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Query: UMLS:C0432222 (SEM)
 47,337 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In this study, the endonuclease inhibitor aurintricarboxylic acid (ATA) was examined for its ability to attenuate both acute and delayed excitotoxicity mediated through NMDA and non-NMDA glutamate receptors. Ex vivo embryonic chick retina, a model system frequently used for studies of excitotoxicity, was exposed to either 100 microM NMDA or kainate (KA) +/- various concentrations of ATA for 60 min, then allowed to recover for 24 h. Lactate dehydrogenase release into the medium and histology were assessed as measures of delayed toxicity. ATA attenuated lactate dehydrogenase release due to NMDA or KA in a dose-dependent manner. Histology revealed that ATA decreased the number of pyknotic profiles in response to either glutamate agonist. The mechanism of ATA protection was addressed. ATA was found to block NMDA- but not KA-mediated 22Na+ influx and cyclic GMP formation. In membrane binding studies, ATA was relatively selective for displacement at the NMDA receptor. The IC50 values for displacement of [3H]CGS 19755, alpha-[3H]amino-3-hydroxy-5-methylisoxazole-4-propionic acid ([3H]AMPA), or [3H]KA were 29.9 +/- 1.3, 313 +/- 46, and > 1,000 microM +/- SEM, respectively. ATA also fully attenuated NMDA-induced and partially attenuated KA-induced acute excitotoxicity as monitored histologically by tissue swelling and by the increase in GABA in the medium. Temporal studies of ATA efficacy indicated that ATA needed to be present during NMDA exposure to afford protection but, versus KA, was equally effective if administered immediately after KA exposure. Questions regarding the cellular penetration of ATA were raised because incubation with 100 microM ATA for 60 min had no effect on lactate formation or [3H]leucine incorporation into trichloroacetic acid-precipitable material, even though, in cell-free systems, ATA is a potent inhibitor of phosphofructokinase activity and protein synthesis. These studies demonstrate that ATA can protect against excitotoxicity mediated through NMDA or non-NMDA glutamate receptors. The mechanism of protection versus NMDA is through interruption of NMDA receptor interactions. ATA has no direct effect at the KA receptor; thus, its mechanism of protection versus KA is distinct from that versus NMDA and is, at present, unknown.
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PMID:Excitotoxicity at both NMDA and non-NMDA glutamate receptors is antagonized by aurintricarboxylic acid: evidence for differing mechanisms of action. 789 Nov 4

The aim of this work was to establish whether a physiological increase in atrial natriuretic peptide (ANP) plasma levels affects pulmonary gas exchange in humans. Ten volunteers received an infusion of either ANP (4 pmol.kg-1.min-1) or physiological saline, for 60 min. Baseline measures of the alveolar-arterial PO2 difference and of the physiological dead space were within normal limits and remained stable during and after the infusion of ANP or saline, although plasma ANP and cGMP rose significantly (p < 0.01) (mean +/- SEM: ANP: 13.4 +/- 3.9 to 56.0 +/- 10.4 pmol/l; cyclic GMP: 3.8 +/- 0.3 to 17.0 +/- 3.8 nmol/l). We conclude that a physiological increase in plasma ANP does not affect pulmonary gas exchange significantly in humans.
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PMID:Effect of intravenous atrial natriuretic peptide on gas exchange in humans. 793 52

