Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0020538 (hypertension)
 170,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Methylene blue (MB) is a soluble guanylate cyclase inhibitor, and known as an endothelium-derived relaxing factor (EDRF) inhibitor in vitro. In the present study, it was demonstrated that intravenous administration of MB caused a dose-dependent hypertensive effect in rats. The hypertensive responses to the higher doses (10 and 20 mg/kg) of MB was followed by a reflex hypotension which did not appear in pithed rats. Noradrenaline depletion by reserpine pretreatment did not inhibit MB-induced hypertension, but abolished the hypotensive response. Both hypertensive and hypotensive phases were not altered by indometacin. These results may suggest that in vivo guanylate cyclase inhibition leads to an increase in blood pressure; prostaglandins and noradrenaline release from sympathetic nerve endings do not contribute to MB-induced hypertension and it may be due in part to the inhibition of EDRF.
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PMID:Effect of methylene blue on blood pressure in rats. 848 67

Ten years ago, the term "oxidative stress" (sigma -O2) was created to define oxidative damage inflicted to the organism. This definition brings together processes involving reactive oxygen species production and action such as free radical production during univalent reduction of oxygen within mitochondria, activation of NADPH-dependent oxidase system on the membrane surface of neutrophils, flavoprotein-catalyzed redox cycling of xenobiotics and exposure to chemical and physical agents in the environment. Since the discovery of the nitric oxide biosynthetic pathway, the deleterious effects of uncontrolled nitric oxide generation are generally classified as oxidative stress. Indeed, products of the reaction of NO and superoxide lead to oxidants such as peroxinitrite, nitrogen dioxide and hydroxyl radical, which are involved in mechanisms of cell-mediated immune reactions and defence of the intracellular environment against microbiol invasion. However NO can also regulate many biological reactions and signal transduction pathways that lead to a variety of physiological responses such as blood pressure, neurotransmission, platelet aggregation, endothelin generation or smooth muscle cell proliferation. Then the uncontrolled NO production can lead to a variety of physiological and pathophysiological responses similar to a Nitric Oxide Stress: activation of guanylate cyclase and production of cGMP: overstimulation of the inducible L-arginine to L-citrulline and NO pathway by bactericidal endotoxins and cytokines has been shown to promote undesired increases in vasodilatation, which may account for hypotension in septic shock and cytokine therapy. stimulation of auto-ADP-ribosylation and modification of SH-groups of glyceraldehyde-3-phosphate dehydrogenase in a cGMP-independent mechanism: by this way, NO in excess can strongly inhibits this important glycolytic enzyme and reduce the cellular energy production. inhibition of ribonucleotide reductase: extensive inhibition of this key enzyme in DNA synthesis in the presence of large amounts of NO could lead to important antiproliferative effects; inhibition of cytochrome P450-dependent metabolism: in Kupffer cells and hepatocytes, LPS-induced overproduction of NO has been shown to inhibit cytochrome P450-dependent metabolism and to mediate the suppression of hepatic metabolism. Moreover, NO synthetized in the peripheral nervous system is known to mediate nonadrenergic noncholinergic (NANC) neurotransmission. Overstimulation of NO synthases might therefore contribute to pathophysiological states such as: gastrointestinal motility, reflux oesophagitis, asthma, adult respiratory distress syndrome (ARDS) and chronic pulmonary artery hypertension. To these NO-mediated biological functions, one could add the biological effects of NO-derivatives such as N-nitrosocompounds, which act as carcinogenic agents, or C-nitrosocompound which were recently used as "zinc-ejecting" agents to inhibit HIV-1 infectivity of human T-lymphocytes.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:[Does nitric oxide stress exist?]. 852 Oct 87

