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 past decade has seen an explosion of new information on the physiology of penile erection, pathophysiology of erectile dysfunction (ED), and development of new oral agents (e.g., three PDE5 inhibitors) to manage ED. Although all three selective PDE5 inhibitors are effective in the majority of ED cases, these oral medications have failed in certain disease states, such as diabetic ED, postprostatectomy ED, and severe veno-occlusive dysfunction. Only about 50% to 60% of these cases benefit from PDE5 inhibitor therapy, prompting the development of new approaches, including gene-based therapies for the treatment of ED. The penis is a convenient tissue target for gene therapy because of its external location and accessibility, the ubiquity of endothelial lined spaces, and low level of blood flow, especially in the flaccid state. Initially, gene therapy has been reserved for the treatment of life-threatening disorders including cancer, hereditary and acquired diseases. However, gene therapy is an attractive therapeutic possibility for the treatment of ED. Evolution of nitric oxide (NO), a small gaseous, lipophilic signaling molecule that is produced by nitric oxide synthase (NOS) activates guanylate cyclase (GC), resulting in increased cyclic guanosine monophosphate (cGMP) production, plays a significant role in our understanding of cavernosal smooth muscle physiology. Many gene therapy strategies have focused on the NO/GS/cGMP pathway. All three NOS isoforms, endothelial NOS (eNOS), neuronal NOS (nNOS), and iNOS have been used for gene therapy in order to modulate erectile response. Various viral and nonviral vectors have been used to date for the transfer of genetic material to the target cell or tissues with various degrees of success. Recently, second generation or "gutless" (helper-dependent) adenovirus vectors have been developed in order to reduce cellular toxicity and immune response, while increasing efficient gene therapy. Varieties of other gene therapy trials have also been undertaken for the treatment of ED and are the focus of this review.
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PMID:Gene therapy for erectile dysfunction. 1597 May 31

A major problem with using nitrates in the treatment of ischemic heart disease is that tolerance develops to their vasodilatory actions. YC-1 was used as the lead compound to synthesize further nitric oxide-independent soluble guanylate cyclase activators, including BAY-41-2272 and BAY-41-8543. A nitric oxide and heme-independent activator of soluble guanylate cyclase, BAY-58-2667, was subsequently discovered by high-throughput screening. Tolerance to the vasodilatory actions of BAY-41-8543 and BAY-58-2667 does not develop. Results from animal studies have suggested that these compounds may have potential in the treatment of ischemic heart disease, essential and pulmonary hypertension, congestive heart failure, glomerulonephritis and erectile dysfunction.
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PMID:Clinical potential of nitric oxide-independent soluble guanylate cyclase activators. 1618 86

Epimedium brevicornum Maxim (EbM) has been reputed to have sexual stimulation effects on males. The study is aimed to test the hypothesis that EbM extracts relaxed the corpus cavernosum (CC) smooth muscle through activation of multitargets on nitric oxide (NO)/cyclic guanosine monophosphate (cGMP) signaling pathway. Water extract of EbM and its subfraction (EP-20) were prepared and standardized by high-performance liquid chromatography. Isolated rabbit CC strips were mounted in organ baths and isometric tension was recorded in the presence or absence of specific inhibitors related to NO/cGMP signaling such as L-N(G)-nitro-arginine methyl ester (L-NAME), 1H-[1,2,4]oxadiazolo-[4,3-a] quinoxalin-1-one (ODQ, a guanylyl cyclase inhibitor) or phosphodiesterase 5 (PDE 5) inhibitors. cGMP level was determined in EP-20-treated CC strips. The results showed that EP-20 enriched the content of L-arginine in the process of purification and relaxed the CC smooth muscle precontracted with phenylephrine (PE, 1 microM) in a concentration-dependent manner. Besides, EP-20 increased the amount of cGMP production in rabbit CC tissues. Coincubation with EP-20 and L-NAME or ODQ significantly decreased EP-20-induced relaxation whereas EP-20 increased sodium nitroprusside-induced relaxation in PE-precontracted CC strips. Besides, EP-20 increased the potency and the duration of the relaxation effects caused by electrical field stimulation. Finally, EP-20 could potentiate PDE 5 inhibitors in relaxation of PE-precontracted CC strips. We concluded that extract of EbM relax the CC smooth muscle through multitargets in NO/cGMP/PDE 5 pathway and might bring into perspective the treatment strategy for those patients with erectile dysfunction.
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PMID:Epimedium brevicornum Maxim extract relaxes rabbit corpus cavernosum through multitargets on nitric oxide/cyclic guanosine monophosphate signaling pathway. 1639 27

