Involvement of neutral sphingomyelinase in the angiotensin II signaling pathway.

The possibility that angiotensin II (ANG II) exerts its effects through the activation of neutral sphingomyelinase (nSMase) has not been tested in kidneys. The results of the present study provide evidence for the activity and expression of nSMase in rat kidneys. In isolated perfused rat kidney, ANG II-induced renal vasoconstriction was inhibited by GW4869, an inhibitor of nSMase. We used nSMase for investigating the signal transduction downstream of ceramide. nSMase constricted the renal vasculature. An inhibitor of ceramidase (CDase), N-oleoylethanolamine (OEA), enhanced either ANG II- or nSMase-induced renal vasoconstriction. To demonstrate the interaction between the nSMase and cytosolic phospholipase A2 (cPLA2) signal transduction pathways, we evaluated the response to nSMase in the presence and absence of inhibitors of arachidonic acid (AA) metabolism: arachidonyl trifluoromethyl ketone (AACOCF3), an inhibitor of cPLA2; 5,8,11,14-eicosatetraynoic acid (ETYA), an inhibitor of all AA pathways; indomethacin, an inhibitor of cyclooxygenase (COX); furegrelate, a thromboxane A2 (TxA2)-synthase inhibitor; and SQ29548, a TxA2-receptor antagonist. In these experiments, the nSMase-induced renal vasoconstriction decreased. ANG II or nSMase was associated with an increase in the release of thromboxane B2 (TxB2) in the renal perfusate of isolated perfused rat kidney. In addition, the coexpression of the ceramide with cPLA2, was found in the smooth muscle layer of intrarenal vessels. Our results suggest that ANG II stimulates ceramide formation via the activation of nSMase; thus ceramide may indirectly regulate vasoactive processes that modulate the activity of cPLA2 and the release of TxA2.

[Role of thromboxane A2 (B2) in the pathogenesis of stress proteinuria in healthy persons]. / Rol' tromboksana A2 (B2) v patogeneze razvitiia proteinurii napriazhdeniia u zdorovykh lits.

Analysis of published data and the author's own findings indicate that processes coursing in the miners of deep coal mines during hard physical work lead to hemodynamic and biochemical shifts, causing decreased production of thromboxane A2 in the kidneys and involvement of the proximal canaliculi. This, in turn, results in increased protein filtration and decrease reabsorption, which eventuates in stress proteinuria.

Urinary excretion of vasoactive substances in chronic renal failure.

To investigate the pathophysiological role of vasoactive substances in the progression of chronic renal disease, we measured the 24-hour urinary excretion of prostaglandin 6-keto F1alpha, thromboxane B2, NOx, cGMP and ET-1 in 26 patients with chronic renal failure under conservative treatment and in 40 control subjects. Urinary 6-keto PgF1alpha, TxB2 and cyclic GMP were evaluated by RIA, and ET-1 was assayed by EIA. NOx were evaluated using a colorimetric assay as nitrate/nitrite. Urinary excretion of prostaglandin 6-keto F1alpha averaged 18.1 +/- 20.9 ng/g Ucreat in patients vs. 240.9 +/- 257.3 in controls (p < 0.0001), thromboxane B2 422 +/- 374 ng/g Ucreat in patients vs. 967 +/- 589 in controls (p < 2x 10(-5)), NOx 7.07 +/- 5.54 mg/g Ucreat in patients vs. 9.79 +/- 3.77 in controls (p < 0.01), cGMP 310 +/- 200 pg/g Ucreat in patients vs. 488 +/- 241 in controls (p < 0.001). In contrast, ET-1 urinary excretion was almost doubled in patients (13.45 +/- 5.84 ng/g of Ucreat) in comparison with controls (6.84 +/- 2.81 p < 1x10(-5)). While in control subjects significant correlations between urinary excretions of prostaglandin 6-keto F1alpha and thromboxane B2 (r = 0.69, p < 0.001) or NOx and ET-1 (r = 0.54, p < 0.001) were present, in patients only the relationship between urinary excretions of prostaglandin 6-keto F1alpha and thromboxane B2 (r = 0.53, p < 0.01) was retained. Our data suggest that in the normal kidney a balance between prostaglandin I2 and thromboxane A2, or nitric oxide and endothelin-1 is present, which contributes to hemodynamic regulation and protects this organ from ischemic damage. This balance is abolished in CRF, where a large increment of vasopressor agent endothelin is present, which, joined to a prevalent decrease of prostaglandin I2 synthesis, could contribute to the ischemic and fibrogenetic damage of the kidney, leading to progression of renal disease.

The response of muscle interstitial prostaglandin E(2)(PGE(2)), prostacyclin I(2)(PGI(2)) and thromboxane A(2)(TXA(2)) levels during incremental dynamic exercise in humans determined by in vivo microdialysis.

