Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:4.6.1.2 (guanylate cyclase)
 8,497 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Nitrate derivatives have to undergo metabolic activation in the smooth muscle cell or in the plasma with a sulflydryl radical. This transformation results in the formation of nitric oxide and/or S-nitrosothiols. These products stimulate an enzyme, the soluble guanylate cyclase in the sarcoplasm of the smooth muscle cell; giving rise to the formation of intracellular cyclic GMP from GTP. The cyclic GMP activates a kinase protein which in turn activates a number of other protein enzymes involved in the recaptation of calcium by the sarcoplasmic reticulum and in the extrusion of calcium from the cell. In addition, cyclic GMP reduces the level of phosphorylation of the myosin light chain, thereby reducing the sensitivity of the contractile proteins to intracellular calcium. All these phenomena cause smooth muscle relaxation so explaining most of the vasodilator effect of nitrate derivatives.
Arch Mal Coeur Vaiss 1992 Apr
PMID:[Mechanism of cellular action of nitrate derivatives]. 132 34

The cell membrane of vascular smooth muscle is lined with many receptor sensitive to signals emitted by the vessel wall or transported in the blood stream. Recent data on the mechanisms by which these receptors regulate vascular tone enable them to be classified into two main groups. The first group includes the receptors carried by the membrane proteins which are under their direct control; ATP-P2x receptors on Na+ and Ca2+ channels, pharmacological receptors (dihydropyridines, diltiazem, phenylalkylamines) situated on a voltage operated channel, receptors to cromakaline-like substances associated with a potassium channel, receptors to atriopeptines (ANF-B) with guanylate cyclase activity. The second group of receptors act through the intermediary of the G protein (which has a high affinity for guanylic nucleotides); it regulates the activity of an effector which may be an enzyme or an ionic channel. The receptors of this type which have been identified in vascular smooth muscle are: --positively (beta-adrenergic, DA1-dopaminergic, P1 purinergic or H2-histaminic) or negatively coupled (alpha 2-adrenergic) to adrenylate cyclase; --positively coupled to C phospholipase (angiotensin II, vasopressin V1, 5-H-T2, alpha 1-adrenergic, M1-cholinergic, H1-histaminic). In addition, the same receptor may act by different mechanisms (V1-vasopressin, alpha 2-adrenergic, for example). Whatever the initial mechanism of action, all these receptors influence the contraction by changing ionic permeability or by producing secondary relaxing (cyclic AMP, cyclic GMP) or contractility messengers (inositol phosphates, diacylglycerol).(ABSTRACT TRUNCATED AT 250 WORDS)
Arch Mal Coeur Vaiss 1991 Jan
PMID:[Current data of the membrane receptors of the vascular smooth muscle fibers]. 164 53

Two phenomena may lead to an increase in intracellular calcium concentration of vascular smooth muscle cells: an increase in the permeability of the cell membrane to Ca2+ ions; liberation of Ca2+ ions from the intracellular reservoirs. The calcium channels of smooth muscle are varied. There are two types of voltage operated calcium channels: the fast (T) and the slow (L) channels. The calcium channels activated by extracellular membrane receptors are not voltage dependent. Only the L calcium channels are sensitive to dihydropyridines. The liberation of Ca2+ from the sarcoplasmic reticulum which is the intracellular reservoir of calcium can be controlled by two different mechanisms: a direct mechanism by the influx of Ca2+ into the cell through the voltage-operated channels; by the intermediary of a second intracellular messenger. High conductance calcium channels controlled by cytosolic Ca2+ and by IP2 have been demonstrated on the membrane of the sarcoplasmic reticulum. The contraction of smooth muscle may therefore be regulated directly through control of the phosphorylation of the contractile proteins by the intermediary of the systems of adenylate and guanylate cyclase.
Arch Mal Coeur Vaiss 1991 Jan
PMID:[The excitation-contraction coupling of the vascular smooth muscle cells]. 164 54

The physiology, the pharmacology and the biochemistry of the atrial natriuretique factor (ANF) have been investigated and documented by numerous studies and works since its discovery and cloning ten years ago. More recently, the physiopathological aspect of ANF biosynthesis and secretion by the whole heart during overload and congestive heart failure was reported in experimental models and in human patients. Moreover the cyclic GMP which is the ANF second messenger, egressed from endothelial cells, was correlated with the production of ANF. Therefore the activation of heart endocrine function from ANF gene over-expression to peripheral cyclic GMP appeared as an independent prognosis indicator in congestive heart failure. Two types of ANF receptors have been recently cloned. One is the particulate guanylate cyclase, the second is a clearance receptor involved in the endocytosis and lysozomial degradation of ANF in target cells. Neutral endopeptidase, an ectoenzyme present in different tissues and particularly in the kidney is also capable to cleave ANF in unefficient peptide. The blockade of ANF metabolism by clearance receptor antagonists and neutral endopeptidase inhibitor potentializes the biological effect of exogenous and endogenous ANF particularly on the renal function. This approach of ANF metabolism-inhibition opens new ways on the future of ANF in cardiovascular therapeutic.
Arch Mal Coeur Vaiss 1990 Dec
PMID:[Atrial natriuretic factor. Current data and future perspectives]. 217 42

