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

Gender differences in the incidence of stroke and migraine appear to be related to circulating levels of estrogen; however, the underlying mechanisms are not yet understood. Using resistance-sized arteries pressurized in vitro, we have found that myogenic tone of rat cerebral arteries differs between males and females. This difference appears to result from estrogen enhancement of endothelial nitric oxide (NO) production. Luminal diameter was measured in middle cerebral artery segments from males and from females that were either untreated, ovariectomized (Ovx), or ovariectomized with estrogen replacement (Ovx + Est). The maximal passive diameters (0 Ca2+ + 1 mM EDTA) of arteries from all four groups were identical. In response to a series of 10-mmHg step increases in transmural pressure (20-80 mmHg), myogenic tone was greater and vascular distensibility less in arteries from males and Ovx females compared with arteries from either untreated or Ovx + Est females. In the presence of NG-nitro-L-arginine methyl ester (L-NAME; 1 microM), an NO synthase inhibitor, myogenic tone was increased in all arteries, but the differences among arteries from the various groups were abolished. Addition of L-arginine (1 mM) in the presence of L-NAME restored the differences in myogenic tone, suggesting that estrogen works through an NO-dependent mechanism in cerebral arteries. To determine the target of NO-dependent modulation of myogenic tone, we used tetraethylammonium (TEA; 1 mM) to inhibit large-conductance, calcium-activated K+ (BKCa) channels. In the presence of TEA, the myogenic tone of arteries from all groups increased significantly; however, myogenic tone in arteries from males and Ovx females remained significantly greater than in arteries from either untreated or Ovx + Est females. This suggests that activity of BKCa channels influences myogenic tone but does not directly mediate the effects of estrogen. Estrogen appears to alter myogenic tone by increasing cerebrovascular NO production and/or action.
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PMID:Estrogen reduces myogenic tone through a nitric oxide-dependent mechanism in rat cerebral arteries. 968 26

HMG-CoA reductase inhibitors are potent cholesterol-lowering drugs. Recent clinical trials and meta-analyses show a 30% stroke reduction after treatment with HMG-CoA reductase inhibitors. Subgroup analyses and experimental findings support the notion that HMG-CoA reductase inhibitors improve endothelial function directly by mechanism(s) independent of cholesterol-lowering. They reduce inflammatory, proliferative and thrombogenic processes in atherosclerotic plaques and improve endothelial dysfunction. Recent findings demonstrate an enhanced production of endothelium-derived nitric oxide (NO) by HMG-CoA reductase inhibitors. Endothelial NO is an important vasodilator and plays a beneficial role in cerebral ischemic injury. Prophylactic treatment with HMG-CoA reductase inhibitors in mice selectively upregulates endothelial NO synthase expression and activity, increases cerebral blood flow at resting state and during ischemia, and reduces cerebral infarct size after experimental stroke. These findings provide a novel mechanism for the prophylactic treatment of ischemia-induced cerebral injury under non-hypercholesterolemic conditions.
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PMID:[HMG-CoA reductase inhibitor and risk of stroke]. 975 26

