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Query: UMLS:C0038454 (stroke)
 147,016 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The changes in mental status during cerebral malaria, heat stroke, and recovery from major surgery are clinically similar, and are associated with high circulating concentrations of cytokines that can induce nitric oxide generation in vascular walls. This vascular nitric oxide could diffuse across the blood brain barrier, causing functional changes that include inhibition of glutamate-induced calcium entry, reduced activity of the calcium-dependent nitric oxide synthase, and thus reduced nitric oxide formation, in post-synaptic neurons. Certain general anaesthetics and ethanol reduce glutamate-induced calcium entry into post-synaptic cells, and so would also reduce the rate of formation of neuronal nitric oxide. In view of the apparent importance of glutamate-induced nitric oxide in excitatory neurotransmission, a reduction in neuronal nitric oxide could help explain why these otherwise unrelated influences alter central nervous system function in a similar manner. In particular, this reduction could rationalise why heat stroke, ethanol excess, morphine poisoning, and conditions with high blood ammonia concentrations are easily confused clinically with cerebral malaria.
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PMID:Possible central role of nitric oxide in conditions clinically similar to cerebral malaria. 138 58

Septic shock is characterized by an increase in cardiac output and a fall in systemic vascular resistance index and mean arterial pressure. Endotoxin alters the smooth muscle function of blood vessels, probably by means of an increased production of the potent vasodilator nitric oxide (NO). The present study was accomplished to determine how the inhibition of NO synthesis influences cardiovascular performance in an ovine model of hyperdynamic endotoxemia. Endotoxemia was induced in five range ewes (41 +/- 2 kg) by continuous infusion of Escherichia coli endotoxin (LPS, 10 ng.kg-1.min-1) over the entire study period. After 24 h of LPS infusion, cardiac output increased from 5.2 +/- 0.3 to 7.9 +/- 0.6 (SE) 1/min (P less than 0.05) and mean arterial pressure and systemic vascular resistance index fell from 92 +/- 5 to 79 +/- 6 mmHg (P = 0.08) and from 1,473 +/- 173 to 824 +/- 108 dyn.s.cm-5.m2 (P less than 0.05), respectively. The pulmonary shunt fraction increased from 0.23 +/- 0.03 to 0.32 +/- 0.03 (P less than 0.05). The intravenous administration of the NO synthase inhibitor N omega-nitro-L-arginine methyl ester (25 mg/kg) 24 h after the start of the LPS infusion changed these values to approximately baseline levels over the subsequent 4 h. Although N omega-nitro-L-arginine methyl ester increased pulmonary arterial pressure and pulmonary vascular resistance (P less than 0.05), right and left ventricular stroke volume index showed no significant changes. It is concluded that NO has a major function in cardiovascular performance in endotoxemia.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Reversal of hyperdynamic response to continuous endotoxin administration by inhibition of NO synthesis. 150 87

In addition to its role in blood vessel and macrophage function, nitric oxide (NO) is a neurotransmitter found in high densities in emotion-regulating brain regions. Mice with targeted disruption of neuronal NO synthase (nNOS) display grossly normal appearance, locomotor activity, breeding, long-term potentiation and long-term depression. The nNOS- mice are resistant to neural stroke damage following middle cerebral artery ligation. Although CO2-induced cerebral vasodilatation in wild-type mice is NO-dependent, in nNOS- mice this vasodilation is unaffected by NOS inhibitors. Establishing a behavioural role for NO has, until now, not been feasible, as NOS inhibitor drugs can only be administered acutely and because their pronounced effects on blood pressure and other body functions obfuscate behavioural interpretations. We now report a large increase in aggressive behaviour and excess, inappropriate sexual behaviour in nNOS- mice.
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PMID:Behavioural abnormalities in male mice lacking neuronal nitric oxide synthase. 747 65

During ischemic stroke, massive neural damage occurs due to excess release of glutamate which acts mainly through N-methyl-D-aspartate (NMDA) receptors. Activation of the NMDA receptor stimulates nitric oxide (NO) production by NO synthase (NOS). NO mediates glutamate neurotoxicity as inhibitors of NOS prevent neuronal death. FK506, an immunosuppressant drug, binds to FK506 binding protein (FKBP). One target of the FK506/FKBP complex is the calcium/calmodulin-dependent protein phosphatase calcineurin, whose activity is inhibited upon interaction with FK506/FKBP. FK506 treatment increases phosphorylation level of calcinurin substrates including NOS. As a potent neuroprotective agent in vitro and in vivo, FK506 increases NOS phosphorylation and decreases NO production. NO activates poly(ADP-ribose) synthetase (PARS), a nuclear enzyme that synthesizes poly(ADP-ribose) from NAD. Prolonged activation of PARS depletes NAD and lowers cellular energy levels. Inhibition of PARS also prevents NO toxicity. NOS inhibitors, immunosuppressants and PARS inhibitors may be useful agents to prevent neuronal damage during stroke.
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PMID:Nitric oxide synthase, immunophilins and poly(ADP-ribose) synthetase: novel targets for the development of neuroprotective drugs. 747 44

