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)

1. The aim of this investigation was to study the relationship between contractile responsiveness, activation of the L-arginine pathway and tissue levels of guanosine 3':5'cyclic monophosphate (cylic GMP) in aortic rings removed from rats 4 h after intraperitoneal administration of bacterial endotoxin (E. coli. lipopolysaccharide, LPS, 20 mg kg-1). 2. LPS-treatment resulted in a reduction of the sensitivity and maximal contractile response to noradrenaline (NA). 3. Depression of the maximal contractile response was restored to control by 6-anilo-5,8-quinolinedione (LY 83583, 10 microM), which prevents activation of soluble guanylate cyclase. 4. Cyclic GMP levels in tissue from LPS-treated rats were 2 fold greater than cyclic GMP levels detected in tissue from control (saline-treated) rats. The LPS-induced increase in cyclic GMP content was observed both in the presence and absence of functional endothelium. 5. Addition of L-arginine 1 mM) to maximally contracted aortic rings produced significantly relaxation of rings from LPS-treated rats but not rings from control animals. In the LPS-treated group, addition of L-arginine was also associated with a significant increase in cyclic GMP content. L-Arginine had no effect on the cyclic GMP content of control rings. D-Arginine (1 mM) was without effect. 6. In rings from LPS-treated rats, NG-nitro-L-arginine methyl ester (L-NAME, 300 microM), an inhibitor of nitric oxide (NO) production, increased the contractile response to NA and prevented the LPS-induced increase in cyclic GMP content. In control rings, L-NAME increased the NA sensitivity only when the endothelium remained intact and reduced the cyclic GMP content of these rings to that of control endothelium-denuded rings. 7. These results demonstrate that LPS-induced hyporeactivity to NA occurs secondarily to activation of the L-arginine pathway and subsequent activation of soluble guanylate cyclase in vascular tissue. In addition they suggest that LPS induces the production of an NO-like relaxing factor in non-endothelial cells.
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PMID:Evidence that an L-arginine/nitric oxide dependent elevation of tissue cyclic GMP content is involved in depression of vascular reactivity by endotoxin. 167 81

We studied the biological activity, stability and interaction of dinitrosyl-iron(II)-L-cysteine with vascular tissue. Dinitrosyl-iron(II)-L-cysteine was a potent activator of purified soluble guanylyl cyclase (EC50 10 nM with and 100 nM without superoxide dismutase) and relaxed noradrenaline-precontracted segments of endothelium-denuded rabbit femoral artery (EC50 10 nM superoxide dismutase). Pre-incubation (5 min; 310 K) of endothelium-denuded rabbit aortic segments with dinitrosyl-iron(II)-L-cysteine (0.036-3.6 mM) resulted in a concentration-dependent formation of a dinitrosyl-iron(II) complex with protein thiol groups, as detected by ESR spectroscopy. While the complex with proteins was stable for 2 h at 310 K, dinitrosyl-iron(II)-L-cysteine in aqueous solution (36-360 microM) decomposed completely within 15 min, as indicated by disappearance of its isotropic ESR signal at gav = 2.03 (293 K). Aortic segments pre-incubated with dinitrosyl-iron(II)-L-cysteine released a labile vasodilating and guanylyl cyclase activating factor. Perfusion of these segments with N-acetyl-L-cysteine resulted in the generation of a low molecular weight dinitrosyl-iron(II)-dithiolate from the dinitrosyl-iron(II) complex with proteins, as revealed by the shape change of the ESR signal at 293 K. The low molecular weight dinitrosyl-iron(II)-dithiolate accounted for an enhanced guanylyl cyclase activation and vasodilation induced by the aortic effluent. We conclude that nitric oxide (NO) produced by, or acting on vascular cells can be stabilized and stored as a dinitrosyl-iron(II) complex with protein thiols, and can be released from cells in the form of a low molecular weight dinitrosyl-iron(II)-dithiolate by intra- and extracellular thiols.
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PMID:The potent vasodilating and guanylyl cyclase activating dinitrosyl-iron(II) complex is stored in a protein-bound form in vascular tissue and is released by thiols. 168 53

