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. Impaired endothelium-dependent relaxation has been previously demonstrated in blood vessels of hypertensive rats and in humans with essential hypertension. Arteries from spontaneously hypertensive rats have been shown to produce, in response to high concentrations of acetylcholine, a vasoconstrictor substance called endothelium-derived contracting factor, the production of which can be inhibited by indomethacin or other cyclo-oxygenase inhibitors, suggesting that it is a prostanoid. The mechanisms involved in endothelium-dependent relaxation of human arteries are unclear, and the potential generation of endothelium-derived contracting factor by endothelium in human hypertension has not been established. 2. We investigated the effects of acetylcholine on precontracted small arteries dissected from gluteal subcutaneous fat biopsies from normotensive subjects and subjects with borderline and mild essential hypertension. Vessels from normotensive subjects and those from borderline hypertensive patients, precontracted by noradrenaline, were relaxed completely by acetylcholine, whereas those from patients with mild essential hypertension relaxed slightly but significantly less, indicating that generation of endothelium-derived relaxing factor (endothelium-derived nitric oxide) was only minimally reduced or that production of minor amounts of endothelium-derived contracting factor occurred in small arteries from these hypertensive subjects. This impairment of endothelium-dependent relaxation was not corrected by indomethacin, which indicated that the contribution of endothelium-derived contracting factor, if any, was minimal in this subset of essential hypertensive patients. In contrast, mesenteric small arteries of adult spontaneously hypertensive rats presented strong contractions in response to the higher concentrations of acetylcholine, which were abolished by exposure to indomethacin. 3. The relaxation induced by acetylcholine in arteries from both hypertensive and normotensive humans was partially blunted (by 30%) by pretreatment with 0.1 mmol/l NG-nitro-L-arginine methyl ester or NG-nitro-monomethyl-L-arginine (inhibitors of nitric oxide synthase) and by 10 mumol/l Methylene Blue (a blocker of soluble guanylate cyclase), indicating the role of endothelium-derived nitric oxide and the generation of its intracellular second messenger cyclic guanosine monophosphate in acetylcholine-induced relaxation. The remaining relaxation elicited by acetylcholine could be blocked with 30 mmol/l KCl or with 10 mumol/l ouabain (inhibitor of Na+, K(+)-ATPase), and, when combined with NG-nitro-L-arginine methyl ester, these interventions abolished acetylcholine-induced relaxation. Tolbutamide at 2 mmol/l or 10 mumol/l glyburide (blockers of ATP-sensitive potassium channels) partially inhibited NG-nitro-L-arginine methyl ester-resistant endothelium-dependent relaxation.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Endothelium-dependent relaxation of small arteries from essential hypertensive patients: mechanisms and comparison with normotensive subjects and with responses of vessels from spontaneously hypertensive rats. 754 95

Increasing evidence points to an important role for nitric oxide in the regulation of pulmonary functions and in pulmonary disease. In the respiratory tract, sensory nerves, endothelial cells, vascular and airway smooth muscle cells, inflammatory cells and the airway epithelium are sources of nitric oxide. Different nitric oxide synthases have been isolated, cloned and sequenced. Functionally, there are constitutive and inducible forms of nitric oxide synthase. A number of cytokines have been shown to inhibit or induce the expression of the inducible nitric oxide synthase. In human airways, endogenous nitric oxide appears to account for the bronchodilator nonadrenergic and noncholinergic response. Nitric oxide-containing vasodilators, such as glyceryl trinitrate and sodium nitroprusside, induce relaxation of the isolated airway smooth muscle, activate guanylate cyclase and raise c-GMP levels. Nitric oxide (constitutive), produced by the epithelial layer, appears to be important in blunting the histamine contractile response of the airway tissue. Furthermore, tracheal relaxation by, e.g., bradykinin or potassium chloride, is mediated by the release of nitric oxide. The virus (Parainfluenza type 3)-induced airway hyperreactivity in guinea-pigs is correlated with a deficiency in endogenous constitutive nitric oxide production by the airways and can be blocked by low doses of L-arginine. In inflamed tissue, nitric oxide quickly reacts with superoxide anion, resulting in the formation of the toxic peroxynitrite which promotes lipid and sulfhydryl oxidation. Asthmatic patients have higher amounts of nitric oxide in the expired air, possibly due to the inflammation. This increased nitric oxide production can be inhibited by inhaled corticosteroids. The effect of inhaled nitric oxide on the lung function of asthmatic patients is variable. In contrast, low doses of inhaled nitric oxide are effective in reversing the pulmonary vasoconstriction. These results point to an important role for nitric oxide in modulating airway reactivity.
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PMID:Nitric oxide and bronchial hyperresponsiveness. 763 22

