Cardiac release of prostacyclin and thromboxane A2 during coronary revascularization

Cardiac surgery stimulates the systemic synthesis of prostacyclin and thromboxane A2, but the cardiac release of these prostanoids has been reported infrequently. Fifty-four patients undergoing elective coronary artery bypass had coronary sinus catheters inserted to evaluate the cardiac release of the stable metabolites of prostacyclin (6-keto-prostaglandin F1 alpha) and thromboxane A2 (thromboxane B2). Arterial concentrations of 6-keto-prostaglandin F1 alpha and thromboxane B2 were elevated after cardiac cannulation and during cardiopulmonary bypass. The cardiac release of 6-keto-prostaglandin F1 alpha was observed after cannulation and during, but not after, cardiopulmonary bypass. Cardiac thromboxane B2 release was detected after cross-clamp release and persisted during the early postoperative period when cardiac 6-keto-prostaglandin F1 alpha release was no longer detectable. Cardiopulmonary bypass stimulated the systemic production of thromboxane and prostacyclin. The cardiac release of thromboxane was unopposed by cardiac prostacyclin production in the early postoperative period and may contribute to reperfusion injury.     

The effect of propofol on the interaction of platelets with leukocytes and erythrocytes in surgical patients

We tested the antiplatelet effect described for propofol in vitro in surgical patients. Platelet aggregation induced by adenosine diphosphate, collagen, and arachidonic acid was tested in samples of whole blood, platelet-rich plasma (PRP), PRP with red blood cells, and PRP with leukocytes. Also measured were platelet production of thromboxane (Tx)B(2) and leukocyte production of 6-keto-prostaglandin F(1 alpha) (a stable metabolite of prostacyclin) and plasma levels of nitrites + nitrates (indicator of nitric oxide production). Anesthesia was induced with a bolus IV injection of sodium thiopental 4 mg/kg (n = 10), with a bolus dose of 2.5 mg/kg of propofol (n = 20), or with propofol total IV anesthesia (n = 20). Sodium thiopental did not modify any of the analytical values. In patients who received a bolus injection of propofol, platelet aggregation was significantly reduced in whole blood and in PRP + leukocytes. Platelet production of TxB(2) was reduced by 35%; the inhibition of 6-keto-prostaglandin F(1 alpha) was not statistically significant. Plasma levels of nitrites + nitrates increased by 37%; this change correlated significantly with the decrease in systolic and diastolic blood pressure (both P < 0.05). Similar changes, albeit of larger magnitude, were seen in patients who were given total IV anesthesia with propofol. In conclusion, propofol inhibited platelet aggregation in surgical patients mainly as a result of the inhibition of Tx synthesis and the increase in nitric oxide production. These effects are thought to be related to the hypotensive effect of this anesthetic. IMPLICATIONS: In vitro experiments have shown that propofol inhibits platelet aggregation and increases nitric oxide production. This study shows that doses habitually used to induce or maintain anesthesia also have these effects. These findings have potential applications for patients at increased risk for bleeding and may partly explain the hypotensive effect of propofol.     

Effect of experimental cardiopulmonary bypass on systemic and transcardiac thromboxane B2 levels

