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 spontaneous contractile force of muscle strips isolated from rabbit urinary bladder dome, base and urethra was dose-dependently inhibited by isoproterenol, an adenylate cyclase activator through beta-adrenoceptors and also by sodium nitroprusside, a guanylate cyclase activator. The relaxation response by isoproterenol was biggest in urinary bladder dome. Percent relaxation to 10(-4) M isoproterenol was 73.6% in bladder dome, 56.1% in bladder base, and 44.1% in urethra. The relaxation response by nitroprusside was biggest in urethra. Percent relaxation to 10(-4) M sodium nitroprusside was 34.8% in bladder dome, 51.2% in bladder base, and 63.2% in urethra. Cyclic adenosine monophosphate (cAMP) accumulation by isoproterenol was greatest in dome. cAMP levels increased by 150% in bladder dome, by 74% in bladder base and by 80% in urethra after 1 min over basal levels to become stable for 5 min. Cyclic guanosine monophosphate (cGMP) accumulation by sodium nitroprusside was greatest in urethra. cGMP levels increased by 445% in urethra after 1 min over basal levels and by 320% in dome, by 380% in base and by 1,100% in urethra after 5 min over basal levels. Dibutyryl cAMP relaxed the dome, base and urethra. 8-bromo cGMP also relaxed them. These results suggest that the role of cGMP is mainly related to urethral relaxation, whereas the role of cAMP is mainly related to urinary bladder relaxation.
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PMID:Regional difference in functional roles of cAMP and cGMP in lower urinary tract smooth muscle contractility. 133 26

The effects of nicorandil on ionic currents recorded from single smooth muscle cells of pig proximal urethra were investigated using patch-clamp techniques. Tension measurement was also performed to study the effects of nicorandil on the resting tone of pig urethra. Nicorandil produced a concentration-dependent sustained outward current that was suppressed by glibenclamide at -50 mV and was carried selectively by K+. In cell-attached configuration, nicorandil activated a 43-pS K+ channel that was reversibly inhibited by 10 microM glibenclamide. This glibenclamide-sensitive 43-pS K+ channel (KGS) "ran down" after excision of the membrane patch. In inside-out configuration, the application of either 1 mM Mg-ATP or 1 mM nucleotide diphosphate reactivated the KGS. In symmetrical 140 mM K+ conditions, 300 microM nicorandil and 300 microM levcromakalim activated a 2.14-pA K+ channel that exhibited the same amplitude and similar channel-opening kinetics. Methylene blue (10-100 microM), a soluble guanylate cyclase inhibitor, did not inhibit the opening of the nicorandil-induced KGS. The KGS was not activated by either sodium nitroprusside (10-100 microM) or 8-bromo guanosine 3':5'-cyclic monophosphate (1 mM). Nicorandil caused a concentration-dependent relaxation of the urethral resting tone but was less potent than levcromakalim. The relaxation induced by 10 microM nicorandil was partially inhibited by glibenclamide (1-10 microM) and also by methylene blue (10-100 microM). These results indicate that two independent nicorandil-induced relaxation mechanisms may be present in pig urethra.
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PMID:Nicorandil activates glibenclamide-sensitive K+ channels in smooth muscle cells of pig proximal urethra. 899 32