The role of nitric oxide (NO) in the cardiovascular actions of diaspirin cross-linked hemoglobin (DCLHb) was studied in anesthetized rats. The regional circulatory and systemic hemodynamic effects of DCLHb (400 mg/kg iv) were studied using a radioactive microsphere technique in control (untreated) and L-arginine (a NO precursor) pretreated rats. DCLHb produced a significant increase in blood pressure (75%), cardiac output (42%), stroke volume (36%), and total peripheral resistance (45%), without affecting heart rate, when administered to control rats. L-Arginine pretreatment significantly attenuated DCLHb-induced systemic hemodynamic effects. DCLHb-induced increase in blood flow to the skin and spleen was completely blocked, and that to the heart was partially blocked, by L-arginine pretreatment, suggesting that cardiovascular actions induced by DCLHb could be antagonized by the NO precursor L-arginine. The NO synthase (NOS) inhibitor NG-nitro-L-arginine methyl ester (L-NAME) produced significant increases in regional vascular resistance, leading to a decrease in blood flow to all the organs except the heart, where an increase in blood flow and a decrease in vascular resistance was observed. DCLHb, when administered in L-NAME-pretreated rats, accentuated the decrease in blood flow to the gastrointestinal system, spleen, mesentery and pancreas, skin, and musculoskeletal system. These studies provide evidence that the NO precursor L-arginine can attenuate the effects of DCLHb and that DCLHb can potentiate the effect of the NOS inhibitor L-NAME. The role of NO in the mechanism of action of DCLHb was further studied by estimating plasma guanosine 3',5'-cyclic monophosphate (cGMP) in control, DCLHb-treated, L-NAME-treated, and L-NAME followed by DCLHb-treated rats. DCLHb and L-NAME significantly decreased the concentration of circulating cGMP in blood plasma. L-NAME pretreatment potentiated DCLHb-induced decrease in cGMP levels. Because the formation of cGMP is stimulated by NO, these studies provide additional evidence for the involvement of NO in the mechanism of action of DCLHb. It is concluded that NO plays an important role in the cardiovascular effects of DCLHb.
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PMID:Role of NO mechanism in cardiovascular effects of diaspirin cross-linked hemoglobin in anesthetized rats. 748 71

Three isozymes of nitric oxide (NO) synthase (EC 1.14.13.39) have been identified and the cDNAs for these enzymes isolated. In humans, isozymes I (in neuronal and epithelial cells), II (in cytokine-induced cells), and III (in endothelial cells) are encoded for by three different genes located on chromosomes 12, 17, and 7, respectively. The deduced amino acid sequences of the human isozymes show less than 59% identity. Across species, amino acid sequences for each isoform are well conserved (> 90% for isoforms I and III, > 80% for isoform II). All isoforms use L-arginine and molecular oxygen as substrates and require the cofactors NADPH, 6(R)-5,6,7,8-tetrahydrobiopterin, flavin adenine dinucleotide, and flavin mononucleotide. They all bind calmodulin and contain heme. Isoform I is constitutively present in central and peripheral neuronal cells and certain epithelial cells. Its activity is regulated by Ca2+ and calmodulin. Its functions include long-term regulation of synaptic transmission in the central nervous system, central regulation of blood pressure, smooth muscle relaxation, and vasodilation via peripheral nitrergic nerves. It has also been implicated in neuronal death in cerebrovascular stroke. Expression of isoform II of NO synthase can be induced with lipopolysaccharide and cytokines in a multitude of different cells. Based on sequencing data there is no evidence for more than one inducible isozyme at this time. NO synthase II is not regulated by Ca2+; it produces large amounts of NO that has cytostatic effects on parasitic target cells by inhibiting iron-containing enzymes and causing DNA fragmentation. Induced NO synthase II is involved in the pathophysiology of autoimmune diseases and septic shock. Isoform III of NO synthase has been found mostly in endothelial cells. It is constitutively expressed, but expression can be enhanced, eg, by shear stress. Its activity is regulated by Ca2+ and calmodulin. NO from endothelial cells keeps blood vessels dilated, prevents the adhesion of platelets and white cells, and probably inhibits vascular smooth muscle proliferation.
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PMID:Nitric oxide synthase isozymes. Characterization, purification, molecular cloning, and functions. 751 53