The potassium-channel openers comprise a large number of molecules that can be classified into three basic groups: (1) agents like levcromakalim that open a small-conductance (10-30 pS) glibenclamide-sensitive K+ channel currently known as the ATP-sensitive K+ channel, KATP; (2) hybrid molecules, such as nicorandil, that open KATP channels and that also activate the enzyme-soluble guanylate cyclase; (3) molecules like dehydrosaponin 1 that open the large-conductance (100-150 pS) calcium-dependent K+ channel, BKCa. K(+)-channel openers in groups 1 and 2 are most potent on smooth muscle, but KATP channels in cardiac muscle, neurones and the pancreatic beta cell are also affected. In vivo, moderate to high doses produce a fall in diastolic pressure with reflex tachycardia; low doses may exert selective dilator effects on specific vascular beds with little effect on systemic pressure. In vitro, all smooth muscles are relaxed with loss of spontaneous electric and mechanical activity; hyperpolarization to the region of EK is often observed. These effects can be antagonized by glibenclamide and also by imidazolines and guanidines, such as phentolamine, guanethidine, and antazoline, agents that also inhibit the smooth muscle delayed rectifier channel, KV. The mode and site of action of the group 1 and 2 K(+)-channel openers is the subject of intense study. Irrespective of their specific mode of action, the K(+)-channel openers, especially the hybrid molecules such as nicorandil, constitute a novel and promising approach to the treatment of cardiovascular disease.
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PMID:Pharmacology of the potassium channel openers. 764 22

Natriuretic peptides inhibit the release and action of many hormones through cyclic guanosine monophosphate (cGMP), but the mechanism of cGMP action is unclear. In frog ventricular muscle and guinea-pig hippocampal neurons, cGMP inhibits voltage-activated Ca2+ currents by stimulating phosphodiesterase activity and reducing intracellular cyclic AMP; however, this mechanism is not involved in the action of cGMP on other channels or on Ca2+ channels in other cells. Natriuretic peptide receptors in the rat pituitary also stimulate guanylyl cyclase activity but inhibit secretion by increasing membrane conductance to potassium. In an electrophysiological study on rat pituitary tumour cells, we identified the large-conductance, calcium- and voltage-activated potassium channels (BK) as the primary target of another inhibitory neuropeptide, somatostatin. Here we report that atrial natriuretic peptide also stimulates BK channel activity in GH4C1 cells through protein dephosphorylation. Unlike somatostatin, however, the effect of atrial natriuretic peptide on BK channel activity is preceded by a rapid and potent stimulation of cGMP production and requires cGMP-dependent protein kinase activity. Protein phosphatase activation by cGMP-dependent kinase could explain the inhibitory effects of natriuretic peptides on electrical excitability and the antagonism of cGMP and cAMP in many systems.
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PMID:Potassium channel stimulation by natriuretic peptides through cGMP-dependent dephosphorylation. 767 99

1. The effect of nitric oxide on the efficacy of synaptic transmission in the chick ciliary ganglion of post-hatched birds has been determined by use of the size of the postganglionic compound action potential resulting from chemical transmission through the ganglion as a measure of synaptic efficacy. 2. Sodium nitroprusside (100 microM) increased the synaptic efficacy by an average 26%. This is likely to be due to its ability to release nitric oxide, as potassium ferricyanide (100 microM) did not cause a potentiation. Sodium azide (100 microM), shown in sympathetic ganglia to stimulate production of cyclic GMP, did not modulate synaptic efficacy significantly. 3. 8-Br-cyclic-GMP (100 microM) increased synaptic efficacy by an average 61%. The addition of 8-Br-cyclic-AMP (100 microM) had less effect, increasing transmission by on average 46%. 4. The nitric oxide synthase blocker, NG-nitro-L-arginine methyl ester (L-NAME, 100 microM) was added prior to the tetanic stimulation of the preganglionic nerves at 30 Hz for 20 s, a procedure known to produce both post-tetanic potentiation and long-term potentiation of synaptic transmission through the ganglion. L-NAME reduced the long-term potentiation by an average of 47% but did not significantly change the post-tetanic potentiation. 5. Following the brief application of 8-Br-cyclic AMP, 8-Br-cyclic GMP and sodium nitroprusside there was an enhancement of the efficacy of synaptic transmission that persisted after the withdrawal of the drugs. The maximum increase in synaptic efficacy following the brief addition of 8-Br-cyclic GMP was 116%, sodium nitroprusside was 110% and 8-Br-cyclic AMP was 126%.6. These results suggest that nitric oxide modulates synaptic transmission through the ganglion by acting on an endogenous guanylate cyclase that produces cyclic GMP.
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PMID:The effect of nitric oxide on the efficacy of synaptic transmission through the chick ciliary ganglion. 769 54

