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

Endothelium exerts an important influence on cerebral vascular tone through the production and release of a diverse group of vasoactive factors. Relaxing factors produced by endothelium include nitric oxide (or a nitric oxide-containing compound), a hyperpolarizing factor, and prostacyclin. Endothelium-derived contracting factors include cyclooxygenase products of arachidonic acid and endothelins. Several pathophysiological conditions are associated with increased formation of endothelium-derived contracting factors. Such endothelial dysfunction in the cerebral circulation may shift the balance of vascular tone toward constriction and may potentially contribute to the onset or maintainance of cerebral ischemia and stroke.
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PMID:Regulation of the cerebral circulation by endothelium. 129 44

Acetylsalicylic acid (ASA) inhibits thromboxane production and hence platelet aggregation. However, individual variations in platelet aggregability and serum thromboxane B2 (TxB2) concentration after a low dose of ASA (40 mg/day) have been reported. To clarify this issue, we studied plasma thromboxane levels and platelet aggregation in 43 ischemic stroke patients. Of the 22 patients who received 100 mg of ASA daily, dissociation between inhibitory effects of ASA on the plasma TxB2 level and threshold concentrations of adenosine diphosphate was found in three cases after one month of drug administration, and in three cases after six, 12 and 18 months of ASA therapy. This dissociation also developed in two patients after one month and six months, respectively, of treatment in the 21 patients who received 300 mg of ASA daily. The dissociation between the inhibitory effects on plasma TxB2 and the circulating platelet aggregate ratio was found in two cases after taking medication for one month, and in four cases after six, 12, 18 and 24 months of therapy in the 100 mg ASA group. In the 300 mg ASA group, dissociation was noted in two cases after one month of medication, and in two cases after six and 12 months of medication. In these patients, although their TxB2 levels were inhibited to almost unmeasurable levels, platelet aggregation was still not inhibited. This ASA inhibitory dissociation phenomenon on platelet function may be due to the low dose of ASA, individual differences in platelet function in response to ASA therapy, or factors other than those involved in the cyclooxygenase system.
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PMID:Dissociation of inhibitory effects of low-dose ASA on thromboxane production and platelet aggregation in ischemic stroke patients. 136 90

The present study examined whether the dual cyclooxygenase/lipoxygenase inhibitor phenidone would protect stroke-prone spontaneously hypertensive rats (SHRSP) from stroke and hypertensive renal disease. Vehicle-treated SHRSP (N = 6), fed stroke-prone rodent diet and 1% saline, exhibited severe systolic blood pressure elevation (261 +/- 10 mm Hg, mean +/- SEM), marked proteinuria (90 +/- 12 mg/day), and stroke, with an average age at death of 14 +/- 1 weeks. In a second group of six saline-loaded SHRSP, treatment with phenidone (60 mg/kg/day) was started at 8.4 weeks of age. Despite establishment of severe hypertension in this group (274 +/- 10 mm Hg), proteinuria remained at basal levels (28 +/- 13 mg/day), and signs of stroke were absent (P less than .01 v vehicle) through at least 16 weeks of age. Phenidone treatment also prevented the declines in body weight and food intake observed in vehicle-treated SHRSP, and maintained urine volume and saline intake. Serum 12-hydroxy-eicosatetraenoic acid (12-HETE) generation was significantly inhibited greater than 50% in incubates of whole blood from phenidone-treated SHRSP. We have previously shown that agents which interfere with the renin-angiotensin system afford protection from renal and cerebrovascular injury in saline-loaded SHRSP; cyclooxygenase inhibition alone will hasten the onset of these pathologic changes. Whether phenidone, which has been reported to attenuate angiotensin II-mediated effects, affords vascular protection by interference with a lipoxygenase-mediated action of angiotensin II remains to be elucidated.
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PMID:The lipoxygenase inhibitor phenidone protects against proteinuria and stroke in stroke-prone spontaneously hypertensive rats. 155 Jun 66

Vascular responses to ATP were studied in aortic rings isolated from stroke-prone spontaneously hypertensive rats (SHRSP) and normotensive Wistar-Kyoto rats (WKY). Low concentrations of ATP (10 nM to 10 microM) caused relaxation and high concentrations (0.1 mM to 10 mM) caused contraction. Both of these responses were accentuated by factors released from the endothelium. The endothelium-derived relaxing factor (EDRF) was blocked by NG-monomethyl-L-arginine (L-NMMA). This is the first time that it has been reported that ATP causes the release of an endothelium-derived contracting factor (EDCF). Its release was diminished but not completely blocked by cyclooxygenase inhibitors. Assays of muscle bath prostanoid composition indicated that ATP stimulation caused the release of prostaglandins I2 and E2 and thromboxane A2 from intact aortic rings. Evidence is presented that neither endothelin nor superoxide anion contributed to the EDCF. No difference was observed between WKY and SHRSP with regard to either the endothelial contributions to the response, or the direct action on vascular smooth muscle of ATP. High concentrations of ATP achieved intravascularly in hypoxia may cause vasospasm by release of endothelial prostanoids.
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PMID:Contraction and relaxation of rat aorta in response to ATP. 185 26