The distribution of nerves with the potential to synthesize nitric oxide was examined within the urinary bladder and proximal urethra of humans and guinea-pigs, using an antibody to nitric oxide synthase. Further experiments identified cells in which cGMP-immunoreactivity was induced following exposure to the nitric oxide donor, sodium nitroprusside. These cells represent the potential physiological targets of neuronally released nitric oxide, since activation of soluble guanylate cyclase, and a consequent rise in intracellular cGMP, mediate many of the effects of this transmitter. Nitric oxide synthase-immunoreactivity was widely distributed in the lower urinary tract. In guinea-pigs, 50-68% of all intrinsic vesical neurons expressed nitric oxide synthase-immunoreactivity, while in humans 72-96% of neurons in the wall of the bladder contained nitric oxide synthase. In both humans and guinea-pigs, varicose nitric oxide synthase-immunoreactive nerve terminals provided a moderate innervation to the detrusor muscle of the bladder body, and a denser innervation to the urethral muscle. Immunoreactive nerves also projected to the subepithelium and around blood vessels, but were rarely observed encircling intramural vesical ganglia. Following stimulation with sodium nitroprusside, smooth muscle cells of the urethra expressed strong cGMP-immunoreactivity, but detrusor muscle cells remained uniformly negative. Although the detrusor muscle fibres did not express cGMP, numerous interstitial cells throughout the bladder body demonstrated an intense induction of cGMP-immunoreactivity by sodium nitroprusside. These cells had long dendritic processes extending parallel to the smooth muscle fibres, and contained vimentin, an intermediate filament expressed by cells of mesenchymal origin. Other cell types in which sodium nitroprusside exposure induced cGMP-immunoreactivity were the uroepithelial cells, vascular smooth muscle cells and pericytes, and a small number of varicose nerve terminals. In the guinea-pig, a minor proportion (less than 10%) of intrinsic neurons in the wall of the bladder also expressed cGMP. No intrinsic neurons were observed in specimens of human bladder processed for cGMP immunohistochemistry. The results provide anatomical evidence that nitric oxide may function as a neurotransmitter in the lower urinary tract. Although nerves with the capacity to produce nitric oxide supply both the detrusor muscle and the urethra, distinct regional differences exist in the effects of nitric oxide on the induction of cGMP. If the nitric oxide-mediated induction of cGMP is a reliable indicator of the physiological responsiveness of a cell to nitric oxide, then smooth muscle cells appear to be the predominant targets of nitric oxide in the urethra, while in the bladder body, interstitial cells may serve this role. These findings support previous studies which have implicated nitric oxide as an inhibitory transmitter involved in the relaxation of the bladder neck. Our experiments further indicate that a number of cell types within the lower urinary tract could potentially mediate the effects of endogenously released nitric oxide.
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PMID:Distribution of nitric oxide synthase-immunoreactive nerves and identification of the cellular targets of nitric oxide in guinea-pig and human urinary bladder by cGMP immunohistochemistry. 905 89

Regional and age specific differences are observed in the sodium nitroprusside induced relaxation responses in the urinary tract. To clarify these differences, guanylyl cyclase activity is assayed in particulate and soluble fractions from the ureter, bladder dome, and urethra of young (11-18 days), adult (90-100 days), and old adult (2-3 years) guinea pigs. The rank order of soluble guanylyl cyclase activities is urethra = ureter > bladder dome with the largest decreases with aging occurring in the bladder. Atrial natriuretic factor (10(7) M) increases particulate guanylyl cyclase activity in the three tissues at all ages tested, with the activity being highest in the ureter. ATP (0.5 mM) activates particulate guanylyl cyclase in the ureter, bladder and urethra of old adult guinea pigs, and enhances atrial natriuretic factor induced activation of particulate guanylyl cyclase in all tissues and at all ages tested. The higher levels of soluble guanylyl cyclase activity in the urethra and ureter compared to the bladder parallel sodium nitroprusside induced relaxation in these tissues.
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PMID:Age-dependent changes in particulate and soluble guanylyl cyclase activities in urinary tract smooth muscle. 908 38

