Arachidonic acid metabolism following aneurysm rupture. Evaluation of cerebrospinal fluid and serum concentration of 6-keto-prostaglandin F1 alpha and thromboxane B2 in patients with subarachnoid hemorrhage

Experimental investigations have suggested an important role of arachidonic acid metabolites in the genesis of cerebral vasospasm following subarachnoid hemorrhage. In this clinical study the cerebrospinal fluid (CSF) and serum levels of the two main arachidonic acid metabolites prostacyclin and thromboxane A2 are evaluated by measuring their stable degradation products 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha) and thromboxane B2 (TXB2) using radioimmunoassay methods during the pre- and postoperative course in patients after aneurysm rupture. Although the serum levels of both substances do not seem to be important for the clinical course of the patients, the CSF concentrations of 6-keto-PGF1 alpha and TXB2 provide important data. A close correlation between the initial TXB2 level of the individual patient and the amount of blood in the basal cisterns as detected by computed tomography scan can be demonstrated. The predictive value of this additional information for the occurrence of cerebral angiospasm is discussed. Comparing the CSF levels of both metabolites the slight preoperative elevation of 6-keto-PGF1 alpha is significantly surmounted by an extraordinary rise in TXB2 concentration. Postoperatively, after cleavage of the basal cisterns there is a decline in the CSF levels of both substances. The pre- and postoperative clinical course in comparison to the CSF levels of 6-keto-PGF1 alpha and TXB2 is demonstrated in four patients. A nearly normal course of TXB2 and 6-keto-PGF1 alpha seems to be associated with an uneventful clinical course, whereas a high TXB2 level--whether occurring preoperatively or, even more important, as a secondary postoperative rise--seems to be associated with ischemic complications and neurological deterioration. It is suggested that pre- and postoperative monitoring of CSF levels of 6-keto-PGF1 alpha and especially TXB2 may serve as a possible indicator for the detection of patients at risk of developing cerebral vasospasm.     

Platelet fibrinogen binding in diabetes mellitus. Differences between binding to platelets from nonretinopathic and retinopathic diabetic patients

While it is known that platelets from diabetic patients bind more fibrinogen than do platelets from normal subjects, there has been no study comparing this phenomenon in platelets from nonretinopathic and retinopathic patients. We have made such a comparison and have found the following. In agreement with previous reports, platelets from nonretinopathic diabetic patients bind abnormally high amounts of fibrinogen. No differences in the amount of fibrinogen bound to platelets (stimulated by collagen or thrombin) were found when data from nonretinopathic and retinopathic patients were compared. However, while aspirin (an inhibitor of thromboxane synthesis) reduced the abnormally high fibrinogen binding of platelets from nonretinopathic patients to normal control levels, it did not normalize the high fibrinogen binding of platelets from retinopathic diabetic patients. The combination of aspirin plus apyrase (an ADP scavenger) almost suppressed fibrinogen binding and aggregation of platelets from normal or nonretinopathic diabetic subjects, whereas it had a somewhat lesser effect on binding and aggregation of platelets from retinopathic subjects. By using a monoclonal antibody (B59.2) to the platelet receptor for fibrinogen, we determined that this receptor was the same in platelets from normal as well as nonretinopathic diabetic subjects and that this antibody could suppress the binding of fibrinogen and the aggregation of platelets from both types of patients just as it did in platelets from normal subjects. Thus, our data indicate that, while platelets from both retinopathic and nonretinopathic patients are hyperaggregable and show abnormally high binding of fibrinogen, they differ in that these abnormalities can be normalized in platelets from nonretinopathic patients by suppressing prostaglandin/thromboxane formation and scavenging ADP, but not in those from retinopathic patients.     

