation of CC muscle. Phosphodiesterase type 5 (PDE5) is responsible for the degradation of cGMP and regulation of CC muscle tone. Specific PDE inhibitors such as sildenafil enhance the intracellular cGMP to improve erection. Increase in intracellular cAMP can also bring about pharmacological erection in man (e.g. PGE1, papaverine and histamine). Inhibition of excessive adrenergic tone with appropriate alpha-adrenergic blocking agents (e.g. phentolamine) can also contribute to the onset of pharmacological erection.
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PMID:Physiological significance of nitrergic transmission in human penile erection. 1122 38

In the isolated, perfused rat thick ascending limb (THAL), L-arginine (L-Arg) stimulates endogenous nitric oxide (NO) production, which inhibits NaCl absorption. However, the intracellular cascade responsible for the effects of NO has not been studied. We hypothesized that endogenous NO inhibits THAL NaCl transport by increasing cGMP, which activates protein kinase G (PKG) and cGMP-stimulated phosphodiesterase (PDE II), which, in turn, decreases cAMP levels. THALs from rats were isolated and perfused, and net chloride flux (J(Cl-)) was measured. L-Arg was used to stimulate NO production. Adding L-Arg (0.5 mmol/L) to the bath decreased J(Cl-) from 154.4+/-9.9 to 101.9+/-14.1 pmol. mm(-1). min(-1), a 35.2% decrease (n=6; P<0.05). In the presence of the soluble guanylate cyclase inhibitor LY-83583 (10 micromol/L), adding L-Arg to the bath did not affect THAL J(Cl-) (143.7+/-28.1 versus 136.7+/-22.2 pmol. mm(-1). min(-1); n=6). LY-83583 alone had no effect on J(Cl-). In the presence of the PDE II inhibitor erythro-9-(2-hydroxy-3-nonyl) adenine (EHNA) 50 micromol/L, L-Arg reduced J(Cl-) by only 13% (142.1+/-8.9 versus 122.7+/-11.5 pmol. mm(-1). min(-1); P<0.05; n=6). EHNA alone had no effect on THAL J(Cl-). In the presence of 10(-5) mol/L dibutyryl (db)-cAMP, L-Arg did not significantly reduce J(Cl-) (116.3+/-18.2 versus 102.6+/-15.6 pmol. mm(-1). min(-1); n=6). db-cAMP (10(-5) mol/L) had no effect on THAL J(Cl-). In the presence of the PKG inhibitor KT-5823 (2 micromol/L), L-Arg lowered J(Cl-) from 142.6+/-14.1 to 85.9+/-8.3 pmol. mm(-1). min(-1), a decrease of 35.6% (n=8; P<0.05). We conclude that (1) endogenous NO inhibits THAL J(Cl-) by stimulating soluble guanylate cyclase and increasing cGMP; (2) NO inhibits THAL J(Cl-) by stimulation of PDE II, which, in turn, decreases cAMP levels; and (3) PKG does not mediate NO-induced inhibition of THAL J(Cl-).
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PMID:NO Inhibits NaCl absorption by rat thick ascending limb through activation of cGMP-stimulated phosphodiesterase. 1123 Mar 20

