Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.11.18 (MAP)
 7,412 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The in vitro vasorelaxant and in vivo cardiovascular effects of synthetic S-nitrosothiols (RSNOs) were compared to standard nitrovasodilators. S-Nitroso-glutathione (GSNO), S-nitroso-N-acetylcysteine (NACysNO), S-nitroso-galactopyranose (GPSNO), S-nitroso-thioglycerol (TGSNO) and S-nitroso-homocysteine (HCysNO) relaxed phenylephrine (PE) contracted rabbit aorta at 50% effective concentrations (EC50s) of 3-46 nM. While nitroglycerin (GTN) exhibited in vitro tolerance after preincubation, the RSNOs were considerably less cross tolerant to GTN. In conscious dogs, GSNO, NACysNO and GPSNO (1-20 mcg/kg/min i.v.) paralleled nitroprusside (SNP) in reducing mean arterial and central venous pressure (MAP; CVP) with mild tachycardia. GSNO, NACysNO and SNP were more hypotensive and more resistant to isosorbide dinitrate (ISDN) cross tolerance than GTN. NACysNO showed mild self tolerance with low infusion (2.5 mcg/kg/min x 4h x 3 days) and blunted GTN's hypotension. These studies demonstrate that GSNO and NACysNO are SNP-like vasodilators in conscious dogs, which exhibit less cross tolerance to ISDN than GTN. Further, RSNOs relax vascular smooth muscle seemingly independent of nitric oxide (NO) liberation, and nitrate tolerance may involve reduced RSNO formation or NO release rather than desensitized guanylate cyclase (GC).
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PMID:In vitro vasorelaxant and in vivo cardiovascular effects of S-nitrosothiols: comparison to and cross tolerance with standard nitrovasodilators. 793 11

1. We investigated whether acute (5 h) and chronic (3 days) transdermal glyceryl trinitrate (GTN) patches could cause the development of tolerance in terms of haemodynamics and vascular reactivity in the conscious rabbit. The effects of haemodynamic tolerance were assessed on arterial pressure, heart rate and the baroreflex control of heart rate, while hindquarter vascular reactivity in response to dilator and constrictor drugs and reactive hyperaemia were used to assess vascular tolerance. 2. Seven days prior to experiments, an inflatable cuff, a pulsed Doppler flow probe and an indwelling intra-aortic catheter (for i.a. agonist infusions) were implanted around the lower abdominal aorta. 3. In acute experiments, the effects of 0-5 h treatment with transdermal GTN (0 Sham), 10 or 20 mg 24 h-1) on MAP, HR and the baroreflex were examined. Chronic experiments were performed on three separated days (days 0 - before, 4 - with GTN patch and 8 - recovery). On each day, the baroreflex, reactive hyperaemic responses and hindquarter vascular dose-response curves to i.a. GTN, adenosine, acetylcholine, S-nitroso-N-acetylpenicillamine (SNAP) and methoxamine were assessed. On days 1-4, GTN was administered transdermally via a patch(es) (10 mg 24 h-1 (low dose) or 20 mg 24 h-1 (high dose); renewed every 24 h). 4. Acute treatment with 20 mg GTN 24 h-1, but not with 0 (n = 4) or 10 mg GTN 24 h-1 (n = 4), caused a significant fall in MAP (8 +/- 1 mmHg; n = 4) and resetting of the baroreflex by 5 h. Chronic GTN caused a significant fall in MAP of 8 +/- 2 and 8 +/- 2 mmHg on day 4 with low (n = 8) and high dose (n = 8), respectively, with no change in HR. There was no significant change to hindquarter vascular reactivity to i.a. infusion of GTN, nor were there any significant differences in the reactivity to i.a. adenosine, acetylcholine, SNAP or methoxamine with either low or high doses of GTN. 5. Chronic GTN treatment with low and high dose patches caused a parallel leftward shift ('resetting') of the baroreflex on day 4. By day 8, the baroreflex had still not recovered from this leftward shift 6. In the rabbit, chronic exposure to clinical nitrate patches caused haemodynamic compensation and baroreflex resetting but no evidence of vascular reactivity tolerance. Novel NO donor drugs and delivery regimens which provide intermittent dosing may prevent the development of haemodynamic resetting rather then preventing vascular tolerance, a commonly perceived difficulty in chronic nitrate therapy.
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PMID:Baroreflex resetting but no vascular tolerance in response to transdermal glyceryl trinitrate in conscious rabbits. 873 81

