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)

It is known that the nucleus accumbens contains all elements of the nitric oxide (NO)-cyclic GMP (cGMP) system but the role of NO in this nucleus is not well understood. We investigated the contribution of the NO-cGMP system in the neurotransmission elicited by hippocampal nerve signals which are propagated to the nucleus accumbens via the fornix/fimbria. This glutamatergic hippocampus-accumbens projection was electrically stimulated for short periods in the urethane-anaesthetized rat. The nucleus accumbens was simultaneously superfused by the push-pull technique with compounds that influence the NO system and the released glutamate, aspartate and GABA were determined in the superfusate. Superfusion of the nucleus accumbens with the NO donor, PAPA/NO, enhanced basal release of the investigated amino acids with a complex concentration dependency. The release of glutamate and aspartate was also increased by the inhibitor of phosphodiesterase 5, UK-114,542. The PAPA/NO-elicited release of glutamate and aspartate was diminished by superfusion with the inhibitor of guanylyl cyclase, NS 2028. Basal release of amino acid transmitters was not influenced by NS 2028 and the NO synthase inhibitor, 7-NINA.Electrical stimulation of the fornix/fimbria increased the outflow of aspartate, glutamate and GABA in the nucleus accumbens. The stimulation-evoked release was abolished by superfusion of the nucleus with tetrodotoxin and strongly diminished by NS 2028, 7-NINA and N(G)-nitro-L-arginine methyl ester (L-name), while PAPA/NO facilitated stimulation-evoked release of these neurotransmitters. UK-114,542 also enhanced the evoked release of glutamate and aspartate while evoked GABA release was not influenced by the phosphodiesterase inhibitor. These findings indicate that NO plays the role of an excitatory transmitter in the nucleus accumbens and that nerve signals from the hippocampus propagated via fornix/fimbria induce NO synthesis in the nucleus accumbens. NO does not exert a tonic influence on basal release but facilitates release of aspartate, glutamate and GABA through increased cGMP synthesis. Phosphodiesterase 5 seems to be involved in the termination of the NO effect in glutamatergic but not in GABAergic neurons.
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PMID:Involvement of nitric oxide, cyclic GMP and phosphodiesterase 5 in excitatory amino acid and GABA release in the nucleus accumbens evoked by activation of the hippocampal fimbria. 1204 51

A spinal reflex and the L-arginine-nitric oxide-guanylyl cyclase-cyclic guanosine monophosphate (cGMP) pathway mediate smooth muscle relaxation that results in penile erection. Nerves and endothelial cells directly release nitric oxide in the penis, where it stimulates guanylyl cyclase to produce cGMP and lowers intracellular calcium levels. This triggers relaxation of arterial and trabecular smooth muscle, leading to arterial dilatation, venous constriction, and erection. Phosphodiesterase 5 (PDE5) is the predominant phosphodiesterase in the corpus cavernosum. The catalytic site of PDE5 normally degrades cGMP, and PDE5 inhibitors such as sildenafil potentiate endogenous increases in cGMP by inhibiting its breakdown at the catalytic site. Phosphorylation of PDE5 increases its enzymatic activity as well as the affinity of its allosteric (noncatalytic/GAF domains) sites for cGMP. Binding of cGMP to the allosteric site further stimulates enzymatic activity. Thus phosphorylation of PDE5 and binding of cGMP to the noncatalytic sites mediate negative feedback regulation of the cGMP pathway.
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PMID:Mechanisms of action of PDE5 inhibition in erectile dysfunction. 1522 27

Cardiovascular smooth muscle cells (SMCs) exist as resting or activated cells. Resting SMCs produce contractile proteins and are nearly transcriptionally inactive; activated SMCs are transcriptionally active and are involved in pathological processes such as atherosclerosis. Soluble guanylate cyclase, protein kinase G, and protein kinase A are present in SMCs, but their levels can be decreased in activated cells. Phosphodiesterase 3 (PDE3) activity is abundant in cardiovascular tissues; both PDE3A and PDE3B are involved in cyclic adenosine monophosphate (cAMP) hydrolysis in these tissues. Cyclic-AMP-hydrolyzing PDE activities are altered during the phenotypic transition of SMCs from the resting to the activated phenotype. Similar changes have been observed in cyclic guanosine monophosphate cGMP-hydrolyzing PDEs, although the impact of these alterations on PDE5 inhibitor-mediated effects requires further study. This report presents the changes in PDE expression that accompany phenotypic modulation of SMCs and discusses the potential impact of these events on PDE5-mediated cell functions.
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PMID:Cardiovascular implications in the use of PDE5 inhibitor therapy. 1522 31