Erectile dysfunction (ED) occurs in varying degrees in an estimated 20 to 30 million American men and is associated with adverse effects on quality of life; particularly personal well-being, family and social interrelationships. Research into ED has focused primarily on the physiologic mechanisms of corpus cavernosum smooth muscle relaxation, and penile erection as the end result of smooth muscle relaxation. These processes are mediated by cholinergic, nonadrenergic, noncholinergic (NANC, e.g., nitric oxide), vasoactive intestinal peptide (VIP), and potentially calcitonin gene-related peptide (CGRP) containing nerves. Release of nitric oxide following sexual stimulation from non-adrenergic, non cholinergic nerves and vascular endothelium activates guanylyl cyclase and induces intracellular cGMP synthesis. In turn, cGMP results in lowering intracellular concentrations, inhibits contractility of the penile smooth muscle, and induces an erectile response. Phosphodiesterase type 5 (PDE 5) is the predominant enzyme responsible for cGMP hydrolysis in trabecular smooth muscle. Activation of PDE 5 terminates NO-induced, cGMP-mediated smooth muscle relaxation, and subsequent penile flaccidity. Sildenafil citrate is a potent PDE type 5 reversible and selective inhibitor which blocks cGMP hydrolysis effectively. FDA approval of sildenafil citrate as the first oral agent for ED in males has resulted in significant interest. We discuss the clinical and pharmacologic properties of sildenafil citrate as well as the urologic and cardiac implications.
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PMID:Sildenafil citrate, a selective phosphodiesterase type 5 inhibitor: urologic and cardiovascular implications. 1128 69

1. The subcellular mechanisms involved in the effect of nitric oxide (NO) on the release of vasoactive intestinal polypeptide (VIP) were examined in synaptosomes isolated from rat small intestine. 2. VIP release was stimulated by the NO donor SNAP (10(-7)-10(-4) M) in an oxyhaemoglobin-sensitive manner. The presence of the guanylate cyclase inhibitor ODQ (10(-5) M), or inhibition of protein kinase G (PKG) by KT 5823 (3 x 10(-6) M) or Rp-8Br-PET-cGMPS (5 x 10(-7) M), antagonized the SNAP-induced VIP release, suggesting a regulatory role of PKG, confirming previously published data from enteric ganglia. This finding was further supported by the fact that direct PKG activation by the stable cGMP analogue 8-pCPT-cGMP stimulated VIP secretion to the same extent as SNAP. 3. Basal VIP secretion was enhanced in the presence of zaprinast, an inhibitor of cGMP-dependent phosphodiesterase 5 (PDE 5), suggesting a functional role of PDE 5 in NO-cGMP signalling. Supportive evidence for this finding was obtained by demonstration of the presence of PDE 5 using RT-PCR. 4. Stimulation of endogenous NO production by L-arginine was also effective in releasing VIP. The effect was abolished in the presence of KT 5823, but was insensitive to oxyhaemoglobin (10(-3) M), suggesting that an interaction between NO and VIP is likely to occur within the same nerve terminal rather than between terminals. 5. NO synthesis was not affected by VIP (10(-8)-10(-5) M), suggesting that there is no feedback regulation between the NO and the VIP pathways. 6. These findings support the notion that an anatomical and functional interrelationship exists between NO and VIP in enteric nerve terminals and that complex signalling mechanisms involving PKG and PDE 5 contribute to NO-induced VIP release.
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PMID:Functional coupling between nitric oxide synthesis and VIP release within enteric nerve terminals of the rat: involvement of protein kinase G and phosphodiesterase 5. 1148 12

1. We tested the hypothesis that nitric oxide (NO) augments vagal neurotransmission and bradycardia via phosphorylation of presynaptic calcium channels to increase vesicular release of acetylcholine. 2. The effects of enzyme inhibitors and calcium channel blockers on the actions of the NO donor sodium nitroprusside (SNP) were evaluated in isolated guinea-pig atrial-right vagal nerve preparations. 3. SNP (10 microM) augmented the heart rate response to vagal nerve stimulation but not to the acetylcholine analogue carbamylcholine (100 nM). SNP also increased the release of [3H]acetylcholine in response to field stimulation. No effect of SNP was observed on either the release of [3H] acetylcholine or the HR response to vagal nerve stimulation in the presence of the guanylyl cyclase inhibitor 1H-(1,2,4)-oxadiazolo-(4,3-a)-quinoxalin-1-one (ODQ, 10 microM). 4. The phosphodiesterase 3 (PDE 3) inhibitor milrinone (1 microM) increased the release of [3H] acetylcholine and the vagal bradycardia and prevented any further increase by SNP. SNP was still able to augment the vagal bradycardia in the presence of the protein kinase G inhibitor KT5823 (1 microM) but not after protein kinase A (PKA) inhibition with H-89 (0.5 microM) or KT5720 (1 microM) had reduced the HR response to vagal nerve stimulation. Neither milrinone nor H-89 changed the HR response to carbamylcholine. 5. SNP had no effect on the magnitude of the vagal bradycardia after inhibition of N-type calcium channels with omega-conotoxin GVIA (100 nM). 6. These results suggests that NO acts presynaptically to facilitate vagal neurotransmission via a cGMP-PDE 3-dependent pathway leading to an increase in cAMP-PKA-dependent phosphorylation of presynaptic N-type calcium channels. This pathway may augment the HR response to vagal nerve stimulation by increasing presynaptic calcium influx and vesicular release of acetylcholine.
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PMID:Nitric oxide-cGMP pathway facilitates acetylcholine release and bradycardia during vagal nerve stimulation in the guinea-pig in vitro. 1153 40