The effects of sodium nitroprusside (SNP) on dopamine synthesis in a porcine renal epithelial cell line (LLC-PK1) were evaluated. Subsequent studies examined the actions of the degradation products of SNP (cyanide, ferrous ion and nitric oxide) on aromatic amino acid decarboxylase (AAAD) activity in tissue supernatants from LLC-PK1 cells and rat renal cortex. SNP (10-500 mumol/l) significantly inhibited dopamine production in LLC-PK1 cells in a dose-related manner. The activation of guanylate cyclase by nitric oxide was not found to be the mechanism whereby SNP inhibited dopamine synthesis in LLC-PK1 nor did the antioxidant glutathione attenuate the actions of SNP. Ferrous sulfate (0.5 mmol/l) and SNP (0.5 mmol/l) were found to inhibit dopamine synthesis in LLC-PK1 cells and to directly inhibit cytosolic AAAD activity from LLC-PK1 cells. A series of studies were conducted using AAAD from rat renal cortex and confirmed that SNP could directly inhibit the conversion of L-dopa to dopamine by AAAD. Furthermore, potassium ferricyanide (1 mmol/l) and potassium cyanide (1 mmol/l) could produce greater than 80% reductions in AAAD activity. Iron (0.5-1 mmol/l) was found to increase rat kidney AAAD activity. Kinetic analysis revealed that potassium cyanide was a potent (Ki = 40-50 mumol/l) noncompetitive/mixed noncompetitive inhibitor of AAAD. SNP was also found to be a noncompetitive inhibitor of AAAD with a Ki of approximately 300-500 mumol/l. In contrast, ferrous sulfate (0.5 mmol/l) was a competitive inhibitor (Ki = approximately 650 mumol/l) that actually increased the Vmax of AAAD. The results of these studies support that cyanide released from SNP can potently inhibit AAAD, although SNP has somewhat more complex interactions with AAAD due to the presence of ferrous ion.
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PMID:Mechanism of sodium nitroprusside-mediated inhibition of aromatic amino acid decarboxylase activity. 771 78

The role of Ca(2+)-dependent potassium channels in mediating vascular responses to activation of adenylate cyclase in vivo is not known. The goal of this study was to examine the hypothesis that dilatation of cerebral arterioles in response to activation of adenylate cyclase is mediated by activation of Ca(2+)-dependent potassium channels. Diameters of cerebral arterioles were measured in vivo in anesthetized rabbits. Topical application of forskolin (1 and 10 mumol/L), a direct activator of adenylate cyclase, dilated cerebral arterioles by 40 +/- 8% (mean +/- SEM) and 71 +/- 9%, respectively, from a control diameter of 85 +/- 4 microns. Iberiotoxin (50 and 100 nmol/L), a selective inhibitor of Ca(2+)-dependent potassium channels, inhibited dilatation in response to both concentrations of forskolin by 45% to 60%. We obtained similar results by using charybdotoxin (50 nmol/L), another inhibitor of Ca(2+)-dependent potassium channels. Vasodilatation in response to dibutyryl cAMP (a cell-permeable cAMP analogue) was also inhibited by iberiotoxin. In contrast, dilatation of cerebral arterioles in response to sodium nitroprusside and acetylcholine (activators of guanylate cyclase) and aprikalim (activator of ATP-sensitive potassium channels) was not inhibited by iberiotoxin. These findings suggest that dilatation of cerebral arterioles in response to forskolin and increases in intracellular concentrations of cAMP are mediated by activation of Ca(2+)-dependent potassium channels. Thus, activation of Ca(2+)-dependent potassium channels may be a major mechanism of cerebral vasodilatation in response to activation of adenylate cyclase in vivo.
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PMID:Dilatation of cerebral arterioles in response to activation of adenylate cyclase is dependent on activation of Ca(2+)-dependent K+ channels. 775 60

