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

Endocardial endothelial morphology and the physiological modulatory role of nitric oxide (NO) were studied in an in vitro preparation of the working intact heart of the frog Rana esculenta, which lacks coronary vasculature and is thus devoid of a coronary vascular endothelium. En face confocal scanning laser microscopy of samples of perfused fixed hearts demonstrated the presence of NO synthase as a cytoplasmic constituent of the endocardial endothelial cells. Stroke volume (as a measure of performance in paced frog hearts) and stroke work (as an index of systolic function) increased by approximately 5 % after inhibition of the NO-cGMP pathway with 10(-4 )mol l-1 NG-nitro-l-arginine methyl ester and by approximately 8 % after inhibition with 10(-6 )mol l-1 Methylene Blue. In contrast, stroke volume and stroke work decreased by approximately 22 % after activation of the NO-cGMP pathway with sodium nitroprusside (10(-4 )mol l-1), while 3-morpholinosydnonimine (5x10(-8) to 10(-5 )mol l-1) caused a decrease of between 15 and 30 % and 8-bromo-cGMP (10(-6 )mol l-1) a decrease of approximately 8 %. These responses were significantly attenuated after exposure of the ventricular luminal to Triton X-100 (0.05 %, 0.1 ml), which itself increased performance (by over 10 %) without detectable morphological changes. These results show that the endocardial endothelium of Rana esculenta produces amounts of NO sufficient to modulate ventricular performance.
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PMID:Endocardial endothelium in the avascular heart of the frog: morphology and role of nitric oxide. 936 19

Inflammatory mediators secreted by activated leukocytes play a role in the pathogenesis of atherosclerosis. They may also affect the production of vasodilatory and platelet antiaggregatory factors such as nitric oxide (NO) and prostacyclin (PGI2) from the vascular endothelium. Production of NO and PGI2, the effecs of which are mediated by cyclic 3',5'-guanosine monophosphate (cGMP) and cyclic 3',5'-adenosine monophosphate (cAMP), respectively, is disturbed in atherosclerosis, whereas increased NO levels have been found in acute cerebral ischemia. To investigate leukocyte activation and its possible influence upon endothelial function in cerebral ischemia we measured plasma neutrophil gelatinase-associated lipocalin (NGAL) and soluble tumor necrosis factor receptor protein-1 (sTNFR-1) by ELISA, and intraplatelet cAMP and cGMP by radioimmunoassay in 59 patients with acute ischemic stroke or transient ischemic attack (mean age 71 years, 27 males) and after a 1-year follow-up in 57/59 (97%) patients. NGAL (152 +/- 58 vs. 126 +/- 48 microgram/l), sTNFR-1 (3.50 +/- 2.2 vs. 2.59 +/- 1.31 microgram/l), and cAMP (5.12 +/- 1.71 vs. 4.06 +/- 0.92 pmol/10(9) platelets) were higher (p < 0.001) after follow-up than in acute cerebral ischemia. At follow-up sTNFR-1 and cGMP partially correlated (r = 0.31; p < 0.05), controlling for age and platelet count. In conclusion, plasma NGAL and sTNFR-1 and intraplatelet AMP increase after acute cerebral ischemia, indicating chronic inflammatory activity and endothelial activation. Plasma sTNFR-1 levels are related to intraplatelet cGMP levels.
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PMID:Increasing levels of leukocyte-derived inflammatory mediators in plasma and cAMP in platelets during follow-up after acute cerebral ischemia. 977 47

Brain ischemia initiates a complex cascade of metabolic events, several of which involve the generation of nitrogen and oxygen free radicals. These free radicals and related reactive chemical species mediate much of damage that occurs after transient brain ischemia, and in the penumbral region of infarcts caused by permanent ischemia. Nitric oxide, a water- and lipid-soluble free radical, is generated by the action of nitric oxide synthases. Ischemia causes a surge in nitric oxide synthase 1 (NOS 1) activity in neurons and, possibly, glia, increased NOS 3 activity in vascular endothelium, and later an increase in NOS 2 activity in a range of cells including infiltrating neutrophils and macrophages, activated microglia and astrocytes. The effects of ischemia on the activity of NOS 1, a Ca2+-dependent enzyme, are thought to be secondary to reversal of glutamate reuptake at synapses, activation of NMDA receptors, and resulting elevation of intracellular Ca2+. The up-regulation of NOS 2 activity is mediated by transcriptional inducers. In the context of brain ischemia, the activity of NOS 1 and NOS 2 is broadly deleterious, and their inhibition or inactivation is neuroprotective. However, the production of nitric oxide in blood vessels by NOS 3, which, like NOS 1, is Ca2+-dependent, causes vasodilatation and improves blood flow in the penumbral region of brain infarcts. In addition to causing the synthesis of nitric oxide, brain ischemia leads to the generation of superoxide, through the action of nitric oxide synthases, xanthine oxidase, leakage from the mitochondrial electron transport chain, and other mechanisms. Nitric oxide and superoxide are themselves highly reactive but can also combine to form a highly toxic anion, peroxynitrite. The toxicity of the free radicals and peroxynitrite results from their modification of macromolecules, especially DNA, and from the resulting induction of apoptotic and necrotic pathways. The mode of cell death that prevails probably depends on the severity and precise nature of the ischemic injury. Recent studies have emphasized the role of peroxynitrite in causing single-strand breaks in DNA, which activate the DNA repair protein poly(ADP-ribose) polymerase (PARP). This catalyzes the cleavage and thereby the consumption of NAD+, the source of energy for many vital cellular processes. Over-activation of PARP, with resulting depletion of NAD+, has been shown to make a major contribution to brain damage after transient focal ischemia in experimental animals. Neuronal accumulation of poly(ADP-ribose), the end-product of PARP activity has been demonstrated after brain ischemia in man. Several therapeutic strategies have been used to try to prevent oxidative damage and its consequences after brain ischemia in man. Although some of the drugs used in early studies were ineffective or had unacceptable side effects, other trials with antioxidant drugs have proven highly encouraging. The findings in recent animal studies are likely to lead to a range of further pharmacological strategies to limit brain injury in stroke patients.
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PMID:Oxidative stress in brain ischemia. 998 55

