thromboxane-a2 and Ischemic-Attack--Transient

Most neurologists concede that thromboembolism is the principal pathogenetic mechanism for ischemic cerebrovascular disease, including both transient ischemic attacks and cerebral infarction. Surgical removal of atherosclerotic lesions may eradicate the site of origin of emboli, but a safer and more rational approach may be found in using antithrombotic drugs. Aspirin has been shown in clinical trials to be an effective agent in treating transient ischemic attacks and preventing infarction. An apparent difference in response between men and women patients was found in the results of one large study but not substantiated by others. It has been suggested that a lower dose of aspirin than that used in these trials may be equally or more effective. This proposition still needs to be tested in a clinical trial.

Topics: Aspirin; Cell Adhesion; Cerebrovascular Disorders; Humans; Ischemic Attack, Transient; Platelet Aggregation; Prostaglandins; Thrombosis; Thromboxane A2

Research into noninvasive techniques for evaluating cerebrovascular insufficiency has shown that hemodynamically significant lesions can be identified with considerable accuracy. Concurrently, recent descriptions of carefully applied medical and surgical therapy indicate that thromboembolic stroke can be effectively prevented when patients are allocated to the proper therapeutic protocols. The approach of these two lines of basic investigation to the clinical focal point of stroke control make it imperative that clinicians review the tools at hand for identifying persons at high risk, as well as the available therapeutic alternatives for effective stroke prevention.

Topics: Aged; Anticoagulants; Aspirin; Auscultation; Blood Platelets; Blood Pressure; Carotid Arteries; Cerebrovascular Disorders; Endarterectomy; Female; Humans; Ischemic Attack, Transient; Male; Middle Aged; Ophthalmic Artery; Pulse; Risk; Thromboxane A2; Ultrasonography

The pharmacological target of aspirin is the inhibition of cyclooxygenase-1 (COX1) and thromboxane-A2 (TX) synthesis. Very few data are available on TX assessment in patients with stroke. We studied platelet TX synthesis, COX1-independent platelet reactivity, the influence of platelet-erythrocyte interactions and the potential association between platelet responses and the severity of stroke, evaluated with a clinical score (NIHSS).. We examined 157 aspirin-treated patients with acute stroke or TIA, 128 aspirin-free and 15 aspirin-treated healthy subjects (HS). Collagen-induced TX, platelet recruitment in whole blood and platelets ± erythrocytes (haematocrit 40%) were assessed in patients on daily-aspirin within three days from onset. Arachidonic-acid-, ADP-, thrombin-receptor activating peptide TRAP-, and collagen-induced aggregation were also evaluated.. Partial TX inhibition (<95% inhibition vs aspirin-free controls) was observed in 13% of patients. This was associated with marked increases in COX1-dependent responses (arachidonic-acid- and collagen-induced aggregation and platelet recruitment; P<0.0001) but not with differences in ADP- or TRAP-induced aggregation. Partial TX inhibition was independently associated with severe stroke (NIHSS ≥ 12) at both admission (P<0.05) and discharge (P<0.05). Among patients with fully blocked TX, those with elevated COX1-independent platelet reactivity (mean+2SD of aspirin-treated HS) were most likely to suffer severe stroke (P<0.05). Platelet-erythrocyte interactions enhanced platelet reactivity in these patients by COX1-dependent and -independent mechanisms (P<0.0001).. TX inhibition by aspirin varied across patients. Partial TX inhibition and COX1-independent platelet hyperfunction were associated with more-severe stroke.

Topics: Acute Disease; Aged; Aspirin; Case-Control Studies; Cyclooxygenase 1; Cyclooxygenase Inhibitors; Female; Humans; Ischemic Attack, Transient; Male; Platelet Aggregation; Stroke; Thromboxane A2

The objectives of the study were to (1) characterize the dose-response relationship to the TXA2 analog, U46619 (0.01, 0.1, and 1 micromol/L) after global cerebral ischemia, (2) determine whether chronic 17beta-estradiol (E2) replacement alters this relationship, and (3) determine if E2's mechanisms are transduced through cognate estrogen receptors. Rats were assigned to five groups (n=6): placebo-implanted ovariectomized (OVX) females, OVX plus chronic E2 (CE), OVX plus acute E2 (AE), OVX plus chronic E2 plus the estrogen receptor inhibitor ICI 182,780 (CEI), and OVX plus acute E2 plus ICI 182,780 (AEI). Rats were anesthetized, intubated, cannulated (femoral artery and vein), fitted with a closed cranial window, and subjected to 15-min reversible forebrain ischemia (4-vessel occlusion, 4-VO) and 60 mins of reperfusion. Arterial blood gases, intrawindow pressure, and temperature were controlled. Vessel diameter was measured before and 5 mins after superfusion of each concentration of U46619. Compared with preischemic responses, contractile response to U46619 was depressed at all concentrations after ischemia in the OVX group. In the chronic E2 and acute E2 groups, contractile response to 1 micromol/L of U46619 was normalized to near baseline values. However, in the CEI and the AEI groups, postischemic vasoconstriction was similar to that observed in the OVX rats. We conclude that E2 targets the cerebral microvasculature to preserve postischemic pial artery reactivity and that the effect is receptor mediated. Restoration of normal constriction to vascular agonists may be an important mechanism by which E2 protects the vasculature and diminishes tissue damage after ischemia.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Animals; Blood Pressure; Cerebral Arteries; Dose-Response Relationship, Drug; Estradiol; Female; Hemoglobins; Hydrogen-Ion Concentration; Ischemic Attack, Transient; Ovariectomy; Oxygen; Prosencephalon; Rats; Rats, Wistar; Receptors, Estrogen; Reperfusion Injury; Thromboxane A2; Vasoconstrictor Agents