Systemic and cardiac metabolism of thromboxane was studied in a canine model (n = 13) of standard cardiopulmonary bypass and surgical cardioplegia. Sterile techniques were applied and no donor blood was used. Systemic samples (thoracic aorta) and transcardiac gradients (coronary sinus - aortic root) were obtained (1) 5 minutes after cannulation, (2) 20 minutes after the onset of partial bypass, (3) 5 seconds after the first administration of cardioplegic solution (CP-1), and (4) 5 seconds after the second administration of cardioplegic solution (CP-2). Cardioplegic doses were administered 30 minutes apart and consisted of 500 ml of hypothermic (8 degrees C), hyperkalemic (25 mEq potassium chloride) solution infused into the aortic root at 60 to 70 mm Hg. Thromboxane B2 was determined by a double-antibody radioimmunoassay (picograms per milliliter +/- standard error of the mean). Onset of partial bypass was followed by a significant rise in systemic arterial thromboxane B2 levels: after cannulation, 115 +/- 21 pg/ml; after the onset of partial bypass, 596 +/- 141 pg/ml; p less than 0.01). Significant transcardiac thromboxane B2 gradients were found during the first and second cardioplegic washouts (CP-1: aortic root 73 +/- 12 pg/ml, coronary sinus 306 +/- 86 pg/ml, p less than 0.01; CP-2: aortic root 65 +/- 11 pg/ml, coronary sinus 355 +/- 98 pg/ml, p less than 0.01). Transcardiac gradients of 6-keto-prostaglandin F1 alpha and thromboxane B2 were obtained at CP-1 and CP-2. Gradients of 6-keto-prostaglandin F1 alpha were not different from thromboxane B2 gradients during CP-1 but were significantly higher than thromboxane B2 gradients during CP-2. In a subgroup of five dogs, transcardiac thromboxane B2, lactate, and platelet gradients were measured simultaneously. Cardiac thromboxane B2 generation was found only in the presence of cardiac lactate production. Transcardiac platelet gradients were significantly higher at CP-1 (13,900 +/- 3,000/mm3) than at CP-2 (4,000 +/- 1,230/mm3) (p less than 0.05), whereas thromboxane B2 gradients were similar at CP-1 and CP-2. Our study demonstrates that thromboxane B2 is released into the coronary circulation during surgical cardioplegic arrest with anaerobiosis.     

Plasma prostanoids in neonatal extracorporeal membrane oxygenation. Influence of meconium aspiration

Thromboxane B2 may be a mediator of neonatal persistent pulmonary hypertension. Elevated levels of plasma thromboxane and prostacyclin have been described previously in hypoxic newborn infants with neonatal pulmonary hypertension. We measured serial plasma levels of thromboxane B2 and 6-keto-prostaglandin F1 alpha (stable metabolite of prostacyclin) in 21 newborn infants with severe respiratory failure and pulmonary hypertension who required extracorporeal membrane oxygenation support. We sought to study (1) the evolution of plasma prostanoids in pulmonary hypertensive infants treated with extracorporeal membrane oxygenation and (2) whether different pulmonary hypertensive diagnostic subgroups have distinctive prostanoid profiles. Our data indicated that infants with meconium aspiration had significantly lower levels of plasma thromboxane B2 and 6-keto-prostaglandin F1 alpha while receiving extracorporeal membrane oxygenation than did infants with persistent pulmonary hypertension but no meconium aspiration. Levels of all infants decreased progressively as extracorporeal membrane oxygenation support continued.     

Platelet aggregability after endoscopic intravariceal injection of 5 per cent ethanolamine oleate into oesophageal varices

Platelet aggregability and the coagulative and fibrinolytic systems were examined in 45 patients who underwent endoscopic injection sclerotherapy for oesophageal varices. Five per cent ethanolamine oleate, the sclerosant used, was injected into the oesophageal varices. There were significant increases in the concentrations of fibrinopeptide A, fibrinopeptide B-beta-15-42 and fibrin degradation products-E after the sclero-therapy. At 1 h after the sclerotherapy the mean(s.e.m.) platelet aggregation was significantly suppressed to 71.9(4.2) per cent of that before the treatment (P less than 0.01). There was a gradual recovery within 1 week to the same level seen before the sclerotherapy. Thromboxane B2 and 6-keto-prostaglandin F1 alpha, both stable products of thromboxane A2 and prostacyclin respectively, showed significant temporary increases after the sclerotherapy (P less than 0.01). The peak increase in the level of thromboxane B2 was noted within 1 h after the sclerotherapy and earlier than that for 6-keto-prostaglandin F1 alpha. This increased ratio of prostacyclin and thromboxane A2 may be related to the marked limitation in platelet aggregation.     