High linoleic acid diets ameliorate diabetic nephropathy in rats

The value of high polyunsaturated fatty acid (PUFA) diets in preventing diabetic nephropathy in rats was studied. Diabetes was induced by intravenous injection of streptozotocin (SZ), 65 mg/kg. Rats were divided in four groups fed diets containing 11% fat for 38 weeks. Dietary fat derived from four sources: beef tallow (BT; rich in saturated fatty acids), evening primrose oil (EPO; rich in gamma linolenic [GLA] and linoleic acids [LA]), safflower oil (SO; rich in LA), and fish oil (FO; rich in eicosapentaenoic [EPA] and docosahexaenoic [DHA] acids). Ultralente insulin was administered every other day to maintain the blood glucose levels between 11.1 and 22.2 mmol/L (200 and 400 mg/dL). The diets prepared with EPO and SO had a clear beneficial effect on proteinuria, glomerular sclerosis, and tubular abnormalities, as compared with BT. Both diets also increased the ratio of renal cortical production of 6-keto-PGF1 alpha to thromboxane B2 (TXB2), the stable metabolites of PGI2 and TXA2, respectively. They did not induce significant changes in plasma lipid composition. The FO diet did not have an effect on renal disease, but decreased plasma lipids and inhibited eicosanoid synthesis by platelets and kidney cortex. FO feeding was associated with a lowered 6-keto-PGF1 alpha/TXB2 ratio. It is concluded that high LA diets are protective in this model of diabetic nephropathy. The effect may be secondary to modifications of the eicosanoid balance. Diets containing FO have a beneficial effect on plasma lipids in this model.     

The relationship between opsonin, endotoxin and chemical mediators in postoperative complications after surgery

The role of various chemical mediators in the development of complications after major surgery was investigated. Phospholipase A2 activity (PLA2), and the levels of pancreatic secretory trypsin inhibitor (PSTI), polymorphonuclear leukocyte elastase (PMNE), thromboxane B2 (TxB2), 6-keto-PGF1 alpha (6-KF), leukotriene (LT) B4, C4, D4, interleukin-beta (IL-1 beta), tumor necrosis factor (TNF), and endotoxin (Et) in the serum were measured in 134 surgical patients of whom 36 developed postoperative complications. PLA2, arterial TxB2 and 6-KF showed significant changes in the patients with post-operative complications, associated with elevated Et levels. The majority of these patients had a significantly higher ratio of TxB2/6-KF. These results suggest TxB2 and 6-KF, and the TxB2/6-KF ratio are useful indices of outcome in critically ill patients with hepatic failure. Our findings revealed marked production of prostanoids in sepsis and indicate a severity of the complication in balance of the thromboxane/prostacyclin axis. It was also suggested that the opsonin and eicosanoid levels are closely related to the serum endotoxin level. LTB4, C4 and D4 were increased in the patients with postoperative sepsis or DIC, especially at the initial onsets. The increased levels of IL-1 beta or TNF were observed in some patients with postoperative complications, especially those with severe postoperative complications.     

Prostaglandin synthesis associated with renal allograft rejection in the dog

Vasospasm and intrarenal thrombosis are characteristics of acute renal allograft rejection. A possible mediator of these phenomena is thromboxane A2. Single kidneys were exchanged between nonimmunosuppressed mongrel dogs. At intervals after transplantation, rejecting and normal kidneys were removed and slices of cortex and medulla were prepared for incubation. The in vitro release of thromboxane B2 (TxB2), prostaglandin E2 (PGE2), and 6-keto-prostaglandin F1a (6-keto-PGF1 alpha) into the incubation media was measured by radioimmunoassay. Within 72 hr of transplantation the cortex of rejecting kidneys synthesized 10 to 30 times as much PGE2 and TxB2 as normal controls. A similar increase was not observed for 6-keto-PGF1 alpha synthesis. In the medulla there was a selective reduction in 6-keto-PGF1 alpha production within five days of transplantation. In both cortex and medulla there was a significant increase in the ratio of TxB2 to 6-keto-PGF1 alpha production. Reversal of the normal TxB2:6-keto-PGF1 alpha ratio could induce the widespread intrarenal thrombosis and vasospasm that characterizes acute renal allograft rejection.     