The ionic mechanisms by which nitric oxide (NO) or a related compound mediates the inhibitory junction potentials (IJPs) of the opossum esophageal circular smooth muscle were studied using microelectrodes and double sucrose gap. The NO donors, 3-morpholino-sydnonimine hydrochloride and sodium nitroprusside, induced 15- to 20-mV hyperpolarizations that reversed near the potassium equilibrium potential as did the IJPs. They inhibited the IJPs and decreased electrotonic potentials (increased conductance) even during restoration of the resting membrane potential by application of depolarizing current. Quinine was more efficacious than apamin in inhibiting the IJPs or NO donor hyperpolarizations, whereas the other K+ channel blockers tested (tetraethylammonium, charybdotoxin, 4-aminopyridine, Cs+, and glibenclamide) were without effect. Glibenclamide abolished the hyperpolarizing effects of the K+ channel opener BRL-34915. Low Cl- Krebs (isethionate substitutions) caused hyperpolarizations, increased electrotonic potentials, and reduced IJPs. The neural blockers, tetrodotoxin, omega-conotoxin GVIA, and N omega-nitro-L-arginine methyl ester, inhibited IJPs but not the responses to NO donors, indicating a postjunctional effect. Methylene blue and cystamine, soluble guanylate cyclase inhibitors, suppressed IJPs and responses to NO donors. We conclude that NO mediates esophageal IJPs, which depend on guanosine 3',5'-cyclic monophosphate elevation and activation of quinine- and apamin-sensitive K+ channels.
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PMID:K+ channel opening mediates hyperpolarizations by nitric oxide donors and IJPs in opossum esophagus. 776 67

1. This study was designed to investigate whether relaxation of isolated guinea-pig sphincter of Oddi preparation by nitrates is mediated by guanylate cyclase activation indirectly by nitric oxide (NO), as in vascular tissues. 2. Sodium nitroprusside, isosorbide dinitrate and amyl nitrite induced dose-dependent relaxations of Oddi's sphincter precontracted by potassium chloride (150 mM). Methylene blue (5 x 10(-5) M), an inhibitor of guanylate cyclase, did not significantly inhibit the relaxations caused by nitrovasodilators. 3. Unlike potassium chloride, acetylcholine (10(-7) - 10(-3) M) induced unsustained contractions which were significantly increased by methylene blue. NG-monomethyl-L-arginine (L-NMMA; 4 x 10(-4) M), an inhibitor of NO biosynthesis, also increased the contractile response to acetylcholine. 4. These results suggest that another mechanism rather than inhibition of guanylate cyclase is involved in the nitrovasodilators-induced relaxations and that acetylcholine releases a relaxing factor, possibly NO, that may modulate its own contraction in this preparation.
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PMID:The action of amyl nitrite and isosorbide dinitrate on the contractility of sphincter of Oddi of guinea-pigs. 783 50

This study was done to determine if a decrease in the aldosterone-suppressant effect of atrial natriuretic factor (ANF) by progesterone and an increase by estrogen was caused by modulation of adrenal zona glomerulosa ANF receptors. Freshly dispersed glomerulosa cells from virgin, 13-15 day pregnant, ovariectomized (OVX) estradiol-17 beta-treated and OVX progesterone-treated rats were used. Competitive displacement of specifically bound [125I]ANF1-28 with unlabelled ANF1-28 yielded concentrations of guanylate cyclase-linked ANF-R1 plus ANF-R2 (clearance) receptors and the displacement with unlabelled ANF4-23 yielded ANF-R2 receptors; the difference between the two was treated as the concentration of ANF-R1 receptors. Pregnancy and progesterone decreased and estrogen increased the number of glomerulosa ANF-R1 receptors. ANF produced a significantly greater suppression of potassium-induced aldosterone secretion in cells from OVX estradiol-treated rats than in cells from OVX progesterone-treated animals. These data suggest that the inhibition of the aldosterone-suppressant activity of ANF by progesterone is the result of a downregulation of ANF-R1 receptors.
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PMID:Hormonal modulation of atrial natriuretic factor receptors and effects on adrenal glomerulosa cells of female rats. 791 2


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