Effects of autologous mesothelial cell seeding on prostacyclin production within Dacron arterial prostheses

Canine abdominal aortas have been replaced with Dacron arterial prostheses to assess the effects of mesothelial cell seeding on graft prostacyclin and thromboxane A2 release. At both 2 weeks and 6 weeks after surgery, three seeded and two unseeded control grafts were examined for prostacyclin release. In addition, thromboxane release was assessed in one seeded and one unseeded graft. Sections of aorta and graft were removed and incubated in PBS containing either 10 microM calcium ionophore A23187 or 20 microM arachidonic acid. The incubation mixture was sub-sampled at 5 min intervals over a 20 min period to assess the progressive release of prostacyclin and thromboxane A2 using a radioimmunoassay for 6-keto-prostaglandin F1 alpha and thromboxane B2 respectively. In seeded grafts, 6-keto-prostaglandin F1 alpha release averaged 15 per cent compared with aorta at 2 weeks and 45 per cent compared with aorta at 6 weeks. By contrast, release from unseeded grafts was undetectable at 2 weeks; however, by 6 weeks there was some release amounting to 15 per cent compared with aorta. There was a statistically significant increase in the release of 6-keto-prostaglandin F1 alpha from mesothelial cell seeded grafts at 6 weeks compared with unseeded grafts (P less than 0.01). Thromboxane release from the graft sections was variable and unrelated to whether the grafts had been seeded or not. These preliminary results, showing that grafts seeded with autologous peritoneal mesothelial cells release more prostacyclin than unseeded grafts, further highlight the role of the mesothelial cell as an alternative to the endothelial cell for improving the patency of arterial Dacron prostheses in the early postoperative days.     

Serum concentrations of prostacyclin and thromboxane in children before, during, and after cardiopulmonary bypass

Twenty-six consecutive pediatric patients undergoing reparative procedures necessitating cardiopulmonary bypass were prospectively studied to determine changes in serum levels of 6-keto-prostaglandin F1 alpha and thromboxane B2. Cardiac lesions included acyanotic lesions (five patients), obstructive lesions (10 patients), and right-to-left shunts (11 patients). There was a significant (p less than 0.05) increase in 6-keto-prostaglandin F1 alpha from preoperative levels measured at the time of arterial and venous cannula insertion. This concentration was maintained throughout cardiopulmonary bypass and remained significantly elevated (p less than 0.001) in the recovery room, but returned to preoperative levels by the morning after the operation. Preoperative levels of thromboxane B2 varied widely and were not significantly different from intraoperative levels. The postoperative levels of thromboxane B2, however, were significantly different (p less than 0.05) from the intraoperative levels. In the pediatric age group undergoing cardiopulmonary bypass, 6-keto-prostaglandin F1 alpha and thromboxane B2 change during bypass but do not significantly differ when preoperative levels are compared to postoperative values.     

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.     

Halothane enhances pulmonary artery endothelial eicosanoid release.

To determine whether anesthetics alter endothelial eicosanoid release, cultured bovine pulmonary artery endothelial cells were studied during constant flow and pressure perfusion at two oxygen tensions (hypoxia, 50 +/- 2 mm Hg; normoxia, 144 +/- 5 mm Hg; mean +/- SEM) with and without 1% halothane. Endothelialized microcarriers containing approximately 5 x 10(6) cells were loaded into cartridges and perfused (3 mL/min) with Krebs' solution (pH 7.4, at 37 degrees C) equilibrated with each gas mixture. Eicosanoids (6-keto prostaglandin F1 alpha, thromboxane B2, and total peptidoleukotrienes [C4, D4, E4, F4]) were measured by radioimmunoassay and quantified per gram of cellular protein per minute. Eicosanoid release did not vary over time. The 6-keto prostaglandin F1 alpha release increased during hypoxia (normoxia 291 +/- 27 vs hypoxia 395 +/- 35 ng.min-1 x g protein-1; P < 0.01). Halothane (H) increased release of each eicosanoid during both normoxia and hypoxia: 6-keto prostaglandin F1 alpha-normoxia 291 +/- 27 versus normoxia + H 356 +/- 32 ng.min-1 x g protein-1, hypoxia 395 +/- 35 versus hypoxia + H 464 +/- 40 ng.min-1 x g protein-1, P < 0.05; thromboxane B2-normoxia 19 +/- 2 versus normoxia + H26 +/- 2 ng.min-1 x g protein-1, hypoxia 20 +/- 2 versus hypoxia + H 38 +/- 5 ng.min-1 x g protein-1, P < 0.001; leukotriene-normoxia 363 +/- 35 versus normoxia + H 489 +/- 52 ng.min-1 x g protein-1, hypoxia 329 +/- 29 versus hypoxia + H 455 +/- 39 ng.min-1 x g protein-1, P = 0.001.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of aprotinin on prostaglandin metabolism and platelet function in open heart surgery.