The effect of ozagrel, a selective thromboxane A(2) (TXA(2)) synthetase inhibitor, on the obstruction after cerebral ischemia-reperfusion was studied in experimental animal models. The reduced spontaneously locomotor activity and the obstruction of motor coordination were improved by the administration of ozagrel in the conscious cerebral ischemia-reperfusion mouse model. Ozagrel suppressed the decrease in specific gravity of the brain tissue induced by the occlusion-reperfusion in the conscious cerebral ischemia-reperfusion SHR model, and recovered the postischemic decrease in cortical PO(2) after middle cerebral artery occlusion-reperfusion in cats. The level of TXB(2), a metabolite of TXA(2), in the brain increased after the cerebral ischemia-reperfusion, and ozagrel prevented this increase. Additionally, ozagrel also increased the level of 6-keto-PGF(1alpha), a metabolite of prostaglandin I(2) (PGI(2)), in the brain tissue after cerebral ischemia-reperfusion, and the administration of PGI(2) improved the reduced spontaneous locomotor activity in the conscious cerebral ischemia-reperfusion mouse model. Our data suggest that ozagrel suppressed the obstruction following cerebral ischemia-reperfusion by preserving the cerebral blood flow via preventing the increase in TXA(2) and causing an increase in the PGI(2) level.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Brain Chemistry; Cerebral Cortex; Enzyme Inhibitors; Epoprostenol; Imidazoles; Ischemic Attack, Transient; Male; Methacrylates; Mice; Motor Activity; Neuroprotective Agents; Oxygen Consumption; Psychomotor Performance; Rats; Rats, Inbred SHR; Reperfusion Injury; Specific Gravity; Thromboxane A2; Thromboxane-A Synthase

The role of the phosphodiesterase type IV isozyme (PDE IV) in the regulation of cerebrovascular tone was investigated in the canine basilar artery in vitro and in vivo. The PDE isozymes extracted from the canine basilar artery were isolated by diethylaminoethanol (DEAE)-Sepharose affinity chromatography and identified based on sensitivity to isozyme-selective PDE inhibitors. [3H]cAMP hydrolysis was observed in one major and one minor peak of activity. The predominant peak was inhibited by the addition of cGMP (25%), siguazodan (26%), rolipram (39%), and the combination of siguazodan and rolipram (95%). Selective PDE IV inhibitors BRL 61063, rolipram, and denbufylline were equieffective inhibitors of [3H]-ccAMP hydrolysis mediated by PDE IV isolated from the canine basilar artery [concentrations producing 50% inhibition (IC50S) = 0.21 +/- 0.05 microM, 0.67 +/- 0.23 microM, and 0.73 +/- 0.16 microM, respectively]. In precontracted isolated ring segments of the canine basilar artery, selective PDE IV inhibitors produced potent and complete relaxation (IC50S < 150 nM). In contrast, zaprinast (a selective PDE V inhibitor) and siguazodan (a selective PDE III inhibitor) produced only weak relaxation of the basilar artery (IC50S = 4.5 microM and > 10 microM, respectively). Vasorelaxation produced by PDE IV inhibitors was not altered by removing the endothelium, 1-NAME, or adenosine receptor antagonism. In a canine model of acute cerebral vasospasm, all three selective PDE IV inhibitors reversed basilar artery spasm produced by autologous blood without altering mean arterial blood pressure. In contrast, prolonged treatment with BRL 61063 failed to alter the development of basilar spasm in the two hemorrhage canine models of chronic cerebral vasospasm. Denbufylline-induced relaxation in vitro was also significantly impaired in basilar arteries obtained from the model of chronic vasospasm. In conclusion, PDE IV appears to be the predominant isozyme regulating vascular tone mediated by cAMP hydrolysis in cerebral vessels. In addition, vasorelaxation modulated by PDE IV is compromised in chronic cerebral vasospasm associated with subarachnoid hemorrhage.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; 3',5'-Cyclic-AMP Phosphodiesterases; Animals; Basilar Artery; Cerebral Arteries; Cyclic AMP; Cyclic Nucleotide Phosphodiesterases, Type 4; Dogs; Drug Evaluation, Preclinical; Ischemic Attack, Transient; Isoenzymes; Male; Phosphodiesterase Inhibitors; Phosphoric Diester Hydrolases; Prostaglandin Endoperoxides, Synthetic; Pyrrolidinones; Rolipram; Second Messenger Systems; Subarachnoid Hemorrhage; Thromboxane A2; Vasoconstrictor Agents; Vasodilator Agents; Xanthines

