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)

Apart from the generally known functions, the heart has also an endocrine function. Atrial cardiocytes, being typical secretory cells, release peptide hormones into the blood stream: atrial natriuretic peptide containing 28 amino acids and cardiodilatin. The structure of atrial peptides was determined. It was shown that both peptides were derived from their common precursor, a protein containing 151 amino acids. The presence of specific receptors is demonstrated on plasmatic membranes of cells of kidney epithelium, arterial smooth muscle, arterial endothelium, kidney cortex and hypophysis. The interaction of atrial peptides with these receptors activates the guanylate cyclase system. The biological action of atrial peptides manifests itself in the quick, massive and instantaneous increase of diuresis and electrolyte excretion, elevated clearance of creatinine, decrease of kidney vascular resistance, intensification of glomerular filtration, inhibition of stimulated secretion of aldosterone, relaxation of blood vessels, elimination of arterial and intestinal spasm induced by various endogenous and exogenous vasoconstrictors and in correction of kidney hypertension. Various radioimmunoassays for the presence of atrial peptides in human plasma were developed; it was shown that in patients with congestive heart failure the content of atrial peptides is increased.
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PMID:[Endocrine function of the heart. Structure and biological properties of peptides secreted by the heart atrium]. 295 15

Besides generally known functions, the heart has also an endocrine function. Atrial cardiocytes, being typical secretory cells, released peptide hormones into the blood stream: atrial natriuretic peptide containing 28 amino acids and cardiodiolatin. The structure of atrial peptides was determined. It was shown that both derived from their common precursor, a protein containing 151 amino acid. The presence of specific receptors was demonstrated on plasmatic membranes of cells of kidney epithelium, arterial smooth muscle, arterial endothelium, kidney cortex and hypophysis. The interaction of atrial peptides with these receptors activated the guanylate cyclase system. The biological action of atrial peptides manifested itself in the quick, massive and instantaneous increase of diuresis and electrolyte excretion, elevation of clearance of creatinine, decrease of kidney vascular resistance, intensification of glomerular filtration, inhibition of stimulated secretion of aldosterone, relaxation of blood vessels, elimination of arterial and intestinal spasm induced by various endogenous and exogenous vasoconstrictors and correction of kidney hypertension. Various radioimmunoassays for detection of atrial peptides in human blood plasma were developed; it was shown that in patients with congestive failure the atrial peptide content was increased.
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PMID:[A new approach to the problem of cardio-vascular regulation: the endocrine function of the heart (review of the literature)]. 295 52

The effect of endothelium on constrictor responses to 5-hydroxytryptamine, histamine, phenylephrine and acetylcholine was studied and shown to be much greater in isolated perfused coronary arteries than aortic strips of the rabbit. Localised endothelial damage predisposed nonspecifically to 'coronary spasm'. Endothelium-dependent dilatation was shown by bioassay to be mediated by a humoral agent, endothelium-derived relaxant factor (EDRF), with half-life of 6 s. Experiments with inactivating agents indicate that EDRF is not a cyclo-oxygenase or lipoxygenase product and not a free radical; they imply that it contains a carbonyl group at or near its active site. Experiments in which guanylate cyclase and cGMP phosphodiesterase were inhibited indicate that EDRF acts by elevating smooth muscle cGMP. Ergometrine was shown to stimulate EDRF activity which may be relevant to its clinical use in provoking coronary spasm. The physiological role and pathophysiological relevance of this novel, ubiquitous and potent endogenous vasodilator are not yet known; it may be of particular importance in modulating coronary vasomotor responses.
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PMID:Studies of endothelium-derived relaxant factor (EDRF), its nature and mode of action. 387 61

The mast cell is the cellular basis for immediate hypersensitivity reactions. The specificity of the immediate hypersensitivity reaction is attributable to IgE molecules fixed to specific membrane receptors which, when stimulated by specific antigen, initiates the process of degranulation of the mast cell. The granules provide three separate sources of biologic activity: performed or primary mediators, newly generated or secondary mediators, and activities associated with the granular matrix. A number of biologic consequences are generated in response to these mediators and these include: increased vascular permeability, vasodilation, smooth muscle spasm, polymorphonuclear leukocyte chemotaxis, stimulation of adenylate and guanylate cyclase, superoxide radical generation, prostaglandin formation, mucous and gastric acid secretion, hypotension, tissue destruction, and mononuclear leukocyte infiltration. This pharmacopia of activities accounts for the clinical aspects of allergic diseases, suggests that the mast cell granule may be involved in the host's defense against parasitic infections, and is compatible with a suggested role of the mast cell as a widely distributed, monocellular endocrine system.
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PMID:The mast cell. 617 51

