dinoprost and Ischemic-Attack--Transient

There are limited prospective data evaluating the role of urinary F2-IsoP and NOX2 as predictive markers in atrial fibrillation (AF). The aim of this study was to analyse the role of urinary prostaglandin PGF2alpha (8-iso-PGF2α) and NOX2, markers of systemic oxidative stress, in predicting cardiovascular (CV) events and mortality in anticoagulated non-valvular AF patients. This was a prospective study including 1,002 anticoagulated AF patients, followed for a median time of 25.7 months (interquartile range: 14.8-50.9). All major CV events, CV deaths and all-cause deaths were considered as primary outcomes of the study. CV events included fatal/nonfatal ischaemic stroke, fatal/nonfatal myocardial infarction (MI), cardiac revascularisation and transient ischaemic attack (TIA). Oxidative stress biomarkers, such as urinary 8-iso-PGF2α and serum sNOX2-dp, a marker of NOX2 activation, were measured. A CV event occurred in 125 patients (12.5 %); 78 CV deaths and 31 non-CV deaths were registered. 8-iso-PGF2α and sNOX2-dp were correlated (Rs=0.765 p< 0.001). A significant increased cumulative incidence of CV events and CV deaths was observed across tertiles for 8-iso-PGF2α and sNOX2-dp. An increased rate of all-cause death was observed across tertiles of urinary 8-iso-PGF2α. In Cox or Fine and Gray models, 8-iso-PGF2α predicted CV events and CV and non-CV deaths. The addition of tertiles of 8-iso-PGF2α to CHA2DS2-VASc score improved ROC curves for each outcome and NRI for CV events (0.24 [0.06-0.53] p=0.0067). The study shows that in AF patients 8-iso-PGF2α and NOX2 levels are predictive of CV events and total mortality. F2-IsoP may complement conventional risk factors in prediction of CV events.

Topics: Aged; Aged, 80 and over; Area Under Curve; Atrial Fibrillation; Biomarkers; Brain Ischemia; Cause of Death; Cerebrovascular Disorders; Dinoprost; Female; Humans; Incidence; Ischemic Attack, Transient; Kaplan-Meier Estimate; Male; Membrane Glycoproteins; Middle Aged; Myocardial Infarction; NADPH Oxidase 2; NADPH Oxidases; Oxidative Stress; Predictive Value of Tests; Proportional Hazards Models; Prospective Studies; Risk Factors; ROC Curve; Rome; Stroke; Time Factors

Short episodes of ischemia and reperfusion in various organs may protect the organ itself, and the heart both as an immediate and a delayed effect. The present study investigates whether a systemic protection of vascular function occurs during adaption to ischemia. Brain ischemia was induced by bilateral ligation of the internal carotid arteries in C57BL6 mice, and 24-36 hours later rings of the thoracic aorta were mounted to study in vitro relaxation and contraction, or proteins were extracted for immunoblotting for endothelial nitric oxide synthase (eNOS) or inducible NOS (iNOS). eNOS decreased, while iNOS increased in the aortic wall after carotid artery ligation. In vitro contraction to increasing concentrations of prostaglandin F(2alpha) (PGF(2alpha)) was attenuated, while relaxation to acetylcholine (ACh) was enhanced. The latter was abolished by the iNOS-inhibitor aminoguanidine. When brain ischemia was induced in iNOS deficient mice, an increase of aortic eNOS was found 24 hours later. The ischemia-induced attenuated relaxation to PGF(2alpha) and enhanced relaxation to ACh were abolished. Aortic rings from mice with severe atherosclerosis (apolipoprotein E and low density lipoprotein receptor double knockout (ApoE/LDLr KO) mice) and spontaneous ischemic events in the heart or brain in vivo were also studied. Spontaneous ischemic events in ApoE/LDLr KO animals did not influence iNOS and eNOS in the vessel wall. A reduced contraction to PGF(2alpha) was observed, but relaxation to ACh was unchanged. These findings suggest that induced brain ischemia as a model of delayed, remote preconditioning protects vessel reactivity, and this protection is mediated by iNOS.

Topics: Acetylcholine; Animals; Aorta, Thoracic; Brain Ischemia; Dinoprost; Disease Models, Animal; In Vitro Techniques; Ischemic Attack, Transient; Mice; Mice, Inbred C57BL; Mice, Knockout; Muscle Contraction; Muscle Relaxation; Muscle, Smooth, Vascular; Myocardial Ischemia; Nitric Oxide Synthase; Nitric Oxide Synthase Type II; Nitric Oxide Synthase Type III; Phenylephrine; Reference Values

Subarachnoid hemorrhage (SAH) impairs both contraction and relaxation response in cerebral arteries. We tested the hypothesis that cerebral vasospasm might be ATP-independent contraction, such as latch state, and protein synthesis might be substantially downregulated due to ATP consumption after long-lasting contraction.. Chronic cerebral vasospasm was induced in the canine 2-hemorrhage model of SAH. The normal and spastic basilar arteries were stabilized in Krebs-Henseleit solution, and contraction was induced by 30 micromol/L prostaglandin F2alpha (PGF2alpha) in vitro and in vivo. Before and at 15 minutes and 1 hour after the treatment with PGF2alpha, the levels of phosphorylated 20-kDa myosin light chain (MLC20) were measured. The time course of expression of contraction proteins actin and MLC20, and contraction-inhibiting proteins h-caldesmon and calponin was determined by immunoblotting techniques.. A significant vasospasm occurred in the basilar artery during days 4 to 21, most prominently on days 7 and 14. There were no significant differences in the baseline levels of phosphorylated MLC20 between normal and spastic basilar arteries. The increase in MLC20 phosphorylation by PGF2alpha was significantly attenuated in the spastic basilar artery in vitro and in vivo (P<0.05). The immunoreactivity for actin, h-caldesmon, and calponin in the spastic basilar arteries was progressively decreased until day 14 and returned to the normal level on day 21. In contrast, protein levels of MLC20 did not significantly change during days 0 to 21.. Chronic cerebral vasospasm closely resembles the latch state, and temporary deficiencies of contractile proteins may result from increased destruction and inhibition of protein synthesis.

