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)

This study was undertaken to examine the possible role of nitric oxide (NO) on brown adipose tissue (BAT) thermogenesis in rats. The chronic administration of N omega-nitro-L-arginine methyl ester (L-NAME; NO synthase inhibitor) in drinking water given to rats decreased interscapular BAT (IBAT) weight as well as DNA content in a warm environment (25 +/- 1 degrees C; 2 and 4 weeks), and inhibited the cold-stimulated (5 +/- 1 degrees C; 2 weeks) increase in IBAT weight and DNA content. L-Arginine administration (4 weeks in a warm environment) increased the DNA content of IBAT. Chronic L-NAME administration (2 weeks in a warm environment) eliminated the NE-stimulated increase in in vivo oxygen consumption (VO2), caused hypothermia in acute cold exposure (0 degree C), and suppressed the NE-stimulated increase in in vitro IBAT VO2. In vitro incubation of native IBAT with L-NAME suppressed the basal and NE-stimulated increase in in vitro VO2. In vitro incubation of IBAT with methylene blue (soluble guanylate cyclase inhibitor and a scavenger of free NO) eliminated the NE-stimulated increase in in vitro IBAT VO2. These results suggest that the nitric oxide and NO-cGMP signaling systems are involved in the regulation of BAT cellularity and thermogenesis in rats.
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PMID:Effects of acute and chronic inhibition of nitric oxide synthase on brown adipose tissue thermogenesis. 904 15

1. The nature and cellular mechanisms that are responsible for endothelium-dependent relaxations resistant to indomethacin and NG-nitro-L-arginine methyl ester (L-NAME) were investigated in phenylephrine (PE) precontracted isolated carotid arteries from the rabbit. 2. In the presence of the cyclo-oxygenase inhibitor, indomethacin (10 microM), acetylcholine (ACh) induced a concentration- and endothelium-dependent relaxation of PE-induced tone which was more potent than the calcium ionophore A23187 with pD2 values of 7.03 +/- 0.12 (n = 8) and 6.37 +/- 0.12 (n = 6), respectively. The ACh-induced response was abolished by removal of the endothelium, but was not altered when indomethacin was omitted (pD2 value 7.00 +/- 0.10 and maximal relaxation 99 +/- 3%, n = 6). Bradykinin and histamine (0.01-100 microM) had no effect either upon resting or PE-induced tone (n = 5). 3. In the presence of indomethacin plus the NO synthase inhibitor, L-NAME (30 microM), the response to A23187 was abolished. However, the response to ACh was not abolished, although it was significantly inhibited with the pD2 value and the maximal relaxation decreasing to 6.48 +/- 0.10 and 67 +/- 3%, respectively (for both P < 0.01, n = 8). The L-NAME/indomethacin insensitive vasorelaxation to ACh was completely abolished by preconstriction of the tissues with potassium chloride (40 mM, n = 8). 4. The Ca(2+)-activated K+ (KCa) channel blockers, tetrabutylammonium (TBA, 1 mM, n = 5) and charybdotoxin (CTX, 0.1 microM, n = 5), completely inhibited the nitric oxide (NO) and prostacyclin (PGI2)-independent relaxation response to ACh. However, iberiotoxin (ITX, 0.1 microM, n = 8) or apamin (1-3 microM, n = 6) only partially inhibited the relaxation. 5. Inhibitors of the cytochrome P450 mono-oxygenase, SKF-525A (1-10 microM, n = 6), clotrimazole (1 microM, n = 5) and 17-octadecynoic acid (17-ODYA, 3 microM, n = 7) also reduced the NO/PGI2-independent relaxation response to ACh. 6. In endothelium-denuded rings of rabbit carotid arteries, the relaxation response to exogenous NO was not altered by either KCa channel blockade with apamin (1 microM, n = 5) or CTX (0.1 microM, n = 5), or by the cytochrome P450 mono-oxygenase blockers SKF-525A (10 microM, n = 4) and clotrimazole (10 microM, n = 5). However, the NO-induced response was shifted to the right by LY83583 (10 microM, n = 4), a guanylyl cyclase inhibitor, with the pD2 value decreasing from 6.95 +/- 0.14 to 6.04 +/- 0.09 (P < 0.01). 7. ACh (0.01-100 microM) induced a concentration-dependent relaxation of PE-induced tone in endothelium-denuded arterial segments sandwiched with endothelium-intact donor segments. This relaxation to ACh was largely unaffected by indomathacin (10 microM) plus L-NAME (30 microM), but abolished by the combination of indomethacin, L-NAME and TBA (1 mM, n = 5). 8. These data suggest that in the rabbit carotid artery: (a) ACh can induce the release of both NO and EDHF, whereas A23187 only evokes the release of NO from the endothelium, (b) the diffusible EDHF released by ACh may be a cytochrome P450-derived arachidonic acid metabolite, and (c) EDHF-induced relaxation involves the opening of at least two types of KCa channels, whereas NO mediates vasorelaxation via a guanosine 3': 5'-cyclic monophosphate (cyclic GMP)-mediated pathway, in which a cytochrome P450 pathway and KCa channels do not seem to be involved.
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PMID:NO/PGI2-independent vasorelaxation and the cytochrome P450 pathway in rabbit carotid artery. 905 10

