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)

Organic nitrates are believed to provide relief from angina principally by dilating the coronary vasculature. Substantial evidence exists, however, to support a potent antiplatelet effect for these agents as well. Each of these compounds ultimately is metabolized to nitric oxide (or an S-nitrosothiol congener thereof), and this metabolite, in turn, is a potent activator of platelet guanylate cyclase. Activation of guanylate cyclase increases platelet cyclic guanosine monophosphate (cGMP), and is accompanied by inhibition of agonist-mediated calcium flux, and, in turn, reduction of fibrinogen binding to the glycoprotein IIb/IIIa receptor. Since fibrinogen binding is essential for platelet aggregation regardless of the agonist involved, its inhibition appears to be the critical mechanism by which platelet function is impaired by these agents. The recently recognized role that platelet-dependent thrombotic processes play in acute coronary syndromes suggests that the inhibition of platelets by nitrates may offer an additional mechanism by which these compounds improve perfusion to ischemic myocardium.
Am J Cardiol 1992 Sep 24
PMID:Antiplatelet and antithrombotic effects of organic nitrates. 152 22

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

Many exogenous and endogenous vasodilator substances produce their effects by stimulation of guanylate cyclase in vascular smooth muscle and increasing cyclic 3',5'-guanosine monophosphate (cGMP) levels. Activation of such enzyme leads to vasodilatation. Possibly as a consequence of a change in the pattern of protein phosphorylation, including dephosphorylation of the light chain myosin and of a decrease in the bioavailability of free calcium. Guanylate cyclase exists in two different forms in the vascular smooth muscle cells: a cytosolic (soluble) and the other associated to membranes (particulate). The nitro vasodilators and vasodilators with endothelium-dependent activity, act by main stimulation of the soluble guanylate cyclase, while the atrial natriuretic factor acts specifically on the particulate form of the enzyme. Guanylate cyclase represents the final path in the vasodilatation induced by diverse endogenous and exogenous substances, an aspect that has created a great interest among investigators due to its possible physiological, physiopathological and therapeutic implications. The more relevant aspects related with the mechanism of action of this numerous group of drugs are deeply analyzed in the present review.
Arch Inst Cardiol Mex
PMID:[Vasodilator drugs that act by stimulating guanylate cyclase in vascular smooth muscle]. 168 18

All nitrovasodilators act intracellularly by a common molecular mechanism. This is characterized by the release of nitric oxide (NO). They are, thus, prodrugs or carriers of the active principle NO, responsible for endothelial controlled vasodilation. The rate of NO-formation strongly correlates with the activation of the soluble guanylate cyclase in vitro, resulting in a stimulation of cGMP synthesis. Nitrovasodilators thus are therapeutic substitutes for endogenous EDRF/NO. The pathways of bioactivation, nevertheless, differ substantially, depending on the individual chemistry of the nitrovasodilator. Besides NO, numerous other reaction products such as nitrite and nitrate anions are formed. The guanylate cyclase is only activated if NO is liberated. In the case of organic nitrates such as GTN, NO is only formed if certain thiol compounds are present as an essential cofactor. The rate of NO-formation correlates with the number of nitrate ester groups and proceeds with a simultaneous nitrite formation (with a ratio of 1:14 in the presence of cysteine). Nitrosamines such as molsidomine do not need thiol compounds for bioactivation. They directly liberate NO from the ring-open A-forms. This process basically depends on the presence of oxygen as electron acceptor from the sydnonimine molecule. Therefore, besides NO also superoxide radicals are formed, which may react with the generated NO under formation of nitrate ions. Organic nitrites (such as amyl nitrite) require the preceding interaction with a mercapto group to form a S-nitrosothiol intermediate, from which finally NO radicals are liberated. Nitrosothiols (like S-nitroso-acetyl-penicillamine) and sodium nitroprusside spontaneously release NO. The molecules themselves do not possess a direct enzyme activating potency. In the presence of thiol compounds organic nitrites (e.g., amyl nitrite) and nitrosothiols may act as intermediary products of NO generation.
Basic Res Cardiol 1991
PMID:Molecular mechanisms of nitrovasodilator bioactivation. 168 27