Topics: Animals; Basilar Artery; Contractile Proteins; Dinoprost; Disease Models, Animal; Dogs; Female; Ischemic Attack, Transient; Male; Myosin Light Chains; Phosphorylation; Subarachnoid Hemorrhage; Vasoconstriction

To study the effects of in vivo transluminal balloon angioplasty (TBA) on the structure and function of the arterial wall, a canine model of hemorrhagic cerebral vasospasm of the high cervical internal carotid artery (ICA) was used. This model was also used to determine whether TBA performed before clot placement could prevent the development of vasospasm.. Twelve dogs underwent surgical exposure of both distal-cervical ICAs, followed by baseline angiography. One randomly selected ICA in each dog was then subjected to in vivo TBA and repeated angiography. Both distal ICAs were then surrounded with blood clots held by silicone elastomer sheaths. Seven days later angiography was repeated, and all animals were killed. The ICAs in four animals were perfusion-fixed in situ for morphological analysis by electron microscopy, and the arteries in the remaining eight animals were removed and immediately immersed in oxygenated Krebs' solution. Contractile responses of isolated arterial rings from each ICA were recorded after treatment with KCl, noradrenaline, serotonin, and prostaglandin F2 alpha, while relaxations in response to the calcium ionophore A23187 and papaverine were recorded after tonic contraction to noradrenaline had been established. The morphology and pharmacological responses of ICAs that had been exposed to blood with or without prior TBA were compared with data obtained from control arterial segments of intact, more proximal regions of the ICAs from each animal.. TBA resulted in immediate angiographic enlargement of the ICA lumen that was still evident 7 days later despite the placement of clotted blood around the artery. Scanning and transmission electron microscopy demonstrated flattening of the intima and internal elastic lamina in these dilated arteries, associated with patchy losses of endothelial cells. In contrast, ICAs that had been exposed to clotted blood but had not undergone prior TBA developed consistent angiographic and morphological vasospasm. In comparison with control vessels and nondilated vasospastic vessels, vessels dilated with TBA and then exposed to clotted blood showed significantly diminished responses to all compounds tested, with the exception of prostaglandin F2 alpha.. These results indicate that in vivo TBA results in a degree of functional impairment of vascular smooth muscle that persists for at least 7 days. This result is consistent with previous observations of the acute effects of TBA in isolated arteries. Furthermore, these results support the hypothesis that normal smooth muscle function is required for the development of vasospasm. Finally, these results indicate that TBA performed before the onset of vasospasm prevents its development.

Topics: Angiography; Angioplasty, Balloon; Animals; Blood Coagulation; Calcimycin; Carotid Artery Diseases; Carotid Artery, Internal; Dinoprost; Dogs; In Vitro Techniques; Ionophores; Ischemic Attack, Transient; Muscle, Smooth, Vascular; Norepinephrine; Papaverine; Potassium Chloride; Serotonin; Vasoconstrictor Agents; Vasodilator Agents

Clot removal at early surgery has been reported to be clinically effective for the prevention of cerebral vasospasm following subarachnoid hemorrhage (SAH) due to rupture of an intracranial aneurysm. We examined the most efficacious timing of mechanical clot removal on pharmacological responses in a monkey SAH model. Cynomolgus monkeys (Macaca fascicularis) were randomized into five groups: sham-operated, clot removal in which the clot was removed 48, 72, or 96 h after SAH, and clot groups. An autologous blood clot was placed around the bilateral major cerebral arteries after craniectomy to mimic the hemorrhage. Seven days after the SAH, proximal and successively distal parts of the middle cerebral arteries were cut into rings for isometric tension measurement. The contractile responses to potassium chloride, 5-hydroxytryptamine, norepinephrine, adenosine triphosphate, prostaglandin F20, and hemoglobin were greater in the proximal parts than in the distal parts in each group. Compared with the sham-operated group, the responses of the clot-removal and clot groups to the drugs were progressively attenuated. The maximum responses to 5-hydroxytryptamine in the proximal parts and to adenosine triphosphate in the distal parts started to decrease, significantly, in the clot-removal group 48 h after SAH, while most of the responses to the other agonists began to decrease in the clot-removal groups later than 72 h after SAH. These results suggest that the attenuation of cerebrovascular contractile responses 7 days after SAH is pharmacologically inevitable, even if the clot is removed as early as 48 h after the SAH. Clot removal may thus be recommended within 48h after SAH to ameliorate the severity of cerebral vasospasm following SAH.