The effects of the protease inhibitor, aprotinin, on plasma prostaglandin levels and platelet function during and after cardiopulmonary bypass (CPB) were studied in a group of 23 patients which consisted of 11 untreated patients (control group) and 12 aprotinin-treated patients (aprotinin group). Thromboxane B2 (TXB2, a stable metabolite of thromboxane A2) and beta-thromboglobulin levels in the control group increased significantly during CPB compared with preoperative values. These increases were significantly suppressed in the aprotinin group. 6-Keto-PGF1 alpha (stable metabolite of prostacyclin) increased significantly during CPB in both groups, and there was no significant difference between the two groups. In the aprotinin group, the TXB2/6-Keto-PGF1 alpha ratio decreased significantly during CPB compared with the preoperative value, whereas no significant decrease was observed in the control group. Platelet counts decreased significantly during and after CPB in both groups. Platelet aggregability decreased significantly during CPB in the control group, whereas no significant decrease was found in the aprotinin group. In conclusion, aprotinin treatment improved prostaglandin metabolism and preserved platelet function during open heart surgery.     

Effect of skin temperature on platelet function in patients undergoing extracorporeal bypass.

Thirty-seven patients undergoing cardiopulmonary bypass operations were studied to assess the effect of skin temperature on platelet function. Differences in skin temperature between the two arms were created during bypass, at the completion of bypass, and at 2 and 24 hours after the completion of bypass. In each of 37 patients the temperature of one arm was increased with a water-filled blanket set at 40 degrees C. In 11 of these patients the other arm was allowed to equilibrate with the environment, and in the other 26 patients the arm was cooled with ice. Except for the differences in local skin temperature between the two arms, all factors known to affect the patient's bleeding time were similar. Measurements were made of bleeding times and the levels of thromboxane B2 and 6-keto-prostaglandin F1 alpha in shed blood obtained at the template bleeding time site. In the 33 patients not treated with aspirin, local hypothermia produced an increased bleeding time and a significant reduction in the thromboxane B2 level at the bleeding time site, but no reduction in 6-keto-prostaglandin F1 alpha level. Local rewarming produced a significant increase in the shed blood thromboxane B2 level. In the four patients treated with aspirin, local hypothermia produced no differences in bleeding times or shed blood levels of thromboxane B2 or 6-keto-prostaglandin F1 alpha. These data show the benefits of rewarming patients with hypothermia who have nonsurgical blood loss to restore to normal both core and peripheral temperatures before resorting to the transfusion of homologous blood products.     

Prostacyclin and thromboxane in acute hemorrhagic pancreatitis in dogs

To study the role of the vasodilatory, antiaggregatory prostacyclin (PGI2) and its endogenous antagonist thromboxane A2 (TxA2) in acute pancreatitis, we measured serum thromboxane B2 (TxB2, which indicates platelet TxA2 production) and plasma 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha, which indicates systemic PGI2 production) from sequential blood samples in trypsin and taurocholate induced acute canine hemorrhagic pancreatitis (AHP). In addition the effect of a prostaglandin synthesis inhibitor, ibuprofen, was studied and systemic (MAP) and pulmonary artery pressure (MPAP) were recorded for 4.5 hr. The animals were divided into a sham-operated group, an AHP group, an ibuprofen prophylaxis group, and an ibuprofen therapy group. In the sham group the parameters remained stable throughout the experiment. In the AHP group MAP decreased steadily and 6-keto-PGF1 alpha rose significantly from 80.0 +/- 7.8 to 956.0 +/- 287.0 pg/ml (P less than 0.001), whereas serum TxB2 and MPAP remained unchanged. Ibuprofen prophylaxis eliminated the initial fall in MAP and the rise of 6-keto-PGF1 alpha. Ibuprofen therapy normalized the initially decreased MAP and depressed the level of 6-keto-PGF1 alpha. We conclude that PGI2 may at least partly mediate the initial hypotension in canine AHP, whereas platelet TxA2 production obviously has a negligible role in the development of hemodynamic changes in AHP.     