1. The distribution of the carbon monoxide (CO) producing enzymes haem oxygenase (HO)-1 and -2 was studied by immunohistochemistry in the pig's lower urinary tract, including bladder extramural arteries, and the oesophagogastric junction (OGJ). In isolated smooth muscle from the urethra and the OGJ, the mechanisms for CO-induced relaxations were characterized by measurement of cyclic nucleotide levels and by responses to the guanylate cyclase inhibitor methylene blue and some K+ channel inhibitors. 2. HO-2 immunoreactivity was observed in coarse nerve trunks within the smooth muscle of the urethra and OGJ, and in nerve cell bodies of the enteric plexuses of the OGJ. Furthermore, the vascular endothelium of the intramural vessels of the urethra, bladder and OGJ, and the extramural vessels of the bladder, displayed HO-2 immunoreactivity. Two different antisera against HO-1 were used, but only one displayed immunoreactivity in neuronal structures. HO-1 immunoreactivity, as displayed by this antiserum, was seen in nerve cells, coarse nerve trunks and varicose nerve fibres in the smooth muscle of the urethra and OGJ. Some HO-2 and/or HO-1 (as displayed by both HO-1 antisera) immunoreactive cells with a non-neuronal appearance were observed within the smooth muscle of the OGJ, bladder and urethra. 3. In the urethral preparations, exogenously applied CO (72 microM) evoked a relaxation amounting to 76 +/- 6%. The relaxation was associated with an increase in cyclic GMP, but not cyclic AMP, content. CO-evoked relaxations were not significantly reduced by treatment with methylene blue, or by inhibitors of voltage-dependent (4-aminopyridine), high (iberiotoxin, charybdotoxin) and low (apamin) conductance Ca(2+)-activated, and ATP-sensitive (glibenclamide) K+ channels. Bladder strips, and ring preparations from the extramural arteries of the bladder, did not respond to exogenously administered CO (12-72 microM). 4. In the OGJ, exogenously applied CO evoked a relaxation of 86 +/- 6%, which was associated with an increase in cyclic GMP, but not cyclic AMP, content. Treatment with 30 microM methylene blue raised the spontaneously developed muscle tone, and reduced the maximum relaxation evoked by CO to 33 +/- 9%. Addition of 4-aminopyridine, apamin, glibenclamide, iberiotoxin, charybdotoxin or glibenclamide had no effect on the relaxations. 4-aminopyridine (0.1-1 mM), iberiotoxin (0.1 microM) and charybdotoxin (0.1 microM) increased the spontaneously developed tone, and a combination of charybdotoxin and apamin reduced CO-induced (24 microM CO) relaxations. 5. The present findings demonstrate the presence of HO in both neuronal and non-neuronal cells in the pig OGJ and lower urinary tract. CO produces relaxation of the smooth muscle in the OGJ and urethra, associated with a small increase in cyclic GMP concentration in both regions. Relaxations evoked by CO in the urethra do not seem to involve voltage-dependent, low and high conductance, or ATP-dependent K+ channels. However, in the OGJ relaxations evoked by CO can be attenuated by methylene blue and a combination of charybdotoxin and apamin.
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PMID:Carbon monoxide-induced relaxation and distribution of haem oxygenase isoenzymes in the pig urethra and lower oesophagogastric junction. 911 25

The inhibitory innervation of guinea-pig urethral smooth muscle was investigated histochemically and functionally. The distribution of immunoreactivities to haem oxygenases (HO), neuronal NO synthase (nNOS), and vasoactive intestinal polypeptide (VIP) was studied, and the functional effects of the corresponding putative transmitters, CO, NO, and VIP, were assessed. HO-2 immunoreactivity was found in all nerve cell bodies of intramural ganglia, localized between smooth muscle bundles in the detrusor, bladder base and proximal urethra. About 70% of the ganglionic cell bodies were also NOS-immunoreactive (IR), whereas a minor part was VIP-IR. Some ganglion cells exhibiting tyrosine hydroxylase (TH) activity were demonstrated. Rich numbers of NOS-IR varicose nerve terminals could be found innervating the smooth muscle of the urethra, whereas VIP-IR terminals were less numerous. A rich number of TH-IR terminals were observed. The bladder showed a similar distribution of nerves, although only a few number of TH-IR nerves could be found. In bladder preparations exposed to sodium nitroprusside, cGMP-IR cells could be seen, forming an interconnecting network with long spindle-shaped processes. The cGMP-IR cells were especially abundant in the outer smooth muscle layers of the bladder, but less numerous in the urethra. In urethral strip preparations, electrical field stimulation evoked long-lasting frequency-dependent relaxations. The relaxations were not inhibited by the NO-synthesis inhibitor, L-NOARG, or enhanced by the NO-precursor, L-arginine. The haem precursor, 5-aminolevulinic acid (5-ALA), or the inhibitor of guanylate cyclase, ODQ, did not affect the urethral relaxations. Exogenously applied NO, SIN-1, and VIP relaxed the preparations by approximately 50%, whereas the relaxation evoked by exogenous CO was minor. These results suggest that CO probably is not involved in non-adrenergic, non-cholinergic inhibitory control of the guinea-pig urethra, where a non-NO/cGMP mediated relaxation seems to be predominant.
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PMID:Inhibitory innervation of the guinea-pig urethra; roles of CO, NO and VIP. 985 22