Intercellular adhesion molecule-1 (ICAM-1) is an adhesion molecule of the immunoglobulin family expressed on endothelial cells that is upregulated in brain as part of the acute inflammatory response to traumatic brain injury (TBI). ICAM-1 mediates neurologic injury in experimental meningitis and stroke; however, its role in the pathogenesis of TBI is unknown. We hypothesized that mutant mice deficient in ICAM-1 (-/-) would have decreased neutrophil accumulation, diminished histologic injury, and improved functional neurologic outcome versus ICAM-1 +/+ wild type control mice after TBI. Anesthetized ICAM-1 -/- mice and wild-type controls were subjected to controlled cortical impact (CCI, 6 m/sec, 1.2 mm depth). Neutrophils in brain parenchyma and ICAM-1 on vascular endothelium were assessed by immunohistochemistry in cryostat brain sections from the center of the contusion 24 h after TBI (n = 4/group). Separate groups of wild-type and ICAM-1-deficient mice (n = 9-10/group) underwent motor (wire grip test, days 1-5) and cognitive (Morris water maze [MWM], days 14-20) testing. Lesion volume was determined by image analysis 21 days following TBI. Robust expression of ICAM-1 was readily detected in choroid plexus and cerebral endothelium at 24 h in ICAM-1 +/+ mice but not in ICAM-1 -/- mice. No differences between groups were observed in brain neutrophil accumulation (9.4 +/- 2.2 versus 11.1 +/- 3.0 per x100 field, -/- versus +/+), wire grip score, MWM latency, or lesion volume (7.24 +/- 0.63 versus 7.21 +/- 0.45 mm3, -/- versus +/+). These studies fail to support a role for ICAM-1 in the pathogenesis of TBI.
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PMID:Effect of traumatic brain injury in mice deficient in intercellular adhesion molecule-1: assessment of histopathologic and functional outcome. 1022 16

Homocystinuria, an inherited disease in which plasma levels of homocysteine are high, was discovered in the sixties and it soon became clear that the affected patients had striking features of generalized atherosclerosis. The most common causes of death were arterial and venous thrombosis, stroke, or myocardial infarction. Observations in this human model of hyperhomocysteinemia led to studies in the general population whose findings suggest - though not conclusively- that homocysteine is a cardiovascular risk factor. The same is true for patients with chronic renal failure who almost always have moderate to severe high blood homocysteine levels. Homocysteine accumulates in relation to the concentration of its precursor, S-adenosylhomocysteine, a powerful competitive transmethylation inhibitor. Inhibition of a methyltransferase required to repair damaged proteins has actually been detected in uremic patients' red blood cells. However, in view of the multiple, widespread metabolic roles of S-adenosylmethionine-dependent methyltransferases, in many organs and tissues including the vascular endothelium, hypomethylation is currently interpreted as one of homocysteine's most important mechanisms of action. Various biological compounds, including small molecules and nucleic acids, as well as proteins, which are involved in the pathophysiology of thrombosis and atherosclerosis, are all potential targets of hypomethylation. Epidemiological studies and experimental models tend to confirm that homocysteine is both a cardiovascular risk factor and a uremic toxin, acting through different mechanisms.
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PMID:Homocysteine, a new cardiovascular risk factor, is also a powerful uremic toxin. 1049 66

1. A common 'stroke model', the rat middle cerebral artery occlusion preparation, was used to compare photocoagulation with mechanical occlusion. 2. Areas of cerebral infarction and of vascular leakage were compared using these two methods. The general pattern of damage was similar, with central infarcted areas surrounded by larger vascular leakage areas. 3. The two models differed in the extent of their vascular leakage areas and in their response to the cerebroprotective agent flunarizine. 4. We conclude that the two models are not equivalent, probably because they do not damage the vascular endothelium to the same degree.
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PMID:Comparative effect of flunarizine in two animal models of stroke. 1069 37