Renal hemodynamics and urinary excretion of 6-keto-prostaglandin F1 alpha and thromboxane B2 in newly diagnosed type I diabetic patients

We have studied the functional importance of renal eicosanoids in renal hemodynamics of seven newly diagnosed insulin-dependent diabetes mellitus (IDDM) patients by treatment with two structurally unrelated inhibitors of cyclooxygenase (i.e., piroxicam and sulindac). Glomerular filtration rate (GFR), renal plasma flow (RPF), daily urinary excretion of 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha, the stable hydrolysis product of prostacyclin), and thromboxane B2 (TXB2, the stable hydrolysis product of thromboxane A2) were measured before, during, and after piroxicam (all patients) or sulindac (3 patients) treatment. Urinary excretion of 6-keto-PGF1 alpha was significantly increased (P less than .01) in diabetic patients compared with seven healthy subjects, whereas urinary excretion of TXB2 was unchanged. The baseline value of GFR was significantly (P less than .01) higher in diabetic compared with normal volunteers, whereas baseline RPF was comparable in both groups. Piroxicam (20 mg/day) reduced urinary excretion of 6-keto-PGF1 alpha and TXB2 by 65.7 +/- 26 and 64.6 +/- 33%, respectively. These biochemical changes were temporally associated with the approximately 19% decrease in GFR (P less than .01). A week after discontinuation of the drug, GFR and urinary excretion of 6-keto-PGF1 alpha were still significantly (P less than .05) reduced, whereas urinary excretion of TXB2 returned to control values. In contrast, urinary excretion of eicosanoids and renal function were not affected by sulindac (0.4 g/day) treatment. No functional changes were detected in healthy subjects despite a similar suppression of renal cyclooxygenase activity when they were treated with piroxicam.(ABSTRACT TRUNCATED AT 250 WORDS)     

Plasma level and effects of thromboxane A2 and 6-keto-PGF1 alpha in patients with acute obstructive suppurative cholangitis

The changes of the plasma thromboxane B2 (TXB2) and 6-keto-PGF1 alpha, the stable metabolites of TXA2 and PGI2, respectively and their effects on platelet counts, platelet aggregation and hypotension were studied in patients with AOSC. The results showed that the plasma TXB2, 6-keto-PGF1 alpha and 6-keto-PGF1 alpha/TXB2 ratios in these patients were markedly increased, however, the platelet counts markedly decreased and platelet aggregation inhibited significantly. After operation, they recovered to normal gradually. There were negative correlation between TXB2 with platelet count and 6-keto-PGF1 alpha with platelet aggregation, as well as both TXB2 and 6-keto-PGF1 alpha with blood pressure. TXA2 was an important factor which lead to platelet decrement and take part in the pathological course of disseminated intravascular coagulation (DIC) and multiple organ failure (MOF), but PGI2 might play an important role in improving microcirculation and preventing DIC and MOF through the inhibition of platelet aggregation.     

Evidence for eicosanoids within the reparative front in avascular necrosis of human femoral head.

Eicosanoids, including prostaglandins and leukotrienes, are important mediators of inflammation. To observe inflammation after necrosis, the histology and the changes of eicosanoid levels were compared in the subchondral cortex and spongy bone of femoral head of sixteen patients with Ficat III or IV idiopathic avascular necrosis (AVN). Neither inflammatory cells nor elevation of eicosanoid levels were observed in the necrotic subchondral cortex or osteochondral junction, whereas infiltration of lymphocytes and plasma cells, fibrosis, and fat emboli were present in the reparative front of necrotic spongy bone. Biochemical analysis in this region revealed significant increases of prostaglandin E2 (PGE2), 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha), thromboxane B2 (TXB2), leukotriene B4 (LTB4), and LTC4. The increased eicosanoids due to initial necrosis become aggravating factors by increasing vascular permeability, which leads to marrow edema and intraosseous hypertension; it ultimately develops into a cycle of inflammation and AVN.     

