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)

Endogenous nitric oxide (NO) may contribute to the maintenance of normal pulmonary vasomotor tone, and inhaled NO is used to treat patients with pulmonary hypertension. Because pulmonary vascular tone is regulated by intracellular free Ca2+ concentration and membrane potential, which are controlled by the K+ channel activity in pulmonary artery (PA) smooth muscle cells, we sought to determine whether K+ channels are involved in NO-induced relaxation and, if so, which types of K+ channels are responsible. Authentic NO (approximately 0.3 microM) and sodium nitroprusside (SNP, 10 pM) both produced significant relaxation in isolated PA rings precontracted by increasing extracellular K+ concentration. Further elevation of the K+ concentration from 20 to 60 mM resulted in a significant increase in contraction but caused a marked decline in SNP- and NO-mediated PA relaxation. The dependence of SNP- and NO-induced relaxation on transmembrane K+ gradient suggests that K+ efflux through K+ channels is involved in these effects. Furthermore, 4-aminopyridine (4-AP, 5-10 mM), which blocks voltage-gated K+ channels (K(V)), and charybdotoxin (200 nM), which blocks Ca2+-activated K+ channels (K(Ca)), both significantly inhibited NO- and SNP-induced PA relaxation. The ATP-sensitive K+ channel blocker glibenclamide, however, had no effect on the relaxation response. The blocking of guanylate cyclase diminished, but did not abolish, the NO-induced relaxation, whereas 4-AP further decreased the NO-induced relaxant response in the presence of the guanylate cyclase inhibitor LY-83583. These data suggest that activation of both K(V) channels and K(Ca) channels by guanosine 3',5'-cyclic monophosphate-dependent and -independent pathways is a mechanism, at least in part, by which NO induces PA relaxation.
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PMID:Inhibition of K(V) and K(Ca) channels antagonizes NO-induced relaxation in pulmonary artery. 912 54

1. We studied the effects of various K+ channel blockers on the vasodilator responses of guinea-pig isolated basilar arteries to nitrergic nerve stimulation, the nitric oxide (NO) donor sodium nitroprusside (SNP), and the membrane permeable guanosine-3',5'-cyclic monophosphate (cyclic GMP) analogue 8-bromo-cyclic GMP (8-Br-cyclic GMP). 2. In endothelium-denuded preparations which were contracted with prostaglandin F2alpha (1 microM), electrical field stimulation (EFS, 10 Hz for 30 s) produced a vasodilatation which was totally blocked by the nitric oxide synthase (NOS) inhibitor N(G)-nitro-L-arginine methyl ester L-NAME; 100 microM) (n=3) and by the selective NO-sensitive guanylate cyclase inhibitor 1H-[1,2,4]oxadiazolo[4,3,-a]quinoxalin-1-one (ODQ; 1 microM) (n=4). The vasodilator response to SNP (100 nM) was not reduced by L-NAME but was abolished by ODQ (1 microM) (n=4). 3. EFS-elicited vasodilatation was partly but significantly reduced by the non-selective K+ channel blockers tetraethylammonium (TEA, 1 and 3 mM) and 4-aminopyridine (4-AP, 3 mM), and by the large-conductance calcium-activated K+ channel (K(Ca) channel) blockers charybdotoxin (ChTX, 150 nM) and iberiotoxin (IbTX, 30 and 100 nM). In contrast, the ATP-sensitive K+ channel (K(ATP) channel) blocker glibenclamide (1-10 microM) and the small-conductance K(Ca) channel blocker apamin (100-500 nM) did not affect EFS-induced vasodilatation. 4. The vasodilator response elicited by SNP (10-100 nM) was significantly reduced by TEA (3 mM) and ChTX (150 nM) but not by apamin (500 nM) or glibenclamide (1 microM). The vasodilatation elicited by 8-Br-cyclic GMP (100 microM) was also reduced by TEA (3 mM) and ChTX (150 nM). 5. The results indicate that the vasodilatations induced by nitrergic nerve stimulation and the NO donor SNP in endothelium-denuded guinea-pig basilar artery depend on the formation of intracellular cyclic GMP. The increased cyclic GMP level activates large-conductance K(Ca) channels which partly mediate the vasodilator response. Neither K(ATP) channels nor apamin-sensitive small-conductance K(Ca) channels are involved in nitrergic transmitter-mediated vasodilatation.
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PMID:Role of potassium channels in the nitrergic nerve stimulation-induced vasodilatation in the guinea-pig isolated basilar artery. 948 60