We investigated the effects of nifedipine on cyclic GMP turnover and the pertinent enzyme activities in cultured coronary smooth muscle cells (SMC). Nifedipine at high concentrations slightly decreased basal soluble guanylate cyclase activity and inhibited the action of sodium nitroprusside (SNP) but had no effect on the particulate form of the enzyme. In contrast, nifedipine inhibited cyclic GMP hydrolysis by directly inhibiting the partially purified calmodulin-stimulated isoform of phosphodiesterase (type I PDE) with IC50 of 4.2 microM. Nifedipine > or = 1.0 microM enhanced cyclic GMP accumulation in response to 1.0 microM SNP, although nifedipine alone exerted no influence on cyclic GMP levels. Enhancement of cyclic GMP accumulation by nifedipine in response to SNP was not affected by BAY K 8644, a calcium channel agonist. These properties may be shared by other dihydropyridines since nicardipine and nisoldipine also inhibited type I PDE with similar IC50. However, some other structurally unrelated calcium channel blockers, diltiazem and verapamil, had little effect on cyclic nucleotide hydrolysis or on cyclic GMP accumulation in response to SNP. Nifedipine may synergistically enhance cyclic GMP accumulation in response to nitric oxide (NO)-releasing agents by directly inhibiting type I PDE in coronary SMC. Such effects of nifedipine may partly contribute to coronary vasodilation and prevention of coronary spasm in patients with ischemic heart disease.
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PMID:Effect of nifedipine on cyclic GMP turnover in cultured coronary smooth muscle cells. 856 20

It has been shown that there is the supersensitivity of the dilator effect of nitrovasodilators in the coronary arteries of patients with coronary spastic angina. This study was aimed to elucidate its mechanism(s) by examination of dilator response of spastic coronary arteries to atrial natriuretic peptide (ANP), which is known to dilate arteries by the same final common pathway through cyclic guanosine monophosphate (cGMP) as nitrovasodilators. Effects of infusion of nitroglycerin and ANP on epicardial coronary diameter of left coronary arteries were thus examined by quantitative coronary angiography in 20 patients with coronary spastic angina, who had spasm in left coronary arteries, and in 27 control subjects. Dilator response of coronary diameter to intracoronary infusion of ANP (0.5 microgram/kg) was found to be comparable between spastic coronary arteries and control arteries, whereas dilator response to nitroglycerin (250 micrograms) was enhanced in the spastic arteries compared with control arteries. The results indicate that spastic coronary arteries exhibit supersensitive dilator response to nitroglycerin but not to ANP. There is a possibility that dilator response to cGMP may be comparable between spastic and control coronary arteries and that soluble guanylate cyclase activity and/or conversion of nitric oxide bio-activity from nitroglycerin may be enhanced in spastic coronary arteries.
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PMID:Supersensitive dilator response to nitroglycerin but not to atrial natriuretic peptide in spastic coronary arteries in coronary spastic angina. 906 17