To study the roles of nitric oxide (NO) in growth of nerve fibers, (+/-)-(E)-ethyl-2-[(E)-hydroxyimino]-5-nitro-3-hexeneamine (NOR3), an NO-donor, was applied to cultured dorsal root ganglion (DRG) neurites from a micropipette. Ejection of a small volume of 1 mM NOR3 solution (not more than 1 pl/s) from a micropipette to terminal branches of neurites caused enlargement of the neurites, and often, elongation of their growth cones. This neurite enlargement was blocked by inhibitors for soluble guanylate cyclase. The neurite enlargement did not occur when protein kinase A (PKA) was inhibited. To prove that NOR3 activated PKA, we introduced a fluorescence peptide probe, ARII that reduces its fluorescence by activated PKA, to monitor PKA activity in DRG neurites. ARII fluorescence was reduced by NOR3, which was not observed when PKA was inhibited by its specific inhibitors. These indicated that PKA was indeed activated by NO. To examine whether the PKA activation is due to inhibition of phosphodiesterase III (PDE III) by cyclic GMP, we applied PDE III-specific inhibitors and found that the inhibitions activated PKA. Since PKA regulates various neuronal functions, our finding that NO activates PKA is important to understand roles of NO in nerve fibers.
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PMID:Activation of protein kinase A by nitric oxide in cultured dorsal root ganglion neurites of the rat, examined by a fluorescence probe, ARII. 1178 15

In vascular tissues including the corpus cavernosum, the organ function is reciprocally regulated by noradrenergic and non-adrenergic, non-cholinergic (NANC) nerves. NANC nerves innervating the corpus cavernosum is thought to be nitroxidergic (nitrergic) nerves which liberate nitric oxide (NO) produced by neuronal NO synthase, and liberated NO activates soluble guanylate cyclase (sGC) in cavernous smooth muscle cells. Intracellular increase in cyclic (c) GMP by activation of sGC dilates cavernous smooth muscle and then induces penile erection. Nitroxidergic (nitrergic) vasodilator nerves also innervate cavernous arteries and veins which regulate the blood volume in the corpus cavernosum. The order of potency of nitroxidergic nerve functions in these tissues (cavernosum > artery >> vein) may be suitable for producing the erection. Therefore, obstruction of the arteries and impairment of nitroxidergic (nitrergic) nerve function are speculated to be one of the causes for erectile dysfunction (ED). On the other hand, NO derived from the cavernous endothelium may partly contribute to erectile function. Sildenafil (Viagra) is one of the potent therapeutics for ED. The agent is a selective phosphodiesterase type 5 (PDE-V) inhibitor that inhibits degradation of cGMP elevated by NO mainly derived from the nerves. To develop more selective and safer therapeutics for ED, further systematic investigations are required.
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PMID:[Nitroxidergic (nitrergic) nerve and erectile dysfunction]. 1186 53


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