Cerebral ischemia is followed by a local inflammatory response that is thought to participate in the extension of the tissue damage occurring in the postischemic period. However, the mechanisms whereby the inflammation contributes to the progression of the damage have not been fully elucidated. In models of inflammation, expression of the inducible isoform of nitric oxide synthase (iNOS) is responsible for cytotoxicity through the production of large amounts of nitric oxide (NO). In this study, therefore, we sought to establish whether iNOS is expressed in the ischemic brain. Rats were killed 6 h to 7 days after occlusion of the middle cerebral artery. iNOS expression in the ischemic area was determined by reverse-transcription polymerase chain reaction. Porphobilinogen deaminase mRNA was detected in the same sample and used for normalization. In the ischemic brain, there was expression of iNOS mRNA that began at 12 h, peaked at 48 h, and returned to baseline at 7 days (n = 3/time point). iNOS mRNA expression paralleled the time course of induction of iNOS catalytic activity, determined by the citrulline assay (17.4 +/- 4.4 pmol citrulline/micrograms protein/min at 48 h; mean +/- SD; n = 5 per time point). iNOS immunoreactivity was seen in neutrophils at 48-96 h after ischemia. The data provide molecular, biochemical, and immunocytochemical evidence of iNOS induction following focal cerebral ischemia. These findings, in concert with our recent demonstration that inhibition of iNOS reduces infarct volume in the same stroke model, indicate that NO production may play an important pathogenic role in the progression of the tissue damage that follows cerebral ischemia.
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PMID:Inducible nitric oxide synthase gene expression in brain following cerebral ischemia. 753 97

We investigated mechanisms by which hypoxia produces relaxation of the aorta and tested the hypothesis that these mechanisms are altered during chronic hypertension. Tension of thoracic aortae from normotensive Wistar-Kyoto (WKY) rats and stroke-prone spontaneously hypertensive rats (SHRSP) was measured in an organ bath under control conditions and at two levels of hypoxia. In WKY rats, mild and severe hypoxia produced relaxation of the aortae (precontracted with phenylephrine) by 33 +/- 4% and 82 +/- 3%, respectively (mean +/- SEM). Removal of endothelium or administration of NG-nitro-L-arginine (10(-4) mol/L), an inhibitor of nitric oxide synthase, abolished relaxation of the aortae in response to mild hypoxia but did not affect relaxation during severe hypoxia. Glibenclamide (10(-6) mol/L), an inhibitor of potassium channels, attenuated relaxation of the aortae during mild and severe hypoxia by 49 +/- 16% and 74 +/- 4%, respectively. In SHRSP, mild hypoxia produced little relaxation of the aortae (3 +/- 4%, P < .05 compared with WKY). Indomethacin did not increase relaxation to mild hypoxia in SHRSP, which suggests that a cyclooxygenase-derived contracting factor does not contribute to impaired relaxation. Severe hypoxia relaxed the aortae by 86 +/- 4% in SHRSP, and glibenclamide inhibited this response by 60 +/- 9%. These findings suggest that relaxation of the aorta in response to mild hypoxia in WKY rats is mediated primarily by endothelium-derived relaxing factor, and the response to mild hypoxia is markedly impaired in SHRSP.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Relaxation of the aorta during hypoxia is impaired in chronically hypertensive rats. 753 13

Nitric oxide (NO) has only recently been appreciated as a normal biologic substance with a role in signal transduction. It was first identified as endothelial-derived relaxing factor in blood vessels and as the mediator of the tumoricidal and bactericidal actions of macrophages. NO's role as a neural messenger may be even more prominent. Biosynthesis of NO involves oxidation of the guanidine group of arginine with stoichiometric formation of citrulline. NO synthase is one of the most extensively regulated enzymes in biology. In the periphery, NO is a likely transmitter of nonadrenergic, noncholinergic neurons. In the brain, NO neurons mediate action of glutamate acting at N-methyl-D-aspartate (NMDA) receptors. Excess release of NO appears to account for a major portion of neural damage following vascular stroke.
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PMID:Nitric oxide in the nervous system. 759 92

We investigated whether a nitric oxide synthase (NOS) inhibitor improves cardiovascular depression associated with anaphylaxis. After induction of anaphylactic circulatory depression, one group received an NOS inhibitor (Group I, n = 6) and the other received saline solution (Group II, n = 5). Mean arterial pressure and right atrial pressure were significantly higher in Group I than in Group II. Hematocrit was significantly lower in Group I than in Group II. Cardiac output, stroke volume, mean pulmonary arterial pressure, the maximum rate of increase in left ventricular pressure, and the time constant of the fall in isovolumic left ventricular pressure did not differ between the groups. In conclusion, L-NAME attenuates hypotension, but does not improve cardiac depression in anaphylaxis in dogs. Our finding that NOS inhibitor did not improve cardiac function implies that the production of NO in anaphylaxis may have a protective effect with regard to cardiac performance.
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PMID:An inhibitor of nitric oxide synthase, N omega-nitro-L-arginine-methyl ester, attenuates hypotension but does not improve cardiac depression in anaphylaxis in dogs. 765 70


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