1. The cellular mechanism(s) of action of endothelium-derived vasodilator substances in the rabbit middle cerebral artery (RMCA) were investigated. Specifically, the subtypes of potassium channels involved in the effects of endothelium-derived relaxing factors (EDRFs) in acetylcholine (ACh)-induced endothelium-dependent vasorelaxation in this vessel were systematically compared. 2. In the endothelium-intact RMCA precontracted with histamine (3 microM), ACh induced a concentration-dependent vasorelaxation, which was sensitive to indomethacin (10 microM) or N(G)-nitro-L-arginine (L-NOARG; 100 microM); pD2 values 8.36 vs 7.40 and 6.38, P < 0.01 for both, n = 6 and abolished by a combination of both agents. ACh caused relaxation in the presence of high K+ PSS (40 mM KCl), which was not affected by indomethacin, but abolished by L-NOARG and a combination of indomethacin and L-NOARG. 3. In the presence of indomethacin, relaxation to ACh in the endothelium-intact RMCA precontracted with histamine was unaffected by either glibenclamide (10 microM), an ATP-sensitive K+ channel (K[ATP]) blocker, 4-aminopyridine (4-AP, 1 mM) or dendrotoxin (DTX, 0.1 microM), delayed rectifier K channel (Kv) blockers. However, relaxation responses to ACh were significantly inhibited by either LY83583 (10 microM) and 1H-[1,2,4]oxadiazolo[4,3,-a]quinoxalin-1-one (ODQ, 10 microM), guanylyl cyclase inhibitors, or charybdotoxin (CTX; 0.1 microM), iberiotoxin (ITX, 0.1 microM) and apamin (APA, 0.1 microM), large conductance Ca2+-activated K+ channels (BK[Ca]) blocker and small conductance Ca2+-activated K+ channel (SK[Ca]) blocker, respectively. 4. In the presence of L-NOARG, relaxation to ACh was unaffected by glibenclamide or the cytochrome P450 mono-oxygenase inhibitor, clotrimazole (1 microM), but was significantly inhibited by either 9-(tetrahydro-2-furanyl)-9H-purin-6-amine (SQ 22,536, 10 microM) and 2',3'-dideoxyadenosine (2',3'-DDA, 30 microM), adenylyl cyclase inhibitors, or 4-AP, DTX, CTX, ITX and APA. 5. In the endothelium-denuded RMCA precontracted with histamine, authentic NO-induced relaxation was unaffected by glibenclamide, 4-AP and DTX, but significantly reduced by ODQ, ITX and APA. Authentic prostaglandin I2 (PGI2)-induced relaxation was unaffected by glibenclamide, but significantly reduced by 2',3'-DDA, 4-AP, DTX, ITX and APA. Forskolin-induced relaxation was significantly inhibited by high K+, CTX and 4-AP. 6. These results indicate that: (1) in the RMCA the EDRFs released by ACh are NO and a prostanoid (presumably PGI2), and there is no evidence for the release of a non-NO/PGI2 endothelium-derived hyperpolarizing factor (EDHF), (2) K(Ca) channels are involved in NO-mediated relaxation of the RMCA but both K(Ca) and Kv channels are involved in PGI2-mediated relaxation.
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PMID:Roles of calcium-activated and voltage-gated delayed rectifier potassium channels in endothelium-dependent vasorelaxation of the rabbit middle cerebral artery. 953 9

The phototransduction mechanism of the extra-ocular photoreceptor cells Ip-2 and Ip-1 in the mollusc Onchidium ganglion was examined. Previous work showed that the depolarizing receptor potential of another extra-ocular photoreceptor cell, A-P-1 is produced by a decrease of the light-sensitive K+ conductance activated by a second messenger, cGMP and is inactivated by the hydrolysis of cGMP. Here, a hyperpolarizing receptor potential of Ip-2 or Ip-1 was associated with an increase in membrane conductance. When Ip-2 or Ip-1 was voltage-clamped near the resting membrane potential, light induced an outward photocurrent corresponding to the above hyperpolarization. The spectral sensitivity had a peak at 510 nm. The shift of reversal potentials of the photocurrent depended on the Nernst equation of K(+)-selective conductance. The photocurrent was blocked by 4-AP and L-DIL, which are effective blockers of the A-P-1 light-sensitive K+ conductance. These results suggested that the hyperpolarization is mediated by increasing a similar light-sensitive K+ conductance to that of A-P-1. The injection of cGMP or Ca2+ into a cell produced a K+ current that mimicked the photocurrent. 4-AP and L-DIL both abolished the cGMP-activated K+ current, while TEA suppressed only the Ca(2+)-activated K+ current. These results indicated that cGMP is also a second messenger that regulates the light-sensitive K+ conductance. The photocurrent was blocked by LY-83583, a guanylate cyclase (GC) inhibitor, but was unaltered by zaprinast, a phosphodiesterase (PDE) inhibitor. Together, the present results suggest that increasing the internal cGMP in Ip-2 or Ip-1 cells light-activates GC rather than inhibits PDE, thereby leading to an increase of the light-sensitive K+ conductance and the hyperpolarization.
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PMID:Light-increased cGMP and K+ conductance in the hyperpolarizing receptor potential of Onchidium extra-ocular photoreceptors. 985 28