Prothrombotic cytotoxicity of cyanoacrylate tissue adhesive

Alkyl-2-cyanoacrylates exhibit properties suggestive of their use as surgical adhesives; however, their cytotoxic and proinflammatory properties have prevented their widespread application. The question of whether cyanoacrylate cytotoxicity may be due to eicosanoid production was investigated. Endothelial cells from rats were exposed to increased concentrations of isobutyl-2-cyanoacrylate. The products from this exposure promoted enhanced, concentration-dependent thromboxane biosynthesis as detected by platelet aggregation. When platelets were pretreated with 1-carboxyheptylimidazole (2.0 mM), an inhibitor of thromboxane biosynthesis, up to 80% less aggregation was observed. Such aggregation was inhibited using 1-carboxyheptylimidazole in a dose-dependent manner. Treatment of endothelial cells with isobutyl-2-cyanoacrylate and 1-carboxyheptylimidazole did not significantly alter the amount of platelet aggregation. A soluble metabolite of isobutyl-2-cyanoacrylate appeared to activate platelet aggregation. The cytotoxicity associated with the surgical use of alkyl-2-cyanoacrylates may be mediated by enhanced local thromboxane production.     

Plasma eicosanoids, platelet function and cold sensitivity

As abnormal eicosanoid (prostaglandin) metabolism has been suggested as a factor in the aetiology of vasospastic diseases we have measured levels of stable eicosanoid metabolites using a radioimmunoassay in 30 normal subjects and 31 patients with Raynaud's phenomenon. There were 13 patients with primary Raynaud's, ten with Raynaud's secondary to scleroderma and eight men with vibration white finger (VWF) disease. We have also measured platelet aggregation to adenosine diphosphate (ADP), collagen and adrenaline in 19 normal subjects, 22 patients with primary Raynaud's, 12 with Raynaud's secondary to scleroderma and 14 men with VWF. When compared with our normal subjects, patients with VWF have an elevated thromboxane B2 level, with a normal 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha) level. Their platelets are less sensitive to ADP and collagen. Patients with primary and secondary Raynaud's have elevated thromboxane B2 levels but this is much more marked in the secondary group. Patients with primary Raynaud's have a normal 6-keto-PGF1 alpha level but in patients with secondary Raynaud's the 6-keto-PGF1 alpha level is markedly raised. The platelets from both groups are more sensitive to ADP and collagen and this is more marked in the secondary group. Whether these phenomena are a cause or an effect of vasospasm remains unknown.     

Biocompatibility of Hemoglobin Solutions. I. Reactions of Vascular Endothelial Cells to Pure and Impure Hemoglobins

Hemoglobin (Hb) solutions can cause vasoconstriction and activation of intravascular coagulation. Because the endothelium plays a major role in the regulation of vascular tone and hemostasis, a study was conducted of human umbilical vein endothelial cells (EC) incubated with various Hbs. Cell injury was evaluated by electron microscopy and the release of lactic dehydrogenase, H2O2, and procoagulant "tissue factor." Cell reaction was assessed by the measurement of 6-keto-prostaglandin F (PGF)1 alpha (metabolite of prostacyclin) and thromboxane B2 (metabolite of thromboxane A2). Incubation with unmodified bovine hemoglobin for 24 h caused no cell injury and a reaction characterized by 48.4 +/- 8.2% increase in 6-keto-PGF1 alpha production, accompanied by 40.2 +/- 9.4% reduction in thromboxane (Tx)B2 (compared with a control group of EC incubated with saline solution). Incubation with a nonpure Hb solution (Hb plus red blood cell membrane aminophospholipids; a-PLs) caused cell injury with significant release of tissue factor, plus a reaction characterized by 97.5 +/- 12.5% increase in TxB2 production accompanied by 25.3 +/- 3% reduction in 6-keto-PGF1 alpha. A second nonpure Hb [Hb plus bacterial environmental endotoxin (E)] caused cell injury, the release of tissue factor, and increased production of both prostaglandins, with greater release of TxB2 (197 +/- 17%) than of 6-keto-PGF1 alpha (112 +/- 8.3%). These data indicate that the endothelium reacts differently to pure and nonpure hemoglobins. The biocompatibility of Hb solutions, with regard to vasoconstriction and activation of intravascular coagulation, depends on the absence of stromal a-PLs and bacterial E.     