1. This study investigated the effects of low dose endotoxin (lipopolysaccharide, LPS) on (i) systemic haemodynamics, (ii) renal blood flow (RBF), (iii) renal cortical and medullary perfusion and (iv) renal function in the anaesthetized rat. We have also investigated the effects of nitric oxide (NO) synthase (NOS) inhibition with NG-methyl-L-arginine (L-NMMA) on the alterations in systemic and renal haemodynamics and renal function caused by endotoxin. 2. Infusion of low dose LPS (1 mg kg-1 over 30 min, n = 6) caused a late fall in mean arterial blood pressure (MAP, at 5 and 6 h after LPS), but did not cause an early (at 1-4 h after LPS) hypotension. The pressor effect of noradrenaline (NA, 1 microgram kg-1, i.v.) was significantly reduced at 1 to 6 h after LPS (vascular hyporeactivity). Infusion of L-NMMA (50 micrograms kg-1 min-1 commencing 60 min before LPS and continued throughout the experiment, n = 7) abolished the delayed hypotension and significantly attenuated the vascular hyporeactivity to NA (at 2-6 h). 3. Infusion of LPS (1 mg kg-1 over 30 min, n = 6) caused a rapid (within 2 h) decline in renal function (measured by inulin clearance) in the absence of a significant fall in MAP or renal blood flow (RBF). L-NMMA (n = 7) attenuated the impairment in renal function caused by LPS so that the inulin clearance in LPS-rats treated with L-NMMA was significantly greater than in LPS-rats treated with vehicle (control) at 3-6 h after infusion of LPS. 4. Endotoxaemia also caused a significant reduction in renal cortical, but not medullary perfusion (measured as Laser Doppler flux). Infusion of L-NMMA caused a significant further fall in cortical perfusion and a significant fall in medullary perfusion in the absence of changes in RBF. 5. Infusion of LPS resulted in a progressive increase in the plasma levels of nitrite/nitrate (an indicator of the formation of NO), so that the plasma concentration of nitrite/nitrate was significantly higher than baseline at 150 to 330 min after LPS. Infusion of L-NMMA attenuated the rise in the plasma concentration of nitrite/nitrate (at 270 and 330 min, P < 0.05) caused by LPS. 6. Thus, the renal dysfunction caused by injection of low dose of endotoxin in the rat occurs in the absence of significant falls in blood pressure or total renal blood flow. Inhibition of NOS activity with L-NMMA attenuates the renal dysfunction caused by endotoxin (without improving intrarenal haemodynamics), suggesting that an overproduction of NO may contribute to the development of renal injury and dysfunction by causing direct cytotoxic effects.
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PMID:Intrarenal haemodynamics and renal dysfunction in endotoxaemia: effects of nitric oxide synthase inhibition. 928 24

Nitric [correction of Nitrous] oxide is most likely a queer "end mediator" giving rise to vasoplegia in septic shock patients. The study is aimed at comparative assessment of kinetic changes in the synthesis of nitric [correction of nitrous] oxide in experimentally induced sepsis model with the corresponding hemodynamic parameters. The laboratory animals--pigs--are divided up in two groups, and exposed to general narcosis induction, orotracheal intubation and mechanical ventilation under controlled regimen. The hemodynamic parameters studied include: MAP, CO and SVR. Additional endotoxin (1 mg/50 ml) in the form of infusion is given to the animals in the sepsis group. Nitrate production mirrors NO synthesis, insofar as there are no other relevant mechanisms of nitrate synthesis. The kinetic parameters of nitrate production are estimated using stable nitrate isotopes--N15. The theory of compartment models and appropriate computerized simulation are used to calculate the respective constants. In the endotoxin treated group (n = 5) a significantly higher level of synthesis of induced NO production is documented--26 +/- 9 mumol/h, as compared to production in the control group--6 +/- 7 mumol/h, as well as a significant increase in cardiac output and systemic vascular resistance reduction. The good correlation between enhanced NO production and hemodynamic response (increase in cardiac output and decrease in systemic vascular resistance) corroborates the validity of the method.
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PMID:[Hemodynamic changes and nitric oxide production in an experimental model of sepsis]. 997 38

