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)

Nitroglycerin and the long-acting nitrates are widely used in all of the anginal syndromes and have proven effectiveness in relieving or preventing myocardial ischemia. Recent developments into nitrate mechanisms of action provide new insights as to the many anti-ischemic effects of these agents. Important concepts relating to coronary arterial endothelial function are germane to nitrate therapy. Endothelial-derived relaxing factor (EDRF) is presently believed to be nitric oxide (NO), which exerts vasodilatory and/or antiplatelet actions by increasing intracellular cyclic guanosine monophosphate as a result of activation of the enzyme guanylate cyclase. In the setting of coronary atherosclerosis, or even hyperlipidemia without histologic vascular disease, endothelial dysfunction may be present, promoting a vasoconstrictor/proplatelet aggregatory milieu. Nitroglycerin and the organic nitrates are NO donors; NO is the final product of nitrate metabolism, and in the vascular smooth muscle NO induces relaxation, resulting in vasodilation of arteries and veins. In the presence of inadequate EDRF production and/or release, it appears that nitroglycerin may partially replenish EDRF-like activity. Nitrates have long been known to have major peripheral circulatory actions resulting in a marked decrease in cardiac work. Venodilation and arterial relaxation result in a decrease in intracardiac chamber size and pressures, with a resultant decrease in myocardial oxygen consumption. In addition, a variety of direct coronary circulatory actions of the nitrates have been documented. These include not only epicardial coronary artery dilation, but the prevention of coronary vasoconstriction, enhanced collateral flow, and coronary stenosis enlargement. Recent work suggests that the nitrates may also act by preventing distal coronary artery or collateral vasoconstriction, which can reduce blood flow downstream from a total coronary obstruction. Thus, there are many anti-ischemic mechanisms of action by which nitroglycerin and the organic nitrates may be beneficial in both acute and chronic ischemic heart disease syndromes. The unique salutory effects of the nitrates in subjects with left ventricular dysfunction or congestive heart failure make these drugs particularly attractive for patients with abnormal systolic function and intermittent myocardial ischemia. Finally, the emergent role of intravenous nitroglycerin in acute myocardial infarction offers new prospects that nitrate therapy may prove to be beneficial in acute myocardial infarction as well as postmyocardial infarction for the reduction of left ventricular remodeling.
Am J Cardiol 1992 Sep 24
PMID:Mechanisms of action of the organic nitrates in the treatment of myocardial ischemia. 152 24

Increasing evidence suggests that organic nitrate action derives from their metabolic conversion to nitric oxide (NO) in the vascular smooth muscle cell. The primary catalytic activity of this process appears to reside at the cellular plasma membrane. There is no concrete evidence to indicate that NO formation is preceded by the production of inorganic nitrite ion or that the NO produced needs to form S-nitrosothiols before it can activate guanylate cyclase to produce cyclic guanosine 3',5'-monophosphate (cGMP). Although sulfhydryl donors can partially reverse nitroglycerin-induced tolerance in patients, this phenomenon (by itself) is not sufficient to implicate intracellular sulfhydryl depletion as an operating mechanism of clinical nitrate tolerance. This is because sulfhydryl donors can react with nitroglycerin extracellularly to form S-nitrosothiols, and nonsulfhydryl compounds, such as enalapril and hydralazine, can prevent the development of in vivo nitrate tolerance. In addition to the cellular biochemical reactions, organic nitrates also produce systemic biochemical effects through altering neurohormonal status. These systemic effects may contribute significantly to the development of nitrate tolerance in therapeutic situations.
Am J Cardiol 1992 Sep 24
PMID:Biochemical mechanism of organic nitrate action. 152 25