Isoprenaline-induced relaxation was investigated in aortas from control and daunomycin-induced nephrotic rats. In the endothelium-intact aortas precontracted with phenylephrine, the isoprenaline-induced relaxation and cyclic adenosine monophosphate (AMP) accumulation were significantly less in nephrotic rats than in control animals. Removal of the endothelium, pretreatment with methylene blue (MB), a guanylate cyclase inhibitor, or NW-nitro-L-arginine methyl ester (L-NAME), a nitric oxide (NO) synthase inhibitor, markedly reduced the relaxation induced by isoprenaline in nephrotic and control animals. The increase in cyclic AMP content induced by isoprenaline also was inhibited by these treatments. In addition, the difference in the isoprenaline-induced relaxation and cyclic AMP accumulation between nephrotic and control preparations was abolished by these treatments. The tissue cyclic guanosine monophosphate (GMP) level was not affected by isoprenaline. In the presence of zaprinast (Zap), a cyclic GMP phosphodiesterase inhibitor, the cyclic GMP level in the endothelium-intact tissues was significantly lower in nephrotic rats than in control animals. Removal of endothelium or pretreatment with MB or L-NAME markedly reduced cyclic GMP content in nephrotic and control animals. In the endothelium-denuded tissues, the isoprenaline-induced relaxation and cyclic AMP accumulation were markedly potentiated by a low concentration of nitroprusside (NP). In the endothelium-intact aortas precontracted with phenylephrine, relaxations induced by dobutamine, salbutamol, and forskolin in nephrotic rats were not significantly different from those in control animals. In the endothelium-intact aortas precontracted with KCl, the isoprenaline-induced relaxation also was significantly less in nephrotic rats than in control animals. Pretreatment with prazosin, but not yohimbine, abolished this difference. These results indicate that nephrosis decreases the relaxing response of the endothelium-intact aortas to isoprenaline. In addition, these results suggest that the endothelium-derived relaxing factor (EDRF) released from the endothelial cells markedly enhances isoprenaline-induced increase in the tissue level of cyclic AMP. The decreased relaxing response to isoprenaline in nephrotic rats may be caused by the decrease in the endothelial-dependent cyclic GMP release caused by alpha 1-adrenoceptor activation by isoprenaline.
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PMID:Impaired relaxing response to isoprenaline in isolated thoracic aorta of nephrotic rats: decrease in release of EDRF from endothelial cells. 905 73