Transient K+ outward currents (Ito) were measured in enzymatically isolated ventricular mouse heart cells with a patch clamp technique in the whole cell configuration. Exposure of the cells to substrate-free anoxia gradually decreased both the peak and the late Ito. The inactivation time course of Ito was fitted with two exponentials. After 4-10 min of anoxia, the contribution of the fast and slow exponential decreased to 60 +/- 7% and 62 +/- 4% of the control value and recovered after reoxygenation within 1-3 min to 84 +/- 5% and 75 +/- 6% (n = 10; all mean +/- SEM), respectively. The time constants of the exponentials were invariant to anoxia. Voltage dependence of activation and inactivation of Ito were not influenced by anoxia. Application of stimulators of protein kinase A and C, cGMP- dependent protein kinase, or of the oxidant diamide during anoxia did not recover Ito. It is concluded that under conditions of metabolic stress, Ito is reversibly down-regulated leaving inactivation kinetics unchanged. The underlying mechanism is as yet unknown but does neither involve a decreased activity of protein kinase A, protein kinase C, nor c-GMP dependent protein kinase.
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PMID:Anoxia decreases the transient K+ outward current in isolated ventricular heart cells of the mouse. 797 Nov 53

1. The present study was designed to investigate the relationships between circulating atrial natriuretic peptide, plasma and urinary cyclic GMP and sodium excretion under basal conditions and in response to changes in dietary sodium intake. 2. Measurements of plasma atrial natriuretic peptide and plasma and urinary (24h collections) cyclic GMP, sodium and creatinine were made in (i) 30 normotensive subjects on their normal sodium intake and (ii) 12 subjects on the 5th day of a low and on the 5th day of a high sodium intake. 3. Plasma cyclic GMP, urinary cyclic GMP and fractional excretion of cyclic GMP in 30 normotensive subjects on their normal sodium intake were (means +/- SEM) 5.4 +/- 0.5 pmol/ml, 434.5 +/- 31.8 pmol/min and 86.9 +/- 8.6%, respectively. There were significant correlations between urinary cyclic GMP and its corresponding filtered load (r = 0.55) and between the renal clearance of cyclic GMP and that of creatinine (r = 0.44), but there were no significant associations between circulating atrial natriuretic peptide and plasma cyclic GMP or the fractional excretion of cyclic GMP or between urinary sodium and the fractional excretion of cyclic GMP. 5. Plasma atrial natriuretic peptide was significantly raised on the 5th day of the high sodium intake compared with the low sodium intake (10.6 +/- 1.6 versus 4.2 +/- 0.9 pg/ml; P < 0.05). Similarly, there were increases in urinary cyclic GMP excretion (692.3 +/- 43.4 versus 427.4 +/- 41.9 pmol/min, P < 0.05), but there were no significant differences in the fractional excretion of cyclic GMP.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Atrial natriuretic peptide-cyclic GMP relationships in normal humans: effects of dietary sodium intake. 814 88

1. Acute pharmacological inhibition of the enzyme neutral endopeptidase (EC 3.4.24.11), which cleaves the cardiac hormone atrial natriuretic peptide, raises endogenous levels of the hormone. Short-term administration of inhibitors causes natriuresis and diuresis in normal and hypertensive subjects; we report here the effects of an orally active neutral endopeptidase inhibitor (candoxatril, 200 mg) given twice daily for 10 days to normal salt-replete male subjects (n = 12) in a placebo-controlled cross-over study. 2. Candoxatril administration caused a transient natriuresis on day 1 of treatment, but this was not sustained, and cumulative sodium excretion at the end of the study was not altered by active therapy [1720 +/- 40 versus 1734 +/- 57 (placebo) mmol; means +/- SEM]; exchangeable body sodium content was similarly unchanged. However, urinary cyclic GMP excretion was elevated throughout the active treatment phase when compared with placebo. 3. Although a change in plasma levels of atrial natriuretic peptide could not be demonstrated, platelet atrial natriuretic peptide binding sites were reduced by active treatment [23 +/- 3 versus 39 +/- 4 (placebo) fmol/10(9); P < 0.001]. 4. Basal blood pressure and heart rate were not affected by candoxatril treatment. After 10 days of therapy subjects were given incremental infusions of angiotensin II (2, 4 and 8 ng min-1 kg-1) followed by phenylephrine. Although active therapy had not altered basal plasma concentrations of active renin and angiotensin II, levels of angiotensin II during infusion of the octapeptide were higher during the active phase.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Renal and hormonal effects of chronic inhibition of neutral endopeptidase (EC 3.4.24.11) in normal man. 814 89