Nitric oxide has a diuretic effect in vivo. We have shown that nitric oxide inhibits antidiuretic hormone-stimulated osmotic water permeability in the collecting duct; however, the mechanism by which this occurs is unknown. We hypothesized that inhibition of antidiuretic hormone-stimulated water permeability by nitric oxide in the collecting duct is the result of activation of cGMP-dependent protein kinase, which in turn decreases intracellular cAMP. To test this hypothesis, we microperfused cortical collecting ducts. Antidiuretic hormone-stimulated water permeability was 317 +/- 47 microm/s (P < .001). Addition of spermine NONOate, a nitric oxide donor, to the bath decreased water permeability to 74 +/- 38 microm/s (P < .002). In the presence of LY 83583, an inhibitor of soluble guanylate cyclase, spermine NONOate did not change water permeability. Addition of spermine NONOate increased cGMP production (P < .01). In the presence of the cGMP-dependent protein kinase inhibitor, spermine NONOate did not change water permeability. Since antidiuretic hormone increases water permeability by increasing cAMP, we hypothesized that nitric oxide inhibits water permeability by decreasing cAMP. In tubules pretreated with antidiuretic hormone, intracellular cAMP was 18.9 +/- 3.9 fmol/mm. In tubules treated with antidiuretic hormone and spermine NONOate, cAMP was 9.3 +/- 1.7 fmol/mm (P < .03). We also examined the effect of spermine NONOate on dibutyryl-cAMP-stimulated water permeability. In the presence of dibutyryl-cAMP, water permeability was 388 +/- 30 microm/s. Addition of spermine NONOate had no significant effect on water permeability. Time controls and inhibitors by themselves did not change antidiuretic hormone-stimulated water permeability. We concluded that nitric oxide decreases antidiuretic hormone-stimulated water permeability by increasing cGMP via soluble guanylate cyclase, activating cGMP-dependent protein kinase and decreasing cAMP.
Hypertension 1996 Mar
PMID:Mechanism of the nitric oxide-induced blockade of collecting duct water permeability. 861 24

Interleukin-1 induced a time-dependent release of high levels of nitric oxide from rat vascular smooth muscle cells up to 96 hours. A time-dependent release of lactate dehydrogenase was also induced by Interleukin-1 from 72 to 96 hours after its stimulation. In situ nick end-labeling assay revealed that incubation for 48 hours with interleukin-1 induced a positive staining of fragmented nuclei. However, NG-monomethyl-L-arginine, an inhibitor of nitric oxide synthase, inhibited both lactate dehydrogenase release and DNA fragmentation induced by interleukin-1. Furthermore, sodium nitroprusside, a nitric oxide donor, also induced lactate dehydrogenase release and DNA fragmentation. Fluorescent staining of DNA revealed patches of irregularly dispersed, brightly staining, and condensed chromatin in rat vascular smooth muscle cells treated with sodium nitroprusside. Flow cytometric analysis with monoclonal antibody against human Fas revealed that expression of Fas was upregulated by sodium nitroprusside in human vascular smooth muscle cells. Methylene blue, an inhibitor of soluble guanylate cyclase, did not affect sodium nitroprusside-induced upregulation of Fas. Furthermore, 8-bromo-guanosine 3':5'-cyclic monophosphate, an analogue of cGMP, did not upregulate Fas expression. These findings indicate that nitric oxide released from vascular smooth muscle cells may induce apoptosis in vascular smooth muscle cells themselves and also induced upregulation of Fas via a cGMP-independent mechanism. Thus, nitric oxide could trigger the remodeling of atherosclerotic plaques.
Hypertension 1996 Mar
PMID:Nitric oxide induces upregulation of Fas and apoptosis in vascular smooth muscle. 861 47

