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)

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.
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PMID:[Antiplatelet effects of nitrate derivatives]. 193 57

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

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.
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PMID:[Antiplatelet properties of nitrogen monoxide]. 909 14

Estrogens are proposed to exert protection against cardiovascular disease, and evidence now suggests that this protection involves a direct vasodilatory effect. We have shown previously that estrogen relaxes endothelium-denuded porcine coronary arteries by opening the large-conductance calcium- and voltage-activated potassium (BKCa) channel of myocytes through guanosine 3',5'-cyclic monophosphate (cGMP)-dependent phosphorylation (35). The present study confirms these results and now demonstrates that this mechanism involves production of nitric oxide (NO). S-nitroso-N-acetylpenicillamine (SNAP), an NO donor, or 8-bromo-cGMP mimicked the effect of estrogen on BKCa channels. Furthermore, inhibition of NO synthase (NOS) attenuated estrogen- or tamoxifen-induced BKCa-channel activity, and this effect was disinhibited by L-arginine. Inhibition of guanylyl cyclase activity blocked the stimulatory effect of estrogen, SNAP, or L-arginine on BKCa channels. Furthermore, 17 beta-estradiol stimulated accumulation of nitrite and cGMP in coronary myocytes. Therefore, we propose that the vasodilatory effect of estrogen on the coronary circulation is mediated by NO. A portion of the beneficial cardiovascular effects of estrogen may be attributed to relaxation of vascular smooth muscle by a process that involves NO- and cGMP-dependent stimulation of BKCa channels.
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PMID:Estrogen relaxation of coronary artery smooth muscle is mediated by nitric oxide and cGMP. 922 56

This study evaluated the vasorelaxant properties of the crude hydroalcoholic extract (CE) of Cuphea carthagenensis, as well as its butanolic (BF) and ethyl acetate (EA) fractions, in rings of rat thoracic aorta. In endothelium-intact rings contracted with phenylephrine (30-100 nM), cumulative additions of increasing concentrations of CE, BF, and EA of C. carthagenensis (0.1 microg/ml-3 mg/ml) caused graded relaxations, with BF displaying the lowest median inhibitory concentration (IC5; mean, 6.8 microg/ml; 95% confidence limits, 3.3-14.2). BF-induced relaxations of endothelium-intact rings were virtually abolished by prior incubation with the NO-synthase inhibitor N(omega)-nitro-L-arginine (L-NOARG; 10 or 30 microM), and were markedly reduced after guanylate cyclase inhibition with either methylene blue (10 microM) or ODQ (1 microM; 1H[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one). The inhibition of BF-induced relaxation by L-NOARG was prevented to a large extent by simultaneous incubation with L-arginine (1 mM). In endothelium-denuded rings contracted with phenylephrine, CE and BF caused graded relaxations only at doses >100 microg/ml, whereas the NO-donors SNAP (S-nitroso-N-acetyl-penicillamine) and SIN-1 (3-morpholino-sydnonimine) induced full relaxation at 1 microM. BF (100 microg/ml), which caused little relaxation per se of endothelium-denuded rings, potentiated the relaxant effects of SNAP and even more so of SIN-1 (which, unlike SNAP, also releases superoxide anion O2- in addition to NO), in a manner qualitatively similar to that seen with SOD (superoxide dismutase) against SIN-1. These data indicate that the BF of C. carthagenensis induces relaxation of the rat thoracic aorta by two mechanisms: (a) an endothelium-dependent component of action, which clearly depends on the NO/cyclic guanosine monophosphate (cGMP) pathway and can be attributed, at least in part, to free radical-scavenging properties; and (b) an endothelium-independent component of action, which becomes evident at higher doses (> or = 100 microg/ml) and remains to be further characterized. These results suggest that this native South American plant might be beneficial in cardiovascular disease.
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PMID:Butanolic fraction from Cuphea carthagenensis Jacq McBride relaxes rat thoracic aorta through endothelium-dependent and endothelium-independent mechanisms. 1067 55

Legume-derived isoflavones such as genistein, diadzein and equol have been associated with a reduction in risk of cardiovascular disease. In the current study, we explore the vascular activity of several isoflavone metabolites namely dihydrodaidzein, cis and trans-tetrahydrodaidzein and dehydroequol for potential cardioprotective properties. Rat isolated aortic rings were used. 17beta-oestradiol, equol, and all four of the metabolites studied significantly antagonized contractile responses to noradrenaline. The direct vasodilatory action of these compounds were examined and in contrast to 17beta-oestradiol, the vasodilatory effect of which was demonstrated to be endothelium independent, the dilatory action of all four compounds could be inhibited by endothelium denudation. Further, the dilatory action of both dihydrodaidzein and cis-tetrahydrodaidzein were inhibited by the nitric oxide synthase inhibitor, N(omega)-nitro-L-arginine (NOLA), by the soluble guanylate cyclase inhibitor, 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ) and by 40 mM KCl. Dilatory responses to dehydroequol and trans-tetrahydrodaidzein, on the other hand, were inhibited by 40 mM KCL but not by NOLA nor ODQ. Finally, we examined the protective potential of these compounds in inhibiting endothelium damage by oxidized low density lipoprotein (ox-LDL). Trans-tetrahydrodaidzein was at least 10 fold more potent than 17beta-oestradiol in protecting against ox-LDL induced damage. We conclude that the isoflavone metabolites, dihydrodaidzein, cis- and trans-tetrahydrodaidzein and dehydroequol, may potentially represent a novel series of cardioprotective therapeutics.
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PMID:The vascular activity of some isoflavone metabolites: implications for a cardioprotective role. 1139 77