Prostacyclin production by internal mammary artery as a factor in coronary artery bypass grafts

Long-term patency of coronary artery bypass grafts (CABG) with internal mammary artery (IMA) is better than with saphenous vein (SV) grafts. To determine if vascular prostacyclin (PGI2) produced by IMA might contribute to the improved outcome, we compared PGI2 generated by IMA and SV fragments from 26 patients undergoing CABG and tested the effect of preoperative, long-term ingestion of of aspirin. Fresh tissues were incubated in buffer +/- 25 mumol/L of sodium arachidonate at 37 degrees C for 5 minutes to stimulate PGI2 production, measured by radioimmunoassay of its major hydrolytic product, 6-keto-PGF1 alpha. Results were expressed in picograms of 6-keto-PGF1 alpha per milligram tissue wet weight for total PGI2 production by vascular segments and picograms per cm2 surface area for endothelial PGI2 production. Endothelial PGI2 production was compared for IMA and SV in template-stirring chambers that exposed only the luminal surface of the vessel, excluding underlying smooth muscle. Endothelial PGI2 production by IMA was significantly higher than production by SV under both basal (mechanical stimulation only 1436 +/- 224 versus 842 +/- 227 pg/cm2, mean +/- SEM, p greater than 0.05) and stimulated (25 mumol/L sodium arachidonate: 3343 +/- 347 versus 2032 +/- 465 pg/cm2, p less than 0.025) conditions in patients not receiving aspirin. For patients receiving aspirin, endothelial PGI2 production by IMA was significantly higher than production by SV in stimulated conditions (1382 +/- 526 versus 683 +/- 124 pg/cm2, p less than 0.05). Histologic examination of the tissue segments revealed intact endothelium after incubation in both IMA and SV. Thus a high capacity for PGI2 synthesis and diminished inhibition of PGI2 after aspirin were demonstrated for IMA compared with SV tissue and may be a factor in the improved patency of IMA grafts.     

Hypertonic saline induces prostacyclin production via extracellular signal-regulated kinase (ERK) activation.

BACKGROUND: Hypertonic saline (HTS) resuscitation exerts protective effects in reperfusion injury including a decrease in pulmonary vascular resistance and an increase in microvascular perfusion and cerebral blood flow; however, the mediators of these effects are unknown. Prostacyclin (PGI2) is a paracrine mediator with two main effects, vasodilation and inhibition of platelet aggregation. We hypothesized that HTS may induce PGI2 production by endothelial cells. METHODS: Human umbilical vein endothelial cells (HUVECs) were treated with varying concentrations of NaCl. After 12 h of incubation, the supernatant was assayed for 6-keto-prostaglandin F1, a stable metabolite of PGI2, by ELISA. Phospho-specific ERK-1 and ERK-2 mitogen-activated protein kinase (MAPK) antibody, which recognizes only activated ERK, was used to determine ERK activation status by Western blotting. RESULTS: Addition of 20-100 mM NaCl or endotoxin [lipopolysaccharide (LPS)] induced PGI2 production by HUVECs. HTS and LPS induced ERK-1 and ERK-2 activation. PGI2 production was inhibited when the HUVECs were pretreated with PD 98059, a specific inhibitor of ERK phosphorylation. CONCLUSION: These data suggest that HTS induces PGI2 production in HUVECs. In addition, HTS and LPS induce activation of ERK which is required for PGI2 production. HTS resuscitation may improve microvascular circulation and decrease reperfusion injury via induction of PGI2 production by endothelial cells.     