The exact mechanism of hemoglobin (Hb) associated vasoconstriction has not been elucidated. We investigated this problem using isolated superfused rat aortic rings with intact endothelium. Human stroma-free hemoglobin solution (SFH) at 2uM reversed vaso relaxation induced by 33uM acetylcholine (Ach). Further, pretreatment with 4uM SFH inhibited Ach(333uM) induced dilation. The SFH induced contraction was reversible by glyceryltrinitrate (GTN), a nitric oxide (NO) donor. Preincubation with a NO synthase inhibitor nitro-L-arginine-methyl ester (NAME, 0.4nM) caused almost complete inhibition of the Hb vasoactivity. Unlike SFH (ferrous oxyHb), prenitrosylated SFH (HbNO) or ferric Hb derivatives (e.g., metHb, HbCN) did not elicit vasoconstriction. The presence of 2uM SFH did not significantly reduce the vasodilatory effectiveness of endothelium independent vasodilators isoproteranol (ISO) and papaverine (PPV). These results suggest that a primary mechanism for Hb vasoconstrictor activity is ferrous Hb scavenging of endothelium derived NO, a signal for guanylate cyclase-cGMP mediated smooth muscle relaxation. Additionally, it appears that the Hb induced vasoactivities may be modulated with NO independent vasodilators.
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PMID:Ferrrous hemoglobin scavenging of endothelium derived nitric oxide is a principal mechanism for hemoglobin mediated vasoactivities in isolated rat thoracic aorta. 908 33

Small arteries (internal diameter 376 +/- 69 microns) from the proximal intestine region of the rainbow trout were mounted in a myograph apparatus where changes in isometric tension could be recorded. VIP (vasoactive intestinal polypeptide) caused a concentration-dependent relaxation (10(-9)-3 x 10(-7) M) of vessels precontracted with the alpha-adrenoceptor agonist phenylephrine (10(-5) M). The nitric oxide synthase inhibitor L-NAME (10(-4) M) did not affect the VIP-relaxation, neither did the lipoxygenase inhibitor esculetin (10(-5) M). However, the cyclooxygenase inhibitor indomethacin (10(-6) M) shifted the concentration-response curve significantly to the right. The VIP-relaxation was still present after mechanical removal of the endothelium. Sodium nitroprusside (10(-9)-10(-6) M) caused a concentration-dependent relaxation of the precontracted vessel, indicating the presence of soluble guanylate cyclase in the vascular smooth muscle cells. VIP-immunoreactivity was found in varicose nerve fibers in these vessels, but nitric oxide synthase-immunoreactivity could not be demonstrated. These results suggest that in rainbow trout, as in mammals, VIP is an endogenous vasodilating neuropeptide. No endothelium-dependent mechanism seems to be involved, neither is production of nitric oxide. Instead the relaxation is mediated, at least in part, via prostaglandin synthesis.
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PMID:Vip-induced relaxation of small arteries of the rainbow trout, Oncorhynchus mykiss, involves prostaglandin synthesis but not nitric oxide. 908 41

Nitric oxide (NO) production reportedly regulates guanosine 3', 5'-cyclic monophosphate (cGMP) formation and Ca2+ influx in pancreatic acini. We have investigated the functional roles of the NO/cGMP messenger system in rat pancreatic acini. In dispersed acini, the levels of amylase secretion, cytosolic [Ca2+]([Ca2+]i), NO synthase, and cGMP were measured. The NO synthase inhibitor NG-nitro-L-arginine methyl ester (L-NAME, 0.01-100 microM) had no effect on amylase secretion induced by various concentrations of carbachol, cholecystokinin octapeptide (CCK-8) or the high affinity CCK agonist, JMV-180. Similarly, L-NAME up to 100 microM did not affect the changes in Ca2+ spiking evoked by these secretagogues; nor was Ca2+ entry, refilling or oscillation altered by L-NAME. Sub- and supramaximal concentrations of these secretagogues did not change NO synthase activities compared with basal levels. While sodium nitroprusside (SNP), a NO donor, caused a 9.4-fold increase in cGMP levels compared with basal levels, carbachol, CCK-8 and JMV-180 had no effect. In addition, the guanylate cyclase inhibitor LY 83583 (10 nM to 10 microM) altered neither amylase secretion nor Ca2+ signaling induced by these secretagogues. These findings indicate that the stimulatory action of carbachol or CCK-8 is not mediated by NO or cGMP. To investigate whether cGMP stimulates pancreatic secretion we showed that both SNP and a cell-permeant cGMP analog at 0.1-1 mM stimulated amylase secretion and Ca2+ transients to a level equal to 10-15% and 13-24%, respectively, of those observed with maximal concentrations of secretagogues. The guanylate cyclase activator guanylin (1-10 microM), which increased cGMP levels 2.4-fold compared with basal levels, elicited a small amount of amylase secretion and a small Ca2+ transient. In conclusion, exogenous NO is capable of increasing endogenous cGMP, which results in a modest increase in the [Ca2+]i transient and pancreatic amylase secretion. However, the NO/cGMP system does not appear to be involved significantly in the mediation of Ca2+ signaling and amylase secretion stimulated by carbachol and CCK-8.
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PMID:Effect of uncoupling NO/cGMP pathways on carbachol- and CCK-stimulated Ca2+ entry and amylase secretion from the rat pancreas. 909 53

