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

To examine whether endothelial dysfunction in hypertension is reversible or not, we studied the effects of imidapril, an angiotensin-converting enzyme inhibitor, on nitric oxide release in stroke-prone spontaneously hypertensive rats (SHR) and deoxycorticosterone acetate (DOCA)-salt hypertensive rats. After a 4-week treatment with imidapril (1 or 10 mg/d SC) or vehicle, acetylcholine-induced vasodilation and nitric oxide release in the isolated kidneys were determined. Nitric oxide release was measured by a chemiluminescense assay. Imidapril lowered blood pressure in stroke-prone SHR in a dose-dependent manner. Untreated stroke-prone SHR exhibited significantly attenuated responses to acetylcholine (10(-8) mol/L) of both renal perfusion pressure (stroke-prone SHE 42 +/- 4% versus Wistar-Kyoto rats [WKY] 58 +/- 4% [mean +/- SE], P < .01) and nitric oxide release (stroke-prone SHR +7.6 +/- 2.1 versus WKY +29.7 +/- 9.7 fmol/min per gram of kidney wt, P < .01). Imidapril at 10 mg/d significantly increased acetylcholine-induced renal vasodilation and nitric oxide release in stroke-prone SHR (renal perfusion pressure, 56 +/- 3%; nitric oxide release, +27.1 +/- 6.4 fmol/min per gram of kidney wt; both P < .01 versus stroke-prone SHR treated with vehicle). On the other hand, imidapril neither decreased blood pressure nor changed nitric oxide release induced by acetylcholine in DOCA-salt hypertensive rats. Staining for endothelial nitric oxide synthase and brain nitric oxide synthase was clearly detected in the kidneys of both stroke-prone SHR and WKY, whereas staining intensity was weaker in DOCA-salt hypertensive rats. Inducible nitric oxide synthase immunoreactivity was barely noticeable in any type of rat. Thus, imidapril restored endothelial damage by pressure-dependent mechanisms. Most of the nitric oxide detected in the perfusate seemed to be derived from constitutive nitric oxide synthase.
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PMID:Nitric oxide release from kidneys of hypertensive rats treated with imidapril. 861 23

A deficiency of nitric oxide may be responsible for the increased vascular resistance associated with human essential hypertension and that seen in animal models of hypertension. Premenopausal females are relatively protected from hypertension and cardiovascular complications. Levels of superoxide can influence the availability of nitric oxide. We hypothesize that there are differences in nitric oxide availability between stroke-prone spontaneously hypertensive rats (SHRSP) and Wistar-Kyoto rats (WKY) and that superoxide may be responsible for at least some of these differences. We studied vascular reactivity in endothelium-intact aortic rings from WKY and SHRSP. We measured nitric oxide synthase activity in endothelial cells removed from aortas and also measured circulating nitrite/nitrate levels. We found the response to N(G)-nitro-L-arginine methyl ester to be significantly greater in WKY compared with SHRSP (95% CI: 20 to 174; P=.015) and in females compared with males in WKY (95% CI: 143 to 333; P=.00004) and SHRSP (95% CI: 70 to 224; P=.0006). Endothelial nitric oxide synthase activity was significantly greater in SHRSP compared with WKY (95% CI: 2.3 to 17.6; P=.016). The EC50 for relaxation to carbachol was significantly greater in male rats compared with female rats (95% CI: -1.1 to -0.2; P=.003) within the SHRSP strain. The maximum relaxation to carbachol was significantly attenuated in stroke prone spontaneously hypertensive compared with Wistar-Kyoto rats (95% CI: 1.7 to 14.4; P=.015). Diethyldithiocarbamate had a significantly greater effect on the stroke prone spontaneously hypertensive rats' carbachol response than that of Wistar-Kyoto rats (95% CI: 14.3 to 47.0; P=.0008). We conclude that superoxide may be responsible for strain differences in vascular reactivity, whereas nitric oxide availability may be responsible for sex differences independently of endothelial nitric oxide synthase activity and superoxide.
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PMID:Sex differences in the abundance of endothelial nitric oxide in a model of genetic hypertension. 940 76