Thromboxane A2 accumulates in the hippocampus after global ischemia and may play a key role in postischemic hypoperfusion. Thromboxane synthetase inhibitor (OKY-046) inhibits the accumulation of thromboxane A2 and promotes prostacycline production. Therefore, we set out to determine whether the inhibition of thromboxane synthesis would ameriolate postischemic neuronal death. Three groups of six Mongolian gerbils were subjected to different treatments: untreated control, untreated ischemia, and treated ischemia. Immediately after forebrain ischemia, OKY-046 (10 mg/kg) was injected intraperitoneally into the treated group. After 7 days of survival, the histopathology of the brain was examined. Pyramidal cell density in the CA1 sector in the treated group was 147 +/- 70 nuclei/mm (mean +/- SD), which was significantly (p < 0.05) higher than than in the untreated group (33 +/- 10 (nuclei/mm). The findings were 231 +/- 7 nuclei/mm for the control group. No significant difference was seen in the profile of temporal muscle temperature before and after ischemia between the groups. Ultrastructurally, the vessels in the CAI sector showed lumen patency in the treated group, whereas occluded vessels with an extended perivascular space were observed in the untreated group. Thromboxane synthetase inhibitor thus partly ameliorates the selective vulnerability of the hippocampus after forebrain ischemia, suggesting that thromboxane A2 is involved in the development of delayed neuronal death, independently of any thermal effect.

Topics: Animals; Cell Count; Cell Death; Gerbillinae; Hippocampus; Ischemic Attack, Transient; Methacrylates; Neurons; Pyramidal Cells; Temperature; Thromboxane A2; Thromboxane-A Synthase

We investigated the effect of KW-3635, a selective thromboxane (TX) A2-receptor antagonist, on the arachidonic acid (AA)-induced transient cerebral ischemia in anesthetized dogs. Intracarotid-arterial injection of AA (0.25-1 mg/kg) produced a transient and reversible decrease in electroencephalographic (EEG) activity. The reduction of EEG power was inhibited by the intravenous injection of KW-3635 or aspirin, a cyclooxygenase inhibitor. Local cortical perfusion (LCP) measured by a laser-doppler flow meter was also reduced concomitantly with the reduction of EEG power. Although KW-3635 at 1 and 3 mg/kg (i.v.) did not affect the maximum reduction of LCP, the duration of the reduction period of LCP was significantly shortened by KW-3635. On the other hand, aspirin at 1 and 3 mg/kg (i.v.) inhibited both the maximum and the delay of LCP reduction. The intravenous administration of KW-3635 or aspirin caused dose-dependent inhibition of ex vivo platelet aggregation stimulated by AA (150 microM) at the doses that improve the EEG activity. These data suggest that TXA2 is one of the important factors in the AA-induced transient reduction of EEG activity in anesthetized dogs. The TXA2-receptor antagonist may be useful for protection against the ischemic brain damage following transient ischemic attack.

Topics: Animals; Arachidonic Acid; Aspirin; Benzimidazoles; Benzoxepins; Blood Pressure; Carotid Arteries; Cerebrovascular Circulation; Dogs; Electroencephalography; Female; Heart Rate; In Vitro Techniques; Injections, Intra-Arterial; Ischemic Attack, Transient; Male; Platelet Aggregation; Thromboxane A2

The reduction of blood flow occurring after global cerebral ischemia, designated as delayed postischemic hypoperfusion, is a consequence of various pathological processes. Employing a cardiac arrest model in cats, we evaluated the possible role of thromboxane A2 (TXA2) in reducing the cerebral blood flow (CBF) after transient global ischemia. Twenty cats were divided into two groups, a cardiac arrest group (N = 13) and a sham operation group (N = 7). Following thoracotomy, cardiac arrest was induced for 30 seconds. The TXA2 receptor antagonist, BAY u3405, was injected at 60 minutes after recirculation. The CBF, brain tissue PO2 (BrPO2), brain tissue pH (BrpH) and mean arterial blood pressure (MABP) were measured continuously. The CBF decreased to 89.6% at 60 minutes after the arrest, suggesting postischemic hypoperfusion. Injection of BAY u3405 significantly increased the CBF and BrPO2, whereas BrpH and MABP remained unchanged. In the sham operation group, the CBF, BrPO2, BrpH and MABP did not change significantly during 10 minutes after drug injection, although the BrPO2 was increased mildly at 10 minutes after the injection. Since the thromboxane A2 antagonist improved the CBF only after the cardiac arrest, thromboxane A2 is thought to be one of the factors causing postischemic hypoperfusion.