Transmural electrical stimulation and nicotine produced a relaxation of dog cerebral artery strips denuded of endothelium, which was abolished by tetrodotoxin and hexamethonium, respectively, and also suppressed by treatment with NG-nitro-L-arginine (L-NA), a nitric oxide (NO) synthesis inhibitor. The inhibition was reversed by L-arginine but not by the D-enantiomer. L-NA also suppressed the endothelium-dependent relaxation by substance P but not the response to NO and nitroglycerin. Treatment with high concentrations of nitroglycerin or sodium nitroprusside markedly inhibited the relaxant response to nicotine, substance P and NO but not the response to papaverine. Slight, slowly developing relaxations caused by L-arginine in the endothelium-denuded arteries were not potentiated by repeated applications of the amino acid or by exposure of the strips for 24 hr to the bathing medium. Ca++ ionophore-induced contractions in the denuded strips were not potentiated by L-NA. Nicotine significantly increased the level of cyclic GMP in the arteries without endothelium; the increment was abolished by treatment with L-NA and hexamethonium. NO does not seem to be synthesized in smooth muscle in an amount sufficient to produce significant relaxation. It may be concluded that NO liberated from vasodilator nerves activates guanylate cyclase in smooth muscle and produces cyclic GMP, resulting in cerebroarterial relaxation.
J Pharmacol Exp Ther 1991 Sep
PMID:Role of nitric oxide in neurally induced cerebroarterial relaxation. 165 33

Atrial natriuretic factor (ANF-R1) receptor is a 130-kDa protein that contains a cytoplasmic guanylate cyclase domain. We report that ATP interacts in an allosteric manner with the ANF-R1 receptor, resulting in reduced ANF binding and enhanced ANF-stimulated guanylate cyclase activity. The modulatory properties of various nucleotides indicate a preference for the adenine family with a rank order of potency of ATP greater than App(NH)p greater than or equal to ADP greater than or equal to AMP while cyclic and guanine nucleotides except GTP are inactive. The negative modulation by ATP of ANF binding is specific for the ANF-R1 receptor subtype since the amount of ANF bound by the guanylate cyclase uncoupled ANF-R2 subtype is increased in the presence of ATP. Furthermore, the effects of ATP on ANF-R1 receptor binding function are still observed with the affinity-purified ANF-R1 receptor, suggesting an allosteric binding site for ATP on the ANF-R1 receptor. In intact membranes, limited proteolysis of the ANF-R1 receptor with trypsin dose-dependently prevents the ATP-induced decrease in ANF binding concomitantly with the formation of a membrane-associated ANF-binding fragment of 70 kDa. These results confirm the direct modulatory role of ATP on hormone binding activity of ANF-R1 receptor and suggest that the nucleotide regulatory binding site is located in the intracellular domain vicinal to the protease-sensitive region.
Biochemistry 1991 Sep 17
PMID:Allosteric modulation by ATP of the bovine adrenal natriuretic factor R1 receptor functions. 165 83

Experiments were performed to elucidate the role of cyclic guanosine monophosphate (cGMP) on platelet activation induced by protein kinase C (PKC) activators and calcium ionophore. Human platelets were pretreated with acetylsalicylic acid and with hirudin and apyrase. Aggregation and ATP secretion in response to the PKC activators 4 beta-phorbol 12-myristate 13-acetate (PMA) and 1-oleoyl 2-acetylglycerol (OAG) were inhibited by the nitrovasodilator sodium nitroprusside (SNP), an activator of guanylate cyclase, and by 8-bromo-cyclic GMP (8-Br-cGMP). The experiments were performed in the presence of M&B 22948, an inhibitor of cGMP phosphodiesterase. SNP and 8-Br-cGMP also inhibited platelet aggregation and secretion evoked by the ionophore ionomycin. In fura-2 loaded platelets SNP did not affect basal cytosolic Ca2+ level nor the rise induced by low concentrations of ionomycin, both in the presence and absence of extracellular Ca2+. The phosphorylation of the 47 and 20 kDa protein induced by ionomycin or PMA were not significantly decreased by SNP or 8-Br-cGMP. The present results suggest that cGMP is able to inhibit both the PKC and the Ca(2+)-dependent pathways leading to platelet activation by interfering, similarly to cAMP, with processes following protein phosphorylation, close to the effector systems.
Biochim Biophys Acta 1991 Sep 24
PMID:Platelet activation by diacylglycerol or ionomycin is inhibited by nitroprusside. 165 43