1. Perfusion of the kidney with methylene blue, a soluble guanylate cyclase inhibitor, significantly enhanced the vasoconstrictor effects of angiotensin II, noradrenaline and phenylephrine but significantly reduced the vasodilator effect of acetylcholine without altering that of iloprost. 2. In the kidneys, which were perfused with Triton X-100 to remove endothelium, acetylcholine-induced vasodilation was completely abolished and angiotensin II-, noradrenaline- and phenylephrine-induced vasoconstriction was greatly reduced. 3. The vasodilator effect of iloprost was unchanged after perfusion of kidney with Triton X-100. 4. Neither methylene blue nor Triton X-100 significantly altered urine volume form normal and angiotensin II induced increase of urine volume. 5. These results were taken as evidence for the involvement of renal vascular endothelium originated EDRF in the responses of various vasoactive agents in the rabbit isolated perfused kidney.
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PMID:Possible involvement of endothelium in the responses of various vasoactive agents in rabbit isolated perfused kidney. 169 98

We investigated the mechanisms by which cytokines lead to a diminished responsiveness of vascular smooth muscle to vasoconstrictors. The attenuation of noradrenaline-induced contraction by 6 to 24 h incubations with the cytokines, tumor necrosis factor and interleukin-1, in endothelium-denuded rabbit aorta was associated with an increase in intracellular cyclic GMP level. This increase was abolished by the stereoselective inhibitor of nitric oxide-synthase, NG-nitro-L-arginine and by cycloheximide. Formation of nitric oxide was detected in the cytosol of cytokine-treated native and cultured smooth muscle cells by activation of purified soluble guanylate cyclase, and depended on tetrahydrobiopterin, but not on Ca2(+)-calmodulin. The results indicate that cytokines induce a nitric oxide-synthase of the macrophage-type in vascular smooth muscle.
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PMID:Induction of nitric oxide synthase by cytokines in vascular smooth muscle cells. 170 67

The effects of exogenous guanosine 5'-triphosphate (GTP) and guanosine on nitroglycerin-, sodium nitrite- and SIN-1-induced guanosine 3',5'-cyclic monophosphate (cyclic GMP) accumulation and smooth muscle relaxation were studied using endothelium-denuded rat mesenteric artery rings precontracted with noradrenaline. Preincubation of contracted artery rings with GTP (100 microM) or guanosine (100 microM) before eliciting relaxations with nitrovasodilators significantly shifted the dose-response curves of nitrocompounds to the left and augmented the increases in cyclic GMP. GTP and guanosine alone also induced cyclic GMP accumulation in pre-contracted artery rings. These effects of GTP and guanosine on nitrovasodilator responses were not related to the preincubation period (0-30 min). The present results raise the possibility of a cell membrane site of action for GTP and guanosine, which mediates the activation of soluble guanylate cyclase and leads to increased nitrovasodilator-induced cyclic GMP accumulation and arterial smooth muscle relaxation.
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PMID:Modification of nitrovasodilator effects on vascular smooth muscle by exogenous GTP and guanosine. 172

Norepinephrine-induced responses in isolated perfused mesenteric vascular bed from normotensive and renovascular hypertensive rats were examined in the presence of adenosine diphosphate (ADP, 2 x 10(-6) M). Responses to norepinephrine were significantly greater in vessels from hypertensive rats. Norepinephrine-induced contractions increased after the removal of endothelium. N omega-Nitro-L-arginine (L-NOARG), a potent inhibitor of nitric oxide formation, similarly increased contractions. The greatest responses were obtained, however, after treatment of the vascular segments with methylene blue. The presence of ADP caused significant endothelium-dependent decreases in contractions. Although decreases caused by ADP in vessels with endothelium after treatment with L-NOARG were not statistically significant, a tendency to decreased responses seems to suggest that L-NOARG diminishes but does not completely prevent the effect of ADP in mesenteric vessels. Methylene blue partially reduced the endothelium-dependent ADP-induced relaxant effects in sham-operated nephrectomized rats. A tendency to increased contractions to norepinephrine was observed in the presence of ADP after removal of endothelium. Thus, in the mesenteric resistance arteries of the rat under stimulation by ADP, it appears that nitric oxide released from L-arginine and the activity of soluble guanylate cyclase account only in part for the endothelium-dependent decreased responses to norepinephrine. When nitric oxide formation or soluble guanylate cyclase activity are depressed simultaneously with endothelium damage, ADP released from platelets or red blood cells may be an important factor that acts synergically with vasoconstrictor stimuli.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Endothelium-dependent and endothelium-independent effects of adenosine diphosphate in renovascular hypertension. 173 85