Topics: Adenosine Triphosphate; Animals; Cerebral Arteries; Dinoprost; Dose-Response Relationship, Drug; Hemoglobins; Ischemic Attack, Transient; Macaca fascicularis; Muscle, Smooth, Vascular; Norepinephrine; Potassium Chloride; Serotonin; Subarachnoid Hemorrhage; Time Factors; Vasoconstriction

Despite growing clinical use of transluminal balloon angioplasty (TBA) to treat cerebral vasospasm after aneurysmal subarachnoid hemorrhage (SAH), the precise mechanism of action of balloon dilation on the cerebral arterial wall is unknown. In this experiment the authors examined the pharmacological and morphological changes in 10 normal and 12 vasospastic canine basilar arteries following in vitro silicone microballoon TBA. For the SAH group in which the double-hemorrhage model was used, vasospasm was confirmed by angiography and the animals were killed on Day 7 after the first SAH. In vitro TBA was performed on basilar arteries from normal and SAH dogs immediately after sacrifice and removal of the brain. The procedure was performed while the arteries were maintained in oxygenated Krebs buffer. In the pharmacological studies, potassium chloride, prostaglandin F2 alpha, serotonin, and noradrenaline were used as vasoconstrictors, and bradykinin and calcium ionophore A23187 were used to produce an endothelium-dependent dilation. In both normal and vasospastic groups, the pharmacological responses of dilated segments of basilar arteries were compared to those of nondilated segments of the same arteries. Vessels from all groups were examined using scanning electron microscopy (EM) and transmission EM. Scanning EM was used to study the intact vessel wall, the smooth-muscle cell layer obtained after digestion with hydrochloric acid, and the extracellular matrix obtained after digestion with bleach. Cross-sections of the vessel wall were examined using transmission EM. The most striking finding was that immediately after in vitro TBA of both normal and vasospastic canine basilar arteries, there was a significant reduction (p < 0.05) of responses to both vasoconstrictors and vasorelaxants. As revealed by scanning EM and transmission EM, both normal and vasospastic vessels dilated with TBA showed flattening and patchy denudation of the endothelium, and straightening and occasional rupturing of the internal elastic lamina. In addition, vasospastic vessels dilated with TBA showed decreased surface rippling and mild stretching and straightening of smooth-muscle cells, and mild thinning of the tunica media. There was no gross vascular disruption or obvious change in the extracellular matrix of the vessel walls of either normal or vasospastic arteries after TBA. These results suggest that functional impairment of vasoreactivity in the vessel wall as a result of mechan

Topics: Analysis of Variance; Angioplasty, Balloon; Animals; Basilar Artery; Bradykinin; Calcimycin; Collagen; Dinoprost; Dogs; Dose-Response Relationship, Drug; Elastin; Endothelium, Vascular; In Vitro Techniques; Ischemic Attack, Transient; Microscopy, Electron; Microscopy, Electron, Scanning; Muscle, Smooth, Vascular; Norepinephrine; Potassium Chloride; Radiography; Serotonin; Subarachnoid Hemorrhage; Vasoconstriction; Vasodilation

The isometric tension recorded from ring segments of branches of human middle cerebral artery was the parameter used to study the inhibition of spasmogen-induced contractions as model for cerebral vasospasm. Concentration-response curves to 5-hydroxytryptamine (10(-9)-3 x 10(-5) M) and prostaglandin F2 alpha (10(-7)-3 x 10(-5) M) were inhibited in Ca(2+)-free medium and in Ca(2+)-free medium to which EGTA (1 mM) had been added, respectively. Nimodipine (10(-7), 10(-5) M), nicardipine (10(-7), 10(-5) M) and Mg2+ (magnesium sulfate 10(-4), 10(-2) M) inhibited the 5-HT-elicited contractions, and this inhibition was similar for the highest concentrations tested. In contrast, nimodipine and nicardipine were more effective than Mg2+ to inhibit the prostaglandin F2 alpha-elicited contractions. Nimodipine (10(-9)-10(-5) M), nicardipine (10(-9)-10(-5) M) and Mg2+ (10(-5)-3 x 10(-2) M) relaxed the arteries precontracted with PGF2 alpha (10(-5) M), but nicardipine was the most potent relaxant drug. Because 5-hydroxytryptamine and prostaglandin F2 alpha may be involved in the pathogenesis of cerebral vasospasm, nimodipine, nicardipine, and Mg2+ could be used in the pharmacological treatment of this disorder. However, dihydropyridines (particularly nicardipine) are more potent anticonstrictors than Mg2+.

Topics: Adult; Aged; Aged, 80 and over; Calcium; Cerebral Arteries; Dinoprost; Female; Humans; In Vitro Techniques; Ischemic Attack, Transient; Magnesium; Male; Middle Aged; Nicardipine; Nimodipine; Serotonin; Vasoconstriction

We have investigated the effect of phenothiazine, a compound known to inhibit calmodulin, on the responses of normal and spastic cerebral arteries, using the canine "two hemorrhage" model of cerebrovascular spasm. Ring preparations from control vessels or vessels removed three or seven days after injection of blood, were contracted with either 5-hydroxytryptamine (5-HT) or prostaglandin F2 alpha (PGF2 alpha) and then exposed to increasing concentrations of phenothiazine. In normal arteries, low concentrations of phenothiazine enhanced the response to PGF2 alpha, while higher concentrations caused relaxation. Responses to 5-HT were inhibited by all concentrations of phenothiazine tested. When normal arteries were compared with arteries from animals injected with blood, in the case of 5-HT, phenothiazine was a less effective antagonist at low doses, but equieffective at higher doses. Similar experiments conducted with PGF2 alpha showed that phenothiazine was a more effective antagonist in spastic vessels. We conclude that 5-HT and PGF2 alpha have significant differences in the mechanism by which they produce contraction of cerebral vessels, that phenothiazine has secondary effects on contraction independent of inhibition of calmodulin, and, finally that the effects of phenothiazine in clinical vasospasm may be insufficient to reverse the condition, despite the observation that vessels in spasm may be more sensitive to this agent.