Nitric oxide (NO) is formed from the conversion of L-arginine by nitric oxide synthase (NOS), which exists in three isoforms: neuronal (nNOS), endothelial (eNOS), and inducible (iNOS). nNOS is expressed in penile neurons innervating the corpus cavernosum, and eNOS protein expression has been identified primarily in both cavernosal smooth muscle and endothelium. NO is released from nerve endings and endothelial cells and stimulates the activity of soluble guanylate cyclase (sGC), leading to an increase in cyclic guanosine-3',5'-monophosphate (cGMP) and, finally, to calcium depletion from the cytosolic space and cavernous smooth muscle relaxation. The effects of cGMP are mediated by cGMP dependent protein kinases, cGMP-gated ion channels, and cGMP-regulated phosphodiesterases (PDE). Thus, cGMP effect depends on the expression of a cell-specific cGMP-receptor protein in a given cell type. Numerous systemic vasculature diseases that cause erectile dysfunction (ED) are highly associated with endothelial dysfunction, which has been shown to contribute to decreased erectile function in men and a number of animal models of penile erection. Based on the increasing knowledge of intracellular signal propagation in cavernous smooth muscle tone regulation, selective PDE inhibitors have recently been introduced in the treatment of ED. Phosphodiesterase 5 (PDE5) inactivates cGMP, which terminates NO-cGMP-mediated smooth muscle relaxation. Inhibition of PDE5 is expected to enhance penile erection by preventing cGMP degradation. Development of pharmacologic agents with this effect has closely paralleled the emerging science.
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PMID:Nitric oxide-cyclic GMP pathway with some emphasis on cavernosal contractility. 1522 23

The purpose of this study was to assess intrinsic smooth muscle mechanisms contributing to greater nitric oxide (NO) responsiveness in pulmonary vascular vs. airway smooth muscle. Canine pulmonary artery smooth muscle (PASM) and tracheal smooth muscle (TSM) strips were used to perform concentration response studies to an NO donor, (Z)-1-[N-(2-aminoethyl)-N-(2-ammonioethyl)amino]diazen-1-ium-1,2-diolate (DETA-NO). PASM exhibited a greater NO responsiveness whether PASM and TSM were contracted with receptor agonists, phenylephrine and acetylcholine, respectively, or with KCl. The >10-fold difference in NO sensitivity in PASM was observed with both submaximal and maximal contractions. This difference in NO responsiveness was not due to differences in endothelial or epithelial barriers, since these were removed, nor was it due to the presence of cGMP-independent NO-mediated relaxation in either tissue. At equal concentrations of NO, the intracellular cGMP concentration ([cGMP]i) was also greater in PASM than in TSM. Phosphodiesterase (PDE) inhibition using isobutylmethylxanthine indicated that the greater [cGMP]i in PASM was not due to greater PDE activity in TSM. Expression of soluble guanylate cyclase (sGC) subunit mRNA (2 +/- 0.2 and 1.3 +/- 0.2 attomol/microg total RNA, respectively) and protein (47.4 +/- 2 and 27.8 +/- 3.9 ng/mg soluble homogenate protein, respectively) was greater in PASM than in TSM. sGCalpha1 and sGCbeta1 mRNA expression was equal in PASM but was significantly different in TSM, suggesting independent regulation of their expression. An intrinsic smooth muscle mechanism accounting for greater NO responsiveness in PASM vs. TSM is greater sGC activity.
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PMID:NO responsiveness in pulmonary artery and airway smooth muscle: the role of cGMP regulation. 1611 48