1. When the web of the anaesthetized Xenopus laevis was perfused with Ringer solution maintained at 20 degrees C, radio frequency (RF) burst-type electromagnetic (EM) field radiation not only dilated arterioles of the web which had been preconstricted with noradrenaline, but also dilated arterioles under non-stimulated conditions. The EM field-induced vasodilatation increased slowly and reached a plateau 60 min after the onset of radiation. After the cessation of radiation, vasodilatation remained for 10-20 min, then slowly subsided. 2. When a 10 MHz, 1 V (peak to peak) generator voltage induced a 7.3 milliGauss, 2.19 V cm-1 EM field, the vasodilatory effect was optimum when bursts were applied 50% of the total time at 10 kHz burst rate. 3. The vasodilatory effect was not secondary to dielectric heat in the web, because the EM field was too weak to have produced enough heat to dilate the arterioles and heat would have been constantly conducted away by the perfusion solution. 4. During perfusion with Ringer solution warmed to 30 degrees C, no vasodilatation was found, but perfusion with Ringer solution warmed to 35 degrees C induced only 11% vasodilatation. Perfusion with Ringer solution warmed to 37 degrees C induced irreversible vasoconstriction. The pattern of vasodilatation induced by warm Ringer solution was different from the vasodilatory effect of weak EM field radiation. 5. The extent of the vasodilatory effect was influenced by Ca2+ concentration of the perfusion medium. Under normal Ca2+ conditions arterioles dilated to 126% of the control diameter, while under Ca(2+)-free conditions arterioles dilated to 131% of the control value and under high-Ca2+ conditions (twice the normal level) arterioles dilated to 111% of the control value. This suggests that the vasodilatory effect may be caused by facilitation of Ca2+ outflow, and the extent of this flow may settle down to the equilibrium level of countercurrent flux between Ca2+ influx and outflow. 6. The vasodilatory effect was not inhibited under perfusion with Na(+)-free Ringer solution, suggesting that Na(+)-Ca2+ exchange system may not be involved in the vasodilatory effect. The vasodilatory effect was inhibited by vanadate, an inhibitor of Ca(2+)-ATPase, and was abolished by Methylene Blue, an inhibitor of guanylate cyclase. The evidence suggests that the mechanism of the vasodilatory effect may depend on an increase in Ca2+ outflow through the plasma membrane of the smooth muscle and/or an increase in Ca2+ influx into the sarcoplasmic reticulum.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Non-thermal vasodilatation by radio frequency burst-type electromagnetic field radiation in the frog. 177 Apr 39

Left kidneys obtained from male Wistar rats were perfused with Tyrode solution; the perfusion pressure was measured continuously and taken as an index of vascular resistance in the kidneys. 5-Hydroxytryptamine (5-HT; 3-50 nmol) caused dose-dependent dilator responses in kidneys preconstricted with noradrenaline (0.6 microM) and pretreated with ritanserin (10 nM) and ICS 205930 (10 nM). The 5-HT1 agonist 5-carboxamidotryptamine (5-CT; 16-64 nmol) also caused renal dilatations under similar conditions. The dilator responses to both 5-HT and 5-CT were antagonized by the non-selective 5-HT receptor antagonist metergoline (0.2 microM) and by the selective 5-HT1A receptor antagonist BMY 7378 (0.4 microM). The guanylate cyclase inhibitor methylene blue (30 microM) and the nitric oxide (NO) synthase inhibitor nitro-L-arginine (L-NNA; 100 microM) significantly attenuated the dilator responses to 5-HT and 5-CT. The 5-HT1A agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT; 0.5-16 nmol) also caused dose-dependent dilator responses in preconstricted rat kidneys. These responses were antagonized by metergoline and BMY 7378 and significantly attenuated by the NO inhibitors hemoglobin (10 microM) and L-NNA. The renal dilator responses noted with the beta-adrenoceptor blocker tertatolol (1-32 nmol) were also antagonized by metergoline and BMY 7378 and significantly reduced by L-NNA and hemoglobin. Both 8-OH-DPAT and tertatolol (1-30 microM) significantly reduced the vasoconstrictor responses to angiotensin II (20 pmol). Our data indicate that 5-HT receptors located on the vascular endothelium of the renal circulation are involved in the dilator actions of 5-HT, 5-CT, 8-OH-DPAT and tertatolol, and suggest that these receptors resemble the 5-HT1A subtype.
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PMID:5-Hydroxytryptamine-induced vasodilatation in the isolated perfused rat kidney: are endothelial 5-HT1A receptors involved? 183 83