UNLABELLED: The microdialysis in vivo technique allows the isolation, purification and quantitative determination of bioactive molecules with low molecular weight (<20.000 Da) from interstitial fluid (IF) of the muscles. PGE(2)and PGI(2)are vasodilator local hormones, while the TXA(2)is a vasoconstrictor. PGI(2)and TXA(2)are unstable and convert to stable products 6-keto-PGF(1a)and TXB(2), respectively. The purpose of this study was to evaluate the response of PGE(2), PGI(2)and TXA(2)in the IF of human muscle (vastus lateralis) during dynamic exercise with a cycle ergometer. In this study two microdialysis probes were inserted with CMA-60 microdialysis catheters into the vastus lateralis muscle of the right leg of eight healthy volunteers aged 24.1+/-2.1 years, height 177.5+/-1.5 cm and body weight 78.1+/-2.4 kg. After insertion the microdialysis probes perfused at a rate of 3.0 microl/min with Ringer acetate solution. The dialysate fluid was collected a) during the 30' rest period, b) during the 30' exercise period at 100 watts, c) during the 30' exercise period at 150 watts and d) during the 30' rest period after exercise. Our measurements (by the RIA method) showed that the levels of PGE(2)and 6-keto-PGF(1a)in the I.F. of the vastus lateralis muscle increased significantly, while there was a significant decrease in TXB(2)during exercise. The changes in the above biomolecules were increased proportionately with the strain of the subject's muscle. CONCLUSION: Dynamic exercise of the muscles produces a local increase of the vasodilators PGE(2)and PGI(2)while the vasoconstrictor TXA(2)is reduced in the IF of the muscles. This is further evidence that exercise induces propitious biochemical changes. Furthermore, the muscle production of arachidonic acid metabolites during exercise depends on the intensity of the exercise.

The roles of platelet function, thromboxane, blood lipids and nitric oxide in hypertension of children and adolescents.

The roles of platelet function, plasma lipids and nitric oxide (NO) were studied in adolescent patients with essential hypertension (JEHT group), with chronic renal failure (CRF) associated with hypertension (CRFH group), and CRF patients with normal blood pressure (CRF group), as compared with normal controls (cont. group). Platelet aggregation and the thromboxane B(2)(TxB(2)) level were significantly higher in the JEHT and CRFH groups as compared with the cont. group, whereas they were significantly lower in the CRF group. On the other hand, the platelet cAMP level was significantly lower in the JEHT and CRFH groups than in the cont. group. The plasma NO level was significantly higher only in the JEHT as compared with the cont. group (120 +/- 39 and 89 +/- 21 microM, respectively). The plasma total cholesterol, triglyceride and LDL cholesterol concentrations were normal in the JEHT group, but high in the CRF and CRFH group, the HDL cholesterol level was lower in the CRF and CRFH groups as compared with the cont. and JEHT groups. There was a positive correlation between the platelet aggregation and the TxB(2)level and between the BP and the platelet aggregation. In conclusion, hyperlipidaemia is commonly present in uraemia with haemodialysis, but is not specific for hypertension in children, while an increased platelet function is frequently associated with hypertension. The increased NO level might play a compensatory role in JEHT.

Prostanoids regulate proliferation of vascular smooth muscle cells induced by arginine vasopressin.

The aim of the present study was to investigate the effect of arginine [Arg(8)]vasopressin (vasopressin) on proliferation of vascular smooth muscle cells and the mechanisms underlying the action of vasopressin. To clarify these issues, we used two different types of vascular smooth muscle cells, cultured adult rat aortic smooth muscle cells and A10 cells, a cell line derived from fetal rat aorta. Vasopressin (10(-8) to 10(-6) M) significantly stimulated the proliferation of rat aortic smooth muscle cells in a dose-dependent manner. In contrast, vasopressin significantly inhibited the proliferation of A10 cells. This inhibition was abolished when A10 cells were treated with indomethacin. Vasopressin stimulated the production of prostanoids several-fold in A10 cells but not in rat aortic smooth muscle cells. These effects were completely blocked by the vasopressin V(1) receptor antagonist, 1-¿1-[4-(3-acetylamino-propoxy)benzoyl]4-piperidyl¿-3, 4-dihydro-2(1H)-quinolinone (OPC21268), but not by the vasopressin V(2) receptor antagonist, (+/-)-5-dimethylamino-1-[4-(2-methylbenzoylamino)benzol]-2, 3,4,5-tetrahydro-1H-benzazepine hydrochloride (OPC31260). These results indicate that vasopressin has diverse effect on proliferation of vascular smooth muscle cells through the vasopressin V(1) receptor, depending on the production of growth regulatory prostanoids.