Decreased cardiac output and increased plasma thromboxane have been observed during aortic cross-clamping under general anesthesia. Amelioration of these changes has been reported by preoperative administration of cyclooxygenase inhibitors, but heterogeneity in patients' intravascular volume status has confounded analysis of the drugs' effects in previous studies. We studied hemodynamic conditions in 24 volume-loaded (pulmonary capillary wedge pressure greater than 10 mm Hg) patients undergoing abdominal aortic aneurysm repair under general plus epidural anesthesia, after preoperative double-blind administration of either ibuprofen 800 mg (n = 12) or placebo (n = 12). The hemodynamic response to aortic cross-clamping was similar in both groups. Pulse and mean arterial pressure remained unchanged; cardiac index decreased after aortic cross-clamping from 2.4 +/- 0.1 (mean +/- standard error of the mean [SEM]) to 2.1 +/- 0.1 1/min/m2 in the ibuprofen group and from 2.5 +/- 0.1 to 2.3 +/- 0.2 1/min/m2 in the placebo group (p less than 0.01 versus preclamp values in both groups, multivariate analysis of variance [MANOVA]), but improved after declamping. Both left and right ventricular stroke work indexes followed a similar pattern. Plasma 6-keto prostaglandin Fl alpha (6-k-PGF1 alpha) increased transiently from a baseline level of 304 +/- 44 to 2083 +/- 698 pg/ml plasma in mixed venous blood 30 minutes after incision in the placebo group (p less than 0.05), but no other significant change in plasma 6-keto prostaglandin Fl alpha or in thromboxane B2 occurred in either group at any other time.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:The effect of ibuprofen on cardiac performance during abdominal aortic cross-clamping. 203 9

Cerebral ischemia, induced in rats by occlusion of the middle cerebral artery resulted in infarcts affecting the basal ganglia and adjacent frontoparietal cortex. Resting oxygen consumption was similar for sham-operated and ischaemic rats immediately after surgery but was elevated in the latter group (peak value 18-21% above controls) 5-6 h post occlusion. By 24 h, these values had returned to control levels. The increase in VO2 was inhibited by injection of the beta-adrenergic antagonist propranolol but was unaffected by injection of the cyclooxygenase inhibitor ibuprofen. The thermogenic activity of brown adipose tissue was assessed from in vitro binding of guanosine diphosphate to mitochondria isolated from intact and surgically denervated lobes of sham-operated and ischemic rats, 6 h after surgery. Brown adipose tissue specific guanosine diphosphate (GDP) binding was elevated by 86% in intact tissue from ischemic compared with sham-operated rats but was identical in denervated tissue from the two groups. Brown adipose tissue activity correlated with resting oxygen consumption in the ischemic group (r = 0.85, p less than 0.01) but not in controls (r = -0.35, NS). Thus occlusion of the middle cerebral artery in the rat may provide a representative model for both stroke and head injury in man. It is associated with a transient increase in metabolic rate and by sympathetically mediated activation of brown adipose tissue in the rat.
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PMID:Sympathetically mediated hypermetabolic response to cerebral ischemia in the rat. 207 25

Endothelial cells modulate vascular tone by releasing endothelium-derived relaxing (EDRF) and contracting factors. An imbalance of these factors in hypertension could contribute to increased peripheral vascular resistance. Mesenteric resistance arteries of Wistar-Kyoto (WKY) and stroke-prone spontaneously hypertensive rats (SHRSP) were suspended in a myograph filled with physiological salt solution (37 degrees C; 95% O2-5% CO2). In WKY rings contracted with norepinephrine, acetylcholine (10(-9)-10(-4) M) evoked endothelium-dependent relaxations (88 +/- 2%, IC50 7.3 +/- 0.1; n = 31). Hemoglobin (10(-5) M) but not meclofenamate (10(-5) M) reversed the relaxations delineating EDRF as the mediator. Nitric oxide (3 X 10(-9)-10(-5) M) induced comparable relaxations as acetylcholine. In SHRSP, relaxations to acetylcholine but not those to nitric oxide were impaired (61 +/- 5%, IC50 greater than 6.6 +/- 0.4; n = 24; P less than 0.005). In SHRSP, meclofenamate but not the thromboxane synthetase inhibitor CGS 13080 normalized endothelium-dependent relaxations. Relaxations to sodium nitroprusside were enhanced in SHRSP both in rings with and without endothelium. Thus our results are compatible with the concept that endothelium-dependent relaxations in resistance arteries are mediated by nitric oxide. In SHRSP, endothelium-dependent relaxations are impaired because of a cyclooxygenase-dependent substance interfering with the release and/or action of EDRF.
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PMID:Impaired endothelium-dependent relaxations in hypertensive resistance arteries involve cyclooxygenase pathway. 210 97