We investigated the nature of cGMP-synthesizing cells in the developing rat forebrain using cGMP-immunocytochemistry in combination with in vitro incubation of brain slices. When brain slices of immature rats, aged between 1 and 4 weeks, were incubated with sodium nitroprusside (SNP), a nitric oxide (NO) donor compound, in the presence of the phosphodiesterase inhibitor isobutylmethylxanthine (IBMX), small round cells with a few processes in and around the corpus callosum were visualized with the cGMP-antibody. The morphology and the distribution of the cGMP-positive cells were consistent with the criteria for oligodendrocytes. Furthermore, the cGMP-positive cells expressed 2'3'-cyclic nucleotide 3'-phosphodiesterase (CNPase) and gelsolin, which are marker proteins for oligodendrocytes. Therefore, we concluded that the cGMP-positive cells were oligodendrocytes. A subpopulation of the oligodendrocyte was found to be cGMP-immunoreactive also when slices were incubated in the absence of SNP. Furthermore, incubation of the slice in the presence of L-NAME, an inhibitor of NO synthase, but in the absence of SNP abolished cGMP immunostaining. In addition, some populations of neurons and astrocytes in restricted brain areas produced cGMP in response to the incubation with SNP as previously reported, whereas both ameboid and ramified microglial cells did not respond to the treatment. Atrial natriuretic peptide, a stimulator of particulate guanylyl cyclase, enhanced cGMP synthesis in astrocytes in some brain regions but not in oligodendrocytes. These findings indicate that oligodendrocytes in the immature rat brain express soluble guanylyl cyclase. No cGMP-positive oligodendrocytes were found in the mature rat brain, suggesting that cGMP may mediate signals related to myelinogenesis in the rat brain.
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PMID:Nitric oxide-mediated cGMP synthesis in oligodendrocytes in the developing rat brain. 909 73

The effects of nitric oxide (NO) on blood pressure and renal hemodynamics are well established, but those of NO on renal tubule HCO3- and Na+ transport are not fully understood. In this study, we combined renal clearance and in situ microperfusion techniques to investigate the effects of NO on the renal excretion of Na (FE(Na%)) and the rates of renal tubule absorption of fluid (J(V)) and bicarbonate (J(HCO3)) in the rat kidney. Administration of the nitric oxide synthase inhibitor, N(G)-nitro-L-arginine methyl ester (L-NAME, 6 mg/kg iv bolus) did not change mean blood pressure and glomerular filtration rate significantly. However, L-NAME significantly increased urine flow rate and FE(Na%), and these effects were maintained over a 60-min period. Addition of L-NAME markedly decreased both J(V) and J(HCO3) in the proximal tubule. In contrast, addition of 1 microM sodium nitroprusside (SNP) or S-nitroso-N-acetylpenicillamine (SNAP) significantly increased both J(V) and J(HCO3). Similar stimulation was also observed when 8-bromoguanosine 3',5'-cyclic monophosphate (8-BrcGMP, 1 microM) was added to the luminal perfusate. The stimulatory effects of SNP and 8-BrcGMP on J(V) and J(HCO3) were not additive. The increments in J(V) and J(HCO3) due to SNP were abolished by the Na+/H+ exchange blocker ethylisopropylamiloride and the guanylate cyclase inhibitor methylene blue. These results indicate that NO stimulates proximal tubule Na+ and HCO3- transport through a cGMP-linked pathway in the kidney proximal tubule.
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PMID:Nitric oxide regulates HCO3- and Na+ transport by a cGMP-mediated mechanism in the kidney proximal tubule. 912 2