Topics: Animals; Carbazoles; Cats; Cerebrovascular Circulation; Ischemic Attack, Transient; Perfusion; Reaction Time; Receptors, Thromboxane; Sulfonamides; Thromboxane A2

Arachidonate metabolites have been implicated in the development of cerebral injury after ischemia. Particular importance has been placed on the balance of thromboxane A2 and prostaglandin I2 because of its regulative activity on platelet functions and arterial tone. The purpose of the present study was to shed light on the role of thromboxane A2 in postischemic brain injury.. We evaluated the effects of S-1452, a novel thromboxane A2 receptor antagonist, on brain edema, infarct areas, and survival rate in rats with middle cerebral artery occlusion. A transient middle cerebral artery occlusion model was produced by inserting a piece of silicon-coated nylon thread into the internal carotid artery.. The ratio of plasma thromboxane B2 to 6-keto-prostaglandin F1 alpha significantly rose at 0 hour (P < .05), 1 hour (P < .01), 3 hours (P < .05), and 12 hours (P < .05) and then nearly returned to the normal level at 24 hours after reperfusion following 1-hour occlusion. Pretreatment with S-1452 (5, 10, or 50 mg/kg PO) significantly attenuated the increase in postischemic water content in the cerebral cortex perfused by the anterior cerebral artery and the cerebral cortex perfused by the middle cerebral artery in a dose-dependent manner but slightly attenuated it in the caudate putamen 24 hours after reperfusion following 1-hour occlusion. Pretreatment with S-1452 (10 mg/kg PO) also significantly decreased the areas of infarction in the front parts of the cerebrum. The survival rate of animals after 2 hours of occlusion tended to be improved by treatment with S-1452 (10 mg.kg-1.d-1 PO), although there was no statistical significance.. Our results suggest that thromboxane A2 is closely related to postischemic brain injury in the early phase of recirculation and that S-1452 may have a protective effect on postischemic brain injury.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Body Water; Brain; Bridged Bicyclo Compounds; Cerebral Infarction; Fatty Acids, Monounsaturated; Ischemic Attack, Transient; Male; Rats; Rats, Wistar; Receptors, Thromboxane; Reperfusion Injury; Survival Analysis; Thromboxane A2; Thromboxane B2; Time Factors

Platelet activation results in the formation of various vasoactive mediators such as thromboxane A2 and serotonin. We investigated the effects of Bay U 3405 [(3R)-3- (4-fluorophenyl-sulfonamido)-1,2,3,4,-tetrahydro-9-carbazolepro panoic acid] on vasocontractions of isolated bovine cerebral arteries induced by U 46.619, a stable thromboxane/prostaglandin-endoperoxide analogue, and authentic thromboxane A2 released from thrombin-stimulated human platelets. Bay U 3405 (0.001-10 mumol/l) potently inhibited the contraction induced by U 46.619 and demonstrated a reduction of the thromboxane-mediated component of platelet-induced contractile response at higher concentrations (0.1-10 mumol).

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Animals; Blood Platelets; Carbazoles; Cattle; Cerebral Arteries; Humans; Ischemic Attack, Transient; Prostaglandin Endoperoxides, Synthetic; Serotonin; Sulfonamides; Thromboxane A2; Thromboxanes; Vasoconstriction

1-(5-Isoquinolinesulfonyl)-homopiperazine, HA1077, is a calcium antagonist with anti-vasospastic properties. This compound blocks intracellular actions of calcium in a variety of experiments. In the present study, we examined the effects of HA1077 on the vascular actions of endothelin, an endothelium-derived vasoactive peptide, in dogs in vitro and in vivo. Intracisternal injections of endothelin (0.01 nmol) produced a significant vasospasm, as measured by angiography, similar to that seen in the canine hemorrhage model. Infusion of HA1077 led to a significant dilatation of the spastic basilar artery in endothelin-treated dogs. The rank order of in vitro contractile activity in canine cerebral arteries was a stable thromboxane A2 analog greater than endothelin greater than 5-hydroxytryptamine greater than prostaglandin F2 alpha greater than histamine greater than noradrenaline. HA1077 effectively antagonized the endothelin-induced contraction of canine basilar arterial strips in both calcium-containing and calcium-free medium. The present results indicate that HA1077 is an effective antagonist for endothelin in vitro and in vivo.

Topics: 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; Animals; Calcium; Cerebral Arteries; Dogs; Endothelins; Female; Ischemic Attack, Transient; Isoquinolines; Male; Muscle Contraction; Thromboxane A2

Topics: Adenosine Diphosphate; Animals; Cerebral Arteries; Ischemic Attack, Transient; Male; Platelet Aggregation; Rabbits; Reference Values; Thromboxane A2

The pharmacological properties of a novel thromboxane A2/prostaglandin endoperoxide receptor antagonist, ONO-3708, on blood vessels were examined in vitro and in vivo. ONO-3708, 10 microM, inhibited the rabbit aorta contractions induced by thromboxane A2, prostaglandin H2, 11,9-epoxymethano-prostaglandin H2 (U-46619) or prostaglandin F2 alpha without affecting the contractions induced by angiotensin II, serotonin or norepinephrine. ONO-3708, at a concentration of 1 to 100 nM, appeared to be a competitive inhibitor of the contractile responses of the canine basilar artery to 9,11-epithio-11,12-methano-thromboxane A2 (STA2), U-46619 and PGF2 alpha, and a non-competitive inhibitor of the contractile responses to 15-hydroperoxy-eicosatetraenoic acid (15-HPETE). In in vivo studies, ONO-3708 (10 and 100 micrograms/kg per min i.v.) ameliorated the decrease in diameter of the basilar artery induced by the i.v. infusion of STA2 (0.1 microgram/kg per min) in cats. Furthermore, infusion of ONO-3708 (10 and 30 micrograms/kg per min i.v.) prevented the cerebral vasospasm in an experimental subarachnoid hemorrhage model in dogs. These results indicate that ONO-3708 is a potent antagonist of the thromboxane A2/prostaglandin endoperoxide receptor in vitro and in vivo and may be of therapeutic use in preventing cerebral vasospasm.