We investigated the molecular mechanisms whereby Ca2+ enters the endothelial cytosol and regulates endothelial nitric oxide synthesis L-arginine-dependent nitric oxide synthesis by isolated endothelial cytosol as quantified by activation of a purified soluble guanylate cyclase was concentration-dependently enhanced by free Ca2+ (EC50 0.3 microM). The Ca(2+)-dependent activation was inhibited by the calmodulin antagonists mastoparan, melittin, and calcineurin (IC50 450, 350, and 60 nM, respectively) in a calmodulin-reversible manner. After removal of endogenous calmodulin the Ca(2+)-dependency of endothelial NO synthase was lost, but could be reconstituted with exogenous calmodulin. The results indicate that Ca(2+)-calmodulin directly activates the endothelial nitric oxide synthase, thereby transducing agonist-induced increases in intracellular free Ca2+ concentration to nitric oxide formation from L-arginine, K(+)-induced depolarization of the endothelial cells markedly inhibited the sustained, but not initial phase of the intracellular Ca2+ response to bradykinin, indicating that K(+)-induced depolarization depresses the transmembrane Ca2+ influx. On the contrary, the K+ channel activator Hoe 234 which elicits hyperpolarization of the endothelial cell membrane, augmented the sustained phase of the agonist-induced intracellular Ca2+ signal, but not the resting intracellular Ca2+ level. The effects of K+ and Hoe 234 on the agonist-induced Ca(2+)-response were reflected by corresponding changes in agonist-induced EDRF/NO release. From these data, we suggest that the endothelial membrane potential may play an important role for the extent of agonist-induced Ca2+ influx and, thereby, the endothelial EDRF/NO synthesis.
Basic Res Cardiol 1991
PMID:Cellular mechanisms controlling EDRF/NO formation in endothelial cells. 171 54

Nitrates are among the most widely prescribed drugs in cardiovascular disease. They are able to prevent and to interrupt episodes of myocardial ischaemia, alleviate anginal symptoms, and exert favourable effects in acute myocardial infarction and in congestive heart failure. Most of these effects can be explained by their ability to relax smooth muscle cells: peripheral vasodilation, in veins and in arteries, reduces cardiac workload, thereby decreasing oxygen consumption; furthermore, nitrates dilate coronary arteries directly, thereby increasing myocardial oxygen supply. However, nitrates also exert effects on blood platelets. These occur by the same mechanisms operating on blood vessels, a stimulation of soluble guanylate cyclase and a consequent increase in cytosolic levels of cyclic GMP. When added to platelet suspensions nitrates inhibit platelet aggregation by almost all known stimuli. Such effects in vitro generally require high concentrations of drugs; evidence has been obtained, however, that nitrates may inhibit platelet function also in vivo. Such evidence derives from ex vivo studies with platelet aggregometry, from experiments showing the synergism of nitrates and prostacyclin and the requirement for nitrate action of sulphydryl group donors such as N-acetyl-cysteine, and from studies on bleeding time. Antiplatelet effects of nitrates may be an explanation for the protection from death and reinfarction, inferred on the basis of meta-analysis of several studies in acute myocardial infarction.
G Ital Cardiol 1991 May
PMID:[Antiplatelet effects of nitrate derivatives]. 193 57

Various analytical approaches have been used to measure endothelium-derived nitric oxide (NO). We have detected NO in perfusates with a sample size as low as 2 ml after acidification with 4 N HC1 to pH less than 2 at 25 degrees C by using a Nitric Oxide Analyser (Sievers, Colorado). This procedure had the advantage that the detectable level of NO was enhanced by the self-decomposition of HNO2 when the PH less than pKa of NHO2 (pKa = 3.15) and also the reaction temperature of 25 degrees C substantially increased the half-line of NO. Palmer, et al., measured NO released by cultured porcine endothelial cells by chemiluminescence after passing cell effluents continuously at a rate of 5 ml/min into 75 ml of 1% sodium iodide in glacial acetic acid. The larger volumes involved in this method for continuous refluxing, made it less desirable for the detection of endothelium-derived nitric oxide. Feelisch et al. utilized the activation of soluble guanylate cyclase, as well as, the quantitative oxidation of oxyhemoglobin to methemoglobin in aqueous solutions by NO as a means of measuring nitric oxide. We describe here a modification of our earlier micromethod which now enables us to detect NO after complete reduction with glacial acetic acid and sodium iodide. A comparison of the two procedures indicate that while freshly prepared NO standard solutions gave identical chemiluminescence response with and without reduction, effluents from bovine intrapulmonary artery under basal conditions gave substantially higher values upon reduction.
J Mol Cell Cardiol 1991 Apr
PMID:Reduction of biological effluents in purge and trap micro reaction vessels and detection of endothelium-derived nitric oxide (edno) by chemiluminescence. 194 75