The arterial wall is structurally and functionally compartmentalized. Each compartment is characterized by a specific cell type and by specific interactions. The endothelial compartment interacts with circulating blood, and the adventitial compartment with the surrounding tissue. The media, which contains the effector smooth muscle cells, perceives centrifugal messages from the endothelium and centripetal messages from metabolically active tissues, from adventitial nerve endings, and from peptides produced in the interstitium. The degree of contraction or relaxation of the vascular smooth muscle cells characterizes the general vasomotor tone, which governs the local blood pressure level and distributes the flow according to metabolic needs. The main physiologic vasoactive agent is nitric oxide (NO) and is produced by the endothelium. In disease states, other agents can become predominant in centrifugal parietal messages. NO is produced by type 3 NO synthase, an enzyme that is constitutively expressed by endothelial cells. The activity of this enzyme on its substrate, arginine, is regulated by the concentration of free calcium and by intracellular phosphorylations. Several peptides, including receptors, are coupled to the phospholipase C pathway in the endothelial cell; endothelial growth factors such as FGF and VEGF, enhance the activity of endothelial NO synthase. However, the main physiologic factor responsible for endothelial NO synthase activation is the shearing stress produced by friction of the flowing blood against the immobile vessel wall. This shearing stress constantly adjusts the diameter of conductance vessels to peripheral metabolic needs. Expression of endothelial NO synthase is modulated by the chronic effects of the same agents. NO has a vasodilating effect that is mediated by the generation of cyclic GMP. Cyclic GMP and cyclic AMP are the main second messengers in smooth muscle cell relaxation. NO binds to a heme-protein, soluble guanylate cyclase, that converts GMP to cyclic GMP. Kinase-G is the main target for cyclic GMP in the smooth muscle cell. Kinase-G phosphorylates phospholambans and releases the repumping activity of calcium ATPase. More importantly, kinase-G phosphorylates the protein G that links seven-domain membrane-spanning receptors to phospholipases, thus inhibiting coupling between the ligand-receptors interaction and the intracellular signaling process that leads to contraction. NO can relax the smooth muscle cell only in the presence of a preexisting contractile tone. Conversely, absence of NO enhances the preexisting contractile tone. All these notions can be analyzed via the experimental model of L-NAME-induced chronic NO synthase blockade in rats. The decrease in parietal cyclic GMP seen in this model is associated with an increase in contractile tone that translates into systemic arterial hypertension. The increase in contractile tone can be blocked by renin-angiotensin system inhibitors. Chronic blockade of NO production rapidly induces vascular wall phenotype changes that lead to renal failure, ischemic stroke, and fibrosis of target organs. These phenotype changes may be related to the increase in the oxidative potential of the various types of parietal cells, as suggested by the abnormal presence of inflammatory cells and by the increased expression of inflammation mediators including cyclooxygenase II, inducible NO synthase, and adhesion molecules such as ICAM and VCAM. This model therefore holds promise for elucidating interactions between NO and arteriosclerosis. NO system dysfunction is also seen in other cardiovascular disorders, including congestive heart failure.
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PMID:[Role of endothelial nitric oxide in the regulation of the vasomotor system]. 976 14

Evidence from investigations of brain microcirculation (pial arterioles) reveals at least 3 different endothelium (EC) dependent mechanisms for dilation. Only one of the three can be triggered by acetylcholine (ACh) and in this vascular bed it is only this path that is dependent upon endothelial nitric oxide synthase (NOS) which produces nitric oxide (NO) from arginine. In this vascular bed the ACh sensitive path cannot be triggered by bradykinin (BK). This state of affairs appears to differ from that found in other beds or in endothelium cultured from conductance vessels. In the cerebral microcirculation there is considerable pharmacological evidence that the endothelium derived relaxing factor (EDRF) for ACh is not NO itself but may contain NO. In many experimental vascular settings the release of the NOS dependent EDRF is shear dependent. In the cerebral microcirculation there are several studies suggesting, in vivo, that this is correct. Among these are the following: (1) vessels narrow when shear is reduced after carotid ligation, and remain so along with unresponsiveness to ACh for at least ten minutes following resumption of flow. This may be important in developing stroke. The collapse is not passive due to low pressure. We know this because the narrowed vessels with their low intraluminal shear and pressure are still capable of large dilation by the NO donor, sodium nitropruside; (2) the antiplatelet effects of EC which are mediated, in part, by the EDRF for ACh are enhanced for 10 to 20 minutes following the transient increase and return of shear within these vessels. If the reverse is also true, reductions of shear may have important harmful proaggregant effects on platelets (and leukocytes) in the microvascular bed of developing infarcts. However most of the cited work depends upon pharmacological inhibitors of NOS to "prove" that NOS and an EDRF/NO are involved. In the last three years evidence in cats and rats shows that many of the NOS inhibitors also block K channels in cerebrovascular smooth muscle and that arginine, the "antidote" to the NOS inhibitors keeps the channels open. This latter work must force a reexamination of the conclusions reached in many studies.
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PMID:Is the EDRF in the cerebral circulation NO? Its release by shear and the dangers in interpreting the effects of NOS inhibitors. 978 59