Ibuprofen has been shown in vitro to modulate production of nitric oxide (NO), a mediator of sepsis-induced hypotension. We sought to determine whether ibuprofen alters NO production and, thereby, vascular tone, in normal and endotoxin-challenged volunteers. Techniques for detecting NO were validated in 17 subjects infused with sodium nitroprusside, a NO donor. Then, endotoxin (4 ng/kg) or saline (vehicle alone) was administered in a single-blinded, crossover design to 12 other subjects randomized to receive either ibuprofen (2400 mg p.o.) or a placebo. Endotoxin decreased mean arterial pressure (MAP; P =.002) and increased alveolar NO flow rates (P =.04) and urinary excretion of nitrite and nitrate (P =.07). In both endotoxemic and normal subjects, ibuprofen blunted the small fall in MAP associated with bed rest (P =.005) and decreased alveolar NO flow rates (P =.03) and urinary excretion of nitrite and nitrate (P =.02). However, ibuprofen had no effect on the decrease in MAP caused by endotoxin, although it blocked NO production to the point of disrupting the normal relationship between increases in exhaled NO flow rate and decreases in MAP (P =.002). These are the first in vivo data to demonstrate that ibuprofen down-regulates NO in humans. Ibuprofen impaired the NO response to bed rest, producing a small rise in blood pressure. Although ibuprofen also interfered with the ability of endotoxin to induce NO production, it had no effect on the fall in blood pressure, suggesting that the hemodynamic response to endotoxin is not completely dependent on NO under these conditions.
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PMID:Down-regulation of nitric oxide production by ibuprofen in human volunteers. 1033 32

Heart failure is associated with an increase in plasma nitrate and nitrite (NOx). To date there is still some controversy regarding the causes of nitrate accumulation during the development of heart failure. The goal of this study was to analyze the underlying mechanisms that cause accumulation of plasma nitrates during the development of heart failure in dogs. Dogs were chronically instrumented for measurement of hemodynamics and renal function. Hearts were paced initially at 210 bpm for 3 weeks and then at 240 until the development of heart failure. Hemodynamics, renal function, renal blood flow, arterial blood gases, hemoglobin, plasma and urine NOx levels, and creatinine levels were measured weekly. Heart failure was assessed by hemodynamic alterations, physical signs such as lethargy, ascites, cachexia, and postmortem evidence of cardiac hypertrophy. LVSP (from 127 +/- 3 to 106 +/- 3 mmHg), LV dP/dt (from 2658 +/- 173 to 1439 +/- 217 mmHg/s), MAP (from 101 +/- 1.9 to 83 +/- 1.8 mmHg) fell, whereas LVEDP tripled (from 6.4 +/- 0.9 to 20 +/- 2.6 mmHg), and heart rate rose (from 101 +/- 4.2 to 117 +/- 6.3 bpm), all changes P < 0.05. RBF (from 146 +/- 10 to 96 +/- 9.9 ml/min), urine output (V) (from 0.26 +/- 0.02 to 0.16 +/- 0.02 ml/min), GFR (from 63 +/- 1.8 to 49 +/- 2 ml/min), and Na excretion (from 45 +/- 4.5 to 14 +/- 4.6 microEq/min) all decreased (P < 0.05), whereas RVR increased (from 0.68 +/- 0.05 to 0.94 +/- 0.1 mmHg/ml/min). These changes took place during a rise in plasma NOx (from 3.7 +/- 0.5 to 16+/-3.3 microM), a decrease in urine NOx (from 33 +/- 9.9 to 8.1 +/- 4.9 microM), and a concurrent increase in NOx reabsorption (from 221 +/- 31 to 818 +/- 166 nmol/min). There was a direct correlation between the increase in plasma NOx levels and an increase in filtered load (r(2) = 0.97, P = 0.02), a negative correlation between NOx levels and NOx excretion (r(2) = 0.65 P < 0.09), and a direct correlation between plasma NOx levels and NOx reabsorption (r(2) = 0.97, P = 0.02). These results indicate that elevated plasma NOx during heart failure are most likely the result of an impairment of the renal function and not increased NOx production. Furthermore, without knowing changes in renal function the measurement of plasma NOx in and of itself is a meaningless index of NO formation.
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PMID:Plasma nitrate accumulation during the development of pacing-induced dilated cardiac myopathy in conscious dogs is due to renal impairment. 1117 32