Topics: Animals; Aorta; Basilar Artery; Blood Vessels; Cats; Dogs; Female; Ischemic Attack, Transient; Male; Muscle Contraction; Rabbits; Receptors, Prostaglandin; Thromboxane A2; Vasoconstriction

To determine whether cerebral arteries in spasm have an altered capacity to synthesize the vasoactive substances prostacyclin and thromboxane A2, we measured levels of these arachidonic acid metabolites using a primate model of vasospasm. Twenty-four cynomolgus monkeys were assigned at random to one of three groups designated sham, clot, or clot-removal. All animals underwent base line cerebral angiography and bilateral dissection of the major cerebral arteries from the arachnoid. The clot and clot-removal groups had autologous hematomas placed around the vessels to simulate subarachnoid hemorrhages. The sham group had a similar volume of saline instilled into the subarachnoid space. Twenty-four hours later, the clot-removal group underwent a second craniotomy to remove the hematomas. Seven days after the initial operation, angiography was repeated on all animals. The animals were then killed, and the cerebral arteries were removed. Basal levels of prostacyclin and thromboxane in the cerebral vessels were measured after incubation in vitro by radioimmunoassay. No detectable leukotriene C4 release by these arteries was measurable using radioimmunoassay. Angiography revealed severe cerebral vasospasm in the clot group, but not in the clot-removal or sham groups. There were no statistical differences among the groups in thromboxane release, but prostacyclin levels were significantly lower in the clot group than in the clot-removal group (P less than 0.05). It thus seems that, if an imbalance in constrictor and dilator eicosanoids occurs in association with vasospasm, this is more likely to arise from a relative lack of the vasodilator component prostacyclin than from a surplus of the vasoconstrictor thromboxane.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Cerebral Angiography; Cerebral Arteries; Epoprostenol; Female; Ischemic Attack, Transient; Macaca fascicularis; Osmolar Concentration; Radioimmunoassay; Thromboxane A2; Thromboxane B2

Topics: Animals; Dogs; Humans; In Vitro Techniques; Ischemic Attack, Transient; Platelet Aggregation; Thrombosis; Thromboxane A2; Vasoconstriction

Vasoactive arachidonic acid metabolites are postulated to play a role in the pathogenesis of cerebral ischemia. In order to characterize the local generation of cyclooxygenase and lipoxygenase metabolites of arachidonic acid in transient ischemia with reperfusion, Mongolian gerbils were studied for regional cerebral blood flow (CBF), using the hydrogen clearance technique, and for cerebral levels of the thromboxane metabolite TXB2, and prostaglandins 6-keto-PGF1 alpha and PGE2, as well as the leukotriene LTB4. The gerbils were anesthetized with pentobarbital, and half of the animals were pretreated with the cyclooxygenase inhibitor indomethacin. All received 10 or 20 minutes of dense forebrain ischemia followed by reperfusion of 10 minutes, 50 minutes, or 100 minutes. A separate control group received no ischemic lesion. Regional CBF decreased significantly from 23.7 +/- 2.6 to 4.3 +/- 1.7 cc/100 gm/min during ischemia (p less than 0.01). Reperfusion resulted in initially normal flows (22.5 +/- 5.1 cc/100 gm/min) followed by a progressive hypoperfusion (11.3 +/- 2.7 cc/100 gm/min). All metabolites showed parallel significant (p less than 0.05) increases after transient ischemia and reperfusion compared to baseline levels (values (in pg/mg protein) were: TXB2 45.5 +/- 7.1 vs 23.3 +/- 3.6; 6-keto-PGF1 alpha 262.8 +/- 47.9 vs 175.8 +/- 26.8; PGE2 256.5 +/- 35.6 vs 112.5 +/- 11.2; and LTB4 37.8 +/- 4.6 vs 24.6 +/- 6). These levels were all significantly decreased (p less than 0.05) by pretreatment with indomethacin except for the leukotriene LTB4, which was increased. Transient cerebral ischemia results in a reperfusion abnormality and the local generation of cyclooxygenase products, which are reduced by pretreatment with indomethacin; however, cyclooxygenase inhibition may result in increased substrate availability for the lipoxygenase system. Studies of such an interaction may lead to new understandings of the pharmacological modification of detrimental vascular changes after transient cerebral ischemia.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Arachidonic Acid; Arachidonic Acids; Cerebrovascular Circulation; Gerbillinae; Ischemic Attack, Transient; Leukotriene B4; Lipoxygenase; Prostaglandin-Endoperoxide Synthases; Prostaglandins E; Thromboxane A2

Our understanding of the biochemistry and biologic actions of AA metabolites has been greatly expanded in recent years. The discoveries of TXA2, PGI2, and LTs have fostered new concepts of the pathophysiology of cerebral ischemia. New approaches to treatment of ischemia include seeking an optimal dose of aspirin, developing drugs that selectively inhibit or antagonize TXA2 or LTs, and administering PGI2 or its analogues. Altering the dietary content of essential fatty acids for prophylaxis is also being studied. Though the results of this thrust are still preliminary, the exploration of these therapeutic strategies in cerebrovascular disorders based on further understanding of the pathophysiologic roles of TXA2, PGI2, LTs and probably other AA metabolites is anticipated with some optimism.