Alkalosis-induced relaxation was measured in precontracted arterial rings from 1-wk-old piglets exposed to normoxia or to 3 days of chronic hypoxia. In normoxic piglet arteries, alkalosis-induced relaxation was blunted in arteries without functional endothelium and in arteries treated with nitric oxide synthase or guanylate cyclase inhibitors but not in arteries treated with cyclooxygenase inhibitors or Ca2+- and ATP-dependent K+-channel inhibitors. Inhibition of voltage-dependent K+ channels with 10(-3) M 4-aminopyridine also failed to block alkalosis-induced relaxation. 4-Aminopyridine at 10(-2) M did block the response, but this may have been due to sustained vascular smooth muscle depolarization. Arteries from hypoxic piglets exhibited greater contraction to the thromboxane mimetic U-46619, decreased endothelium-dependent relaxation, and blunted alkalosis-induced relaxation. The residual relaxation was eliminated by nitric oxide synthase but not by cyclooxygenase or voltage-dependent K+-channel inhibition. Alkalosis-induced relaxation of newborn piglet pulmonary arteries appears to be mediated by the nitric oxide-cGMP pathway and is attenuated after 3 days of hypoxia, likely because of decreased nitric oxide activity.
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PMID:Mediators of alkalosis-induced relaxation in pulmonary arteries from normoxic and chronically hypoxic piglets. 988 68

1. Mice lacking the apolipoprotein E and low density lipoprotein receptor genes (E degrees xLDLR degrees ) develop atherosclerosis. The aim of this study was to investigate changes in endothelium-dependent vasodilation and vasomotion in thoracic aortic rings of E degrees xLDLR degrees mice. 2. K+-induced contractions of the aorta from E degrees xLDLR degrees mice were stronger than those from control mice. The sensitivity of E degrees xLDLR degrees aorta to phenylephrine (PE) was decreased but the maximal contractions were increased. Acetylcholine-induced, but not sodium nitroprusside-induced, relaxations of E degrees xLDLR degrees aorta was decreased. 3. PE induced rhythmic activity in both E degrees xLDLR degrees and control aorta but the amplitude was larger in E degrees xLDLR degrees than in control mice. PE-induced rhythmic activity in both E degrees xLDLR degrees and control aorta was augmented by increase in extracellular Ca2+-concentration, but was abolished by removal of the endothelium, the nitric oxide (NO) synthase inhibitor N-nitro-L-arginine methyl ester, the guanylate cyclase inhibitor LY-83583, high K+ solution and ryanodine. 4. 4-Aminopyridine, a voltage-dependent potassium (KV) channel blocker, increased basal tension and induced rhythmic activity in E degrees xLDLR degrees aorta but not in control aorta. 5. The Ca2+-activated potassium (KCa) channel blockers tetraethylammonium and charybdotoxin abolished PE-induced rhythmic activity in E degrees xLDLR degrees aorta. 6. In conclusion, opening of Kv channels in E degrees xLDLR degrees mice aorta is reduced and it is susceptible to be depolarized resulting in Ca2+ entry. The vascular smooth muscle is then dependent on compensatory mechanisms to limit Ca2+-entry. Such mechanisms may be decreased sensitivity to vasoconstrictors, or increased opening of KCa channels by NO via a cyclic GMP-dependent mechanism.
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PMID:Enhanced phenylephrine-induced rhythmic activity in the atherosclerotic mouse aorta via an increase in opening of KCa channels: relation to Kv channels and nitric oxide. 1051 43