Two subtypes of atrial natriuretic factor (ANF) receptors are present in vascular smooth muscle cells: B(biologically active) receptors coupled to a guanylate cyclase and C (clearance) receptors (95 per cent of the total number of ANF binding sites) non coupled to any identified second messenger system. We compared the homologous receptor regulation induced by ANF to the heterologous one elicited by angiotensin II (Ag II). Binding of (3-[125I]iodotyrosyl) rat ANF and cGMP production stimulated by ANF were measured after 18 hours preincubation of rat cultured vascular smooth muscle cells (10(6) cells/dish) at 37 degrees C with ANF or Ag II. The hormones (10 nM) decreased to the same extent the total apparent number of ANF binding sites (control: 208 +/- 25 fmol/10(6); ANF : 82 +/- 20 fmol/10(6) cells; Ag II : 90 +/- 9 fmol/10(6) cells) The diminution of the number of ANF binding sites induced by ANF exposure was reversed by 85 per cent following 10 minutes treatment of the cells with 10 mM AcOH. Moreover, treatment with ANF (10 nM) led to a diminution of cGMP stimulation induced by ANF, this effect being still present after washing the cells with 10 mM AcOH. In contrast, diminution of ANF building sites consecutive to Ag II exposure was not affected by AcOH treatment and a potentiation of cGMP production elicited by ANF was observed. These results suggest that, in rat vascular smooth muscle cells, B receptors are sensitive to homologous down regulation and C receptors are sensitive to heterologous regulation by Ag II.
Arch Mal Coeur Vaiss 1989 Jul
PMID:[Homologous and heterologous regulation of atrial natriuretic factor receptors in smooth muscle cells]. 255 38

Nitric (correction of nitrous) oxide (NO) plays a fundamental part in the haemostatic equilibrium between the endothelium and platelets, an equilibrium of established clinical importance in cardiovascular disease. NO stimulates the enzyme guanylate cyclase which is responsible for synthesis of GMPc, the increase of which results in platelet inhibition. Synthesis of NO may have endogenous auto or paracrine origine from platelets or endothelial cells and participates in the local regulation of platelet function in association with other products of endothelial or platelet synthesis. Exogenous administration is common in therapeutics either in molecules which release NO (nitrate derivatives, sodium nitropruside, molsidomine, etc) or by NO gas administered by inhalation. The antiplatelet effect of NO has been clearly demonstrated in vitro, in vivo or ex vivo, in animals and humans, and probably explains, at least partially, the efficacy of nitrate derivatives in ischaemic coronary artery disease. Nevertheless, the platelet inhibition observed with intravenous NO releasing drugs is associated with potentially harmful systemic hypotension. Platelet inhibition by inhalation of NO could be an alternative means of avoiding this unwanted effect.
Arch Mal Coeur Vaiss 1996 Nov
PMID:[Antiplatelet properties of nitrogen monoxide]. 909 14

Mammalian endothelium acts as a mediator in arterial and venous relaxation and contraction. Endothelium-dependent relaxation is due to endothelial release of powerful, non-prostanoid vasodilatory substances. The best known of these is the endothelial factor EDRF identified as nitrous oxide (NO). It is the end result of the metabolism of L-arginine by the NO synthetase of endothelial cells. In arterial smooth muscle, the relaxation induced by EDRF is explained by NO stimulation of soluble guanylate cyclase, leading to accumulation of GMPc (cyclic guanosine monophosphate). In some animal vessels and in human coronary arteries, endothelial cells release a substance which induces hyperpolarisation of the cell membrane (endothelial derived hyperpolarising factor, EDHF). Release of EDRF by the cell membrane may be mediated by G proteins sensitive to pertussis toxin (activation of the alpha 2 adrenoreceptor, serotonin, platelet aggregation, leukotrienes) or non-sensitive G proteins (adenosine-diphosphate (ADP), bradykinin). In animal blood vessels where the endothelium is regenerated and reperfused, and/or atherosclerotic, a selective loss of the mechanism of EDRF release is observed, sensitive to pertussis toxin, which favors vasospasm, thrombosis and cellular proliferation. The available data on isolated or in situ human blood vessels concord with studies on isolated animal tissues. In addition to the relaxation factors, endothelial cells can also secrete contracting factors (endothelium derived contracting factors: EDCF); these include superoxide anions, endoperoxides, thromboxane A2 and endothelin. Animal studies indicate that the tendency to release EDCF is maintained or even increased in damaged vessels. The change from normally dominant EDRF release to EDCF release could play an important role in atherosclerosis.
Arch Mal Coeur Vaiss 1997 Nov
PMID:[Endothelial dysfunction and atherosclerosis]. 951 9