Both nitric oxide (NO) and endothelin-1 (ET-1) are important mediators in the regulation of vascular tone during pregnancy and preeclampsia. This study was designed to investigate the ET-1-induced hypotensive effect in late pregnant rats (P) and in NO-deprived hypertensive pregnant rats (TP), a model of preeclampsia. From day 13 of pregnancy Wistar rats were fed a control or an N(omega)-nitro-L-arginine-enriched diet. On gestational day 20, mean arterial pressure (MAP +/- SEM, in mm Hg) and heart rate (HR) were measured with a carotid catheter in anesthetized rats after a bolus intravenous injection of several agonists and antagonists. After 7 days of chronic NO synthase inhibition, there was a significant increase in MAP (+45 +/- 3.9, P < .01) and 24-h urinary nitrate excretion was significantly decreased (P < .05). ET-1 bolus injection (0.1 nmol/kg) was rapidly followed by a significant decrease in MAP and a slight delayed increase, with no change in HR. The magnitude of the decrease had significantly dropped off in P (-30 +/- 2.2) as compared to that in TP (-46 +/- 5.1) and in virgin rats (-51 +/- 6.3) (P < .05). In P and TP, in vivo depressor effect was also obtained with sarafotoxin S6c, a specific ETB agonist, and blocked by the specific ETB antagonist BQ-788. After inhibition of cyclooxygenase with acetylsalicylic acid, the ET-1-induced hypotension was not modified either in P or in TP. In conclusion, the present data highlight an enhanced ETB receptor mediated hypotensive effect of ET-1 in anesthetized TP as compared to P. The magnitude of the hypotensive effect of ET-1 observed in TP is of the same order as that in virgin rats and neither NO nor vasodilator prostaglandins seem to be involved in TP. The enhanced hypotensive effect of ET-1 could be a beneficial counter-balancing mechanism in this rat model of preeclamptic pathology where an increased sensitivity to vasoconstrictor agents is generally described.
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PMID:Hypotensive effect of endothelin-1 in nitric oxide-deprived, hypertensive pregnant rats. 1141 40

To assess the potential therapeutic effect of propofol in the treatment of endotoxemia, 76 rats were randomly assigned to 5 groups: control group(A), endotoxemic group(B), pre-treatment group(C), simultaneous treatment group(D) and post-treatment group(E). Five h after endotoxin injection, PO2, pH, MAP, plasma concentrations of Nitrite/nitrate (NO2-/NO3-) and mortality rates were assessed in each group. After the rats were sacrificed, lung tissue was sampled to measure myeloperoxidase (MPO) activity and tumor necrosis factor (TNF)-alpha contents. It was found that endotoxin injection produced progressive hypotension, metabolic acidosis, and a large increase in the plasma NO2-/NO3- concentrations and increased mortality rates in 5 h. Endotoxin injection significantly increased MPO activity and TNF-alpha contents in lung tissue (P < 0.01 or P < 0.05). These changes response to endotoxin were significantly attenuated in the groups B, C and D. But these beneficial effects were blunted in the group E. The results suggest that propofol administration may offer advantages in endotoxemia.
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PMID:Therapeutic effect of propofol in the treatment of endotoxin-induced shock in rats. 1452 47