The role of cGMP in myocardial contraction is not established. Recent reports suggest that nitric oxide, released by endothelial cells or within myocytes, modifies myocardial contraction by raising cGMP. We studied the effects of 8-bromo-cGMP (8bcGMP, 50 mumol/L) on contraction (cell shortening) and simultaneous intracellular Ca2+ transients (indo 1 fluorescence ratio) in intact adult rat ventricular myocytes (0.5 Hz and 25 degrees C) 8bcGMP reduced myocyte twitch amplitude and time to peak shortening (-19.6 +/- 4.2% and -17.6 +/- 1.3%, respectively) and increased steady-state diastolic cell length (+0.6 +/- 0.1 microns, mean +/- SEM, n = 8; all P < .05) but had no effect on shortening velocity, systolic or diastolic fluorescence ratio, or time to peak fluorescence ratio (all P = NS). In 7 of 13 myocytes, this negative inotropic effect was preceded by a transient positive inotropic effect, with small increases in twitch amplitude, shortening velocity, and cytosolic Ca2+ transient. Analysis of 8bcGMP effects on both the dynamic and steady-state relation between cell shortening and intracellular Ca2+ (during twitch contraction and tetanic contraction, respectively) indicated reduction in the myofilament response to Ca2+ in all cases. These 8bcGMP effects were inhibited by KT5823 (1 mumol/L), an inhibitor of cGMP-dependent protein kinase, or by the presence of isoproterenol (3 nmol/L). 8bcGMP had no effect on cytosolic pH in cells (n = 4) loaded with the fluorescent probe carboxyseminaphthorhodafluor-1. These data indicate that cGMP may modulate myocardial relaxation and diastolic tone by reducing the relative myofilament response to Ca2+, probably via cGMP-dependent protein kinase.
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PMID:8-bromo-cGMP reduces the myofilament response to Ca2+ in intact cardiac myocytes. 815 44

Hypotension in septic shock is a reflection of unregulated nitric oxide (NO) production and vascular smooth muscle guanylyl cyclase activation. We examined the effect of methylene blue on lipopolysaccharide (LPS)-induced shock in anesthetized rabbits. Shock was induced with 150 micrograms/kg LPS after measurement of mean arterial pressure, platelet cGMP, and total plasma NO (nitrogen monoxide+S-nitrosothiol) content. Measurements were repeated before and after the intravenous administration of 1, 5, and 10 mg/kg methylene blue in response to a 55% reduction in mean arterial pressure. At baseline, mean +/- SEM arterial pressure was 88 +/- 3 mm Hg, which fell to 51 +/- 3 mm Hg after LPS (P < .05). Methylene blue at doses of 1, 5, and 10 mg/kg produced a prompt dose-dependent increase in mean arterial pressure to 69 +/- 2, 77 +/- 3, and 81 +/- 2 mm Hg, respectively (P < .05 versus mean arterial pressure after LPS) in association with normalization of plasma total NO content (P < .05); however, methylene blue did not significantly affect intraplatelet cGMP levels. Thus, methylene blue restores normal arterial pressure in rabbits with septic shock. This effect is associated with persistent elevation of intraplatelet cGMP levels and normalization of total plasma NO content. These data are consistent with methylene blue-mediated inhibition of NO synthase and/or degradation of NO in this model and suggest a novel therapeutic approach to the treatment of septic shock.
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PMID:Methylene blue reverses endotoxin-induced hypotension. 818 78