The aim was to determine in circulating mononuclear cells from patients with erectile dysfunction (ED), the level of expression of endothelial nitric oxide synthase (eNOS), soluble guanylate cyclase (sGC) beta1-subunit and phosphodiesterase type-V (PDE-V). Peripheral mononuclear cells from nine patients with ED of vascular origin and nine patients with ED of neurological origin were obtained. Fourteen age-matched volunteers with normal erectile function were used as control. Reduction in eNOS protein was observed in the mononuclear cells from patients with ED of vascular origin but not in those from neurological origin. Although sGC beta1-subunit expression was increased in mononuclear cells from patients with ED, the sGC activity was reduced. However, only the patients with ED of vascular origin showed an increased expression of PDE-V. This work shows for the first time that, independently of the aetiology of ED, the expression of sGC beta1-subunit was increased in circulating mononuclear cells; however, the expression of both eNOS and PDE-V was only modified in the circulating mononuclear cells from patients with ED of vascular origin.
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PMID:Soluble guanylate cyclase beta1-subunit expression is increased in mononuclear cells from patients with erectile dysfunction. 1652 91

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

Soluble guanylyl cyclase (sGC) is the major effector molecule for nitric oxide (NO) and as such an interesting therapeutic target for the treatment of erectile dysfunction. To assess the functional importance of the sGCalpha(1)beta(1) isoform in corpus cavernosum (CC) relaxation, CC from male sGCalpha(1)(-/-) and wild-type mice were mounted in organ baths for isometric tension recording. The relaxation to endogenous NO (from acetylcholine, bradykinin and electrical field stimulation) was nearly abolished in the sGCalpha(1)(-/-) CC. In the sGCalpha(1)(-/-) mice, the relaxing influence of exogenous NO (from sodium nitroprusside and NO gas), BAY 41-2272 (NO-independent sGC stimulator) and T-1032 (phosphodiesterase type 5 inhibitor) were also significantly decreased. The remaining exogenous NO-induced relaxation seen in the sGCalpha(1)(-/-) mice was significantly decreased by the sGC-inhibitor 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one. The specificity of the impairment of the sGC-related responses was demonstrated by the unaltered relaxations seen with forskolin (adenylyl cyclase activator) and 8-pCPT-cGMP (cGMP analog). In conclusion, the sGCalpha(1)beta(1) isoform is involved in corporal smooth muscle relaxation in response to NO and NO-independent sGC stimulators. The fact that there is still some effect of exogenous NO in the sGCalpha(1)(-/- mice suggests the contribution of (an) additional pathway(s).
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PMID:Role of the soluble guanylyl cyclase alpha1-subunit in mice corpus cavernosum smooth muscle relaxation. 1805

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 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

Erectile dysfunction (ED) can be elicited by a variety of pathogenic factors, particularly impaired formation of and responsiveness to nitric oxide (NO) and the downstream effectors soluble guanylate cyclase (sGC) and cGMP-dependent protein kinase I (PKGI). One important target of PKGI in smooth muscle is the large-conductance, Ca2+ -activated potassium (BKCa) channel. In our previous report (42), we demonstrated that deletion of the BKCa channel in mice induced force oscillations and led to reduced nerve-evoked relaxations and ED. In the current study, we used this ED model to explore the role of the BKCa channel in the NO/sGC/PKGI pathway. Electrical field stimulation (EFS)-induced contractions of corpus cavernosum smooth muscle strips were significantly enhanced in the absence of BKCa channel function. In strips precontracted with phenylephrine, EFS-induced relaxations were converted to contractions by inhibition of sGC, and this was further enhanced by loss of BK channel function. Sildenafil-induced relaxations were decreased to a similar extent by inhibition of sGC or BKCa channels. At concentrations >1 microM, sildenafil caused relaxations independent of inhibition of sGC or BKCa channels. Sildenafil did not affect the enhanced force oscillations that were induced by the loss of BKCa channel function. Yet, these oscillations could be completely eliminated by blocking L-type voltage-dependent Ca2+ channels (VDCCs). These results suggest that therapeutically relevant concentrations of sildenafil act through cGMP and BKCa channels, and loss of BKCa channel function leads to hypercontractility, which depends on VDCCs and cannot be modified by the cGMP pathway.
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PMID:Hypercontractility and impaired sildenafil relaxations in the BKCa channel deletion model of erectile dysfunction. 1848 Feb 46

This review aims to elucidate the possible effects of phosphodiesterase-5 (PDE5) inhibitors on sperm functions. PDEs hydrolyze cyclic nucleotides, and together with adenylyl and guanylyl cyclase, which catalyze the formation of cAMP and cGMP, regulate the levels of these second messengers in cells. cGMP-specific PDE5 is one of the PDEs that have been intensively studied because of its fundamental pharmacological relevance, as oral PDE5 inhibitors are used successfully in treating erectile dysfunction. In addition, they have shown diverse beneficial actions in different disease categories. Specific relevance of the cGMP system in reproductive functions has been recently proposed. Its use was shown to be devoid of effects on semen volume, concentration, sperm membrane integrity or sperm penetration assay. Most available studies demonstrated a significant increase in sperm motility and viability both in vivo and in vitro, which seems to be enhanced at low doses and reduced at high concentrations. Also, these molecules showed a role in capacitation and a debated one concerning acrosome reaction. However, due to the relative short period since the launching of oral PDE5 inhibitors, more investigations should be carried out in wider scales to assess their effect(s) on variant sperm function that could be beneficial as potential therapeutic approaches.
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PMID:Oral phosphodiesterase-5 inhibitors and sperm functions. 1859 4


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