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)

The vascular endothelium is the site of formation of several powerful mediators. One of these is NO, a chemically unstable radical formed by enzymatic conversion of L-arginine in the presence of molecular oxygen. NO elicits relaxation of VSMC by activating cytosolic guanylate cyclase. NO also counteracts platelet adhesion and aggregation. The biological actions of NO make it a key substance in the endogenous defense against vascular occlusion and thrombosis. The basal formation of NO maintains a moderate but significant vasodilation in the systemic resistance vessels and counteracts platelet activity. When blood flow in conduit arteries is increased there is an augmented endothelial formation of NO, eliciting flow-dependent vasodilation. Beside this, several vasodilators (acetylcholine, bradykinin, histamine, substance P) operate by stimulating endothelial NO formation. On the other hand, drugs like nitroglycerin and papaverine operate independently of the vascular endothelium. Vasodilator mechanisms, physiological as well as pharmacological, may therefore be characterized as endothelium-dependent (i.e. NO-mediated), or endothelium-independent (i.e. not mediated by NO). Physiologically, mixed mechanisms occur. Failure of the vascular endothelium to elicit NO-mediated vasodilatation may be due to decreased formation, increased degradation, decreased sensitivity to the NO formed, or a mixture of these factors. Irrespective of the mechanism behind, this is referred to as endothelial dysfunction. Endothelial dysfunction occurs in several cardiovascular settings, like atherosclerosis, hypercholesterolaemia, diabetes, and essential hypertension. Endothelial dysfunction leads to an impaired tissue perfusion, increased local vascular resistance, decreased defense against thrombus formation, and possibly also decreased defense against hypertrophy of the VSMC in the vessel wall media. In patients with CHD, endothelial dysfunction leads to an impaired coronary flow response to physical and mental stress, and to promotion of platelet adherence and aggregability. Endothelial dysfunction is thereby a probable aggravating factor in the atherosclerotic process, adding a functional component on top of the structural lesions characterizing this disease. A particular form of endothelial dysfunction, limited to the arterial resistance vessels, may explain the symptoms and clinical characteristics of microvascular angina. In patients with essential hypertension, endothelial dysfunction prevails, adding a functional component to the structural factors also in this disease. Hitherto, the only therapeutic tools available to restore endothelial dysfunction appear to be restriction of the dietary intake of lipids, possibly reinforced with intake of antioxidants like fish oil and vitamin E. However, large clinical trials to confirm the efficacy of such therapy in reversing endothelial dysfunction have not been conducted. In the future, more directly acting therapeutic regimens, aimed at supporting or substituting the endogenous formation of NO, are likely to appear as well.
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PMID:Endothelial nitric oxide and cardiovascular disease. 815 Dec 63

Interactions between erythrocytes and vascular endothelium have been implicated in the pathogenesis of vaso-occlusion in sickle cell anemia. Sickle erythrocytes adhere to endothelial cells and facilitate trapping of rigid sickle cells in microvessels. Compensatory dilation of precapillary arterioles may mitigate the occlusion. The endothelium regulates vasoreactivity by elaborating endothelium-derived relaxing factor (EDRF), a small molecule that passes freely into vascular smooth muscle where it initiates vasorelaxation by activating soluble guanylate cyclase in the smooth muscle cell cytoplasm. Endothelial release of EDRF can be stimulated by agonists such as acetylcholine. It is highly sensitive to decomposition by superoxide anions and is rapidly bound and inactivated by oxyhemoglobin in solution. The purpose of this study was to determine whether sickle cell interaction with endothelium disrupts this mechanism of endothelial regulation of vasomotor tone. Transverse strips of rabbit aorta, mounted isometrically in organ baths, were contracted with norepinephrine, and relaxation responses to acetylcholine or other agonists were determined. Responses were measured under control conditions and again in the presence of oxyhemoglobin A or S, or erythrocytes or ghosts from normal control subjects or patients with homozygous sickle cell anemia. Sickle erythrocytes inhibited vasorelaxation to acetylcholine by 83%. Approximately half of the inhibition was attributable to a small amount of oxyhemoglobin S that was leaked into the buffer from the erythrocytes. Consistent with this, sickle erythrocyte ghosts inhibited vasorelaxation to acetylcholine by up to 45%. Ghosts from normal erythrocytes did not inhibit vasorelaxation to acetylcholine, and the inhibition seen with normal erythrocytes was entirely attributable to leakage of oxyhemoglobin A into the bath buffer.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Inhibition of endothelium-dependent vasorelaxation by sickle erythrocytes. 833 4