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

The recent advances in the histopathology of ischemia have set forth new proposals, particularly in regard to excitotoxicity by the glutamate receptor, NMDA. The participation of the nitric oxide (NO) in normal and pathological conditions and its relationship with toxicity in ischemia, suggest new alternatives for the modulation of the NMDA receptor REDOX site through its pharmacologic manipulation. This event would potentially limit the consequences of the activation-calcium flow and the production of peroxoinitrite during the ischemic phenomenon. The present work delivers two proposals: 1) A modified technique to the ones that have been described, of endovascular, without craniectomy, for experimental cerebral ischemia in Wistar rats, and with particular harmful effect upon the hippocampus. 2) It promotes the use of nitrates as an additional alternative to other elements, in order to restrict excitotoxicity in the described experimental cerebral ischemia, and paying attention to CA1-CA2 of the hippocampus. This area, specially sensitive to hypoxia-ischemia, offers an excellent study option for focal, experimental, cerebral ischemia associated with toxicity mediated by excitatory amino acids, since it stores an important concentration of NMDA receptors (R1/R2 A) as well as endothelial nitric oxide synthase. Our parameters are supported by quantitative-qualitative cell analysis, and not by the extension of the stroke which offers a more objective perspective upon the assessment of the focal ischemic event. By means of this technique, these results confirm the extent of the ischemic injury to the cell at the level of the hippocampus compared to a control/basal group, P = 0.0006. Furthermore, it suggests a neuroprotective effect of isosorbide dinitrate since it preserves the viable cells, and limits the appearance of hypoxic-ischemic cells at the hippocampus when the middle cerebral artery (MCA) is occluded endovascularly, as compared to the animals with no treatment P = 0.0080. However, other research lines are needed to compare the efficacy of this present work with other therapeutic proposals.
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PMID:Neuroprotection in selective focal ischemia in rats by nitrates, an alternative redox manipulation on nitric oxide: experimental model. 980 40

Therapeutic interventions for acute ischemic stroke have not yet been established in clinical practice. The recognition of an area of reduced blood flow in which neuronal death may be prevented has focused attention on treatments aiming at minimizing ischemic brain damage, if they are initiated within short time after occlusion. The combination of restoring blood flow and providing neuroprotection may be the most productive approach in human acute ischemic stroke, but this combined therapy requires testing through clinical trials. To gain insight into the molecular mechanisms of cerebral ischemia, this review examines the excito-toxic cascade, synthesis and role of nitric oxide and oxidants, gene regulation and possible neuroprotective therapeutic targets. As neuroprotectants, glutamate-antagonists, calcium-antagonists and free radical scavengers have been investigated. The role of nitric oxide is very complex, as it can be cytotoxic or cytoprotective in relation to sources, time of synthesis, and medium redox state. Animal gene studies suggest that nitric oxide produced by endothelial nitric oxide synthase may be advantageous, while nitric oxide produced by neuronal and inducible nitric oxide synthase disadvantageous. A treatment strategy could involve the use of selective inhibitors of different types of nitric oxide synthase. Cell death after cerebral ischemia occurs through the dual pathway of ischemic necrosis and apoptosis. Novel therapies may be directed at genes mediating either recovery or apoptosis. There are, as yet, no conclusive data concerning the safety and efficacy of neuroprotectants in humans. Differences between animal models and clinical conditions may justify the discrepancy between experimental data and clinical practice.
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PMID:[The molecular mechanisms of cerebral ischemia: the possible therapeutic interventions]. 1039 71