We examined some of the mechanisms by which the aspirin metabolite and the naturally occurring metabolite gentisic acid induced relaxation of the guinea pig trachea in vitro. In preparations with or without epithelium and contracted by histamine, gentisic acid caused concentration-dependent and reproducible relaxation, with mean EC(50) values of 18 microM and E(max) of 100% (N = 10) or 20 microM and E(max) of 92% (N = 10), respectively. The relaxation caused by gentisic acid was of slow onset in comparison to that caused by norepinephrine, theophylline or vasoactive intestinal peptide (VIP). The relative rank order of potency was: salbutamol 7.9 > VIP 7.0 > gentisic acid 4.7 > theophylline 3.7. Gentisic acid-induced relaxation was markedly reduced (24 +/- 7.0, 43 +/- 3.9 and 78 +/- 5.6%) in preparations with elevated potassium concentration in the medium (20, 40 or 80 mM, respectively). Tetraethylammonium (100 microM), a nonselective blocker of the potassium channels, partially inhibited the relaxation response to gentisic acid, while 4-AP (10 microM), a blocker of the voltage potassium channel, inhibited gentisic acid-induced relaxation by 41 +/- 12%. Glibenclamide (1 or 3 microM), at a concentration which markedly inhibited the relaxation induced by the opener of ATP-sensitive K(+) channels, levcromakalim, had no effect on the relaxation induced by gentisic acid. Charybdotoxin (0.1 or 0.3 microM), a selective blocker of the large-conductance Ca(2+)-activated K(+) channels, caused rightward shifts (6- and 7-fold) of the gentisic acid concentration-relaxation curve. L-N(G)-nitroarginine (100 microM), a NO synthase inhibitor, had no effect on the relaxant effect of gentisic acid, and caused a slight displacement to the right in the relaxant effect of the gentisic acid curve at 300 microM, while methylene blue (10 or 30 microM) or ODQ (1 microM), the inhibitors of soluble guanylate cyclase, all failed to affect gentisic acid-induced relaxation. D-(P)-Cl-Phe(6),Leu(17)[VIP] (0.1 microM), a VIP receptor antagonist, significantly inhibited (37 +/- 7%) relaxation induced by gentisic acid, whereas CGRP (8-37) (0.1 microM), a CGRP antagonist, only slightly enhanced the action of gentisic acid. Taken together, these results provide functional evidence for the direct activation of voltage and large-conductance Ca(+2)-activated K(+) channels, or indirect modulation of potassium channels induced by VIP receptors and accounts for the predominant relaxation response caused by gentisic acid in the guinea pig trachea.
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PMID:The mechanism of gentisic acid-induced relaxation of the guinea pig isolated trachea: the role of potassium channels and vasoactive intestinal peptide receptors. 1126 90

The purpose of this study was to determine the effects of sodium nitroprusside (SNP), 2,2'-(hydroxynitrosohydrazino)bis-ethanamine (DETA/NO) and 3-morpholinosydnonimine (SIN-1), NO donors which yield different NO reactive species (NO+, NO* and peroxynitrite, respectively), as well as exogenous peroxynitrite, on gall bladder contractility. Under resting tone conditions, SNP induced a dose-dependent contraction with a maximal effect (10.3 +/- 0.7 mN, S.E.M.) at 1 mM. Consistent with these findings, SNP caused a concentration-dependent depolarization of gall bladder smooth muscle. The excitatory effects of SNP were dependent on extracellular calcium entry through L-type Ca2+ channels. Furthermore, the contraction and depolarization were sensitive to tyrosine kinase blockade, and an associated increase in tyrosine phosphorylation was detected in Western blot studies. DETA/NO induced dose-dependent relaxing effects. These relaxations were sensitive to the guanylyl cyclase inhibitor 1H-[1,2,4]oxidiazolo[4,3-a]quinoxaline-1-one (ODQ, 2 microM) but they were not altered by treatment with the potassium channel blockers tetraethylammoniun (TEA, 5 mM) and 4-aminopyridine (4-AP, 5 mM). When tested in a reducing environment (created by 2.5 mM 1,4-dithiothreitol, DTT), SNP caused a relaxation of gall bladder muscle strips. Similarly, the SNP-induced contraction was converted to a relaxation, and associated hyperpolarization, when DTT was added during the steady state of an SNP-induced response. SIN-1 (0.1 mM), which has been shown to release peroxynitrite, induced relaxing effects that were enhanced by superoxide dismutase (SOD, 50 U ml(-1)). The relaxations induced by either SIN-1 alone or SIN-1 in the presence of SOD were strengthened by catalase (1000 U ml(-1)) and abolished by ODQ pretreatment. However, exogenous peroxynitrite induced a concentration-dependent contraction, which was dependent on activation of leukotriene (LT) metabolism and extracellular calcium. The peroxynitrite-induced contraction was abolished in the presence of the peroxynitrite scavenger melatonin. These results suggest that SIN-1 behaves as an NO* rather than a peroxynitrite source. We conclude that, depending on the redox state, NO has opposing effects on the motility of the gall bladder, being a relaxing agent when in NO * form and a contracting agent when in NO+ or peroxynitrite redox species form. Knowledge of the contrasting effects of the different redox forms of NO can clarify our understanding of the effects of NO donors on gall bladder and other smooth muscle cell types.
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PMID:A redox-based mechanism for the contractile and relaxing effects of NO in the guinea-pig gall bladder. 1131 47