Urinary prostaglandins and thromboxane in patients with chronic glomerulonephritis

To evaluate the potential contribution of prostaglandins (PGs) and thromboxane (TX) to the development of chronic glomerulonephritis, we measured the urinary excretion of PGE, PGF2 alpha, 6-keto-PGF1 alpha and TXB2 by radioimmunoassay in 36 patients with chronic glomerulonephritis. In patients with nephrotic syndrome, urinary excretion of PGE and TXB2 was highly increased, whereas that of PGF2 alpha and 6-keto-PGF1 alpha remained normal. In patients with non-nephrotic chronic glomerulonephritis, urinary excretion of TXB2 was significantly increased, whereas that of PGE and 6-keto-PGF1 alpha remained normal and that of PGF2 alpha was significantly decreased. In patients with chronic renal failure, the urinary excretion of all PGS and TX was markedly decreased presumably due to a decrease in the number of cells which can metabolize arachidonic acid. These results suggest that TXA2 plays an important role as an exaggerating factor in the development of chronic glomerulonephritis, particularly that accompanying nephrotic syndrome, and that renal synthesis of PGE is compensatorily increased to maintain renal function in nephrotic syndrome.     

Changes in arterial thromboxane B2 and 6-keto-prostaglandin-F1 alpha levels in cirrhotic and non-cirrhotic patients after hepatectomy

Following hepatectomy, arterial concentrations of thromboxane B2(TXB2) and 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha), which are stable metabolites of thromboxane A2(TXA2) and prostaglandin I2(PGI2), were measured by radioimmunoassay in 17 cirrhotic and 9 non-cirrhotic patients to assess the role of TXB2 and PGI2 in patients with liver dysfunction during hepatectomy. In both cirrhotic and non-cirrhotic patients, arterial TXB2 and 6-keto-PGF1 alpha levels significantly increased during hepatectomy and decreased to preoperative levels at the 1st postoperative day (1-POD). The TXB2/6-keto-PGF1 alpha ratio significantly decreased during hepatectomy and at 1-POD. There were no significant differences in changes of TXB2 and PGI2 levels between cirrhotic and non-cirrhotic patients. In cirrhotic patients with poor hepatic reserve, whose ICG K values were less than 0.08, arterial 6-keto-PGF1 alpha levels were significantly higher and the ratio were significantly lower than in cirrhotic patients with good hepatic reserve and non-cirrhotic patients before and after operation. Based on these results, it is concluded that the TXA2/PGI2 ratio becomes low after hepatectomy and the ratio is lower in cirrhotic patients with poor hepatic reserve.     

Evidence that renal prostaglandin and thromboxane production is stimulated in chronic cyclosporine nephrotoxicity

Previous reports suggest that cyclosporine (CsA) may have direct effects on arachidonic acid (AA) metabolism in several different tissues. However, the effects of CsA on renal eicosanoid production are unclear. Furthermore, the potential role of changes in renal prostaglandin and thromboxane metabolism in mediating CsA nephrotoxicity is not known. Therefore, in this study, we evaluated the effects of CsA toxicity on the production of AA metabolites by the kidney. In a postischemic, denervated rat model, CsA (50 mg/kg/day) administered for 12-14 days resulted in significant nephrotoxicity with marked decreases in both glomerular filtration rate and renal blood flow. This reduction in renal function was associated with an increase in the renal production of TXB2, PGE2, and 6-PGF1 alpha in vitro. Arachidonic acid significantly stimulated renal eicosanoid production above control values. Increased urinary excretion of TXB2, 2,3-dinorTXB2 (a major TXB2 metabolite), and 6-keto-PGF1 alpha also occurred in rats with CsA nephrotoxicity and reflected the increase in renal production of these eicosanoid products. In contrast, urinary PGE2 excretion was not increased in CsA toxic rats. Thus, CsA nephrotoxicity is associated with specific alterations in renal AA metabolism. Furthermore, alterations in AA metabolism may be important in modulating renal hemodynamics and excretory function in this model. These studies suggest that specific inhibition of vasoconstrictor products of AA metabolism might ameliorate the nephrotoxic effects of CsA.     