Uroguanylin and guanylin are newly discovered endogenous heat-stable peptides that bind to and activate a membrane bound guanylyl cyclase signaling receptor (termed guanylyl cyclase C; GC-C). These peptides are not only found in blood but are secreted into the lumen of the intestine and effect a net secretion of electrolytes (Na+, K+, Cl-, HCO3-) and fluid into the intestine via a cyclic guanosine-3', 5'-monophosphate (cGMP) mechanism. GC-C is also the receptor for Escherichia coli heat-stable enterotoxin (STa) and activation by STa results in a diarrheal illness. Employing mouse renal in vivo models, we have demonstrated that uroguanylin, guanylin, and STa elicit natriuretic, kaliuretic, and diuretic effects. These biological responses are time- and dose-dependent. Maximum natriuretic and kaliuretic effects are observed within 30-40 min following infusion with pharmacological doses of the peptides in a sealed-urethra mouse model. Our mouse renal clearance model confirms these results and shows significant natriuresis following a constant infusion of uroguanylin for 30 min, while the glomerular filtration rate, plasma creatinine, urine osmolality, heart rate, and blood pressure remain constant. These data suggest the peptides act through tubular transport mechanisms. Consistent with a tubular mechanism, messenger RNA-differential display PCR of kidney RNA extracted from vehicle- and uroguanylin-treated mice show the message for the Na+/K+ ATPase gamma-subunit is down-regulated. Interestingly, GC-C knockout mice (Gucy2c -/-) also exhibit significant uroguanylin-induced natriuresis and kaliuresis in vivo, suggesting the presence of an alternate receptor signaling mechanism in the kidney. Thus, uroguanylin and guanylin seem to serve as intestinal and renal natriuretic peptide-hormones influencing salt and water transport in the kidney through GC-C dependent and independent pathways. Furthermore, our recent clinical probe study has revealed a 70-fold increase in levels of urinary uroguanylin in patients with congestive heart failure. In conclusion, our studies support the concept that uroguanylin and guanylin are endogenous effector peptides involved in regulating body salt and water homeostasis.
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PMID:Renal effects of uroguanylin and guanylin in vivo. 1055 34

Recent studies suggest that the body produces two gaseous messengers, nitric oxide (NO) and carbon monoxide (CO), both of which activate soluble guanylyl cyclase and thus modulate the activity of smooth muscle cells. In the present study, the effects of NO and CO on the smooth muscle of the lower urinary tract were compared. In addition, the modulation of tissue NO- and CO-induced relaxation by hydrogen peroxide was examined. NO, produced endogenously by electrical field stimulation (EFS) or applied exogenously as a solution, induced a concentration-dependent relaxation of rabbit cavernosal and urethral smooth muscle strips, but not of bladder tissues. The cavernosal tissue was found to be three times more sensitive to the actions of NO than the urethra. CO also induced relaxation of both tissue types, but with no apparent difference in sensitivity between the tissues. However, CO was much less potent than NO with respect to smooth muscle relaxation. The mechanism of action of the two mediators was cyclic guanosine monophosphate (cGMP)-dependent, as evidenced by enhanced formation of cGMP and inhibition of relaxation by the guanylyl cyclase inhibitor, oxadiazoloquinoxaline-1-one (ODQ.) The data suggests that NO is the dominant messenger in these tissues, but does not exclude a role for CO. In the presence of hydrogen peroxide, the relaxation responses induced by both NO and CO were significantly increased, regardless of tissue type. The mechanism for this effect is unclear, but evidence points to a requirement for the activation of guanylyl cyclase and enhanced formation of cGMP, since potentiation by the peroxide was blocked by a specific guanylyl cyclase inhibitor. We suggest that H(2)O(2) may play a positive role in the amplification or NO and CO-mediated responses.
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PMID:Relaxation of rabbit lower urinary tract smooth muscle by nitric oxide and carbon monoxide: modulation by hydrogen peroxide. 1065 Jan 79