1. The mechanism by which neuropeptide Y (NPY) potentiates the vasoconstriction induced by alpha 1-adrenoceptor agonists was investigated in 3rd generation mesenteric arterioles of the rat. 2. At a maximally active concentration, nitrendipine (10(-6) M) displaced to the right the concentration-response curves to noradrenaline (pD2 decreased from 6.2 +/- 0.06 to 5.7 +/- 0.03) and phenylephrine (pD2 decreased from 5.6 +/- 0.03 to 5.3 +/- 0.03). Diltiazem (10(-5) M) also shifted to the right the concentration-response curve to phenylephrine (pD2 decreased from 6.0 +/- 0.06 to 5.5 +/- 0.04). In addition, the maximal response to phenylephrine was significantly decreased in the presence of either nitrendipine or diltiazem. 3. In the absence of a calcium channel blocking agent, NPY (100 nM) produced a leftward shift of the concentration-response curves to noradrenaline (pD2 increased from 6.2 +/- 0.06 to 6.5 +/- 0.05) and phenylephrine (pD2 increased from 5.6 +/- 0.03 to 6.0 +/- 0.06 and from 6.0 +/- 0.06 to 6.3 +/- 0.11). In the presence of either nitrendipine (10(-6) M) or diltiazem (10(-5) M), NPY (100 nM) did not alter the concentration-response curves to either noradrenaline or phenylephrine. 4. NPY was added to arterioles brought to the same level of tension (40% of the maximal contraction) either by phenylephrine alone (1.5 x 10(-6) M) or by a higher concentration of phenylephrine (3 x 10(-6) M) followed by the addition of prazosin (1.3 x 10(-9) M; a concentration at which it partially blocks alpha 1-adrenoceptors). In these conditions, the response to phenylephrine was completely abolished by nitrendipine (10-6 M) or by diltiazem (10-5M). Furthermore, NPY (10-1" to 10-7M) increased the arteriolar tension up to the maximal contractile capacity of the vessels with pD2 values of 8.6 + 0.02 and 8.7 + 0.01, in the absence and presence of prazosin, respectively. 5. Prazosin was replaced in the above protocol by other vasodilator agents acting through different mechanisms. Whether in the presence of 2 x 10-7M forskolin, 6 x 10-7M sodium nitroprusside (which stimulate adenylate cyclase or guanylate cyclase, respectively) or 2 x 10- 7M diltiazem (a concentration at which calcium entry is partially blocked), NPY enhanced phenylephrine-induced contraction to the maximum level with an identical potency (pD2 values of the peptide ranged from 8.3 to 8.7). 6. The results show that, in rat mesenteric arterioles, NPY potentiates only the calcium entry blockersensitive component of contraction induced by stimulation of alpha,-adrenoceptors. In addition, they provide evidence that the peptide counteracts with an equal potency the inhibitory effect of partial block of alpha,-adrenoceptors and of relaxing agents acting through different mechanisms. It is suggested that NPY enhances calcium entry induced by stimulation of alpha l-adrenoceptors in this tissue.
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PMID:Enhancement by neuropeptide Y (NPY) of the dihydropyridine-sensitive component of the response to alpha 1-adrenoceptor stimulation in rat isolated mesenteric arterioles. 197 Feb 70

In ring sections of the sheep middle cerebral artery, electrical field stimulation elicits a complex response due to the simultaneous release of vasodilator and vasoconstrictor neurotransmitters. Haemolysate abolishes the relaxant effects of the vasodilator neurotransmitter and causes a marked augmentation of the contractile response in both the presence (448 +/- 191%) and absence (409 +/- 134%) of an intact endothelium. The haemolysate also reverses relaxation induced by sodium nitroprusside or sodium nitrite but has no effect on relaxation induced by 8-Br-cGMP. The vasodilator neurotransmitter therefore appears to act directly on the smooth muscle to cause relaxation by the stimulation of guanylate cyclase. The vasoconstrictor neurotransmitters that are released are antagonised by prazosin (100 nM), ketanserin (100 nM) and atropine (100 nM), which suggests that the transmitters involved are noradrenaline, 5-hydroxytryptamine (5-HT), and acetylcholine, respectively. In the presence of these three antagonists at 10 microM, there was 86.9 +/- 4.8% inhibition. Incubation with 5-HT (10 microM) causes a marked augmentation of the contractile response (267 +/- 56%) to field stimulation that can be reduced by pretreatment with either desipramine or citalopram, inhibitors of noradrenergic and serotoninergic uptake mechanisms, respectively. The 5-HT appears to be taken up into noradrenergic nerves and released as an alternative neurotransmitter upon subsequent stimulation. These actions of haemolysate and 5-HT may be involved in the cerebral vasospasm observed following subarachnoid haemorrhage.
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PMID:Neurotransmission in the sheep middle cerebral artery: modulation of responses by 5-HT and haemolysate. 197 Mar 42


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