Topics: Blood Platelets; Diet; Epoprostenol; Indomethacin; Ischemic Attack, Transient; Leukotriene B4; SRS-A; Thromboxane A2; Thromboxane-A Synthase

Imbalance between the two arachidonic acid metabolites, prostacyclin (PGI2) and thromboxane A2 (TXA2), is thought to be at least in part responsible for the development of cerebral vasospasm following aneurysm rupture. In 12 patients with subarachnoid hemorrhage the pre- and postoperative serum and CSF levels of PGI2 and TXA2 were measured as a function of their stable hydrolysis products, 6-Keto-PGF1 alpha (PGI2) and thromboxane B2 (TXA2), with a highly specific radioimmunoassay. Serum levels of both metabolites were elevated in half of the patients, but no correlation to the clinical course could be found. However, TXB2 concentration in the CSF was significantly increased preoperatively with close correlation to the amount of intracisternal blood, as detected by CT scan. Furthermore, it could be demonstrated that the postoperative course of the TXB2 concentrations in the CSF reflects the clinical course in such a way that a characteristic secondary rise of TXB2, concentration postoperatively is closely related to the occurrence of cerebral vasospasm and clinical deterioration. The conclusion is drawn that measurement of arachidonic acid metabolites in the CSF may provide important information concerning the pathophysiological events following subarachnoid hemorrhage, especially with regard to incipient cerebral vasospasm.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Arachidonic Acid; Arachidonic Acids; Blood-Brain Barrier; Carotid Artery Diseases; Carotid Artery, Internal; Epoprostenol; Female; Humans; Intracranial Aneurysm; Ischemic Attack, Transient; Male; Middle Aged; Rupture, Spontaneous; Subarachnoid Hemorrhage; Thromboxane A2; Thromboxane B2

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

Topics: Adenosine Diphosphate; Animals; Arteries; Cerebrovascular Circulation; Ischemic Attack, Transient; Male; Platelet Aggregation; Rabbits; Thromboxane A2

OKY-1581, a thromboxane A2 (TXA2) synthetase inhibitor, was administered to cats with normal and constricted basilar arteries. At a dose of 60mg/kg (i.v.), both normal and constricted vessels dilated, and the mean arterial blood pressure (MABP) fell from 55 to 75 mmHg. If MABP remained constant, vessel diameter did not change. Subarachnoid hemorrhage (SAH) was simulated by intracisternal injection of autologous arterial blood. Regional cerebral blood flow (rCBF) was assessed by the heat clearance and H2 clearance methods. The two methods presented similar response profiles. rCBF responses to intravenous OKY-1581 fell into 3 categories: A) no change in rCBF, B) decrease in rCBF related to MABP and C) increase in rCBF in the presence of hypotension. Types A and B were observed in 3 out of 10 control cats and 4 out of 14 SAH-induced cats, with Type C responses in the remainder. There was no significant difference between the groups. While the results do not support a major role for TXA2 in cerebral vasospasm pathogenesis, OKY-1581 may still be useful in the treatment of cerebral vasospasm, as it improves distal and deep circulation and inhibits platelet aggregation.

Topics: Acrylates; Animals; Blood Pressure; Cats; Cerebrovascular Circulation; Epoprostenol; Ischemic Attack, Transient; Mathematics; Methacrylates; Oxidoreductases; Thromboxane A2; Thromboxane-A Synthase; Vasodilation

Subarachnoid hemorrhage (SAH) was induced in 50 rabbits by injecting 1.25 cc/kg of autologous, well heparinized, fresh arterial blood into the cisterna magna, followed by suspending the animals in a head-down position at 30 degrees for 15 minutes. The animals were evenly divided into five groups: a control group, or groups receiving post-SAH prostacyclin (PGI2), carbacyclin, thromboxane A2 (TXA2) synthetase inhibitor (OKY-1581), or nutralipid. Radiographic vertebrobasilar arterial spasm was demonstrated on the 3rd day post-SAH in the control animals. This was decreased in the prostacyclin and the carbacyclin groups and was absent in the OKY-1581 and the nutralipid groups. Cerebral blood flow (CBF) measurements on the 4th day post-SAH using the xenon-133 technique failed to reveal any significant difference between the prostacyclin, the carbacyclin, and the control groups, but flows in the nutralipid and the OKY-1581 groups were significantly higher. There was a good correlation between the clinical status and the CBF. Intracytoplasmic vacuolation and detachment of the vascular endothelium, seen ultrastructurally, may account for the impaired synthesis of prostacyclin. Exogenous prostacyclin and carbacyclin decreased vasospasm but failed to improve cerebral perfusion. OKY-1581 blocked the synthesis of the potent vasoconstrictor, TXA2, which is not only formed during platelet aggregation but also induces platelet aggregation. Nutralipid contains linolenic acid, a precursor of eicosapentaenoic acid (EPA), which is more potent in inhibiting platelet aggregation and in blocking TXA2 production. The various fatty acid constituents of nutralipid bind to albumin and thereby shorten the half-life of TXA2.