Angiogenesis is a complex process involving endothelial cell (EC) proliferation, migration, differentiation, and organization into patent capillary networks. Nitric oxide (NO), an EC mediator, has been reported to be antigenic as well as proangiogenic in different models of in vivo angiogenesis. Our aim was to investigate the role of NO in capillary organization using rat microvascular ECs (RFCs) grown in three-dimensional (3D) collagen gels. RFCs placed in 3D cultures exhibited extensive tube formation in the presence of transforming growth factor-beta 1. Addition of the NO synthase (NOS) inhibitors L-nitro-arginine methylester (L-NAME, 1 mmol/L) or L-monomethyl-nitro-l-arginine (1 mmol/L) inhibited tube formation and the accumulation of nitrite in the media by approximately 50%. Incubation of the 3D cultures with excess L-arginine reversed the inhibitory effect of L-NAME on tube formation. In contrast to the results obtained in 3D cultures, inhibition of NO synthesis by L-NAME did not influence RFC proliferation in two-dimensional (2D) cultures or antagonize the ability of transforming growth factor-beta 1 to suppress EC proliferation in 2D cultures. Reverse transcriptase-polymerase chain reaction revealed the constitutive expression of all three NOS isoforms, neuronal, inducible, and endothelial NOSs, in 2D and 3D cultures. Moreover, Western blot analysis demonstrated the presence of immunoreactive protein for all NOS isoforms in 3D cultures of RFCs. In addition, in the face of NOS blockade, co-treatment with the NO donor sodium nitroprusside or the stable analog of cGMP, 8-bromo-cGMP, restored capillary tube formation. Thus, the autocrine production of NO and the activation of soluble guanylate cyclase are necessary events in the process of differentiation and in vitro capillary tube organization of RFCs.
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PMID:Nitric oxide synthase inhibitors attenuate transforming-growth-factor-beta 1-stimulated capillary organization in vitro. 913 6

1. The flavoprotein binder diphenyleneiodonium (DPI) is a potent, irreversible inhibitor of nitric oxide synthase (NOS), but produces only a transient pressor response following systemic administration to animals, despite evidence of persistent NOS inhibition. To characterize further the effects of DPI on vascular tone, isometric tension was recorded from rat isolated aortic rings mounted between steel wires in an organ bath. 2. The NOS inhibitor NG-nitro-L-arginine methyl ester (L-NAME, 1 mM) initiated an additional contraction of prostaglandin F2 alpha-preconstricted rings with endothelium which was sustained throughout the period of L-NAME exposure (+234 +/- 39% at 15 min). In contrast, addition of DPI (5 microM) to rings with endothelium produced a transient initial contraction (+111 +/- 27% at 2 min) followed by a more sustained relaxation (-27 +/- 19% at 15 min, P < 0.001 vs L-NAME). 3. The contraction to DPI was also observed in rings without endothelium, was abolished by L-NAME pretreatment, and was unaffected by the alpha-adrenoreceptor inhibitor prazosin. Relaxation in response to DPI was not inhibited by endothelium removal or by pretreatment with either L-NAME or with the ATP-sensitive potassium channel blocker glibenclamide. 4. The endothelium-independent relaxation to DPI was inhibited at 23 degrees C and its time course was delayed by pretreatment with the guanylate cyclase inhibitor methylene blue. 5. Thus, in addition to a transient initial contraction due to NOS inhibition, DPI produces an endothelium-independent, temperature-dependent relaxation which appears in part due to activation of guanylate cyclase. This relaxant effect of DPI may explain the transient nature of its pressor effect in vivo despite sustained NOS inhibition.
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PMID:Endothelium-independent relaxation of aortic rings by the nitric oxide synthase inhibitor diphenyleneiodonium. 913 92


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