The influence of endothelium-derived nitric oxide (EDNO) on relaxation induced by the nitrovasodilators, sodium nitroprusside and sodium nitrite was assessed in phenylephrine-stimulated hamster thoracic aortas, a preparation that displays significant basal release of EDNO. Removal of the endothelium or treatment with the NO synthase inhibitors, NG-nitro-L-arginine (L-NAG, 10-30 microM) or NG-methyl-L-arginine (L-NMMA; 100 microM) increased the potency and, except for sodium nitroprusside in endothelium-denuded segments, also increased the efficacy of the nitrovasodilators. Removal of the endothelium had no effect on relaxations induced by isoproterenol, an indication that these effects were specific for the nitrovasodilators. Removal of the endothelium, treatment of endothelium-intact preparations with L-NAG or L-NMMA, or exposure of these vessels to the guanylate cyclase inhibitor, methylene blue (10 microM) increased reactivity of the aortas to the guanosine 3':5'-cyclic monophosphate (cGMP) analogue, 8-Br cGMP. Measurement of cGMP revealed that endothelium-intact segments had a 6.5 fold higher level of cGMP than endothelium-denuded preparations and that sodium nitroprusside increased cGMP in both preparations by similar amounts in a concentration-dependent fashion. Exposure of endothelium-denuded or L-NAG-treated segments to sodium nitroprusside, to mimic the effects of basally released EDNO, depressed sodium nitrite and 8-Br cGMP reactivity in a manner similar to endothelium-intact segments. These data indicate that EDNO increases cGMP levels in vascular smooth muscle and that the elevated cGMP levels depress nitrovasodilator and 8-Br cGMP reactivities.
Naunyn Schmiedebergs Arch Pharmacol 1991 Sep
PMID:Elevated guanosine 3':5'-cyclic monophosphate mediates the depression of nitrovasodilator reactivity in endothelium-intact blood vessels. 166 Jan 5

Endothelial relaxing factor has been identified as nitric oxide, formed from L-arginine by the soluble enzyme nitric oxide synthase. Nitric oxide inhibits platelet aggregation and adhesion by stimulating a soluble guanylate cyclase and increasing the intracellular concentration of cyclic GMP. Nitrovasodilators, such as sodium nitroprusside, release the active moiety, nitric oxide. In the present study, we have investigated the effect of sodium nitroprusside and of a permeable cGMP derivative on the aggregation and ATP secretion of human platelets stimulated with the protein kinase C activators 1-oleoyl-2-acetylglycerol or 4 beta-phorbol-12- myristate-13-acetate. Human platelets were treated with lysine acetylsalicylate, washed and resuspended in Tyrode-buffered solution. ATP secretion was evaluated by luciferin-luciferase luminescence. Nitroprusside (4-40 microM) or 8-Br-cGMP (0.1-2.4 mM) inhibited both platelet aggregation and ATP secretion evoked by 1-oleoyl-2-acetylglycerol (40 microM) or 4 beta-phorbol-12-myristate-13- acetate (4 nM) in a dose-dependent manner, in the presence of the selective inhibitor of cGMP phosphodiesterase, M&B 22948 (5 microM). The inhibitory effect of nitroprusside was reversed by hemoglobin, known to bind and inactivate nitric oxide. To study the calcium-dependent pathway, we treated platelets with the ionophore ionomycin. The ensuing aggregation and ATP secretion were rapid and were dependent on agonist concentration. Nitroprusside (4-40 microM) inhibited the aggregation evoked by ionomycin (0.4 microM) as well as ATP release, in a dose-dependent manner. We conclude that cGMP is able to inhibit both the protein kinase C-dependent and the calcium-dependent pathways leading to platelet activation.
Cardioscience 1991 Sep
PMID:Nitrovasodilators and cGMP inhibit human platelet activation. 166 Mar 21