Topics: Acrylates; Animals; Cerebrovascular Circulation; Epoprostenol; Fatty Acids; Female; Ischemic Attack, Transient; Male; Methacrylates; Rabbits; Subarachnoid Hemorrhage; Thromboxane A2; Thromboxane-A Synthase

Prolonged vasospasm was produced in the canine basilar artery by injection of 0.75 ml/kg of fresh autologous arterial blood into the cisterna magna (subarachnoid hemorrhage, SAH group) or by subarachnoid application of oxyhemoglobin (oxyHb induced group). Lipoperoxide contents of the arterial wall was measured by thiobarbituric acid test. Prostaglandin I2 (PGI2) and thromboxane A2 (TXA2) biosynthetic activity of arterial wall was measured by radioimmunoassay as their stable metabolites, 6-keto-prostaglandin F1 alpha, thromboxane B2, respectively. Ultrastructual examination was carried out to reveal morphological localization of lipoperoxide of the spastic artery by a new method of lipoperoxide stain using thiocarbohydrazide and silver protein, the former was considered to react malondialdehyde. Lipoperoxide appeared in the electron microscope as discrete black granules. The value of lipoperoxide content of the spastic arterial wall elevated up to 7 days. Comparing with the control group, the increasing lipoperoxide contents of both day 4 SAH group and oxyHb induced group showed statistically significant difference (p less than 0.05). PGI2 biosynthetic activity in SAH group and in oxyHb induced group diminished, but statistically there was no significant difference. TXA2 biosynthetic activity did not alter. With increasing lipoperoxide value of arterial wall their PGI2 biosynthetic activity tended to diminish. Positive staining products of lipoperoxide stain were noted along the cell membrane of smooth muscle cell and endothelial cell in spastic arteries of both SAH and oxyHb induced groups. The result of this study suggests that oxyhemoglobin associated with lysis of the subarachnoid clot initiates lipid peroxidation damage of the smooth muscle cell and endothelial cell which diminishes PGI2 synthesis. This lipid peroxidation is suspected to be involved in the pathogenesis of vasospasm following SAH.

Topics: Animals; Basilar Artery; Dogs; Epoprostenol; Ischemic Attack, Transient; Lipid Peroxides; Subarachnoid Hemorrhage; Thromboxane A2; Thromboxanes

The effect of nizofenone on prostacyclin synthesis was investigated using rat arterial walls. Incubation of arterial walls with [14C] arachidonic acid resulted in a time-dependent formation of prostacyclin, which was radiochromatographically detected as the stable breakdown product, 6-keto prostaglandin F1 alpha. The addition of nizofenone dose-dependently stimulated the prostacyclin formation, and significant increases of 47 and 106% were observed at 0.1 and 0.3 mM, respectively. No stimulation of prostaglandin E2 and thromboxane A2 synthesis was observed in the experiments with ram seminal vesicle microsomes and human platelet microsomes. These findings suggest that nizofenone has a selective stimulatory action on prostacyclin synthesis.

Topics: Animals; Arachidonic Acid; Arachidonic Acids; Arteries; Blood Platelets; Epoprostenol; Humans; Imidazoles; In Vitro Techniques; Ischemic Attack, Transient; Male; Rats; Seminal Vesicles; Sheep; Thromboxane A2

Topics: Animals; Blood-Brain Barrier; Cats; Cell Membrane Permeability; Epoprostenol; Indomethacin; Ischemic Attack, Transient; Prostaglandins; Thromboxane A2

Our previous experimental and clinical studies yielded the following results: CSF flow around the subarachnoid vessels is often interrupted by subarachnoid clots; anaerobical incubation of CSF-blood mixture led to a marked fall in the pH value; the vasocontractility of anaerobically incubated CSF-blood mixtures was greater than that of aerobically incubated samples; vasocontraction induced by anaerobically incubated samples was inhibited to a far greater extent the prostaglandin synthesis inhibitor meclofenamic acid than by phenoxybenzamine; cases of asymptomatic marked angiographical vasospasm or of cerebral ischemia with relatively slight angiographical vasospasm were not rarely encountered. Those results lead us to a hypothesis that, in the pathogenesis of cerebral vasospasm, subarachnoid focal acidosis resulting from anaerobical changes of subarachnoid clots may be factor upsetting the balance of the synthesis of TXA2 and PGI2 from PG endoperoxides on the inner surface of cerebral arteries, in favor of TXA2--which plays a role in arterial contraction and in thrombosing with platelet aggregation. On this basis we have been testing the administrations of trapidil, an antagonist and selective synthesis inhibitor of TXA2, in 20 consecutive suitable cases so far, for the prevention of cerebral vasospasm after aneurysmal rupture. Angiographical vasospasm was seen in 9 of the 20 cases, but no signs of cerebral ischemia were detected in 7 of the 9 cases, either clinically or in CT scan. The importance of thrombus formation by platelet aggregation in symptomatic vasospasm are thus suggested.