Topics: Animals; Calmodulin; Cerebral Arteries; Dinoprost; Disease Models, Animal; Dogs; Female; Ischemic Attack, Transient; Isometric Contraction; Male; Muscle Spasticity; Muscle, Smooth, Vascular; Phenothiazines; Serotonin

We investigated the hypothesis that cerebral prostanoid and peptidoleukotriene (LTs) (LTC4/D4/E4/F4) synthesis are increased during postischemic reperfusion of newborn pig brains. Prostanoids and LTs extracted from brain tissue were determined by RIA in sham-control piglets and at 1h, 3h, or 12h after a 20-min period of total cerebral ischemia. During reperfusion following ischemia, all regional brain tissue (cerebrum, brain stem and cerebellum) prostanoids (6-keto-PGF1 alpha, TXB2, PGE2 and PGF2 alpha) were increased at 1h compared with those in sham-control piglets. Only cerebral and brain stem 6-keto-PGF1 alpha and cerebral TXB2 remained elevated at 3h postischemia and all prostanoids returned to control levels by 12h postischemia. Brain tissue LTs were lower than prostanoids and were not altered 1, 3, or 12h following ischemia. These data indicate that 1) newborn pig brain tissue prostanoids are increased initially, and then returned to control levels at later stages of reperfusion following ischemia; 2) LTs are present in newborn pig brain tissue, but are not increased by ischemia/reperfusion injury and therefore probably do not play a significant role in cerebral ischemia-reperfusion injury.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Animals, Newborn; Brain; Brain Stem; Cerebellum; Dinoprost; Dinoprostone; Female; Ischemic Attack, Transient; Leukotriene E4; Male; Prostaglandins; Reperfusion; SRS-A; Swine; Thromboxane B2

In order to evaluate various spasmogens, which are candidates for cerebral vasospasm after subarachnoid haemorrhage, the intracellular calcium mobilizations were examined in cultured vascular smooth muscle cells preloaded with a fluorescent Ca2+ probe fura-2. Endothelin, oxyhaemoglobin, 5-hydroxytryptamine, norepinephrine, prostaglandin F2 alpha, leukotrienes C4 and D4 produced dose-dependent increases in intracellular Ca2+ concentration ([Ca2+]i). However, bilirubin did not induce any significant [Ca2+]i elevation. The maximal levels of [Ca2+]i peak attained by endothelin or oxyhaemoglobin were higher than those of other compounds. Endothelin was the most potent in that it induced a high sustained [Ca2+]i elevation at much lower concentrations compared with others. The combination of oxyhaemoglobin and endothelin induced a transient increase in [Ca2+]i followed by a sustained lower plateau, then the [Ca2+]i level was again increased slowly followed by a sustained higher plateau which lasted for more than 10 min after the exposure. These results suggest that endothelin and/or oxyhaemoglobin may play a crucial role in contraction of vascular smooth muscle after subarachnoid haemorrhage.

Topics: Animals; Aorta, Thoracic; Calcium; Cells, Cultured; Dinoprost; Dose-Response Relationship, Drug; Endothelins; Endothelium, Vascular; Inositol 1,4,5-Trisphosphate; Ischemic Attack, Transient; Kinetics; Male; Models, Biological; Norepinephrine; Oxyhemoglobins; Rats; Rats, Inbred Strains; Serotonin; SRS-A

We previously suggested that activation of the protein kinase C-mediated contractile system may participate in the occurrence of chronic cerebral vasospasm. In the present study, we compared segments of normal beagle basilar arteries in vitro with segments of arteries undergoing chronic vasospasm to determine the responsiveness to various agonists such as serotonin, prostaglandin F2 alpha, and phorbol 12,13-diacetate as well as to external Ca2+. We also compared the effects of W-7 (a calmodulin inhibitor), nicardipine (a calcium channel blocker), and H-7 (a protein kinase C inhibitor) on the spontaneous tonus of arterial segments stabilized at a resting tension of 3 g. Compared with normal segments, the responsiveness to each agonist in segments undergoing vasospasm was essentially unchanged whereas the the responsiveness to external Ca2+ was significantly decreased (p less than 0.001). In segments undergoing vasospasm the decrease in resting tension induced by W-7 was markedly diminished (p less than 0.01), that induced by nicardipine was unchanged, and that induced by H-7 was significantly increased (p less than 0.01). Our results indicate that spontaneous tonus due to activation of the protein kinase C system is significantly augmented in segments undergoing vasospasm. Thus this system, rather than the Ca2+/calmodulin system, appears to play a major role in the occurrence of chronic vasospasm.