Native and oxidized low-density lipoproteins (LDL) were investigated for their direct influence on EDRF-formation, EDRF-activity, and vascular smooth muscle tone. Native (n) LDL, isolated from fresh human plasma, was oxidized by Cu(2+)-incubation. EDRF released from cultured endothelial cells was inactivated by both n-LDL and ox-LDL (1 mg/ml) as detected in a bioassay system. n-LDL reduced the EDRF-mediated vasodilations of the detector segments by 38.5 +/- 5.3%, and ox-LDL by 55.5 +/- 4.6%. The effects of lipoproteins on EDRF-formation were studied on cultured endothelial cells, preincubated with either n-LDL or ox-LDL (1 mg/ml, 1 h) and stimulated for EDRF-release with bradykinin after washout of the lipoproteins. EDRF was assessed by measuring its stimulatory effect on the activity of a purified soluble guanylate cyclase. Preincubation with both n-LDL and ox-LDL did not reduce the bradykinin-induced EDRF-formation. Accordingly, acetylcholine-induced, EDRF-mediated dilations of intact rabbit femoral artery segments were not impaired by luminal exposure to n-LDL or ox-LDL (1 h, 1mg/ml). Effects of n-LDL and ox-LDL on vascular smooth muscle tone were investigated in isolated perfused rabbit femoral arteries. Perfusion of endothelium-intact and -denuded segments with ox-LDL (80-500 micrograms protein/ml) caused no or only weak vasoconstrictions in the absence of contractile agonists. However, in the presence of ox-LDL, vasoconstrictions to threshold concentrations of norepinephrine (NE), serotonin (5-HT), phenylephrine (PE) or potassium were significantly enhanced. Native LDL (80-1000 micrograms/ml) had no effect on vascular tone, neither in presence nor in absence of contractile agonists. Preincubation with verapamil, diltiazem, and nitrendipine inhibited vasoconstrictions evoked by ox-LDL. The contractile responses to ox-LDL were significantly greater in endothelium-denuded segments than in endothelium-intact segments. In conclusion, neither n-LDL nor ox-LDL acutely impair the formation of EDRF, but do inactivate EDRF after its release from endothelial cells. n-LDL has no direct influence on vascular smooth muscle tone, but ox-LDL greatly enhances vasoconstrictions to various contractile agonists by direct interaction with vascular smooth muscle. Thus, in regions of lipoprotein-accumulation in the arterial wall, both n-LDL and ox-LDL may favor inappropriate vasoconstrictions.
Basic Res Cardiol 1991
PMID:Effects of native and oxidized low-density lipoproteins on endothelium-dependent and endothelium-independent vasomotion. 195 5

The present study was carried out to evaluate the effects of biologically active atriopeptin II (APII) in synchronously contracting monolayer cultures of rat ventricular myocytes. The effects of 10 nM APII on Ca influx, contractile behavior and cyclic nucleotide content of the cells were measured. Applied acutely APII had no effect on Ca influx. There was however a time-dependent effect such that after 30 min Ca influx (pmol/cm2/s) had declined from a control (mean +/- S.E.M.) of 1.53 +/- 0.16 to 1.02 +/- 0.07 (P less than 0.001; n = 6). There was parallel decline in both the magnitude and velocity of cell edge motion which was maximal in 30 min at which time cell edge motion measured 65.3 +/- 4.4% of control. Treatment with APII for 30 min decreased cAMP (pmol/mg protein) from 5.35 +/- 0.17 to 2.86 +/- 0.24 (P less than 0.001; n = 5). At the same time cGMP (pmol/mg protein) increased from 0.86 +/- 0.21 to 2.14 +/- 0.33 (P less than 0.001; n = 5). Further studies elucidated the fact that the decline in Ca influx and contractile behavior was dependent on the decrease in cAMP rather than the increase in cGMP. Pre-treatment of the cells with 5 ng/ml of pertussis toxin to ADP-ribosylate the Gi protein abolished the effects of APII on cAMP, Ca influx and contractile behavior. The results indicate that in myocardial cells, as in other cells, APII stimulates guanylate cyclase and inhibits adenylate cyclase. The resultant fall in cAMP decreases Ca influx and negatively influences the contractile behavior of the cells.
J Mol Cell Cardiol 1990 Feb
PMID:Effect of atriopeptin II on Ca influx, contractile behavior and cyclic nucleotide content of cultured neonatal rat myocardial cells. 196 67


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