Ischemic stroke is the most common life-threatening neurological disease and has limited therapeutic options. One component of ischemic neuronal death is inflammation. Here we show that doxycycline and minocycline, which are broad-spectrum antibiotics and have antiinflammatory effects independent of their antimicrobial activity, protect hippocampal neurons against global ischemia in gerbils. Minocycline increased the survival of CA1 pyramidal neurons from 10.5% to 77% when the treatment was started 12 h before ischemia and to 71% when the treatment was started 30 min after ischemia. The survival with corresponding pre- and posttreatment with doxycycline was 57% and 47%, respectively. Minocycline prevented completely the ischemia-induced activation of microglia and the appearance of NADPH-diaphorase reactive cells, but did not affect induction of glial acidic fibrillary protein, a marker of astrogliosis. Minocycline treatment for 4 days resulted in a 70% reduction in mRNA induction of interleukin-1beta-converting enzyme, a caspase that is induced in microglia after ischemia. Likewise, expression of inducible nitric oxide synthase mRNA was attenuated by 30% in minocycline-treated animals. Our results suggest that lipid-soluble tetracyclines, doxycycline and minocycline, inhibit inflammation and are neuroprotective against ischemic stroke, even when administered after the insult. Tetracycline derivatives may have a potential use also as antiischemic compounds in humans.
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PMID:Tetracyclines inhibit microglial activation and are neuroprotective in global brain ischemia. 986 Oct 45

Recently, we have shown that chronic administration of N-Nitro-L-Arginine Methyl Ester (L-NAME, an inhibitor of nitric oxide synthase) precipitates stroke in stroke-prone spontaneously hypertensive rats (SHRSP). Enalapril maleate, an angiotensin converting enzyme inhibitor was shown to delay the onset of such stroke. In the present study, five groups of 4-week-old SHRSP were used. Three groups of SHRSP were made diabetic using streptozotocin (100 mg/kg i.p.). One week later, the SHRSP from groups I (non-diabetic) and III (diabetic) chronically received L-NAME (0.5 g/L) in saline as drinking water. Two SHRSP groups, II (non-diabetic) and IV (diabetic) received L-NAME (0.5 g/L) and enalapril maleate (20 mg/L) in saline as drinking water. Control SHRSP (group C; diabetic) received only saline to drink. SHRSP groups I and III developed stroke in 10+/-2 and 11+/-2 days, respectively. The average stroke-free period in groups II and IV was 19+/-2 and 28+/-2 days, respectively. Protective effect of streptozotocin-induced diabetes disappeared when SHRSP drinking L-NAME and enalapril, concurrently received subcutaneous injections of insulin (2 units daily per 100 g rat). Present data suggest that experimental diabetes delays the onset of L-NAME-induced stroke in SHRSP only in the absence of angiotensin converting enzyme activity. In addition, diabetes-induced enhancement of stroke-protective effect of enalapril appears to be independent of reduction in mean and systolic blood pressures.
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PMID:Streptozotocin-induced diabetes enhances protective effects of enalapril on nitric oxide-deficient stroke in stroke-prone rats. 987 25

The gaseous signal molecule, nitric oxide (NO*), is generated enzymatically by NO synthase (NOS) from L-arginine. Overproduction of NO contributes to cell and tissue damage as sequelae of infection and stroke. Strategies to suppress NO synthesis rely heavily on guanidino-substituted L-arginine analogs (L-NAME, L-NA, L-NMMA, L-NIO) as competitive inhibitors of NOS, which are often used in high doses to compete with millimolar concentrations of intracellular arginine. We show that these analogs are also a source for non-enzymatically produced NO. Enzyme-independent NO release occurs in the presence of NADPH, glutathione, L-cysteine, dithiothreitol and ascorbate. This non-enzymatic synthesis of NO can produce potentially toxic, micromolar concentrations of NO and can oppose the effects of NOS inhibition. NO production driven by NOS inhibitors was demonstrated ex vivo in the central nervous and peripheral tissues of gastropod molluscs Aplysia and Pleurobranchaea using electron paramagnetic resonance and spin-trapping techniques. These results have important implications for therapeutic regulation of NO homeostasis.
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PMID:Non-enzymatic production of nitric oxide (NO) from NO synthase inhibitors. 991 69