In the central nervous system, glutamate receptor activation and other stimuli can lead to the cellular production of nitric oxide (NO), an activator of the cyclic GMP-synthesising enzyme, soluble guanylate cyclase. Four 'nitrovasodilators' which yield NO were tested for their ability to elevate cGMP levels in rat cerebellar slices. Nitroprusside (NP), SIN-1, S-nitroso-N-penicillamine (SNAP) and hydroxylamine all caused very large (up to 300-fold) increments. Their threshold concentrations were between 1 and 30 microM. SNAP was the most potent (EC50 approximately 50 microM) followed by hydroxylamine (200 microM) and SIN-1 (1 mM), the latter compound having the highest efficacy. No maximal response to NP was evident at concentrations up to 10 mM. Slices could be challenged a second time with NP (300 microM) with no evidence of a change in sensitivity. The NO-donors are likely to be valuable for studying the functions of NO in brain tissue; however, the concentrations of NP, SNAP and SIN-1 required to elevate cGMP in the slices are orders of magnitude higher than those needed to stimulate guanylate cyclase activity in broken cell preparations, suggesting that rapid inactivation of NO takes place in the intact tissue.
Neurosci Lett 1991 Sep 02
PMID:Comparative effects of some nitric oxide donors on cyclic GMP levels in rat cerebellar slices. 166 Sep 68

This experiment was designed to determine whether chronic hypoxia affects endothelium-dependent relaxation and cGMP content of rat pulmonary artery (PA). Both Ach and ATP were found to induce endothelium-dependent relaxation of PA; and this relaxation was not prevented by indomethacin, but was completely abolished by methylene blue. Chronic hypoxia significantly depressed the endothelium-dependent relaxation: the relaxation responses of intra-PA (IPA) and extra-PA (EPA) to 10(-6) mol/L Ach in the hypoxic group were 61.3% and 59.2% of those in control, and the relaxation responses of IPA and EPA to 1.8 x 10(-5) mol/L ATP in the hypoxic group were 64.9% and 55.2% of those in the control, respectively. Chronic hypoxia significantly decreased the basic level and Ach-induced accumulation of cGMP in the PA. Our data suggest that chronic hypoxia might depress rat pulmonary artery endothelium-dependent relaxation through the inhibition of cytosolic soluble guanylate cyclase in vascular smooth muscle cells.
Chin Med Sci J 1991 Sep
PMID:Effect of chronic hypoxia on endothelium-dependent relaxation and cGMP content in rat pulmonary artery. 166 62

Natriuretic peptides are structurally related hormones that regulate hemodynamics of the physiological processes of diuresis, water balance, and blood pressure. One of the second messengers of these hormones is cGMP, and the type of receptor that is involved in the generation of cGMP is also a guanylate cyclase. Recent genetic evidence has revealed such a receptor family; two family members, GC-A and GC-B, have been cloned. We now describe the molecular cloning, sequencing, and expression of a cDNA clone from rat adrenal gland that encodes a membrane guanylate cyclase, GC alpha, that, with the exception of two amino acids, is structurally identical to GC-A and conforms to the purported topographical model of GC-A. The two amino acid changes are the substitutions Gln338----His338 and Leu364----Pro364, involving single nucleotide changes, CAG----CAC and CTG----CCG, respectively. Expression studies indicate that GC alpha cyclase activity is independent of the known natriuretic peptides, and direct binding studies demonstrate that GC alpha is not an ANF receptor. To determine the importance of Gln338 and Leu364 in ANF signaling, the GC alpha cDNA regions encoding amino acid residues 338 and 364 were remodeled by oligonucleotide-directed mutagenesis. A double mutant encoding Gln338 and Leu364, and a single-substitution mutant encoding Leu364 expressed both ANF binding and ANF-dependent cyclase activities, but the mutant encoding Gln338 and a deletion mutant lacking residue 364 did not express either of the above activities. These results define the critical role of Leu364 in ANF signal transduction.
Proc Natl Acad Sci U S A 1991 Sep 01
PMID:Site-directed mutational analysis of a membrane guanylate cyclase cDNA reveals the atrial natriuretic factor signaling site. 167 39


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