Topics: 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; Animals; Basilar Artery; Chronic Disease; Dinoprost; Dogs; Enzyme Activation; In Vitro Techniques; Ischemic Attack, Transient; Isoquinolines; Muscle Contraction; Muscle, Smooth, Vascular; Nicardipine; Phorbol Esters; Piperazines; Protein Kinase C; Protein Kinase Inhibitors; Serotonin; Subarachnoid Hemorrhage; Sulfonamides

Normal cytoarchitecture of smooth muscle cells of monkey cerebral arteries was studied using scanning electron microscopy after removal of adventitial connective tissue by hydrolysis with HCl. Cerebral arteries were also examined after contraction in vitro with prostaglandin F2 alpha (PGF2 alpha). Anterior cerebral arteries were studied after exposure for 6 days in vivo to whole blood, oxyhemoglobin, methemoglobin, bilirubin, mock cerebrospinal fluid, or supernatant fluid from an incubated mixture of autologous blood and mock cerebrospinal fluid. Normal smooth muscle cells were spindle-shaped and oriented circumferentially around the vessel. They were often grouped into bundles of 5 to 10 cells; bundles were recognizable because cells within them were joined by multiple intercellular contacts. Groups of smooth muscle cells oriented longitudinally were present outside the circular layers of cells. The adventitial surface of muscle cells was smooth apart from fine longitudinal striations in some areas. Arteries contracted with PGF2 alpha had markedly convoluted and folded cell membranes. Muscle cells of vasospastic arteries and of arteries exposed to oxyhemoglobin and supernatant fluid appeared identical to cells contracted with PGF2 alpha. The outer surface of cells of arteries exposed to bilirubin, methemoglobin, and mock cerebrospinal fluid were normal. Marked similarity between vasospastic smooth muscle cells and smooth muscle cells from arteries contracted with PGF2 alpha suggest that smooth muscle contraction occurs during "vasospasm" due to whole blood and to intrathecal injection of oxyhemoglobin.

Topics: Animals; Cerebral Arteries; Dinoprost; Female; In Vitro Techniques; Ischemic Attack, Transient; Macaca fascicularis; Microscopy, Electron, Scanning; Muscle, Smooth, Vascular; Reference Values

The effects of subarachnoid hemorrhage (SAH) on intracranial prostaglandins (PGs) were studied in canines. Subarachnoid hemorrhage was produced by the "two hemorrhage" method. Basilar artery caliber and regional cerebral blood flow (rCBF) in the occipital cortex were reduced by 42% and 43% during delayed vasospasm, respectively. Once delayed vasospasm had developed, intravenous infusion of OKY-046, a selective inhibitor of thromboxane (TX) A2 synthetase, induced no significant change in angiographic vasospasm but caused a significant increase in rCBF. In delayed vasospasm, cortical levels of PGF2 alpha were significantly decreased, whereas plasma levels of PGF2 alpha and TXB2 in the transverse sinus were significantly increased. The intravenous infusion of OKY-046 in delayed vasospasm induced a significant increase in cortical PGF2 alpha and PGE in the occipital cortex, and caused a significant increase in plasma 6-keto-PGF1 alpha and a significant decrease in plasma TXB2 in the transverse sinus. In delayed vasospasm, decreased cortical levels of PGF2 alpha may reflect a decrease in rCBF and increased plasma PGF2 alpha and TXB2 levels may reflect enhancement of intravascular coagulation. These PGs have very strong and various biological activities. The results suggest that SAH induces complicated changes of intracranial PGs and OKY-046 can improve these pathological changes.

Topics: Animals; Basilar Artery; Brain; Cerebrovascular Circulation; Dinoprost; Dogs; Infusions, Intravenous; Ischemic Attack, Transient; Methacrylates; Prostaglandins E; Subarachnoid Hemorrhage; Thromboxane-A Synthase

Cerebral vascular tone is modulated, at least in part, by the vascular endothelium. This probably results from a balance between the release of the endothelium-derived relaxing factor(s) and the endothelium-derived constricting factor(s) (e.g., endothelin). The time course of the induction and the decay of these mutually antagonizing substances differ considerably. Endothelium-derived relaxing factor is probably involved in rapid changes in vascular tone whereas endothelin may be more important in long-term modulation. We have studied the vasoconstrictor properties of endothelin in human cerebral artery strips. Endothelin typically produced an intense, sustained increae in tone over a dose range similar to that seen with other vasoconstrictor substances such as serotonin and prostaglandin F2 alpha (ED50 = 10(-8) M). The response was resistant to selective antagonists of norephinephrine, serotonin, isoproterenol, histamine, acetycholine, and angiotensin II. Only sodium nitroprusside, verapamil, and a disulfide bond reducing agent (dithiothreitol) inhibited the response. The physiological properties of this response are similar to those of a vasoconstrictor protein found in cerebrospinal fluid from patients with cerebral vasospasm after subarachnoid hemorrhage. The time course of the induction of endothelin production is consistent with the temporal sequence of vasospasm, further supporting the hypothesis that endothelin may be involved in this pathological process.

Topics: Cerebral Arteries; Dinoprost; Endothelins; Humans; In Vitro Techniques; Ischemic Attack, Transient; Muscle Contraction; Peptides; Serotonin; Vasoconstrictor Agents

The aim of our study was to investigate the changes of various biochemical parameters (concentrations of lactate, free arachidonate, cyclo- and lipoxygenase products) in rat brain after ischemia and reperfusion and the effects of pretreatment with the ganglioside derivative GM1-lactone on the same parameters. Ischemia was induced by reversible occlusion of common carotid arteries for 20 min, which included a final 5 min of respiration of 5% oxygen in nitrogen. Reperfusion was obtained by removing the occlusion. Pre-ischemic conditions were obtained on sham-operated animals. Animals were killed by microwave irradiation of their heads. Brain levels of lactate and of free arachidonate were markedly increased after ischemia and returned to normal values at 5 min of reperfusion. Levels of the cyclooxygenase metabolites prostaglandin F2 alpha, 6-keto-prostaglandin F1 alpha, and thromboxane B2 were increased after ischemia, whereas levels of the lipoxygenase metabolite leukotriene C4 (LTC4) did not change. After reperfusion, a very marked increase of the cyclooxygenase products occurred but not of LTC4. Treatment with GM1-lactone prevented the elevation of cyclo- and lipoxygenase metabolites especially during reperfusion, with limited effects on lactate and free arachidonate levels.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Arachidonic Acid; Arachidonic Acids; Brain; Dinoprost; G(M1) Ganglioside; Ischemic Attack, Transient; Lactates; Lactic Acid; Lipoxygenase; Male; Prostaglandin-Endoperoxide Synthases; Rats; Rats, Inbred Strains; SRS-A; Thromboxane B2