The effects of superoxide anion generators, the nitric oxide (NO) scavenger 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoine-1-oxyl 3-oxide (carboxy-PTIO), the specific guanylate cyclase inhibitor 1H-[1,2,4]-oxadiazole-[4,3-a]-quinoxalin-1-one (ODQ), and thiol modulating agents were investigated on relaxations induced by nitrergic stimulation and exogenous NO addition in the sheep urethra. Methylene blue (MB, 10 microM), pyrogallol (0.1 mM) and xanthine (X, 0.1 mM)/xanthine oxidase (XO, 0.1 u ml(-1)) inhibited NO-mediated relaxations, without affecting those induced by nitrergic stimulation. This resistance was not diminished following inhibition of endogenous Cu/Zn superoxide dismutase (Cu/Zn SOD) with diethyldithiocarbamic acid (DETCA, 3 mM), which almost abolished tissue SOD activity. Carboxy-PTIO (0.1 - 0.5 mM) inhibited NO-mediated relaxations but had no effect on responses to nitrergic stimulation, which were not changed by treatment with ascorbate oxidase (2 u ml(-1)). Relaxations to NO were reduced, but not abolished, by ODQ (10 microM), while nitrergic responses were completely blocked. The thiol modulators, ethacrynic acid (0.1 mM), diamide (1.5 mM), or 5,5'-dithio-bis (2-nitrobenzoic acid) (DTNB, 0. 5 mM), and subsequent treatment with dithiothreitol (DTT, 2 mM) had no effect on responses to nitrergic stimulation or NO. In contrast, N-ethylmaleimide (NEM, 0.2 mM) markedly inhibited both relaxations. L-cysteine (L-cys, 0.1 mM) had no effect on responses to NO, while it inhibited those to nitrergic stimulation, in a Cu/Zn SOD-independent manner. Our results do not support the view that the urethral nitrergic transmitter is free NO, and the possibility that another compound is acting as mediator still remains open. British Journal of Pharmacology (2000) 129, 53 - 62
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PMID:Effects of superoxide anion generators and thiol modulators on nitrergic transmission and relaxation to exogenous nitric oxide in the sheep urethra. 1069 2

We examined the contribution of K+ channels to the relaxation responses induced by different redox forms of nitric oxide (NO., NO- and NO+) in comparison with those evoked by electrical field stimulation (EFS) of nitrergic nerves in the sheep urethra. K+ channel blockers with different selectivity profile were used. Sodium nitroprusside (SNP) and different S-nitrosothiols were used as NO+ donors, Angeli's salt as an NO- donor and nitroglycerin (GTN) was chosen as a representative compound known to require metabolic activation in the target tissue. Pure NO gas was used to prepare NO. solutions. Relaxation evoked by EFS of nitrergic nerves or by exogenous NO was not inhibited by any of the K+ channel blockers, but was enhanced by 4-aminopyridine [inhibitor of voltage-dependent K+ (KV) channels]. This suggests that, whereas K+ channel activation and hyperpolarization of the postsynaptic membrane do not contribute to relaxation, prejunctional modulation of the nitrergic neurotransmission by Kv channels may be relevant. Relaxation induced by NO+ or NO- donors was not affected by K+ channel blockade with the following exceptions: glybenclamide, a blocker of ATP-sensitive K+ channels (KATP), enhanced responses to SNP and Angeli's salt, 4-aminopyridine inhibited relaxation evoked by Angeli's salt and GTN, and charybdotoxin, a blocker of large-conductance, Ca2+-activated K+ channels (BKCa) inhibited those induced by the S-nitrosothiol S-nitrosoglutathione. These results do not suggest the existence of a general mechanism of action on K+ channels for compounds releasing either NO+ or NO- in the sheep urethra. None of the K+ channel blockers affected relaxation induced by the membrane-permeable analogue of cGMP, 8-bromo-cGMP. However, the fact that the addition of the phosphodiesterase inhibitor zaprinast (0.1 mM) enhanced the relaxation to Angeli's salt, while preventing the inhibition induced by 4-aminopyridine, suggests that involvement of guanylate cyclase activation in the action of NO donors on K+ channels can not be excluded. Accordingly, the guanylate cyclase inhibitors 1H-[1,2,4]-oxadiazole-[4,3-a]-quinoxalin-1-one (ODQ, 10 microM) and 4H-8-bromo-1,2,4-oxadiazolo(3,4-d)benz(b)(1,4)oxazin-1-one (NS 2028, 10 microM) almost abolished relaxations to EFS and Angeli's salt. In contrast, ODQ only moderately inhibited relaxations to NO.. In addition, the NO scavenger 2-(4-carboxyphenyl)-4,4,5,5-tetramethyl imidazoline-1-oxyl 3-oxide (carboxy-PTIO) effectively inhibited responses to NO. whilst not affecting those to EFS or NO-, suggesting a close similarity between the nitrergic transmitter and nitroxyl ion. We conclude that nitrergic relaxation induced either by the endogenous transmitter or by exogenous NO donors in the ovine urethra is not mediated by postsynaptic alterations in the K+ conductance; only a prejunctional modulation through Kv channels seems to be significant. In addition, the production and/or release of alternative redox forms of NO, such as NO-, may be involved in neurotransmission processes in the urethra.
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PMID:Nitrergic relaxation in urethral smooth muscle: involvement of potassium channels and alternative redox forms of NO. 1177 6


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