Because diabetes is associated with impaired vascular endothelium, we have investigated endothelium-dependent cGMP stimulation in isolated glomeruli and renal vasodilation in normal and diabetes mellitus (DM) rats. Rats treated with streptozotocin (60 mg/kg iv) developed high blood glucose, polyuria, enlarged kidneys, and slow weight gain compared with control animals. Chronic treatment with insulin reversed these changes. In isolated glomeruli, the endothelium-dependent vasodilator, acetylcholine (ACh), stimulated cGMP accumulation concentration dependently; however, the response was significantly attenuated in glomeruli from DM rats when compared with normal rats or DM rats treated with insulin. Sodium nitroprusside-induced cGMP accumulation was also slightly but significantly reduced in glomeruli from DM rats, however, the response to atriopeptin III was unaltered. In rats, intravenous infusion of ACh (1 and 10 micrograms.kg-1.min-1) moderately decreased blood pressure and increased renal blood flow without a significant change in glomerular filtration rate. The renal vasodilatory response to ACh was significantly diminished in DM rats, but not in DM rats treated with insulin. Acute treatment with insulin did not restore the ACh response, although the blood glucose level was normalized. We conclude that there is a reduced renal vasodilatory response observed in DM, and this is due to an impairment of the renal vascular endothelium to produce endothelium-dependent relaxation factor (nitric oxide) and/or a defective soluble guanylate cyclase.
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PMID:Attenuated glomerular cGMP production and renal vasodilation in streptozotocin-induced diabetic rats. 838 64

Ephedrine is the preferred vasoconstrictor for the treatment of hypotension after epidural and spinal anesthesia in obstetrics because it preserves uterine perfusion better than pure alpha-adrenergic agonists. Previous studies of uterine vascular rings in vitro suggested that direct uterine vasoconstriction from ephedrine is reduced during pregnancy. This study examined the hypothesis that nitric oxide synthase (NOS) is up-regulated in uterine arteries during pregnancy, and that ephedrine stimulates NOS to release nitric oxide (NO) and diminish direct vasoconstriction. Uterine arterial vessels were obtained from 12 pregnant and 9 nonpregnant ewes, and vessel tension was monitored in vitro in response to escalating concentrations of ephedrine or metaraminol. In some experiments, vascular endothelium was mechanically removed, while in others antagonists of NO synthesis (N omega-nitro-L-arginine methyl ester [L-NAME], NO diffusion (hemoglobin [Hgb]), or guanylate cyclase (methylene blue [MB]) were included. In other experiments, solutions containing ephedrine were superfused over uterine arteries from pregnant ewes onto uterine arteries from nonpregnant ewes. Finally, NOS activity, determined by 14C-citrulline generation, was determined in uterine arteries from pregnant and nonpregnant ewes. Both ephedrine and metaraminol caused concentration-dependent constriction of uterine arterial rings from pregnant and nonpregnant animals. Pregnancy reduced maximum constriction from ephedrine more than metaraminol. Similarly, ephedrine-induced constriction was increased more than that of metaraminol in uterine arteries from pregnant animals treated to diminish the effects of nitric oxide (L-NAME, Hgb, MB, endothelium removal). Ephedrine's constriction of uterine arteries from nonpregnant animals was reduced when it was superfused over uterine arteries from pregnant animals. NOS activity was increased in uterine arteries from pregnant compared to nonpregnant animals. These studies confirm decreased direct uterine arterial vasoconstriction during pregnancy from ephedrine and support the hypothesis of increased release of an endogenous vasodilator (NO), either from the vascular endothelium or the vessel wall, as the cause for this decreased vasoconstriction.
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PMID:Pregnancy and ephedrine increase the release of nitric oxide in ovine uterine arteries. 856 28

Levels of calcitonin gene-related peptide (CGRP), a vasodilator peptide present in nerves and airway endocrine cells of the rat respiratory tract, are increased in hypoxic lung and decreased in plasma, suggesting impaired CGRP release. We wanted to determine whether there was an adaptive functional response to reduced CGRP levels in hypoxia. Density of binding sites for CGRP were compared with its vascular actions following hypoxia, and with binding following administration of the sensory neurotoxin capsaicin to deplete neural CGRP. Autoradiography of lung sections incubated with 125I-labelled CGRP and other vasoactive peptides was used to quantify their binding sites, in male Wistar rats exposed to periods of hypoxia (inspiratory oxygen fraction (FI,O2) = 0.1) ranging 0-10 days (n = 5 each), in controls, and in rats treated neonatally with capsaicin. Relaxation to CGRP was compared in pulmonary artery of control and hypoxic rats. CGRP binding was seen in the vascular endothelium and was significantly elevated after 5 days of hypoxia (mean +/- SEM: control 4.6 +/- 0.4 versus hypoxic 16.6 +/- 2.4 amol.mm-2). CGRP-induced (5 x 10(-7)M) relaxation of pulmonary artery was reduced, compared with controls, following 8 and 21 days of hypoxia (mean +/- SEM) percentage of relaxation to phenylephrine: 78 +/- 3, 36 +/- 5 and 32 +/- 3, respectively) and was abolished by removal of endothelium. Capsaicin treatment also significantly elevated vascular CGRP binding. Atrial natriuretic peptide (ANP) binding levels were decreased in smooth muscle of all blood vessels after 7 days of hypoxia, but endothelin-1 (ET-1) and vasoactive intestinal peptide (VIP) binding was unchanged. We conclude that the vasodilator effects of CGRP are endothelium-dependent and, whilst they are reduced in hypoxic lung, this is not due to reduction in receptors, thereby implicating alterations in the nitric oxide guanylyl cyclase system. Furthermore, adaptive responses in some peptide binding sites occur in hypoxia, which may be due to changes in endogenous peptide levels.
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PMID:Decreased endothelium-dependent pulmonary vasodilator effect of calcitonin gene-related peptide in hypoxic rats contrasts with increased binding sites. 866 97