Severe chronic cerebral vasospasm was produced in dog basilar arteries by two injections, 2 days apart, of autologous blood into the cisterna magna of 25 dogs. Treatment with ibuprofen (n = 8) or high-dose methylprednisolone (n = 8) after the first injection of blood prevented or reduced angiographic vasospasm. Cerebrospinal fluid concentrations of prostaglandin E2, prostaglandin F2 alpha, 6-ketoprostaglandin F1 alpha (a metabolite of prostacyclin), and thromboxane B2 (a metabolite of thromboxane A2) were measured in both treated and untreated (n = 7) dogs. In untreated dogs, the level of prostaglandin E2 increased 94-fold by Day 8 after the first injection of blood and was strongly and positively correlated with the degree of angiographic vasospasm. Treatment with ibuprofen and high-dose methylprednisolone prevented or significantly reduced this increase in prostaglandin E2 concentration. Smaller increases in cerebrospinal fluid concentrations of thromboxane B2 and 6-ketoprostaglandin F1 alpha occurred after experimental subarachnoid hemorrhage; the magnitude of these increases was also reduced by ibuprofen or high-dose methylprednisolone treatment. In contrast, prostaglandin F2 alpha levels were not significantly altered during the study. These data show that enhanced prostaglandin E2 synthesis occurs during experimental subarachnoid hemorrhage, and the by-products generated in its synthesis may play a role in the pathogenesis of cerebral vasospasm.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Dinoprost; Dinoprostone; Dogs; Ibuprofen; Ischemic Attack, Transient; Methylprednisolone; Subarachnoid Hemorrhage; Thromboxane B2

a./Great regional differences were observed in the vasospastic effect of hemoglobin. Namely, hemoglobin was far more potent in the middle cerebral artery than in the mesenteric artery. b./The role of potassium ions as well as activation of calcium mobilizing adrenergic, serotoninergic and PGF2 alpha smooth muscle receptors were excluded in the mechanism of cerebral vasospasm induced by hemoglobin. c./First in the literature we showed that atropine significantly attenuates the vasospastic effect of hemoglobin, and hemoglobin releases peptidergic neurotransmitters and modulators from nerve terminals that are located in the adventitia of the middle cerebral artery.

Topics: Acetylcholine; Animals; Atropine; Cats; Cerebral Arteries; Dinoprost; Hemoglobins; Indomethacin; Ischemic Attack, Transient; Mesenteric Arteries; Norepinephrine; Propranolol; Serotonin; Vasoconstriction

This study was performed as part of a series of investigations into the relation between cerebral vasospasm following subarachnoid hemorrhage and the sympathetic nervous system. We studied the effect of phenoxybenzamine chloride (POB) and prazosin hydrochloride (Prazosin) on the cerebral vasoconstriction in the basilar arteries of cats induced by application of oxyhemoglobin (Oxy-Hb), noradrenaline (Nor) and prostaglandin F2 alpha (PGF2 alpha). Adult cats were anesthetized with intramuscular pentobarbital and maintained on a respirator through a tracheostomy. By the transclival approach, a bone window was formed in the clivus, and the dura was opened, exposing the basilar artery. A cannule was inserted into the subarachnoid space, and through it, Oxy-Hb, Nor and PGF2 alpha were injected. The sequential changes in caliber of the basilar artery were measured using photography. First, we determined the doses of POB and Prazosin necessary for decreasing the vasoconstriction induced by Nor, and 20 mg/kg of POB and 10 mg/kg of Prazosin were found to decrease the vasoconstriction induced by 10(-3) M Nor, statistically. Second, we investigated the effect of 20 mg/kg of POB and 0.5 mg/kg and 10 mg/kg of Prazosin on the cerebral vasoconstriction induced by Oxy-Hb or PGF2 alpha. POB (20 mg/kg) was infused for 2 hours before the application of Oxy-Hb or PGF2 alpha. Prazosin was given intravenously. In the first group, 0.02% Prazosin (0.5 mg/kg) was administered intravenously for 1.5 hours before the application of Oxy-Hb or PGF2 alpha. In the second group, 1.5 hours elapsed between the beginning of Prazosin (10mg/kg) infusion and the application of Oxy-Hb or PGF2 alpha.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adrenergic alpha-Antagonists; Animals; Cats; Cerebrovascular Circulation; Dinoprost; Ischemic Attack, Transient; Norepinephrine; Oxyhemoglobins; Phenoxybenzamine; Prazosin; Sympathetic Nervous System; Vasomotor System

The changes in prostaglandin F2-alpha (PG F2 alpha) staining over 3 days of recirculation in both fore- and hindbrains were studied. Five minutes of global ischemia was produced in 24 rats by Pulsinelli's method with hypotension around 50 mm Hg of mean arterial blood pressure. Eight rats (including three pretreated with indomethacin) were recirculated for 5 min, three for 1 h, five for 2 h and five for 3 days. Five normal rats without occlusion of vessels served as controls. The brains were snap frozen. Ten-micrometer cryosections were stained for PG F2 alpha by the indirect immunofluorescence method after fixation in carbodiimide and in Zamboni's solution. Positive staining for PG F2 alpha was noted in pial vessels in all normal and ischemic rats. Recirculated rats revealed the strongest reaction at 5 min after recirculation in blood vessels and in neuronal cytoplasm (especially in hippocampi and in Purkinje cells). The intensity of staining was markedly reduced after 1 h. Rats pretreated with indomethacin showed less increase in staining. The above results indicate that recirculation after ischemia produces a transient increase in PG F2 alpha in blood vessels and neurons of both fore- and hindbrains.