Increased thromboxane biosynthesis in childhood hemolytic uremic syndrome

Vascular endothelial cell damage plays a central role in the pathogenesis of the hemolytic uremic syndrome (HUS), resulting in intravascular platelet activation and thrombotic microangiopathy. A deficiency of the antiaggregatory prostacyclin (PGI2) has been postulated by experiments under ex vivo conditions. However, this observation has not been confirmed in vivo. The pathophysiological contribution of thromboxane (Tx)A2, a potent vasoconstrictor and platelet-aggregating prostanoid which is predominantly produced by platelets, has not been elucidated so far. In order to quantitate endogenous formation of TxA2 in children with HUS, plasma concentrations of the enzymatic metabolite 11-dehydro-TxB2 of TxA2 and urinary excretion rates of three major TxA2 metabolites, TxB2, 11-dehydro-TxB2 and 2,3-dinor-TxB2 were analyzed using gas chromatography/mass spectrometry. PGI2 biosynthesis was assessed by measuring urinary excretion of an index metabolite of its systemic production, 2,3-dinor-6-keto-prostaglandin (PG) F1 alpha, and an index of its renal production, 6-keto-PGF1 alpha. TxA2 biosynthesis was markedly elevated in the acute phase of HUS. This activation could be detected for a longer period of time than the presence of thrombocytopenia. Concomitantly in the acute phase, renal PGI2 formation was significantly elevated and systemic PGI2 formation was elevated in 50% of the patients. These data indicate that TxA2 formation is increased in the acute phase in patients with HUS. This enhanced biosynthesis is consistent with increased platelet activation, whereas the increased PGI2 biosynthesis reflects predominantly renal endothelial cell damage.     

Effects of Dexibuprofen on Platelet Function in Humans: Comparison with Low-dose Aspirin

Background: The aim of the current study is to evaluate the antiplatelet effect of dexibuprofen in healthy volunteers in comparison with low-dose aspirin.

Methods: Healthy volunteers (n = 12) were treated in a crossover manner with 100 mg daily aspirin or with 800 mg daily dexibuprofen. Blood samples were obtained within 24 h; 3, 7, and 14 days after repeated doses; and 24 h after the last dose. In each sample, the authors measured platelet aggregation, thromboxane B2, 6-keto-prostaglandin F1[alpha], and nitric oxide.

Results: The antiplatelet effect of dexibuprofen (maximal inhibition of aggregation was 48-55% for adenosine diphosphate and 90-95% for collagen and arachidonic acid) was equal to the effect of aspirin. The main difference between the two drugs was in the degree of recovery of platelet function. The effect of aspirin persisted for 24 h after the last dose (remaining inhibition 50%, respect to the pretreatment value), whereas platelet aggregation had returned to baseline pretreatment values within 24 h after dexibuprofen was stopped.     

Magnesium lithospermate B improves renal function via the kallikrein-prostaglandin system in rats with renal failure.

The effect of magnesium lithospermate B on the renal responses of rats with renal failure was investigated in the presence and absence of pretreatment with the kallikrein inhibitor, aprotinin. Magnesium lithospermate B caused a marked increase in the levels of the renal functional parameters (glomerular filtration rate, renal plasma flow and renal blood flow), accompanied by significant increases in urinary prostaglandin excretion (increases of prostaglandin E2 and 6-keto-prostaglandin F1 alpha excretion by 82% and 36%, respectively). The urinary excretion of kallikrein was also increased following magnesium lithospermate B administration. However, pretreatment with aprotinin abolished the renal function-facilitating action of magnesium lithospermate B concomitantly with a markedly increased urinary excretion of prostaglandin E2, 6-keto-prostaglandin F1 alpha and kallikrein. These results suggest that the kallikrein-kinin-prostaglandin B.