Increased oxidative stress and reduced nitric oxide (NO) bioactivity are key features of diabetes mellitus that eventually result in cardiovascular abnormalities. We assessed whether N-acetylcysteine (NAC), an antioxidant and glutathione precursor, could prevent the hyperglycaemia induced increase in oxidative stress, restore NO availability and prevent depression of arterial blood pressure and heart rate in vivo in experimental diabetes. Control (C) and streptozotocin-induced diabetic (D) rats were treated or not treated with NAC in drinking water for 8 weeks, initiated 1 week after induction of diabetes. At termination, plasma levels of free 15-F2t-isoprostane, a specific marker of oxygen free radical induced lipid peroxidation, was increased while the plasma total antioxidant concentration was decreased in untreated diabetic rats as compared to control rats (P<0.05). This was accompanied by a significant reduction of plasma levels of nitrate and nitrite, stable metabolites of NO, (P<0.05, D vs. C) and a reduced endothelial NO synthase protein expression in the heart and in aortic and mesenteric artery tissues. Systolic, diastolic and mean arterial blood pressures (SBP, DBP and MAP) and heart rate (HR) were reduced in diabetic rats (P<0.05 vs. C) and NAC normalised the changes that occurred in the diabetic rats. The protective effects may be attributable to restoration of NO bioavailability in the circulation.
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PMID:Antioxidant N-acetylcysteine restores systemic nitric oxide availability and corrects depressions in arterial blood pressure and heart rate in diabetic rats. 1639 Aug 27

Hemodynamic support of patients with septic shock is often complicated by a tachyphylaxis against exogenous catecholamines. Because an increase in somatotropic hormones may play a pivotal role in the regulation of the inflammatory response to endotoxin, intravenous supplementation of the neuroendocrine hormone somatostatin (SOMA) may attenuate hemodynamic dysfunction resulting from endotoxemia. The objective of the present study was to assess the short-term effects of SOMA alone and in combination with norepinephrine (NE) on cardiopulmonary hemodynamics, global oxygen transport, plasma nitrate/nitrite levels, and intestinal integrity compared with single NE therapy in ovine endotoxemia. After a baseline measurement in healthy sheep (n = 16) had been performed, Salmonella typhosa endotoxin was centrally infused (10 ng x kg(-1) x min(-1)) to induce a hypotensive-hyperdynamic circulation using an established protocol. Animals surviving 16 h of endotoxemia were randomly assigned to one of the two groups (each n = 6). Sheep allocated to the SOMA + NE group received SOMA as a loading dose of 10.5 microg x kg(-1) x min(-1) for 1 h, followed by a continuous infusion of 3.5 microg x kg(-1) x min(-1) for the next 2 h. After the SOMA loading dose had been given, NE was concurrently infused (0.3 microg x kg(-1) x min(-1)) for 2 h. In the NE group (control), NE (0.3 microg x kg(-1) x min(-1)) was continuously infused for 3 h. Endotoxemia caused a decrease in MAP and systemic vascular resistance index in both groups, but to a greater extent in the NE group. Arterial hypotension persisted despite administration of the study drugs. Infusion of SOMA alone and in combination with NE did not significantly increase systemic vascular resistance index. Neither SOMA nor NE infusion alone affected pulmonary vasoregulation. Plasma nitrate/nitrite levels did not differ between groups. However, combined infusion of SOMA and NE significantly increased arterial lactate concentrations, oxygen consumption index, and oxygen extraction rate (P < 0.05) and aggravated ileal mucosal injury. In conclusion, short-term treatment with SOMA failed to attenuate cardiocirculatory shock resulting from endotoxemia and did not improve vasopressor response to NE. In addition, combined SOMA and NE therapy resulted in intestinal injury. Therefore, SOMA does not seem to represent a therapeutic option to treat arterial hypotension resulting from sepsis and systemic inflammatory response syndrome.
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PMID:Somatostatin infusion increases intestinal ischemia and does not improve vasoconstrictor response to norepinephrine in ovine endotoxemia. 1839 53


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