Recent experimental evidence suggests that arterial insufficiency precedes the structural and functional changes in corpora cavernosa (CC) leading to organic erectile dysfunction (ED). The present review gives an overview of the physiological factors involved in the regulation of penile vasculature. Sympathetic nerves maintain flaccidity and tonically released noradrenaline induces vasoconstriction of both arteries and veins through alpha(1)- and alpha(2)-postsynaptic receptors and downregulates its own release and that of nitric oxide (NO) through alpha(2)-presynaptic receptors. The sympathetic cotransmitter neuropeptide Y (NPY) modulates noradrenergic vasoconstriction in penile small arteries by both enhancing and depressing noradrenaline contractions through Y(1)- and Y(2)-postsynaptic and a NO-independent atypical endothelial receptor, respectively. Activation of alpha(1)-adrenoceptors involves both Ca(2+) influx through L-type and receptor-operated Ca(2+) channels (ROC) and Ca(2+) sensitization mechanisms mediated by protein kinase C (PKC), tyrosine kinases (TKs) and Rho kinase (RhoK). In addition, RhoK can regulate Ca(2+) entry in penile arteries upon receptor stimulation. Vasodilatation of penile arteries and large veins during erection is mediated by neurally released NO. The subsequent increased arterial inflow to the cavernosal sinoids and shear stress on the endothelium lining penile arteries activates endothelial NO production through Akt phosphorylation of endothelial NO synthase (eNOS). NO stimulates guanylate cyclase and increased cyclic guanin 3'-monophosphate (cGMP) levels in turn activate protein kinase G (PKG), which enhances K(+) efflux through Ca(2+)-activated (K(Ca)) and voltage-dependent Ca(2+) (K(v)) channels in penile arteries and veins, respectively. PKG-mediated decrease in Ca(2+) sensitivity and its regulation by RhoK remains to be clarified in penile vasculature. Phosphodiesterase type 5 (PDE5) inhibitors are potent vasodilators of penile resistance arteries and increase the content and effects of basally released endothelial NO. Endothelium-dependent relaxations of penile small arteries also include an endothelium-derived hyperpolarizing factor (EDHF)-type response, which is impaired in diabetes and hypertension-associated ED. Locally produced contractile and relaxant prostanoids regulate penile venous and arterial tone, respectively. The latter activates prostaglandin I (IP) and prostaglandin E (EP) receptors coupled to adenylate cyclase and to the increase of cyclic adenosine monophosphate (cAMP) levels, which in turn stimulates K(+) efflux through ATP-sensitive K(+) (K(ATP)) channels. There is a crosstalk between the cGMP and cAMP signaling pathways in penile small arteries. Relevant issues such as the mechanisms underlying the excitation-secretion coupling of the endothelial cells, as well as those involved in cell proliferation and vascular remodeling of the penile vasculature remain to be elucidated. In addition, only few studies have investigated the changes in structure and function of penile arteries in cardiovascular risk situations leading to ED.
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PMID:Physiological regulation of penile arteries and veins. 1763 89

The treatment of erectile dysfunction (ED) has been revolutionized during the last 2 decades with several treatment options now available. Most of these treatments are associated with high efficacy rates and favourable safety profiles. A MEDLINE search was undertaken to evaluate all currently available data on treatment modalities for ED. Phosphodiesterase type 5 (PDE5) inhibitors (sildenafil, tadalafil, vardenafil) are currently the first-choice treatment option for ED by most physicians and patients. In addition, several new PDE5 inhibitors are candidates to enter the market in forthcoming years (avanafil, udenafil, SLx-2101, mirodenafil [SK3530]). However, obvious pharmacokinetic differences that result in a faster time-to-onset, longer half-life time and better safety profile are required for these drugs to be considered a truly better option for patients. Other molecules in development include selective dopamine, glutamate, serotonin and melanocortin receptor agonists, guanylate cyclase activators, rho-kinase inhibitors and hexarelin analogues, while the first trials on gene therapy and tissue engineering for reconstruction of corporal tissue are under way. Patients must be aware of all treatment options since no ideal treatment exists. It is expected that the availability of drugs with different mechanisms of action will allow physicians to offer more personalized medicine to their patients in the future. The development and adaptation of a patient-centred care model in sexual medicine will increase the efficacy and safety of current and future treatments.
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PMID:Looking to the future for erectile dysfunction therapies. 1819 27

Phosphodiesterase (PDE) and guanylyl cyclase (GC) enzymes are key components of the cGMP signalling pathway and are encoded in the genome of Plasmodium falciparum. Here we investigate the role of specific GC and PDE isoforms in gamete formation--a process that is essential for malaria transmission and occurs in the Anopheles mosquito midgut following feeding on an infected individual. Details of the intracellular signalling events controlling development of the male and female gametes from their precursors (gametocytes) remain sparse in P. falciparum. Previous work involving the addition of pharmacological agents to gametocytes implicated cGMP in exflagellation--the emergence of highly motile, flagellated male gametes from the host red blood cell. In this study we show that decreased GC activity in parasites having undergone disruption of the PfGCbeta gene had no significant effect on gametogenesis. By contrast, decreased cGMP-PDE activity during gametocyte development owing to disruption of the PfPDEdelta gene, led to a severely reduced ability to undergo gametogenesis. This suggests that the concentration of cGMP must be maintained below a threshold in the developing gametocyte to allow subsequent differentiation to proceed normally. The data indicate that PfPDEdelta plays a crucial role in regulating cGMP levels during sexual development.
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PMID:Disruption of a Plasmodium falciparum cyclic nucleotide phosphodiesterase gene causes aberrant gametogenesis. 1845 84