1. Subarachnoid haemorrhage (SAH) is a unique disorder and a major clinical problem that most commonly occurs when an aneurysm in a cerebral artery ruptures, leading to bleeding and clot formation. Subarachnoid haemorrhage results in death or severe disability of 50-70% of victims and is the cause of up to 10% of all strokes. Delayed cerebral vasospasm, which is the most critical clinical complication that occurs after SAH, seems to be associated with both impaired dilator and increased constrictor mechanisms in cerebral arteries. Mechanisms contributing to development of vasospasm and abnormal reactivity of cerebral arteries after SAH have been intensively investigated in recent years. In the present review we focus on recent advances in our knowledge of the roles of nitric oxide (NO) and cGMP, endothelin (ET), protein kinase C (PKC) and potassium channels as they relate to SAH. 2. Nitric oxide is produced by the endothelium and is an important regulator of cerebral vascular tone by tonically maintaining the vasculature in a dilated state. Endothelial injury after SAH may interfere with NO production and lead to vasoconstriction and impaired responses to endothelium-dependent vasodilators. Inactivation of NO by oxyhaemoglobin or superoxide from erythrocytes may also occur in the subarachnoid space after SAH. 3. Nitric oxide stimulates activity of soluble guanylate cyclase in vascular muscle, leading to intracellular generation of cGMP and relaxation. Subarachnoid haemorrhage appears to cause impaired activity of soluble guanylate cyclase, resulting in reduced basal levels of cGMP in cerebral vessels and often decreased responsiveness of cerebral arteries to NO. 4. Endothelin is a potent, long-lasting vasoconstrictor that may contribute to the spasm of cerebral arteries after SAH. Endothelin is present in increased levels in the cerebrospinal fluid of SAH patients. Pharmacological inhibition of ET synthesis or of ET receptors has been reported to attenuate cerebral vasospasm. Production of and vasoconstriction by ET may be due, in part, to the decreased activity of NO and formation of cGMP. 5. Protein kinase C is an important enzyme involved in the contraction of vascular muscle in response to several agonists, including ET. Activity of PKC appears to be increased in cerebral arteries after SAH, indicating that PKC may be critical in the development of cerebral vasospasm. Recent evidence suggests that PKC activation may occur in cerebral arteries after SAH as a result of decreased negative feedback influence of NO/cGMP. 6. Cerebral arteries are depolarized after SAH, possibly due to decreased activity of potassium channels in vascular muscle. Decreased basal activation of potassium channels may be due to several mechanisms, including impaired activity of NO (and/or cGMP) or increased activity of PKC. Vasodilator drugs that produce hyperpolarization, such as potassium channel openers, appear to be unusually effective in cerebral arteries after SAH. 7. Thus, endothelial damage and reduced activity of NO may contribute to cerebral vascular dysfunction after SAH. Potassium channels may represent an important therapeutic target for the treatment of cerebral vasospasm after SAH.
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PMID:Subarachnoid haemorrhage: what happens to the cerebral arteries? 980 57

Current evidence strongly suggests that coronary atherosclerosis is a common denominator in patients with stable effort angina pectoris. The concept of pathophysiology of coronary atherosclerosis is presented--angiographic and pathologic evidence now suggest presence of eccentric and irregular atherosclerotic lesions (sometimes associated with plaque rupture) and simultaneously present endothelial dysfunction increases sensitivity of vascular smooth muscles to physical and biochemical stimuli with propensity to spasm. Ischemia is due to an increased myocardial oxygen demand (increased heart rate or blood pressure) that cannot be met because of fixed coronary reserve. The organic nitrates are important drugs for the treatment of patients wit angina. The mechanism(s) of their action is presented--biotransformation and liberation of nitric oxide which stimulates guanylyl cyclase and conversion of GTP (by guanylyl cyclase) to cGMP, which causes vasodilatation but reduces platelet adhesion and aggregation too. Sublingual nitroglycerin and isosorbide dinitrate are effective in the treatment of acute episodes of angina. Long-acting nitrate preparations are effectiveness include intermittent transdermal nitroglycerin, standard formulation and sustained-release isosorbid dinitrate (but better isosorbid-5-mononitrate because of longer duration of action of action and no 1st pass hepatic metabolism) (nitrate-free interval should be of 8-10 hours duration). The place of the therapy with betablockers and calcium channel blockers in angina pectoris is presented as well and their combination with nitrates.
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PMID:[Anti-angina treatment in stable forms of angina pectoris with emphasis on nitrates]. 1564 Dec 33