Effects of lipid mediator antagonists on predominant mediator-controlled asthmatic reactions in passively sensitized guinea pigs.

The role of cysteinyl leukotrienes (cys-LTs) and thromboxane A(2) (TXA(2)) in guinea pig models of aspects of bronchial asthma was investigated. In a novel antigen (BSA)-induced asthmatic model using passively sensitized guinea pigs, pretreatment with varying doses of indomethacin controlled the ratio of followed lipid mediators, LTC(4)/D(4)/E(4) and TXB(2), in lungs of challenged guinea pigs. The predominant mediator in indomethacin-untreated asthma was TXA(2), and complete inhibition of cyclooxygenase by i.v. injection of 5-mg/kg indomethacin-induced cys-LTs mainly mediated asthmatic response. Furthermore, a 1-mg/kg indomethacin dose induced an asthmatic state where both cys-LTs and TXA(2) equally participated. Either LTD(4) or TXA(2) receptor antagonists given alone inhibited the asthmatic response in conditions where the corresponding mediator plays a predominant role. The combination of LTD(4) and TXA(2) receptor antagonists exhibited significant effects irrespective of the condition used. Under conditions where both mediators equally participate, a combination of both receptor antagonists showed additive inhibition. YM158, a newly synthesized and orally active dual antagonist for LTD(4) and TXA(2) receptors, showed the same antiasthmatic effect as a combinated LTD(4) receptor antagonist and a TXA(2) receptor antagonist mixture. Therefore, broad-acting compounds such as YM158 are expected to have antiasthmatic efficacies in a broader class of asthmatic patients than single-acting drugs.

Prostanoids: early mediators in the secondary injury that develops after unilateral pulmonary contusion.

BACKGROUND: We have previously shown a sequence of events after unilateral pulmonary contusion that suggests the release of blood-borne prostanoid mediators and that culminates in refractory bilateral pulmonary failure. PURPOSE: To determine the role of platelet-derived thromboxane and endothelial-derived prostacyclin in the primary and secondary injury after unilateral blunt chest trauma, and to determine whether pretreatment with the cyclooxygenase inhibitor indomethacin alters the progression of secondary injury. METHODS: Anesthetized, ventilated (FIO2 = 0.50) pigs received a unilateral, blunt injury to the right thorax (n = 20) or sham injury (n = 5) and were monitored for 24 hours. Either indomethacin (5 mg/kg i.v.; n = 10) or its saline vehicle (n = 10) were administered 15 minutes before injury. Serial bronchoalveolar lavages of each lung were analyzed for protein and neutrophil (polymorphonuclear neutrophil (PMN)) content. RESULTS: Contusion caused profound hypoxemia; PaO2 partially recovered within 1 hour of injury to 50% of baseline. Thereafter, worsening hypoxemia required positive end-expiratory pressure. With indomethacin compared with vehicle, PaO2 was higher at any given level of positive end-expiratory pressure (p < 0.05). There was an early increase in serial bronchoalveolar lavage protein on the injured side (peak at 2 hours), with a delayed pulmonary capillary leak on the contralateral side (peak at 6 hours), which correlated with increasing PMN infiltration; this was reduced by 40 to 60% with indomethacin (p < 0.05). Thromboxane peaked within 1 hour after contusion at 800% baseline, then fell off rapidly. This peak preceded the maximal increase in permeability and was completely blocked by indomethacin. Prostacyclin slowly rose to 300% baseline by 3 hours and remained elevated; this change was blocked by indomethacin for 18 hours. CONCLUSIONS: Contusion of the right thorax induced a delayed pulmonary capillary leak in the left lung, which reflects a progressive secondary inflammatory response. Elevations in thromboxane and prostacyclin preceded progressive bilateral PMN infiltration. Indomethacin blocked thromboxane and prostacyclin and attenuated, but did not prevent, the progression to pulmonary failure. Overall, these data suggest that prostanoids are released soon after unilateral contusion and initiate an inflammatory response in both lungs that is sustained by PMN infiltration.

Thromboxane-dependent platelet activation in vivo precedes arterial thrombosis in thrombocythaemia: a rationale for the use of low-dose aspirin as an antithrombotic agent.