Human essential hypertension is a complex, multifactorial, quantitative trait under a polygenic control. Several strategies have been developed over the last decade to dissect genetic determinants of hypertension. Of these, the most successful have been studies that identified rare mendelian syndromes in which a single gene mutation causes high blood pressure. The attempts to identify multiple genes, each with a small contribution to the common polygenic form of hypertension, have been less successful. Several laboratories focused their attention on rat models of genetic hypertension, which can be considered as a reductionist paradigm for human disease. Using numerous crosses between hypertensive and normotensive strains, investigators identified several quantitative trait loci (QTL) for blood pressure subphenotypes and for cardiovascular complications such as left ventricular hypertrophy, kidney failure, stroke, and insulin resistance. Furthermore, congenic strains have been produced to confirm the existence of some of these QTL and to narrow down the chromosomal regions of interest. A number of interesting strategies have been developed, including a "speed" congenic strategy perfected by our group in Glasgow. However, the limit of congenic strategy is estimated at 1 cM, which corresponds to 2x10(6) base pairs of DNA and approximately 50 candidate genes. It is envisaged that gene expression profiling with cDNA microarrays might allow a quick progression toward the gene identification within cardiovascular QTL. In parallel experimental effort, several laboratories have been developing gene transfer/therapy strategies with adenoviral or adeno-associated viral vectors used, for example, to overexpress protective vascular genes such as vascular endothelial growth factor or endothelial nitric oxide synthase. It is anticipated that further developments in positional cloning of susceptibility and severity genes in hypertension and its complications will lead to a direct transfer of these discoveries to essential hypertension in humans and will ultimately produce novel targets for local and systemic gene therapy in cardiovascular disease.
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PMID:Genes and hypertension: from gene mapping in experimental models to vascular gene transfer strategies. 1064 93

In this study, we investigated the outcome of lifelong treatment with the angiotensin II type 1 receptor (AT(1)) blocker fonsartan (HR 720) in young stroke-prone spontaneously hypertensive rats (SHR-SP). In addition to the primary end point, lifespan, and to determine the mechanisms involved in the treatment-induced effects, parameters such as left ventricular hypertrophy, cardiac function/metabolism, endothelial function, and the expression/activity of endothelial nitric oxide synthase and of angiotensin-converting enzyme (ACE) were also investigated. Ninety 1-month-old SHR-SP were allotted to 2 groups and treated via drinking water with an antihypertensive dose of fonsartan (10 mg. kg(-1). d(-1)) or placebo. Fonsartan doubled the lifespan to 30 months in SHR-SP, which was comparable to the lifespan of normotensive Wistar-Kyoto rats. After 15 months, a time when approximately 80% of the placebo group had died, left ventricular hypertrophy was completely prevented in fonsartan-treated animals. Furthermore, cardiac function and metabolism as well as endothelial function were significantly improved. These effects were correlated with increased endothelial nitric oxide synthase expression in the heart and carotid artery and with markedly decreased tissue ACE expression/activities. Lifespan extension and cardiovascular protection by long-term AT(1) blockade with fonsartan led to similar beneficial effects, as observed with long-term ACE inhibition.
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PMID:Long-term angiotensin II type 1 receptor blockade with fonsartan doubles lifespan of hypertensive rats. 1077 60

Ischaemic stroke can be caused by a number of monogenic disorders, and in such cases stroke is frequently part of a multisystem disorder. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL), due to mutations in the NOTCH: 3 gene, is increasingly appreciated as a cause of familial subcortical stroke. The genetics and phenotypes of monogenic stroke are covered in this review. However, the majority of cases of ischaemic stroke are multifactorial in aetiology. Strong evidence from epidemiological and animal studies has implicated genetic influences in the pathogenesis of multifactorial ischaemic stroke, but the identification of individual causative mutations remains problematic; this is in part limited by the number of approaches currently available. In addition, genetic influences are likely to be polygenic, and ischaemic stroke itself consists of a number of different phenotypes which may each have different genetic profiles. Almost all human studies to date have employed a candidate gene approach. Associations with polymorphisms in a variety of candidate genes have been investigated, including haemostatic genes, genes controlling homocysteine metabolism, the angiotensin-converting enzyme gene, and the endothelial nitric oxide synthase gene. The results of these studies, and the advantages and limitations of the candidate gene approach, are presented. The recent biological revolution, spurred by the human genome project, promises the advent of novel technologies supported by bioinformatics resources that will transform the study of polygenic disorders such as stroke. Their potential application to polygenic ischaemic stroke is discussed.
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PMID:Genetics and ischaemic stroke. 1096 44