The eventration syndrome: prostacyclin liberation and acute hypoxemia due to eventration of the small intestine

In 13 patients undergoing infrarenal aortic bypass operation under neuroleptic anaesthesia, prostaglandins (KH2PGF2 alpha, PGF2 alpha, 6-keto-PGF1 alpha) and thromboxane (TXB2) were measured immediately prior to, 5 min after and 15 min after eventration of the gut. Blood gas analyses were performed at the same points in time. The levels of PGF2 alpha, although slightly elevated, remained stable, as did the levels of TXB2 (more than half the values being below the limit of detection). In 9 patients there was an immediate increase in the level of 6-keto-PGF1 alpha (a stable metabolite of prostacyclin), associated with a significant fall in the arterial oxygen tension. In 4 patients, the levels of 6-keto-PGF1 alpha remained low and no decrease in arterial oxygen tension was observed. KH2PGF2 alpha levels remained within the normal range, indicating that there was no stimulation of general prostaglandin secretion, but an isolated release of prostacyclin. In 7 patients, a mild, moderate or pronounced flush developed which did not, however, correlate to increases in the concentration of 6-keto-PGF1 alpha. These findings indicate that eventration of the gut is followed by prostacyclin liberation in considerable amounts due to the manipulation involved or to the impairment of the intestinal circulation. The concomitant fall in the oxygen tension is caused by pulmonary vasodilation, which increases the perfusion of underventilated parts of the lung.     

Alpha 2-adrenergic receptor levels in obstructive and spastic Raynaud's syndrome

The present study examines the hypothesis that alterations in the activity of alpha 2-adrenergic receptors (A2R) may underlie the clinical vasospasm seen in patients with Raynaud's syndrome. Platelets were isolated from 13 normal subjects, from 50 patients with vasospastic Raynaud's syndrome, and from 20 patients with obstructive Raynaud's syndrome and A2R levels measured. Binding capacity as determined in femtomoles per milligram of protein (fmol/mg of protein) and affinity were measured by Scatchard plot analysis. In a separate experiment normal human platelets were incubated with either buffer, normal serum, or serum from patients with spastic Raynaud's syndrome and A2R levels were measured. A2R levels in normal subjects averaged 112 +/- 18 fmol/mg; in the patients with spastic Raynaud's syndrome, 191 +/- 14 fmol/mg, p less than 0.01; and in the patients with obstructive Raynaud's syndrome, 164 +/- 31 fmol/mg, p greater than 0.05 (ns). Of the patients with spastic Raynaud's syndrome, 26% had values that were less than the mean value of the normal subjects (69 +/- 7 fmol/mg, p less than 0.05). The A2R levels decreased after incubation with serum from patients who had spastic Raynaud's syndrome by 17.4 +/- 3.1 fmol/mg (p less than 0.05). These results indicate that most patients with vasospastic Raynaud's syndrome have increased platelet A2R levels, which may constitute a primary pathophysiologic abnormality underlying this condition. The presence of subnormal A2R levels in a portion of the patients and the finding of a decrease in measurable A2R levels after incubation in serum from patients with spastic Raynaud's syndrome suggests the possibility of receptor modulation as a mechanism for increased cellular receptor synthesis.     

Differentiation of primary and secondary Raynaud's disease by carotid arterial stiffness.

INTRODUCTION: primary Raynaud's disease may be difficult to differentiate clinically from the secondary form with an underlying connective tissue, haematological, neurovascular or drug-induced disorder. We undertook a study to determine the elastic carotid and muscular femoral arterial biomechanical properties and intima-media thickness (IMT) in subjects with primary and secondary Raynaud's disease, to assess whether these parameters could differentiate the two conditions. METHODS: twenty patients with primary Raynaud's disease and 53 subjects with secondary Raynaud's associated with scleroderma (systemic sclerosis, SSc) had measurements of their carotid and femoral wall mechanics with a duplex scanner coupled to a Wall Track system. Their age, gender, body mass index, heart rate, systolic and diastolic blood pressures, presumed cardiovascular load, plasma creatinine, fasting cholesterol, triglyceride and glucose concentrations were also measured. RESULTS: the carotid elastic properties [mean (SD): elastic modulus: 560 (180) vs 1204 (558) mmHg,p <0.001 and stiffness index: 5.69 (1.35) vs 11.92 (6.4), p<0.001 for primary and secondary Raynaud's respectively] were significantly impaired in patients with secondary Raynaud's disease even after adjustment for potentially influencing physiological and biochemical variables. There were no statistical differences in the femoral elastic properties or the carotid and femoral IMTs between the two groups. CONCLUSION: Duplex determination of the carotid elasticity or stiffness is different in primary Raynaud's phenomenon compared with secondary Raynaud's associated with SSc. This may be a useful non-invasive tool, in addition to autoantibody markers and nail-fold capillaroscopy, to differentiate between the two forms of Raynaud's phenomenon.     