1. Epidemiological studies have suggested that moderate consumption of natural dietary polyphenolic compounds might reduce the risk of cardiovascular disease and also protect against cancer. The present study investigates the effects of delphinidin, an anthocyanin present in red wine, on bovine aortic endothelial cells apoptosis. 2. Based on flow cytometry, terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling analysis and detection of mitochondrial cytochrome c release, we show that delphinidin (10(-2) g l(-1)) alone had no effect either on necrosis or on apoptosis, but it significantly reduced apoptosis elicited by actinomycin D (1 micro g ml(-1), 24 h) and 7beta-hydroxycholesterol (10 micro g ml(-1), 18 h). 3. The protective effect of delphinidin was abolished by inhibitors of nitric oxide-synthase (NOS) (L-NA, 100 micro M and SMT, 100 micro M), guanylyl cyclase (ODQ, 100 micro M) and MAP kinase (PD98059, 30 micro M). 4. Western blot analysis and protein detection by confocal microscopy demonstrate that the antiapoptotic effect of delphinidin was associated with an increased endothelial NOS expression mediated by a MAP kinase pathway. 5. Finally, delphinidin alone had no effect on cytosolic-free calcium ([Ca(2+)](i)), but normalized the changes in [Ca(2+)](i) produced by actinomycin D towards the control values, suggesting that the antiapoptotic effect of delphinidin is associated with the maintenance of [Ca(2+)](i) in the physiological range. 6. All of the observed effects of delphinidin may preserve endothelium integrity, the alteration of which lead to pathologies including cardiovascular diseases, such as atherosclerosis, and is often associated with cancers. In conclusion, the protective effect of delphinidin against endothelial cell apoptosis contributes to understand the potential benefits of a consumption rich in polyphenols.
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PMID:Delphinidin, an active compound of red wine, inhibits endothelial cell apoptosis via nitric oxide pathway and regulation of calcium homeostasis. 1287 27

Myocardial hypertrophy and extended cardiac fibrosis are independent risk factors for congestive heart failure and sudden cardiac death. Before age 50, men are at greater risk for cardiovascular disease than age-matched women. In the current studies, we found that cardiac hypertrophy and fibrosis were significantly more pronounced in males compared with females of guanylyl cyclase-A knockout (GC-A KO) mice at 16 wk of age. These gender-related differences were not seen in wild-type mice. In the further studies, either castration (at 10 wk of age) or flutamide, an androgen receptor antagonist, markedly attenuated cardiac hypertrophy and fibrosis in male GC-A KO mice without blood pressure change. In contrast, ovariectomy (at 10 wk of age) had little effect. Also, chronic testosterone infusion increased cardiac mass and fibrosis in ovariectomized GC-A mice. None of the treatments affected cardiac mass or the extent of fibrosis in wild-type mice. Overexpression of mRNAs encoding atrial natriuretic peptide, brain natriuretic peptide, collagens I and III, TGF-beta1, TGF-beta3, angiotensinogen, and angiotensin converting enzyme in the ventricles of male GC-A KO mice was substantially decreased by castration. The gender differences were virtually abolished by targeted deletion of the angiotensin II type 1A receptor gene (AT1A). Neither castration nor testosterone administration induced any change in the cardiac phenotypes of double-KO mice for GC-A and AT1A. Thus, we suggest that androgens contribute to gender-related differences in cardiac hypertrophy and fibrosis by a mechanism involving AT1A receptors and GC-A.
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PMID:Androgen contributes to gender-related cardiac hypertrophy and fibrosis in mice lacking the gene encoding guanylyl cyclase-A. 1459 59

In addition to the classic roles that cyclic-3',5-guanosine monophosphate (cGMP) is thought to play in cell function regulation, such as smooth muscle regulation, inhibition of platelet aggregation, visual signal conduction and neutrophil degranulation, it is now understood to be involved with various physiological functions. The tissue levels and hence activity of cGMP are determined by the balance between production rates from guanosine triphosphate (GTP) through the guanylyl cyclase pathways, and degradation to GMP by specific cyclic nucleotide phosphodiesterases (PDEs). PDE5 inhibitors were initially developed for a possible role in cardiovascular disease; their role in the treatment of erectile dysfunction was brought to the forefront by the development of sildenafil. The focus of this article is the current patent literature around the use of PDE5 inhibitors for neuropathy. It also explores the possible hypotheses that may help to explain the mechanism(s) by which cGMP PDE5 inhibitors could have potential benefits in neuropathy.
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PMID:Use of cGMP PDE5 inhibitors in the treatment of neuropathy: a review of the patent literature. 1557 Apr 64

Nitric oxide (NO) inhibits platelet aggregation primarily via a cyclic 3'5'-guanosine monophosphate (cGMP)-dependent process. Sildenafil is a phosphodiesterase type 5 (PDE5) inhibitor that potentiates NO action by reducing cGMP breakdown. We hypothesised that sildenafil would augment the inhibitory effects of NO on in vitro platelet aggregation. After incubation with sildenafil or the soluble guanylate cyclase inhibitor H-(1,2,4)oxadiazolo(4,3-a)quinoxallin-1-one (ODQ), collagen-mediated human platelet aggregation was assessed in the presence of two NO donors, the cGMP-dependent sodium nitroprusside (SNP) and the cGMP-independent diethylamine diazeniumdiolate (DEA/NO). SNP and DEA/NO caused a concentration-dependent inhibition of platelet aggregation. ODQ inhibited and sildenafil augmented the effect of SNP, and to a lesser extent the effect of DEA/NO. We conclude that sildenafil potentiates NO-mediated inhibition of platelet aggregation through blockade of cGMP metabolism and that PDE5 inhibitors may have important antiplatelet actions relevant to the prevention of cardiovascular disease.
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PMID:Sildenafil potentiates nitric oxide mediated inhibition of human platelet aggregation. 1618 64


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