Nitroglycerin and the long-acting nitrates have been used in cardiovascular medicine for >100 years. Nitrates are widely utilized for the various anginal syndromes and are also used in congestive heart failure and patients with left ventricular dysfunction. The potential mechanisms for relief of myocardial ischemia with nitrates are multiple. The nitrovasodilators are a related group of drugs that result in the formation of nitric oxide (NO) within vascular smooth muscle cells. NO stimulates the enzyme guanylate cyclase, which results in increases in cyclic guanosine monophosphate and vasodilation. In the presence of atherosclerosis, endothelial dysfunction is ubiquitous and associated with decreased NO availability, probably due to increased destruction of NO by free radical anions. Nitrovasodilators, including the nitrates, supply exogenous NO to the vascular wall and improve the vasodilator state. When nitrates are administered, endothelial-dependent stimuli cause relaxation rather than constriction in the setting of endothelial dysfunction. Nitrates also have antiplatelet effects, and recent evidence confirms that these drugs decrease platelet aggregation and thrombosis formation. This may play an important role in the therapy of acute unstable myocardial ischemia, including unstable angina and myocardial infarction. Nitrate hemodynamic effects have been long known. They are primarily modulated through a decrease in myocardial work that results from smaller cardiac chambers operating with lower systolic and diastolic pressures. These changes are caused by a redistribution of the circulating blood volume away from the heart to the venous capacitance system, with a fall in venous return to the heart. The afterload or arterial effects of nitrates are also useful in decreasing myocardial oxygen consumption. Considerable evidence confirms a variety of mechanisms whereby nitrates increase coronary blood flow, including epicardial coronary artery dilation, stenosis enlargement, enhanced collateral size and flow, improvement of endothelial dysfunction, and prevention or reversal of coronary artery vasoconstriction. These effects help increase nutrient coronary blood flow to zones of myocardial ischemia. Recent data with the nitroglycerin patch confirm that myocardial ischemia is decreased after nitrate administration. Nitroprusside, another nitrovasodilator, is a commonly used intravenous agent for lowering arterial pressure and left ventricular filling pressure. This drug is highly effective for the treatment of acute or severe hypertension and congestive heart failure. However, there are data suggesting that nitroprusside may be deleterious in the presence of acute myocardial ischemia, perhaps by shunting blood away from zones of jeopardized myocardial blood flow. Therefore, nitroprusside cannot be recommended to treat myocardial ischemia; intravenous nitroglycerin should be used in this context.
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PMID:Beneficial actions of nitrates in cardiovascular disease. 863 24

Brain natriuretic peptide (BNP) is a cardiac hormone with a spectrum of activities quite similar to those of atrial natriuretic peptide (ANP), including diuretic, natriuretic, hypotensive and smooth muscle relaxant activities. These effects are due to the stimulation of guanylate cyclase-linked natriuretic peptide receptors, leading to an increase in cyclic GMP concentration in target cells. BNP has a lower affinity than ANP for C (clearance) receptors, and is less susceptible to degradation by neutral endopeptidase-24.11, resulting in a longer half-life. In the kidney, BNP increases the glomerular filtration rate and inhibits sodium reabsorption in the distal tubule. It also inhibits the release of renin and aldosterone. Unlike ANP, produced by the atria, BNP is mainly synthesized and released into circulation by the left ventricle and is therefore influenced by stimuli involving this cardiac chamber, such as an increase in arterial pressure, left ventricular hypertrophy and dilation. Plasma BNP levels are very low in healthy subjects, and respond modestly, although significantly to physiological stimuli such as changes in posture or sodium intake. In contrast, plasma BNP concentrations increase in disease states such as cirrhosis with ascites, hypertension, chronic renal failure, acute myocardial infarction and congestive heart failure. In the latter condition, plasma BNP concentration is a reliable prognostic index. Evidence obtained by administering BNP to healthy subjects and hypertensive patients suggests that BNP, at physiological and pathophysiological plasma concentrations, markedly influences cardiovascular homeostasis, mainly due to its effects on sodium excretion and the renin-aldosterone axis.
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PMID:[Brain natriuretic peptide]. 871 58

This study examined the activity of sodium nitroprusside (SNP) in the human fetal-placental circulation in vitro in pathological and experimental conditions in which vascular function may be impaired. SNP (13-3400 nM) caused a concentration-dependent reduction in fetal arterial perfusion pressure (FAP) in Krebs' perfused placental cotyledons, at basal tone and following pre-constriction with prostaglandin F2 alpha (PGF2 alpha). SNP-induced reduction in FAP in the PGF2 alpha pre-constricted fetal-placental circulation was enhanced approximately six-fold (5.85) in those placentae pre-treated with the nitric oxide (NO) synthase inhibitor N omega-nitro-L-arginine (100 microM). Reductions in FAP in the preconstricted fetal-placental vasculature caused by SNP were not altered by prior infusion of ouabain (100 nM) into the fetal circulation or during low oxygen perfusion (O2 tension < 50 mmHg). No differences were observed in the responses obtained to SNP in placentae obtained from women with normotensive pregnancies or those associated with (i) pregnancy-induced hypertension, (ii) intra-uterine growth retardation, or (iii) an elevated umbilical-artery Doppler-ultrasound systolic/diastolic ratio, in either preconstricted placentae or those at basal tone. These findings are consistent with an up-regulation of guanylate cyclase/cGMP-mediated vasodilatation in the fetal-placental vasculature following complete blockade of endogenous NO production.
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PMID:Vascular responses to sodium nitroprusside in the human fetal-placental circulation. 874 64