Thrombosis associated with atrial fibrillation (AF) is usually caused by a left atrial (LA) thrombus, but it is not always detected. The present study was based on the hypothesis that abnormalities in peripheral artery are responsible for the ischemic stroke associated with AF. Peripheral arterial coagulability was investigated in a rabbit experimental model in which AF was induced by high-frequency stimulation of the right atrium, creating stenosis of the carotid artery together with endothelial damage. The rabbits were classified into 4 groups: (i) sinus rhythm only (group 1), (ii) sinus rhythm after 6 h of pacing (group 2), (iii) short AF (continuous pacing for 5 min; group 3) and (iv) long AF (continuous pacing for 6 h: group 4). The carotid blood flow developed a typical pattern, called cyclic flow reductions (CFRs), the frequency of which (CFRF) was 18.59+/-2.85 in AF (group 3+4) compared with 14.46+/-2.1 in sinus rhythm (group 1+2) (p<0.0005). Among the groups with AF, correlation analysis showed an association between CFRF and pulse dispersion (p<0.02, r=0.58). This study suggests that the distinctive hemodynamic effects with AF, in particular pulse dispersion, substantively influence thrombus formation on injured vascular endothelium.
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PMID:Pulse dispersion due to atrial fibrillation causes arterial thrombosis in a rabbit experimental model. 1092 80

During the past year epidemiological studies have linked elevated plasma total homocysteine concentrations with an increased risk of ischaemic stroke because of arterial disease. Laboratory studies have further explored the mitogenic effects of total homocysteine on vascular smooth muscle, and cytotoxic and thrombophilic effects on vascular endothelium. Also, a clinical trial has shown that lowering total homocysteine by means of multivitamin therapy decreases the rate of abnormal exercise electrocardiography tests. However, it remains to be determined whether lowering total homocysteine prevents hard clinical outcome events, such as stroke and other serious vascular events. An alternative explanation for the observed association between elevated total homocysteine and stroke is a confounding effect of factors associated with hyperhomocysteinaemia (e.g. cigarette smoking, renal impairment, an atherogenic diet, cystine deficiency, folate deficiency) or perhaps even the acute vascular events themselves, whereby the tissue damage temporarily increases total homocysteine levels. The results of ongoing clinical trials in stroke patients to determine the impact of multivitamin therapy on recurrent stroke and other serious vascular events are awaited.
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PMID:Homocysteine and stroke. 1117 24

Although hormone replacement therapy (HRT) can have many favorable effects on serum lipids and on vascular endothelium that presumably mediate the decreased risk for heart attack and stroke associated with HRT in observational epidemiology, oral estrogen also has various pro-coagulant effects: increases in serum triglycerides and factor VII activity, decreases in serum antithrombin III and protein S. This may explain the increased risk for venous thromboembolism observed with HRT and oral contraceptives, as well as the temporary increase in coronary risk noted when women with preexisting coronary disease initiate HRT. The well-tolerated hypolipidemic agent bezafibrate has anticoagulant actions that are diametrically opposed to the procoagulant effects of oral estrogen: namely, reductions in serum triglycerides and factor VII activity, and an increase in antithrombin III. However, bezafibrate could be expected to complement the protective effects of oral estrogen on serum lipids and on serum IGF-I activity. Thus, there is reason to believe that concurrent bezafibrate administration would minimize any thrombotic risk associated with HRT or oral contraception, while amplifying the health benefits of oral estrogen, and would make it more feasible to administer these therapies in women at increased vascular risk. These predictions require confirmation in controlled clinical studies. Certain natural hypolipidemic agents may also have potential as adjuvants to oral estrogen, but their effects on hemostasis require further investigation.
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PMID:Concurrent administration of sustained-release bezafibrate may counteract the increased thrombotic risk associated with oral estrogen therapy. 1146 Nov 76

Abnormal platelet reactivity has been linked to unstable angina, myocardial infarction, post angioplasty stenosis, cerebral ischemia, thrombotic stroke and a variety of inflammatory vascular disorders associated with transplantation. Drugs that inhibit blood coagulation, promote fibrinolysis or block platelet activation are important therapeutic agents in cardiovascular medicine. However, many of the current antiplatelet modalities are nonspecific, ineffective or associated with severe side effects that limit their usefulness. In this article, we discuss some basic aspects of platelet pathophysiology to illustrate the importance of ADP stimulation and signaling in platelet activation. CD39, the ATP diphosphohydrolase (ATPDase) expressed on quiescent vascular endothelium, modulates platelet purinoreceptor activity by the sequential hydrolysis of extracellular ATP or ADP directly to AMP. This thromboregulatory potential of CD39 has been recently demonstrated by the generation of mutant mice with disruption of the gene, and by a series of experiments where high level ATPDase expression has been attained by adenoviral vectors in the injured vasculature. Systemic administration of soluble derivatives of CD39 or targeted expression of the native protein to sites of vascular injury may have future therapeutic application.
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PMID:New developments in anti-platelet therapies: potential use of CD39/vascular ATP diphosphohydrolase in thrombotic disorders. 1146 20


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