Gene therapy may, be a promising approach for treatment of cerebrovascular disease. An adenoviral vector encoding beta-galactosidase was administered intracisternally or intraventricularly into the brain of rats. Efficient expression of the reporter gene was observed at the cerebral blood vessels and perivascular tissues. When the adenoviral vector was delivered into CSF of dogs suffering from subarachnoid hemorrhage, prominent expressions of transgene were observed. Introduction of the vector to the ischemic brain of rats provided efficient transgene expression in the peri-ischemic area. Therefore, gene transfer to the cerebral blood vessel and brain may be a promising approach for gene therapy of stroke. Atherosclerotic lesion plays an important role in stroke. We evaluated efficacy of adenovirus-mediated gene transfer to the atherosclerotic vessels from monkeys and rabbits using an ex vivo gene transfer system. Efficiency of transgene expression in the atherosclerotic endothelium was better than that of normal vessels in both animals. Thus, the endothelium of atherosclerotic vessels may be a good target for gene therapy. Next, we transfected atherosclerotic carotid arteries from rabbits with an adenoviral vector encoding endothelial nitric oxide synthase (eNOS). After overexpression of eNOS in the atherosclerotic arteries, the response to acetylcholine was augmented, showing similar relaxation with normal vessels. These results suggest that gene transfer to atherosclerotic vessels improves endothelial function, which may be a new therapeutic approach for cerebrovascular disease.
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PMID:Adenovirus-mediated gene transfer to cerebral circulation. 1099 9

While a number of laboratories have begun to examine gender differences in outcome following experimental stroke, little is known about the relative response of male and female brains to traumatic injury. In the following series of experiments, we used the Marmarou impact-acceleration head injury model (with a 500-g, 1.5-m weight drop) to compare the pathophysiological responses of male and female rats to closed-head injury. Cortical blood flow (CBF; laser-doppler flowmetry), mean arterial blood pressure (MAP), blood gas levels, blood pH, and body temperature were measured preinjury and at regular intervals postinjury. Acute survival was assessed 1 h after injury. The role of estrogen in the observed gender differences was assessed by examining these physiological measures after injury in ovariectomized females, with or without 17beta-estradiol replacement, and in intact males, with or without exogenous 17beta-estradiol administration. In the first experiment, significantly more females (100%) survived the acute injury period (60 min) after injury than did males (72%). Survival appeared related to the magnitude and persistence of the posttraumatic drop in MAP. In a second experiment, females showed a less dramatic reduction in and better recovery of CBF than males. The gender difference in CBF was paralleled to some degree by differences in the pattern of MAP changes after injury. Differences in body weight, blood gas levels, or blood pH did not account for the gender difference in CBF. Postinjury CBF was higher in female and male rats given 2 weeks of daily 17beta-estradiol injections prior to injury compared to those given the vehicle only. However, 17beta-estradiol administration did not alter MAP, suggesting that the gender difference in CBF was not strictly due to MAP changes. Our findings suggest that estrogen plays a role in maintaining adequate cerebral perfusion in the acute period following closed-head injury. This protective mechanism may underlie the gender difference in acute survival observed in this study, and may help explain observations of better outcome in females than in males after brain injury. We conclude that CBF preservation is one mechanism by which estrogen is neuroprotective following traumatic brain injury. We hypothesize, based upon known effects of estrogen, that the beneficial microvascular effects of estrogen most likely involve a combination of endothelial nitric oxide synthase induction and an antioxidant effect.
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PMID:Estrogen-related gender difference in survival rate and cortical blood flow after impact-acceleration head injury in rats. 1118 29


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