Phosphodiesterase type 5 (PDE5) inhibitors are used to treat erectile dysfunction, and growing evidence supports potential cardiovascular utility. Their efficacy declines with reduced nitric-oxide synthase (NOS) activity common to various diseases. We tested whether direct soluble guanylate cyclase (sGC) stimulation restores in vivo cardiovascular modulation by PDE5 inhibition despite acute or chronically suppressed NOS activity. Mice (C57/Bl6; n = 62) were studied by in vivo pressure-volume analysis to assess acute modulation by the PDE5 inhibitor sildenafil (SIL; 100 microg/kg/min) of the cardiac response to isoproterenol (ISO) with or without NOS inhibition [N(omega)-nitro-L-arginine methyl ester (L-NAME)] and cotreatment by the sGC stimulator 2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-(4-morpholinyl)pyrimidine-4,6-diamine (BAY 41-8543). SIL induced mild vasodilation but no basal cardiac effects and markedly blunted ISO-stimulated contractility. Acute BAY 41-8543 at a dose lacking cardiovascular effects did not alter ISO responses. However, after acute L-NAME, SIL ceased to influence cardiovascular function, but adding BAY 41-8543 fully restored SIL effects. After 1 week of L-NAME, neither SIL nor SIL + BAY 41-8543 acutely induced vasodilation or blunted ISO responses. However, sustained BAY 41-8543 despite concurrent NOS inhibition restored the cardiovascular efficacy of SIL. The disparity between acute and chronic NOS inhibition related to diffusion of PDE5 away from myocyte z-bands coupled with reduced protein kinase G activation. Both were restored by sustained sGC costimulation. Thus, PDE5 regulation of adrenergic reserve and systemic vasodilation depends upon NOS-induced cGMP/protein kinase G and can be enhanced by sustained low-level stimulation of sGC. This may prove beneficial for enhancing the efficacy of PDE5 inhibitors in conditions with chronically reduced NOS activity.
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PMID:Sustained soluble guanylate cyclase stimulation offsets nitric-oxide synthase inhibition to restore acute cardiac modulation by sildenafil. 1845 72

We have shown that increased luminal flow induces O(2)(-) and nitric oxide (NO) production in thick ascending limbs (TALs). However, the interaction of flow-stimulated NO and O(2)(-) in TALs is unclear. We hypothesized that NO inhibits flow-induced O(2)(-) production in TALs via cGMP-dependent protein kinase (PKG). We measured flow-stimulated O(2)(-) production in rat TALs using dihydroethidium in the absence and presence of L-arginine (0.3 mM), the substrate for NO synthase. The addition of L-arginine reduced flow-induced net O(2)(-) production from 68 +/- 9 to 17 +/- 4 AU/s (P < 0.002). The addition of the NO synthase inhibitor N(G)-nitro-l-arginine methyl ester (L-NAME; 5 mM) in the presence of L-arginine stimulated production (L-arginine: 15 +/- 4 AU/s vs. L-arginine + L-NAME: 63 +/- 7 AU/s; P < 0.002). The guanylate cyclase inhibitor LY-83583 (10 microM) also enhanced flow-induced net O(2)(-) production in the presence of L-arginine (L-arginine: 7 +/- 4 AU/s vs. L-arginine + LY-83583: 53 +/- 7 AU/s; P < 0.01). In the presence of LY-83583, L-arginine only reduced flow-induced net O(2)(-) by 36% (LY-83583: 80 +/- 7 AU/s vs. LY-83583 + L-arginine: 51 +/- 3 AU/s; P < 0.006). The cGMP analog dibutyryl (db)-cGMP reduced flow-induced net O(2)(-) from 39 +/- 9 to 7 +/- 3 AU/s (P < 0.03). The PKG inhibitor KT-5823 (5 microM) partially restored flow-induced net O(2)(-) in the presence of L-arginine (L-arginine: 4 +/- 4 AU/s vs. L-arginine + KT-5823: 32 +/- 9 AU/s; P < 0.03) and db-cGMP (db-cGMP: 9 +/- 7 AU/s vs. db-cGMP + KT-5823: 54 +/- 5 AU/s; P < 0.01). Phosphodiesterase II inhibition had no effect on arginine-inhibited O(2)(-) production. We conclude that 1) NO reduces flow-stimulated O(2)(-) production, 2) this occurs primarily via the cGMP/PKG pathway, and 3) O(2)(-) scavenging by NO plays a minor role.
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PMID:Nitric oxide reduces flow-induced superoxide production via cGMP-dependent protein kinase in thick ascending limbs. 1924 1


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