The radial artery (RA) is used as a spastic coronary bypass graft. This study was designed to investigate the mechanism of vasorelaxant effects of YC-1 (3-(5'-hydroxymethyl-2'-furyl)-1-benzyl indazole), a nitric oxide (NO)-independent soluble guanylate cyclase (sGC) activator, and DEA/NO (diethylamine/nitric oxide), a NO-nucleophile adduct, on the human RA. RA segments (n = 25) were obtained from coronary artery bypass grafting patients and were divided into 3-4 mm vascular rings. Using the isolated tissue bath technique, the endothelium-independent vasodilatation function was tested in vitro by the addition of cumulative concentrations of YC-1 (10-10 to 3 x 10-7 mol/L) and DEA/NO (10-8 to 3 x 10-5 mol/L) following vasocontraction by phenylephrine in the presence or absence of 10-5 mol/L ODQ (1H-(1,2,4)oxadiazole(4,3-a)quinoxalin-1-one), the selective sGC inhibitor, 10-7 mol/L iberiotoxin, a blocker of Ca2+-activated K+ channels, or 10-5 mol/L ODQ plus 10-7 mol/L iberiotoxin. We also evaluated the effect of YC-1 and DEA/NO on the cGMP levels in vascular rings obtained from human radial artery (n = 6 for each drug). YC-1 (10-10 to 3 x 10-7 mol/L) and DEA/NO (10-8 to 3 x 10-5 mol/L) caused the concentration-dependent vasorelaxation in RA rings precontracted with phenylephrine (10-5 mol/L) (n = 20 for each drug). Pre-incubation of RA rings with ODQ, iberiotoxin, or ODQ plus iberiotoxin significantly inhibited the vasorelaxant effect of YC-1, but the inhibitor effect of ODQ plus iberiotoxin was significantly more than that of ODQ and iberiotoxin alone (p < 0.05). The vasorelaxant effect of DEA/NO almost completely abolished in the presence of ODQ and iberiotoxin plus ODQ, but did not significantly change in the presence of iberiotoxin alone (p > 0.05). The pEC50 value of DEA/NO was significantly lower than those for YC-1 (p < 0.01), with no change Emax values in RA rings. In addition, YC-1-stimulated RA rings showed more elevation in cGMP than that of DEA/NO (p < 0.05). These findings indicate that YC-1 is a more potent relaxant than DEA/NO in the human RA. The relaxant effects of YC-1 could be due to the stimulation of the sGC and Ca2+-sensitive K+channels, whereas the relaxant effects of DEA/NO could be completely due to the stimulation of the sGC. YC-1 and DEA/NO may be effective as vasodilator for the short-term treatment of perioperative spasm of coronary bypass grafts.
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PMID:Investigation of the vasorelaxant effects of 3-(5'-hydroxymethyl-2'-furyl)-1-benzyl indazole (YC-1) and diethylamine/nitric oxide (DEA/NO) on the human radial artery used as coronary bypass graft. 1763 87

In a brief overview, in NO-sGC-cGMP signaling in a blood vessel, l-arginine is converted in the endothelium monolayer by the endothelial nitric oxide synthase (eNOS) to NO which diffuses into both the vessel lumen and the vessel wall, thereby activating soluble guanylate cyclase (sGC). Heme-dependent sGC stimulators and hem-independent sGC activators increase the cellular cGMP concentration via the direct activation of sGC, which results in both vasorelaxation and inhibition of platelet aggregation. Studies of the 90's definitively established the role of endothelium in all cardiovascular diseases, which were associated with endothelial dysfunction by impaired release of endothelium-derived relaxing factors with consequent risk of spasm and thrombosis. The rationale of this review is based on the fact that the discovery of NO changed the concepts of cardiovascular disease mechanisms. However, considering the jargon "from the bench to clinical practice" we concluded that a potential therapeutic revolution did not follow the pathophysiological revolution. The review is focused on general aspects without regard for advanced research aspects, and designed in two main groups: the NO/cGMP positive stimulators and blockers as "future and encouraging" new therapeutic drugs. The potential vasodilators include 1) NOS uncoupling; 2) NOS enhancers (AVE compounds); 3) NO donors (nitrovasodilators); 4) NO-independent activators (BAY compounds), and; 5) PDE5 inhibitors. The potential vasoconstrictors include 1) NOS-blockers (L-NAME, L-NMMA); 2) sGC-blockers (methylene blue), and; 3) PDEs. Few texts, selected by excellence and relevance, were crucial and considerably facilitated the elaboration of this text, in addition to our own experimental and clinical experience working on vasoplegic endothelium dysfunction.
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PMID:Cardiovascular therapeutics targets on the NO-sGC-cGMP signaling pathway: a critical overview. 2271 77


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