Patients with systemic hypertension of various etiologies maintain their pulmonary artery pressures within normal limits. We have reported in isolated perfused rat lungs that low basal tone appears to be regulated by nitric oxide (NO)-dependent and -independent mechanisms of soluble guanylate cyclase activation, and similar results are seen in isolated small pulmonary arteries (PA) from these animals. The abdominal aorta of rats was ligated above the left and below the right renal artery (aortic coarctation, AC). The mean arterial pressure (MAP) and pulmonary artery pressure (PAP) of 24-h post-AC rats (MAP 123 +/- 7.1 mm Hg and PAP 4.2 +/- 0.9 mm Hg) showed no significant change when compared with those of sham control rats (MAP 116 +/- 7.0 mm Hg and PAP 5.0 +/- 0.04 mm Hg). Hypoxic contractions in isolated small rat PA (160 to 260 microns diameter) were significantly increased from 56.7 +/- 12.0 mg in the control group to 139 +/- 31 mg in the 24-h post-AC rats (P < 0.05). PA contractions in the presence of 100 microM nitro-L-arginine (NLA) increased from 102 +/- 34 mg among the sham control group to 261 +/- 30 mg among the 24-h post AC rats (P < 0.05). After NLA, the hypoxic contractions decreased to 15 +/- 2.9 mg in the control rats and 45 +/- 16 mg in the 24-h post-AC rats when compared with pre-NLA values (P < 0.05). Western and Northern blotting of protein and messenger ribonucleic acid (mRNA) extracted from the whole rat lung showed a significant rise in endothelial cell nitric oxide synthase (EcNOS; 207 +/- 34%) and EcNOS mRNA (2-fold) when comparing controls with 24-h post-AC rats. These data indicate that there is increased EcNOS activity and synthesis that maintain low PA tone in these rat models as early as 24 h after AC; in addition, this effect is independent of the systemic blood pressure.
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PMID:Early regulatory changes in rat pulmonary artery of renin-dependent systemic hypertension models. 887 80

Cicletanine [particularly the levorotatory (-)enantiomer] inhibits calcium/calmodulin cyclic GMP phosphodiesterase (PDE) in vascular smooth muscle (VSM) and potentiates the vasorelaxant actions of the guanylate cyclase activators sodium nitroprusside (SNP) and atriopeptin II, but the possible interference with vasopressor mechanisms remains to be determined. We tested racemic (+/-) cicletanine for its ability to modify the vascular responses to vasocontractant agents in pithed rats. The most significant results were obtained with angiotensin II (AII). Therefore, the dose of AII that increased the carotid artery blood pressure (BP) 50 mm Hg was twice as high in cicletanine-pretreated (50 mg/kg orally, p.o.) as that in vehicle-pretreated animals (ED50 = 0.48 +/- 0.012 vs. 0.25 +/- 0.007 microgram/kg, p < 0.05). The displacement by cicletanine represented 47.2% of that obtained with losartan (40 micrograms/kg, intravenously, i.v.). Similar results were obtained with (-)-cicletanine (p.o. or i.v.), but not with (+)-cicletanine. In isolated rat aorta, the contraction induced by AII was reduced by (-)-cicletanine in a noncompetitive manner (the percent reduction was independent of the AII concentration). (-)-Cicletanine reduces the vascular reactivity to AII, which plays a key role in several forms of hypertension. These findings are compatible with an action of (-)-cicletanine at any of the numerous steps that couple the occupation of AII receptors to the final contractile response, such as calcium/calmodulin cyclic GMP PDE.
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PMID:Reduction by (-)-cicletanine of the vascular reactivity to angiotensin II in rats. 889 83

The major objective of this lecture is to describe the effects of inhaling low levels of nitric oxide (NO) on the hemodynamic and gas exchange function of both the normal and diseased lung. Considerable attention will be paid to safety and hazards of inhaled NO therapy. During the past few years remarkable progress has been made in understanding the NO-guanylate cyclase signal transduction system. NO has been given considerable clinical investigation in pulmonary artery hypertension and the adult respiratory distress syndrome (ARDS) patients. This lecture concentrates on this area of clinical research.
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PMID:Inhaled nitric oxide. 890 57


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