Alpha-adrenergic receptors in platelets from patients with Raynaud's syndrome

The pathophysiologic basis for spastic Raynaud's syndrome remains undefined but may be related to altered adrenergic activity. The relationship between Raynaud's syndrome and alterations in adrenergic receptor populations was examined in the present study by evaluation of alpha 2-adrenergic receptors in platelets. Direct binding assays revealed 78 +/- 8 fm/mg protein of alpha 2-adrenergic receptors in the platelets from control subjects. Similar levels of alpha 2-adrenergic receptors were observed in patients with obstructive Raynaud's syndrome. In contrast, platelet alpha 2-adrenergic receptor levels were significantly elevated (182 +/- 15 fm/mg protein) in the platelets from patients with spastic Raynaud's syndrome. These results indicate the presence of an altered alpha 2-adrenergic receptor population in the platelets from patients with spastic Raynaud's syndrome, which may be related to the vasospasm experienced by these patients.     

Experimental study on the pathophysiology of endotoxin shock as analysed by alterations in thromboxane B2 and 6-keto-PGF1 alpha levels

To evaluate the pathophysiological role of thromboxane A2 (TXA2) in endotoxin shock, plasma concentrations of TXA2 and PGI2 following E. coli endotoxin (ET) administration were measured in dogs and rats by radioimmunoassay of their stable metabolites TXB2 and 6-keto-PGF1 alpha, respectively. Also, the effects of TXA2 synthetase inhibitor (OKY046) on eicosanoid levels, haemodynamics and survival were assessed. The following results were obtained: 1) Survival rates of the rats given 50 mg/kg of ET were 31% at 12 hrs and 17% at 24 hrs. Pretreatment with OKY046 markedly improved the survival rates. 2) Plasma concentrations of TXB2 were rapidly elevated in untreated control dogs and rats following ET administration, whereas plasma 6-keto-PGF1 alpha levels were gradually elevated. TXB2/6-keto-PGF1 alpha ratio showed an early elevation at 15 minutes after ET administration. The ratio became lower than base line, thereafter. 3) In contrast to the controls, animals pretreated with OKY046 did not exhibit significant elevations in plasma TXB2 levels. On the other hand, plasma levels of 6-keto-PGF1 alpha were not altered by OKY046 treatment. 4) In the control dogs given ET, the early elevations in pulmonary artery pressure (PAP) and reduction in lung compliance correlated with the early elevation in plasma TXB2/6-keto-PGF1 alpha ratio. 5) In OKY046-treated dogs, the early elevation in TXB2/6-keto-PGF1 alpha ratio was not seen and PAP increase and lung compliance reduction were prevented. The results suggest that TXA2 plays an important pathophysiological role in the development of endotoxin shock.     

Regional disparity in the vascular response to subarachnoid hemorrhage--relationship between alteration of the concentration of eicosanoids and electron microscopic findings

In an attempt to document the apparent regional disparity of the vascular response to subarachnoid hemorrhage (SAH), the authors measured the concentrations of eicosanoids in various arterial segments corresponding to alterations observed on electron microscopy, using cats with experimentally produced SAH. The level of thromboxane B2 was elevated in both the arterial walls and cerebral cortices, particularly in the latter, on day 7 after SAH production. The 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha) levels in the SAH group were decreased in the basilar and pial arteries after the production of SAH. The mean concentration of 6-keto-PGF1 alpha in the cerebral cortices showed only slight, erratic changes. Ultrastructural observations revealed that the vessels of smaller diameter, such as the pial vessels, underwent more marked spastic changes than did those of larger diameter. These results suggest that the ischemic events following SAH may have been induced by vasospasm and increased coagulability caused by changes in the concentrations of arachidonic acid metabolites in arteries of relatively small diameter.     