Nitric oxide (NO) was discovered to be a potent vasodilator, inhibitor of platelet aggregation, and active species of nitroglycerin before the discovery of endothelium-derived relaxing factor (EDRF) in 1980. Subsequent studies revealed that EDRF is NO, and is synthesized by mammalian cells from L-arginine through a complex oxidation reaction catalyzed by the flavo-hemoprotein NO synthase (NOS). NOS catalyzes the NADPH- and oxygen-dependent oxygenation of L-arginine to NO plus L-citrulline in a reaction that requires at least six cofactors including NADPH, FAD, FMN, tetrahydrobiopterin, heme, and calmodulin. NO elicits its known physiological actions by activating cytosolic guanylate cyclase, which converts GTP to cyclic GMP. Endothelial NOS and neuronal NOS are constitutively present and activated by increases in intracellular calcium triggered by endogenous chemicals. NO then diffuses into nearby target cells to elevate cyclic GMP levels and thereby trigger cell function. NOS activity can also be regulated by a negative feedback mechanism involving NO itself. Much greater quantities of NO are produced pathophysiologically by a distinct form of NOS that can be induced in vascular endothelium, smooth muscle and macrophages by endotoxin and cytokines. This high-output production of NO is not regulated by calcium and is cytotoxic by mechanisms involving interaction with iron-containing proteins.
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PMID:Physiology and pathophysiology of nitric oxide. 874 1

1. During their reproductive years women have a much lower incidence of coronary heart disease than men of similar age. A cardioprotective effect of circulating oestrogen appears to be responsible for this decrease in cardiovascular mortality in women. 2. Oestrogen can enhance nitric oxide (NO) production by the vascular endothelium, possibly through enhanced production of the enzyme NO synthase. 3. Pressure-induced constrictions in isolated coronary arteries from rats with physiological circulating levels of oestrogen are reduced compared to oestrogen-deficient animals. This difference is abolished by endothelial removal or inhibition of NO synthase. 4. NO through stimulation of guanylyl cyclase increases levels of the cytosolic second messenger cyclic GMP (cGMP) which activates a cGMP-dependent protein kinase in vascular smooth muscle cells. 5. Potassium currents through calcium-activated channels in vascular smooth muscle cells are increased in response to NO or upon exposure to cGMP-dependent protein kinase. 6. In rat coronary arteries dilations to NO are reduced by agents which inhibit calcium-activated potassium channels. NO can also hyperpolarize this tissue, suggesting membrane potential changes are involved in the response to NO. 7. We propose that oestrogen increases NO production leading to more negative membrane potentials and decreased calcium entry in coronary vascular smooth muscle cells.
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PMID:A proposed mechanism for the cardioprotective effect of oestrogen in women: enhanced endothelial nitric oxide release decreases coronary artery reactivity. 893 19

Nitric oxide is synthesized from the amino acid I-arginine by a family of enzymes, the nitric oxide synthases. The synthesis of nitric oxide by vascular endothelium is responsible for the vasodilatator tone that is essential for the regulation of blood pressure. NO also contributes to the control of platelet aggregation and the regulation of cardiac contractility. These actions are all mediated by the activation of soluble guanylate cyclase and the consequent increase in the concentration of cGMP in target cells. Several studies suggests that some diseases are related to defects in the generation or action of nitric oxide. Some of the features of septic shock, including hypotension, vascular hyporeactivity, myocardial depression and tissue damage appears to result from excess production of NO. Controlled clinical trials to assess the effects of nitric oxide synthase inhibitors on mortality and morbidity in septic shock seem justified and are already planned.
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PMID:[Nitric oxide--a basic mediator of vasodilation and septic shock]. 896 35