We investigated the effect of volume overload on the plasma concentrations of brain and atrial natriuretic peptides as well as cyclic GMP, using specific radioimmunoassays, in 49 patients with chronic renal failure on regular hemodialysis treatment. Markedly elevated levels of the brain (16.2 +/- 1.3 pmol/l) as well as atrial (39.0 +/- 2.8 pmol/l) natriuretic peptide in plasma were found before the dialysis session, as compared to healthy volunteers (range for brain natriuretic peptide, 0.7-7.3 pmol/l, mean level 2.55 +/- 0.32 (SEM) pmol/l). In contrast to the levels of the atrial natriuretic peptide, those of the brain natriuretic peptide were lowered less efficiently by the dialysis procedure: The mean pre-/postdialytic concentration differences were -1.5 pmol/l and -14.2 pmol/l for brain and atrial natriuretic peptide, respectively. The concentrations of the intracellular mediator of the natriuretic peptides, cyclic GMP, were found to be excessively elevated (34.8 +/- 2.8 nmol/l) and returned to near-normal values (12.4 +/- 1.6 nmol/l) at the end of the dialysis session. Concentrations of BNP in plasma of the patients were well correlated to those of ANP. Significant though less marked correlations were also observed between the plasma concentrations of cyclic GMP and BNP, or ANP, respectively. In contrast to those of ANP, pre-/postdialysis differences in plasma BNP concentrations were not correlated to the extent of volume reduction during dialysis. Our findings show that pathophysiologic states resulting in elevations of the plasma concentrations of the atrial natriuretic peptide can also lead to increased levels of the brain natriuretic peptide.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Differential regulation of brain and atrial natriuretic peptides in hemodialysis patients. 822 77

We obstructed renal lymph drainage from a single kidney in diabetic rats who had received 65 mg/kg streptozotocin 6 months prior to the study. Lymphatic obstruction led to a progressive fall in systematic blood pressure from a mean arterial pressure of 101 +/- 5 (SEM) mm Hg (n = 7) to 62 +/- 4 mm Hg (n = 5) (p < .02) after 1.5 h. No change was seen in a sham-operated animal. Despite the decline in systemic blood pressure there was no significant change in the GFR of either kidney. Sodium excretion increased significantly in the experimental kidney. There was no change in the urinary excretion of cyclic GMP from either kidney, and plasma levels of atrial natriuretic peptide (ANP) did not change (55 +/- 21 pg/mL pre- to 64 +/- 18 postobstruction). The results are consistent with a systemic vasodilatation after lymphatic obstruction. The mechanism of this response is still under investigation, but apparently it does not involve ANP.
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PMID:Renal lymphatic obstruction in diabetic rats induces systemic hypotension. 844 34

The mechanism by which soluble mediators of immune cell origin depress myocardial contractility, either globally as in systemic sepsis, or regionally in areas of inflammatory myocardial infiltrates, remains unclear. When freshly isolated ventricular myocytes from adult rat hearts were preincubated for at least 24 h in medium conditioned by endotoxin (LPS)-activated rat alveolar macrophages, their subsequent inotropic response to the beta-adrenergic agonist isoproterenol was reduced from 225 +/- 19% to 155 +/- 10% of the baseline amplitude of shortening (mean +/- SEM, P < 0.05). Neither baseline contractile function nor the contractile response to high extracellular calcium were affected. To determine whether an endogenous nitric-oxide (NO)-signaling pathway within ventricular myocytes was responsible for their decreased responsiveness to isoproterenol, the L-arginine analogue L-NMMA was added to the preincubation medium. While L-NMMA did not affect baseline contractile function or the response of control myocytes to isoproterenol, it completely restored the positive inotropic response to isoproterenol in myocytes preincubated in LPS-activated macrophage medium. Release of NO by ventricular myocytes following exposure to activated macrophage medium was detected as an increase in cGMP content in a reporter-cell (RFL-6) bioassay and also as increased nitrite content in myocyte-conditioned medium. Thus, the depressed contractile response of adult rat ventricular myocytes to beta-adrenergic agonists by a 24-h exposure to soluble inflammatory mediators is mediated at least in party by induction of an autocrine NO signaling pathway.
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PMID:Abnormal contractile function due to induction of nitric oxide synthesis in rat cardiac myocytes follows exposure to activated macrophage-conditioned medium. 848 92


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