1. In phenylephrine (PHE) (1 micro M)-precontracted superior mesenteric arteries from adult rats, low concentration of hydrogen peroxide (H(2)O(2), 10-100 micro M) caused only contraction, while high concentration of H(2)O(2) (0.3-1 mM) caused a biphasic response: a transient contraction followed by a relaxation response. 2. Endothelium removal did not affect the biphasic response. 7,7-Dimethyl-(5Z,8Z)-eicosadienoic acid, diclofenac, furegrelate, or SQ 29548 greatly inhibited the contraction but did not affect the relaxation. 17-Octadecynoic acid, eicosatriynoic acid, ICI 198615, SQ 22536, or ODQ did not inhibit the biphasic response. 3. KCl at 40 mM inhibited the relaxation response to H(2)O(2) by 98+/-24%. 4-Aminopyridine (4-AP) inhibited while tetraethylammonium chloride (TEA), charybdotoxin, or glibenclamide attenuated the relaxation response. A combination of 4-AP, TEA and glibenclamide mimicked the effects of 40 mM KCl. Iberiotoxin, apamin, or barium chloride did not inhibit the relaxation response. 4. H(2)O(2) at 1 mM hyperpolarized membrane potential and reversibly augmented K(+) current in smooth muscle cells of mesenteric artery. These effects of H(2)O(2) were attenuated significantly by 4-AP. 5. In summary, in PHE-precontracted rat mesenteric artery: (1) the response to H(2)O(2) shifted qualitatively from contraction to a biphasic response as H(2)O(2) increased to 0.3 mM or higher; (2) the relaxation response is caused by the activation of K(+) channels, with voltage-dependent K(+) channels playing a primary role; and the contraction is likely to be mediated by thromboxane A(2); (3) the K(+) channel activation by H(2)O(2) is independent of phospholipase A(2), cyclooxygenase, lipoxygenase, cytochrome P450 monooxygenase, adenylate or guanylate cyclase.
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PMID:Mechanisms of hydrogen-peroxide-induced biphasic response in rat mesenteric artery. 1268 64

The effects induced by nitric oxide (NO) in different tissues depend on direct and/or indirect interactions with K+ channels. The indirect interaction of NO is produced by activation of guanylyl cyclase which increases the intracellular cGMP. Since NO, cGMP and 4-aminopyridine alone induce tetanic fade and increase amplitude of muscular contractions in isolated rat neuromuscular preparations, the present study was undertaken to determine whether or not the neuromuscular effects of NO and 8-Br-cGMP can be modified by 4-aminopyridine. Using the phrenic nerve and diaphragm muscle isolated from male Wistar rats (200-250 g), we observed that L-arginine (4.7 mM) and 8-Br-cGMP (18 M), in contrast to D-arginine, induced an increase in the amplitude of muscle contraction (10.5 0.7%, N = 10 and 8.0 0.7%, N = 10) and tetanic fade (15 2.0%, N = 8 and 11.6 1.7%, N = 8) at 0.2 and 50 Hz, respectively. N G-nitro-L-arginine (4 mM, N = 8 and 8 mM, N = 8) antagonized the effects of L-arginine. 4-Aminopyridine (1 and 10 M) caused a dose-dependent increase in the amplitude of muscle contraction (15 1.8%, N = 9 and 40 3.1%, N = 10) and tetanic fade (17.7 3.3%, N = 8 and 37.4 1.3%, N = 8). 4-Aminopyridine (1 M, N = 8) did not cause any change in muscle contraction amplitude or tetanic fade of preparations previously paralyzed with d-tubocurarine or stimulated directly. The effects induced by 4-aminopyridine alone were similar to those observed when the drug was administered in combination with L-arginine or 8-Br-cGMP. The data suggest that the blockage of K+ channels produced by 4-aminopyridine inhibits the neuromuscular effects induced by NO and 8-Br-cGMP. Therefore, the presynaptic effects induced by NO seem to depend on indirect interactions with K+ channels.
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PMID:4-Aminopyridine inhibits the neuromuscular effects of nitric oxide and 8-Br-cGMP. 1284 82


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