1. The distribution of the carbon monoxide (CO) producing enzymes haem oxygenase (HO)-1 and -2 was studied by immunohistochemistry in the pig's lower urinary tract, including bladder extramural arteries, and the oesophagogastric junction (OGJ). In isolated smooth muscle from the urethra and the OGJ, the mechanisms for CO-induced relaxations were characterized by measurement of cyclic nucleotide levels and by responses to the guanylate cyclase inhibitor methylene blue and some K+ channel inhibitors. 2. HO-2 immunoreactivity was observed in coarse nerve trunks within the smooth muscle of the urethra and OGJ, and in nerve cell bodies of the enteric plexuses of the OGJ. Furthermore, the vascular endothelium of the intramural vessels of the urethra, bladder and OGJ, and the extramural vessels of the bladder, displayed HO-2 immunoreactivity. Two different antisera against HO-1 were used, but only one displayed immunoreactivity in neuronal structures. HO-1 immunoreactivity, as displayed by this antiserum, was seen in nerve cells, coarse nerve trunks and varicose nerve fibres in the smooth muscle of the urethra and OGJ. Some HO-2 and/or HO-1 (as displayed by both HO-1 antisera) immunoreactive cells with a non-neuronal appearance were observed within the smooth muscle of the OGJ, bladder and urethra. 3. In the urethral preparations, exogenously applied CO (72 microM) evoked a relaxation amounting to 76 +/- 6%. The relaxation was associated with an increase in cyclic GMP, but not cyclic AMP, content. CO-evoked relaxations were not significantly reduced by treatment with methylene blue, or by inhibitors of voltage-dependent (4-aminopyridine), high (iberiotoxin, charybdotoxin) and low (apamin) conductance Ca(2+)-activated, and ATP-sensitive (glibenclamide) K+ channels. Bladder strips, and ring preparations from the extramural arteries of the bladder, did not respond to exogenously administered CO (12-72 microM). 4. In the OGJ, exogenously applied CO evoked a relaxation of 86 +/- 6%, which was associated with an increase in cyclic GMP, but not cyclic AMP, content. Treatment with 30 microM methylene blue raised the spontaneously developed muscle tone, and reduced the maximum relaxation evoked by CO to 33 +/- 9%. Addition of 4-aminopyridine, apamin, glibenclamide, iberiotoxin, charybdotoxin or glibenclamide had no effect on the relaxations. 4-aminopyridine (0.1-1 mM), iberiotoxin (0.1 microM) and charybdotoxin (0.1 microM) increased the spontaneously developed tone, and a combination of charybdotoxin and apamin reduced CO-induced (24 microM CO) relaxations. 5. The present findings demonstrate the presence of HO in both neuronal and non-neuronal cells in the pig OGJ and lower urinary tract. CO produces relaxation of the smooth muscle in the OGJ and urethra, associated with a small increase in cyclic GMP concentration in both regions. Relaxations evoked by CO in the urethra do not seem to involve voltage-dependent, low and high conductance, or ATP-dependent K+ channels. However, in the OGJ relaxations evoked by CO can be attenuated by methylene blue and a combination of charybdotoxin and apamin.
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PMID:Carbon monoxide-induced relaxation and distribution of haem oxygenase isoenzymes in the pig urethra and lower oesophagogastric junction. 911 25

We recently demonstrated that nitric oxide (NO) significantly contributes to the mitogenic effect of vascular endothelial growth factor (VEGF), suggesting a role for the NO pathway in the signaling cascade following kinase-derivative receptor activation in vascular endothelium. The aim of this study was to investigate the intracellular pathways linked to VEGF/NO-induced endothelial cell proliferation. We assessed the activity of the mitogen-activated protein kinase (MAPK) that is specifically activated by growth factors, extracellular-regulated kinase (ERK1/2), on cultured microvascular endothelium isolated from coronary postcapillary venules. ERK1/2 was immunoprecipitated, and its activity was assessed with an immunocomplex kinase assay. In endothelial cells exposed for 5 min to the NO donor drug sodium nitroprusside at a concentration of 100 microM, ERK1/2 activity significantly increased. VEGF produced a time- and concentration-dependent activation of ERK1/2. Maximal activity was obtained after 5 min of stimulation at a concentration of 10 ng/ml. The specific MAPK kinase inhibitor PD 98059 abolished ERK1/2 activation and endothelial cell proliferation in a concentration-dependent manner in response to VEGF and sodium nitroprusside. The NO synthase inhibitor Nomega-monomethyl-L-arginine, as well as the guanylate cyclase inhibitor 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one, blocked the activation of ERK1/2 induced by VEGF, suggesting that NO and cGMP contributed to the VEGF-dependent ERK1/2 activation. These results demonstrate for the first time that kinase-derivative receptor activation triggers the NO synthase/guanylate cyclase pathway to activate the MAPK cascade and substantiates the hypothesis that the activation of ERK1/2 is necessary for VEGF-induced endothelial cell proliferation.
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PMID:Nitric oxide is an upstream signal of vascular endothelial growth factor-induced extracellular signal-regulated kinase1/2 activation in postcapillary endothelium. 946 19


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