Aspirin inhibits thromboxane A2 and prostaglandin formation in platelets and prostaglandin I2 (prostacyclin) in vascular cells. It prevents platelet aggregation by irreversible acetylation of cyclooxygenase, a key enzyme in the arachidonic acid metabolism. Oral aspirin can be extensively hydrolyzed to inactive salicylate in the stomach and the liver (first-pass) before it enters the systemic circulation. Presystemic acetylation of platelets thus occurs during aspirin absorption, with a concomitant sparing of peripheral vascular cyclo-oxygenase, mainly exposed to salicylate. On the basis of its antiplatelet effect, aspirin has been assessed during the past two decades in patients with a history of myocardial infarction, stroke, transient ischemic attack or unstable angina. A meta-analysis of randomized controlled trials of long term aspirin treatment for secondary prevention of vascular disease indicated that aspirin (300-1500 mg daily) significantly reduced fatal and non-fatal vascular events. More recently aspirin (160 mg daily) produced a significant reduction in hospital vascular mortality and in non-fatal events in patients with suspected acute myocardial infarction. Combination of aspirin with streptokinase was significantly better than either drug alone. On the other hand two primary prevention trials of aspirin in healthy doctors did not show any modification of vascular mortality despite an overall reduction of non-fatal myocardial infarction. Resolution of some problems related to the mechanism of action of aspirin and to selection of trial populations will possibly increase the benefit/risk ratio of aspirin treatment for prevention of vascular disease.
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PMID:Aspirin as an antithrombotic drug: from the aggregometer to clinical trials. 215 Jul 36

The endothelium releases a variety of factors which can affect vascular tone. Endothelium-derived relaxing factor or nitric oxide is a very potent vasodilator and inhibitor of platelet function. Its release has been demonstrated in a variety of human blood vessels. In most human vascular preparations, prostacyclin does not significantly contribute to the endothelium-dependent relaxations. Prostacyclin is, however, an endothelium-derived product which can evoke vasodilation and inhibition of platelet aggregation. In addition, the endothelium of human veins can release endothelium-derived contracting factors produced by the cyclooxygenase pathway. Endothelin is an endothelium-derived vasoactive peptide which has profound vasoconstrictor properties in human arteries and particularly in veins. Its action can only be partially inhibited by calcium antagonists, while endothelium-derived nitric oxide and exogenous nitrovasodilators are effective antagonists of the peptide. The mechanisms and amounts of endothelin released in human blood vessels remains to be defined. Under physiological conditions, endothelium-derived relaxing factors appear to dominate. The release of endothelium-derived nitric oxide is reduced in atherosclerotic human arteries. This indicates that in cardiovascular disease endothelial dysfunction occurs; this may contribute in the pathogenesis of coronary artery disease, pulmonary hypertension and stroke.
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PMID:Endothelium-derived vasoactive factors and regulation of vascular tone in human blood vessels. 216 86

Many nonsteroidal anti-inflammatory drugs exert their effects by inhibiting the synthesis of prostanoids. More specifically, these agents block the synthesis of prostaglandin endoperoxide G2 from arachidonic acid by competing with arachidonate for binding to the cyclooxygenase active site of prostaglandin endoperoxide synthase. Studies of the molecular biology of prostaglandin endoperoxide synthase indicate that there is a single gene for the enzyme. Thus, tissue-specific effects of nonsteroidal anti-inflammatory drugs probably result from differences in drug distribution and/or metabolism and not from the existence of tissue-specific prostaglandin endoperoxide synthase isozymes. Aspirin causes inactivation of prostaglandin endoperoxide synthase by first binding to the cyclooxygenase active site and then acetylating the protein at Ser530. Although the cyclooxygenase activity is inactivated, the hydroperoxidase activity of prostaglandin endoperoxide synthase is unaltered by Aspirin or other nonsteroidal anti-inflammatory drugs. Replacement of Ser530 of the native enzyme with an alanine residue by site-directed mutagenesis yields a prostaglandin endoperoxide synthase with unaltered catalytic and substrate binding activities. Thus, the hydroxyl group of Ser530 is not essential for enzyme activity. Instead, it appears likely that acetylation of prostaglandin endoperoxide synthase by Aspirin simply places a bulky acetyl group at or near the cyclooxygenase active site, thereby interfering with arachidonic acid binding.
Stroke 1990 Dec
PMID:Molecular basis for the inhibition of prostanoid biosynthesis by nonsteroidal anti-inflammatory agents. 217 60


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