thromboxane-a2 and Subarachnoid-Hemorrhage

All mammalian tissue investigated to date is capable of eicosanoid biosynthesis in response to various activating stimuli. While the importance of these metabolites as major mediators of many normal physiological processes and some pathophysiological conditions has not been proven, it is evident that these compounds are at least important modulators of many cellular and organ system functions. This review is intended to provide the reader with a brief overview of eicosanoid biology, with specific reference to the neurosciences. The increasing knowledge about the role of the eicosanoids in neurobiology may contribute to the understanding and treatment of many neurological diseases. The eicosanoids comprise several groups of biologically active unsaturated fatty acids: the "primary" prostaglandins, the cyclic endoperoxides, the prostanoids, the leukotrienes, and other acid lipids. This article includes a review of the enzymatic pathways of biosynthesis and metabolism of eicosanoids in man, and the pertinent structural nomenclature. The general basic and clinical pharmacological effects of the more important compounds on vascular perfusion, platelet function, intracellular enzyme activity, and interactions with other mediators of cellular activity are reviewed. A more detailed review of the actions of eicosanoids as mediators or modifiers of central nervous system physiology and pathophysiology is presented. Recent animal and human studies on the use and alterations of the eicosanoid metabolites is summarized, specifically where they relate to several clinical problem areas of interest to the neurosurgeon and neurobiologist. These areas include cerebrovascular circulation physiology, cerebral ischemia, cerebral vasospasm following subarachnoid hemorrhage, migraine headaches, hypothalamic function, neurotransmission, and nociception. A bibliography of 92 articles for further review is also included.

Topics: Central Nervous System; Cerebrovascular Circulation; Chemical Phenomena; Chemistry; Epoprostenol; Humans; Hydroxyeicosatetraenoic Acids; Hypothalamus; Nociceptors; Prostaglandins; Prostaglandins E; Prostaglandins F; Subarachnoid Hemorrhage; Synaptic Transmission; Thromboxane A2; Thromboxane B2

Delayed cerebral ischemia due to cerebral vasospasm remains a major cause of morbidity and mortality following subarachnoid hemorrhage. Oxyhemoglobin (OxyHb) and vasoconstrictor prostanoids have been suggested as putative spasmogens. We have previously reported a synergistic vasoconstrictive action between thromboxane A(2) (TXA(2)) and OxyHb. In the present study we examine the effect of neomycin, a phospholipase C inhibitor, on the cerebral vasoconstriction induced by TXA(2) and OxyHb.. Using an in vitro tissue bath method, we assess the effect of neomycin in a concentration-dependent manner, on isolated porcine basilar arteries constricted by U-46619 (TXA(2) analogue) and OxyHb.. The functional synergism between TXA(2) and OxyHb, leading to significant cerebral vasoconstriction, is attenuated in a dose-dependent manner by neomycin.. Blockade of phospholipase C may provide an alternative strategy in the treatment of subarachnoid-hemorrhage-induced cerebral vasospasm.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Animals; Basilar Artery; Dose-Response Relationship, Drug; Drug Synergism; Enzyme Inhibitors; Neomycin; Oxyhemoglobins; Subarachnoid Hemorrhage; Swine; Thromboxane A2; Type C Phospholipases; Vasoconstriction; Vasoconstrictor Agents; Vasospasm, Intracranial

RS-5186, which inhibits thromboxane A2 (TXA2) synthetase activity, ameliorated delayed cerebral vasospasm in a canine two-hemorrhage model. Subarachnoid hemorrhage was induced in 15 dogs, which were divided into two groups. In the RS-5186-treated group (9 dogs), 50 mg kg-1 of RS-5186 was administered twice a day for seven days. The remaining six dogs without administration of RS-5186 were used as a control group. In the RS-5186-treated group, the angiographic diameter of the basilar artery on Day 7 after subarachnoid hemorrhage was constricted to 60.9% +/- 11.6% (n = 9, mean +/- SD) of that on Day 0, before subarachnoid hemorrhage. The corresponding value was 42.8% +/- 6.1% (n = 6) in the control group. There was a statistically significant difference between these percentages. In the RS-5186-treated group, plasma thromboxane B2 level on Day 7 was 144.3 +/- 28.1 pg ml-1 (n = 4), which was lower than the 815.5 +/- 162.0 pg ml-1 (n = 4) in the control group (p < 0.0005). The plasma 6-keto-prostaglandin F1 alpha level on Day 7 was 180.5 +/- 66.5 pg ml-1 (n = 4) in the RS-5186-treated group, and higher than 107.3 +/- 12.4 pg ml-1 (n = 4) in the control group (p = 0.0734). Thus, administration of RS-5186 reduced TXA2 plasma level and had a beneficial effect on angiographically-detected delayed vasospasm.

Topics: Animals; Basilar Artery; Dogs; Drug Evaluation, Preclinical; Enzyme Inhibitors; Epoprostenol; Neuroprotective Agents; Subarachnoid Hemorrhage; Thiophenes; Thromboxane A2; Thromboxane-A Synthase; Vasospasm, Intracranial

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

The effects of subarachnoid hemorrhage on platelet-derived vasoconstriction of the isolated rabbit basilar artery were examined using an isometric tension recording method. The subarachnoid hemorrhage was induced by injecting arterial blood in the cisterna magna. The following points were confirmed: (1) the maximal contraction produced by the platelets (10(7)/mL) treated with indomethacin or dazoxiben (thromboxane synthetase inhibitor) were suppressed (65% or 70% of the control); (2) the contraction of the arteries treated with ONO-3708 (thromboxane A2 antagonist) or ketanserin was inhibited (73% or 8.4%), as was contraction after subarachnoid hemorrhage (67% or 14%); (3) platelet-induced contraction was potentiated after subarachnoid hemorrhage; and (4) serotonin-induced contraction was potentiated after subarachnoid hemorrhage. However, synthetic thromboxane A2-induced contraction was not potentiated. The present experiments suggest that both serotonin and thromboxane A2 contribute to vasoconstrictions induced by the platelets, before and after subarachnoid hemorrhage. The platelet-derived contraction response is potentiated after subarachnoid hemorrhage and serotonin is responsible for the increased reactivity.

Topics: Animals; Basilar Artery; Blood Platelets; Imidazoles; Indomethacin; Isometric Contraction; Ketanserin; Male; Rabbits; Serotonin; Subarachnoid Hemorrhage; Thromboxane A2; Vasoconstriction

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

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

Prostaglandins E2, F2 alpha, 6 oxo F1 alpha and thromboxane B2 increased in cisternal CSF following mock subarachnoid haemorrhage in dogs, particularly PGE2 (X25.5). Concentrations were increased also in lumbar CSF of five patients some 8 days after subarachnoid haemorrhage. Subarachnoid haemorrhage did not alter the production of prostaglandins by dog whole cortex or choroid plexuses in vitro, but production by pooled dissected cerebral arteries of PGE2 was increased and of 6 oxo F1 alpha was decreased. Intravenous indomethacin decreased prostaglandin production by cerebral tissues, and caused a marked decrease in the prostacyclin metabolite in CSF. The implications of our findings for the aetiology of cerebral vasospasm are discussed.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Blood Platelets; Cerebral Arteries; Cerebral Cortex; Choroid Plexus; Dinoprost; Dinoprostone; Dogs; Humans; Indomethacin; Prostaglandins; Prostaglandins E; Prostaglandins F; Subarachnoid Hemorrhage; 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

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