Topics: Adult; Aged; Cerebral Arteries; Epoprostenol; Female; Humans; Intracranial Aneurysm; Intracranial Embolism and Thrombosis; Ischemic Attack, Transient; Male; Middle Aged; Platelet Aggregation; Subarachnoid Hemorrhage; Thromboxane A2; Trapidil

The authors have studied the ability of prostacyclin to reverse contractions of human basilar arteries in vitro that were induced by a wide range of substances implicated in the etiology of cerebral arterial spasm. Prostacyclin (10(-10) to 10(-6)M) caused a dose-related reversal of contractions induced by 5-hydroxytryptamine, noradrenaline, angiotensin II, prostaglandin (PG)F2 alpha, and U-46619 (a thromboxane-A2 mimetic). These agents were tested at concentrations or volumes that produced almost maximum or maximum responses and those that produced approximately 50% of the maximum response. Contractions induced by maximum concentrations of angiotensin II and U-46619 were least affected by prostacyclin. In addition, contractions induced by thromboxane-A2 generated from guinea-pig lung were reversed in a dose-dependent fashion by prostacyclin. This ability of prostacyclin to physiologically antagonize contractions of the human basilar artery in vitro induced by high concentrations of various spasmogenic agents suggests that such a potent vasodilator agent or more stable analogue may be of value in the treatment of such disorders as cerebral arterial spasm following subarachnoid hemorrhage.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Angiotensin II; Animals; Basilar Artery; Cerebrospinal Fluid; Dose-Response Relationship, Drug; Epoprostenol; Guinea Pigs; Ischemic Attack, Transient; Norepinephrine; Prostaglandin Endoperoxides, Synthetic; Prostaglandins; Prostaglandins F; Serotonin; Serotonin Antagonists; Thromboxane A2; Vasoconstriction

Using rabbit cerebral arteries in an in vitro chamber, we examined the cerebral arterial contraction initiated by clotting whole blood. By using methysergide maleate and a novel thromboxane synthetase inhibitor, 1-carboxyheptylimidazole (1-CHI), we studied the contributions of both serotonin and the prostaglandin metabolite thromboxane A2. Nontreated platelet-rich plasma (PRP) in the presence of methysergide produced a reliable contraction, whereas platelet-poor plasma did not. PRP from a rabbit pretreated with 1-CHI (50 mg/kg) compared to nontreated PRP caused a significantly smaller contraction. Blockade of this cerebral arterial contraction occurred without the disruption of platelet aggregation. Whole blood (1 ml) plus thrombin produced a consistent contraction over the 1 hour that was monitored. Whole blood drawn from a rabbit pretreated with 1-CHI (50 mg/kg) produced a smaller contraction, which began to dissipate in 5 minutes. When nontreated whole blood was added to the chamber in the presence of methysergide maleate (1.3 X 10(-5) g/ml), a contraction less than control was produced, and it persisted at 30 minutes. When whole blood pretreated with 1-CHI (50 mg/kg) was added to the chamber containing methysergide, there was a transient contraction that dissipated to nearly zero at 30 minutes. From our results, it is apparent that the thromboxane synthetase inhibitor has a profound effect on the later phase of blood-induced vasoconstriction. In contrast, the serotonin antagonist affected primarily the initial vasoconstriction and left the later phase largely unaltered. The role of thrombin, used to initiate coagulation, was also examined, and it was found to have a minimal direct constrictive effect when in a plasma solution.

Topics: Animals; Basilar Artery; Blood Coagulation; Blood Platelets; Collagen; Dose-Response Relationship, Drug; Female; Imidazoles; In Vitro Techniques; Ischemic Attack, Transient; Male; Methysergide; Models, Biological; Platelet Aggregation; Rabbits; Serotonin; Serotonin Antagonists; Subarachnoid Hemorrhage; Thromboxane A2

The results of our previous experimental and clinical studies led us to the hypothesis that, in the pathogenesis of cerebral vasospasm, subarachnoid focal acidosis resulting from anaerobic changes of subarachnoid clots may be a factor upsetting the balanced synthesis of both thromboxane A2 and prostaglandin I2 from prostaglandin endoperoxides on the inner surface of cerebral arteries. Thus, there is a higher concentration of thromboxane A2, a prostanoid that causes arterial contraction and platelet aggregation. We tested the administration of trapidil, an antagonist and selective synthesis inhibitor of thromboxane A2, in a series of 20 cases for the prevention of cerebral vasospasm and cerebral ischemia after aneurysmal rupture. Vasospasm was demonstrated by angiography in 9 of these cases, but only 2 of the 9 showed mild signs of cerebral ischemia. Of the 20 patients, 15 were discharged from the hospital as cured and 3 had a neurological deficit at discharge. Our findings suggest the significance in symptomatic vasospasm of thrombus formation by platelet aggregation and the effectiveness of trapidil as a preventive.

Topics: Adult; Aged; Cerebral Angiography; Female; Humans; Intracranial Aneurysm; Ischemic Attack, Transient; Male; Middle Aged; Pyrimidines; Rupture, Spontaneous; Thromboxane A2; Thromboxanes; Tomography, X-Ray Computed; Trapidil