Topics: Animals; Cerebellum; Cerebrovascular Circulation; Dinoprost; Hippocampus; Immunohistochemistry; Ischemic Attack, Transient; Male; Rats; Rats, Inbred Strains; Time Factors

Fifteen patients with subarachnoid hemorrhage (SAH) were divided into two groups; eight patients exhibiting vasospasm (VS) (VS-group), and another seven patients exhibiting no vasospasm (NS-group) during a period of 2-3 weeks after the occurrence of hemorrhage. The cerebrospinal fluid (CSF) of the patients in the VS-group demonstrated a slight but significant decrease in [Mg++] from 1.15 to 0.95 mM on the 6-8th day after the hemorrhage, whereas CSF in the NS-group showed no significant change in [Mg++]. CSF [Ca++] remained relatively unchanged in both groups. The decrease in CSF [Mg++] in the VS-group was not associated with a decrease in [Mg++] in their blood. Probably, it was due to local derangement of the blood-CSF barrier near the site of the actual hemorrhage. Whether or not such a small decrease in CSF [Mg++] could actually influence the occurrence of vasospasm was examined experimentally in vitro. Using helical strips of the bovine middle cerebral arteries, the changes in muscular tension during isometric contraction were recorded on the polygraph. Generally the vascular contractions induced by High K+ (4 X 10(-2) M), PGF2 alpha (10(-6) M), and Oxy-hemoglobin (Oxy-Hb, 3 X 10(-6) M) were augmented when [Mg++] of the perfusing media was reduced from 1.2 to 0.9 mM, and depressed when [Mg++] was increased to 2.4 mM. In descending order, a greater effect of [Mg++] was seen in Oxy-Hb-, and in High K+-, and PGF2 alpha-induced contractions.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Aged; Animals; Calcium; Cattle; Cerebral Arteries; Dinoprost; Female; Humans; Ischemic Attack, Transient; Magnesium; Male; Middle Aged; Muscle Contraction; Muscle, Smooth, Vascular; Oxyhemoglobins; Subarachnoid Hemorrhage

Immunohistochemical localization of prostaglandin F2 alpha (PG F2 alpha) was studied in 24 rats. In 21 rats, global brain ischemia was produced for 5 min by Pulsinelli's method. Prior to decapitation, 13 were recirculated for 5 min, while the remaining eight were not. Three recirculated rats were pretreated with indomethacin before the occlusion. Hypotension was induced during the occlusion to 40-50 mm Hg of mean arterial blood pressure in 11 rats including those unrecirculated, recirculated and pretreated with indomethacin. Three normal rats without occlusion of arteries served as control. The brains were snap frozen and 10-microns cryostat sections were incubated in rabbit anti-PG F2 alpha serum and stained by the indirect immunofluorescence method after fixation in carbodiimide and in Zamboni's solution. Positive staining for PG F2 alpha was noted mainly in pial vessels in normal and ischemic rats both with and without hypotension. The rats recirculated without hypotensive ischemia revealed a positive reaction in the walls of pial and parenchymal vessels. All rats recirculated after the hypotensive occlusion showed positive staining in blood vessels, in the cytoplasm of neurons (especially in hippocampi) and in the interfascicular oligodendrocytes. The above results indicate that recirculation after ischemia results in an increase in PG F2 alpha in parenchymal vessels, neurons and oligodendrocytes.

Topics: Animals; Brain; Dinoprost; Hippocampus; Ischemic Attack, Transient; Male; Neurons; Prostaglandins F; Rats; Rats, Inbred WKY; Reference Values

Release of arachidonate metabolites from isolated canine cerebral arteries into perfusing medium were estimated using radioimmunoassay (RIA) in vitro. The cerebral arteries were isolated from dogs sustained experimental subarachnoid hemorrhages (SAH) and the results were compared with that of normal canine cerebral arteries. The amount of 6-Keto-PG F1 alpha (stable metabolite of PGI2) and PGE2 released from normal cerebral arteries were 455 +/- 84 (n = 7) and 177 +/- 72 (n = 8) ng/min/g dry weight (mean +/- SEM), respectively. Among other arachidonate metabolites, TXB2 (stable metabolite of TXA2), PGF2 alpha, PGD2 were also measured, but release of these arachidonate metabolites were little compared with PGI2 or PGE2. The amount of 6-Keto-PGF1 alpha and PGE2 released from the cerebral arteries subjected to subarachnoid hemorrhage were 110 +/- 34 (n = 6), 169 +/- 40 (n = 6) ng/min/g dry weight respectively. In SAH group, release of 6-Keto-PGF1 alpha had diminished remarkably, but no remarkable quantitative change were seen among other arachidonate metabolite between normal and SAH groups. The diminution of PGI2 release in the cerebral artery subjected to SAH may be involved in the pathogenesis of cerebral vasospasm. The release of PGs from canine pial arteries induced by the exposure of the pial arteries to red blood cell hemolysate was also estimated by RIA. The release of PGE2 tended to increase following to exposure to hemolysate but no other arachidonate was increased.