Recently, we have shown that chronic administration of N-Nitro-L-Arginine Methyl Ester (L-NAME, an inhibitor of nitric oxide synthase) precipitates stroke in stroke-prone spontaneously hypertensive rats (SHRSP). Angiotensin receptor antagonist (L-158,809) was shown to delay the onset of such stroke. In the present study, five groups of 4-week-old SHRSP were used. Three groups of SHRSP were made diabetic using streptozotocin (100 mg/kg i.p.). SHRSP from groups I (non-diabetic) and III (diabetic) chronically received L-NAME(0.5 g/L) and L-158,809 (20 mg/L) in saline to drink. Diabetic SHRSP (group C) received only saline to drink. SHRSP groups I and III developed stroke in 10+/-2 and 11+/-2 days. Average stroke-free period in groups II and IV was 18+/-2 and 29+/-2 days, respectively. Protective effect of streptozotocin-induced diabetes disappeared when SHRSP drinking L-NAME and L-158,809, also received subcutaneous injections of insulin. Present data suggest that experimental diabetes delays the onset of L-NAME-induced stroke in SHRSP and this protection is seen in the absence of renin-angiotensin system.
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PMID:Effect of experimental diabetes on the protection by angiotensin blockers on nitric oxide deficient stroke in stroke-prone spontaneously hypertensive rats. 1005 40

Damage to the mitochondrial electron transport chain has been suggested to be an important factor in the pathogenesis of a range of neurological disorders, such as Parkinson's disease, Alzheimer's disease, multiple sclerosis, stroke and amyotrophic lateral sclerosis. There is also a growing body of evidence to implicate excessive or inappropriate generation of nitric oxide (NO) in these disorders. It is now well documented that NO and its toxic metabolite, peroxynitrite (ONOO-), can inhibit components of the mitochondrial respiratory chain leading, if damage is severe enough, to a cellular energy deficiency state. Within the brain, the susceptibility of different brain cell types to NO and ONOO- exposure may be dependent on factors such as the intracellular reduced glutathione (GSH) concentration and an ability to increase glycolytic flux in the face of mitochondrial damage. Thus neurones, in contrast to astrocytes, appear particularly vulnerable to the action of these molecules. Following cytokine exposure, astrocytes can increase NO generation, due to de novo synthesis of the inducible form of nitric oxide synthase (NOS). Whilst the NO/ONOO- so formed may not affect astrocyte survival, these molecules may diffuse out to cause mitochondrial damage, and possibly cell death, to other cells, such as neurones, in close proximity. Evidence is now available to support this scenario for neurological disorders, such as multiple sclerosis. In other conditions, such as ischaemia, increased availability of glutamate may lead to an activation of a calcium-dependent nitric oxide synthase associated with neurones. Such increased/inappropriate NO formation may contribute to energy depletion and neuronal cell death. The evidence available for NO/ONOO--mediated mitochondrial damage in various neurological disorders is considered and potential therapeutic strategies are proposed.
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PMID:Nitric oxide, mitochondria and neurological disease. 1007 28

The inducible or "immunological" isoform of nitric oxide synthase (iNOS) is induced in many cell types by inflammatory stimuli and synthesizes toxic amounts of NO. In rodent models of focal cerebral ischemia, iNOS is expressed in neutrophils invading the injured brain and in local blood vessels. Studies with iNOS inhibitors and iNOS null mice indicate that NO produced by iNOS contributes to ischemic brain injury. In the present study, we sought to determine whether iNOS is also expressed in the human brain after ischemic stroke. Studies were conducted using immunohistochemistry on autopsy brains with neuropathological evidence of acute cerebral infarction. iNOS immunoreactivity was observed in neutrophils infiltrating the ischemic brain and in blood vessels within the ischemic territory. iNOS-positive cells also were immunoreactive for nitrotyrosine, reflecting protein nitration by NO-derived peroxynitrite and nitrites. iNOS or nitrotyrosine immunoreactivity was not detected outside the region of the infarct. These observations provide evidence that iNOS is expressed in the human brain after ischemic infarction and support the hypothesis that iNOS inhibitors may be useful in the treatment of ischemic stroke in humans.
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PMID:Inducible nitric oxide synthase expression in human cerebral infarcts. 1009 Jun 67


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