Beneficial effect of a selective TXA2 synthetase inhibitor, OKY-046, both on thromboxane B2 production and vascular damage after spinal cord injury in rat spinal cord

Thromboxane A2 (TXA2) is an eicosanoid with potent platelet aggregation and vasoconstricting activity, while prostaglandin I2 (PGI2) antagonizes its activity. But these eicosanoids are so labile that the stable degradation products, thromboxane B2 (TXB2) and 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha), are determined in biological materials. In a rat spinal cord compression injury model, a production of TXB2 reached a peak (133.6 +/- 13.8 pmol/g cord) 5 minutes after compression injury, while that of 6-keto-PGF1 alpha slightly increased (26.2 +/- 11.7 pmol/g cord). And the magnitude of the increase in TXB2 and the extent of post-traumatic vascular damage as determined by fluorescein uptake were both dependent on the degree of spinal cord compression injury. We also studied the effect of a selective TXA2 synthetase inhibitor, OKY-046 [E)-3-[4-(1-imidazolylmethyl)phenyl]-2-propenoic acid), both on TXB2 production in the injured spinal cord and post-traumatic vascular damage. When OKY-046 was administered intravenously 10 minutes prior to compression injury at a dose of 500 micrograms/kg body weight, the increased production of TXB2 was inhibited by about 80% and uptake of sodium fluorescein was reduced by a maximum of 40%. When the compression injury was induced before OKY-046 was administered, the inhibitory effect of OKY-046 on TXB2 production decreased depending on the duration before administration. In contrast, the 6-keto-PGF1 alpha level was not affected in the presence of OKY-046.     

Role of eicosanoids and white blood cells in the beneficial effects of limited reperfusion after ischemia-reperfusion injury in skeletal muscle

Limiting the rate of reperfusion blood flow has been shown to be beneficial locally in models of ischemia-reperfusion injury. We investigated the effects of this on eicosanoids (thromboxane B2, 6-keto-PGF1 alpha, and leukotriene B4), white blood cell activation, and skeletal muscle injury as quantitated by triphenyltetrazolium chloride and technetium-99m pyrophosphate after ischemia-reperfusion injury in an isolated gracilis muscle model in 16 anesthetized dogs. One gracilis muscle in each dog was subjected to 6 hours of ischemia followed by 1 hour of limited reperfusion and then by a second hour of normal reperfusion. The other muscle was subjected to 6 hours of ischemia followed by 2 hours of normal reperfusion. Six dogs each were used as normal reperfusion controls (NR) and limited reperfusion controls (LR), with 5 dogs being treated with a thromboxane synthetase inhibitor (LR/TSI) and another five with a leukotriene inhibitor (LR/LI). LR in all three groups (LR, LR/TSI, and LR/LI) showed a benefit in skeletal muscle injury as measured by triphenyltetrazolim chloride and technetium-99m pyrophosphate when compared with NR. However, there was no significant difference between the groups with LR regarding eicosanoid levels and white blood cell activation when compared with NR. These results demonstrate that LR produces benefits by mechanisms other than those dependent upon thromboxane A2, prostacyclin, or white blood cell activation.     

Thromboxane B2 Production During Erection

The effect of erection on 6-keto-PGF1 alpha and thromboxane B2 in penile blood during electrically evoked erection was studied in the chacma baboon. 6-keto-PGF1 alpha remained at a low concentration, but thromboxane B2 showed a statistically significant rise 8-10 minutes after commencement of erection. Elevated thromboxane B2 during erection may potentiate platelet aggregation and may be one of the key events in the pathogenesis of ageing impotence.