Topics: Animals; Cerebral Arteries; Dinoprost; Dinoprostone; Dogs; Epoprostenol; Fatty Acids, Unsaturated; Ischemic Attack, Transient; Prostaglandins D; Prostaglandins E; Prostaglandins F; Subarachnoid Hemorrhage; Thromboxane A2

1. Despite extensive research no explanation has been put forward to account for the fact that cerebral arterial spasm complicates the course of disease of many but not all patients suffering from rupture of an intracranial aneurysm. Although vasoactive material in hemorrhagic cerebrospinal fluid (CSF) most probably is of major importance in the pathophysiology of delayed cerebral vasospasm, recent studies have failed to demonstrate a correlation between CSF vasoconstrictor activity and the development of delayed cerebral vasospasm. 2. In the present study the reactivity of isolated human pial arteries to various vasoactive agents [prostaglandin F2 alpha, noradrenaline, serotonin, human plasma and CSF from patients with aneurysmal subarachnoid hemorrhage (SAH)] was investigated. 3. There was a very marked variability in the spectrum of responses between arteries from different individuals with regard to the contractile responses to plasma, hemorrhagic CSF and amines. On the other hand, the contractions produced by prostaglandin F2 alpha and potassium were consistent. 4. The markedly individual profile in terms of reactivity toward vasoactive substances emphasizes the importance of a human cerebral vessel wall factor and may explain the capricious occurrence of cerebral vasospasm after aneurysmal SAH.

Topics: Adult; Aged; Cerebrovascular Circulation; Dinoprost; Female; Humans; Ischemic Attack, Transient; Male; Middle Aged; Muscle, Smooth, Vascular; Norepinephrine; Potassium; Prostaglandins F; Serotonin

Differences between human and canine basilar arteries in contractile responses to various agents were studied in vitro. Human basilar arteries were obtained at postmortem. Serotonin or prostaglandin F2 alpha contracted greatly both human and canine basilar arteries. There was no difference between the two vessels in serotonin- or prostaglandin F2 alpha-induced contractions. In contrast, great differences were found between the two arteries in response to norepinephrine or hemoglobin. Human basilar arteries contracted markedly to norepinephrine while canine basilar arteries did not contract to norepinephrine. This data suggests that sympathetics might play a more important role in the genesis of vasospasm after subarachnoid hemorrhage than has been previously thought. Hemoglobin did not elicit a contraction in human basilar arteries whereas it produced marked contractions in canine basilar arteries. This result indicates that possible participation of hemoglobin as a causative agent in vasospasm could be ruled out. In view of these differences between human and canine cerebral arteries, the canine seems unsuitable for an experimental model of cerebral vasospasm.

Topics: Animals; Basilar Artery; Dinoprost; Dogs; Hemoglobins; Humans; In Vitro Techniques; Ischemic Attack, Transient; Norepinephrine; Prostaglandins F; Serotonin; Vasoconstriction

Topics: Animals; Basilar Artery; Blood Physiological Phenomena; Dinoprost; Dogs; Female; Ischemic Attack, Transient; Male; Muscle Contraction; Muscle, Smooth, Vascular; Prostaglandins; Prostaglandins F; Serotonin

Total Ca and Ca++ in cerebrospinal fluid were measured from the patient with subarachnoidal hemorrhage due to ruptured cerebral aneurysm. Relationship was studied between the values of total Ca and Ca++ and grades of cerebral vasospasm on cerebral angiograms. Additionally, experimental studies were performed on helical strip of dogs' basilar arteries with constrictable substances such as serotonin (5-HT), prostaglandin F2 alpha (PGF2 alpha), KC1 and oxy-hemoglobin (Oxy-Hb). Findings were as follows: There was a gradual increasing of vasospasm in the patients whose cerebrospinal fluid contained high values of total Ca at one or two days after rupture of aneurysm. In all samples of bloody cerebrospinal fluid, values of Ca++ were almost the same or lower than that of control group. The time course of Ca++ concentrations was remarkably decreased in the groups with increased vasospasm. In the experimental study, continuous constriction of helical strips were induced with high concentration of KC1 and physiological values of Oxy-Hb, but 5-HT and PGF2 alpha constricted only in a short time. The effects of KC1 and Oxy-Hb were remarkably inhibited when Ca++-antagonist was added to the artificial cerebrospinal fluid or Ca++ was freed from the fluid. With these results, it was thought that Oxy-Hb might be the most important substance for cerebral vasospasm and it may affect cerebral vessels with Ca++ in cerebrospinal fluid. It was, however, an unreasonable result that time course of Ca++ decreased on the patients with severe vasospasm when vasospasm increased. Then, high concentration of total Ca at acute stage after subarachnoidal hemorrhage was considered as it may trigger the incidence of cerebral vasospasm.

Topics: Adult; Aged; Animals; Calcium; Dinoprost; Dogs; Female; Humans; Ischemic Attack, Transient; Male; Middle Aged; Nifedipine; Oxyhemoglobins; Potassium Chloride; Prostaglandins F; Serotonin; Subarachnoid Hemorrhage

Topics: Adult; Alprostadil; Cerebral Infarction; Cerebrovascular Disorders; Dinoprost; Dinoprostone; Humans; Ischemic Attack, Transient; Middle Aged; Platelet Aggregation; Prostaglandins; Prostaglandins E; Prostaglandins F