The clinical course of patients with polycythaemia vera (PV) and essential thrombocythaemia (ET) is frequently complicated by arterial thrombotic events. The pathogenesis is not clearly understood but attributed to abnormalities in platelet function. An increase in platelet thromboxane formation has been described in the majority of asymptomatic patients with thrombocythaemia, probably reflecting spontaneous platelet activation in vivo. In the present study we prospectively investigated whether an increase in platelet thromboxane formation actually precedes arterial microvascular thrombosis. In addition, we studied the effect of selective inhibition of platelet thromboxane formation on clinical outcome by reinstitution of low-dose aspirin (50 mg/ d). Six ET patients and one PV patient participated in this study. Within 10 d after withdrawal of aspirin, three patients developed arterial microvascular thrombosis of extremities (erythromelalgia), which was preceded by a 3-30-fold increase in urinary thromboxane excretion as compared with patients who remained asymptomatic. The increased urinary thromboxane excretion and clinical signs could be inhibited by a platelet-specific aspirin regimen of 50 mg/d without affecting vascular cyclooxygenase, indicating that platelets were the main source of the increased thromboxane generation. These data suggest that in symptomatic patients an enhanced formation of thromboxane by platelets, reflecting platelet activation in vivo, precedes the development of arterial microvascular thrombosis. These data provide a rationale for using low-dose aspirin as an antithrombotic agent in thrombocythaemia.

Role of thromboxane and leukotriene B4 in patients with acute respiratory distress syndrome after oesophagectomy.

We have studied prospectively the clinical course and serum concentrations of thromboxane B2 (TxB2) and leukotriene B4 (LTB4) in patients developing adult respiratory distress syndrome (ARDS) after oesophagectomy. The clinical course was assessed according to a validated ARDS score, and intra- and postoperative measurements of TxB2 and LTB4 in pre- and post-pulmonary blood were performed in 18 patients undergoing oesophagectomy for oesophageal carcinoma and 11 control patients undergoing thoracotomy and pulmonary resection. Six of 18 patients undergoing oesophagectomy, but no control patient, developed ARDS. The ARDS score was highest on day 8 after operation. Only patients with ARDS had a significant postoperative increase in post-pulmonary, but not pre-pulmonary, TxB2 concentrations (P < 0.05 vs patients without ARDS). This study provides evidence that TxA2, originating from the lungs, was associated with the development of ARDS after oesophageal resection. In view of the high incidence of ARDS after oesophagectomy (10-30%), prophylactic treatment of patients undergoing oesophageal resection with clinically applicable thromboxane synthetase inhibitors may be warranted.

Intravillous eicosanoid compartmentalization and regulation of placental blood flow.

OBJECTIVE: To determine the roles of the eicosanoids thromboxane and prostacyclin, and their compartmentalization, in the regulation of placental blood flow. METHODS: First, the sites of production of thromboxane and prostacyclin were determined within the placental villus using immunohistochemical staining for thromboxane and prostacyclin synthetase. Second, the production of both eicosanoids was studied in cultured trophoblasts and compared with that in the villous core by measuring the metabolites thromboxane B2 and 6-keto-prostaglandin F 1 alpha. Finally, eicosanoid production was assessed in intact villi after stimulation by an acute change in oxygen content, 5% to 95%. RESULTS: Immunohistochemical staining showed that thromboxane production was primarily within the trophoblasts, whereas prostacyclin production was localized to the endothelial cells within the villi. In culture, we found preferential production of prostacyclin by the villous core cells and increased production of thromboxane by trophoblasts. Perifusion of intact villi demonstrated increased production of thromboxane by trophoblasts in response to an increase in oxygen content. Prostacyclin levels were too low to be detected. CONCLUSIONS: Placental blood flow appears to be regulated by compartmentalized eicosanoids, with thromboxane affecting primarily the maternal side of the placental circulation and prostacyclin affecting primarily the fetal side.

Thromboxane-mediated alveolar responses to acute obstruction of the pulmonary vasculature.

To investigate the mechanisms responsible for the accelerated radioaerosol transalveolar clearance rates caused by acute balloon occlusion of the pulmonary arterial tree in dogs, the effects of vagal tone (n = 5) and prostaglandins (n = 21) including thromboxane were evaluated. In 15 animals, serial pulmonary arterial and aortic blood samples were acquired to evaluate pertinent metabolic products. Balloon occlusion of a localized arterial territory caused significant acceleration of technetium-99m diethylenetriamine pentaacetic acid (Tc-99m DTPA) clearance in the zone immediately distal to the occlusion (baseline clearance half-time 23.1 +/- 0/7 min versus 19.3 +/- 0.4 min, mean +/- SEM, p < 0.05). Vagotomy had no effect on occlusion-accelerated clearance. However, significant (p < 0.05) normalization did occur in the presence of indomethacin (21.9 +/- 0.4 min) and meclofenamic acid (20.4 +/- 0.5 min). Plasma values of thromboxane rose dramatically (pulmonary blood baseline 119 pg/ml to > 40,000 pg/ml) and transiently immediately after pulmonary vascular occlusion, and this rise was blunted significantly (peak pulmonary thromboxane B2 [TXB2] concentration = 668 pg/ml, p < 0.05) by meclofenamic acid. Significant normalization of local DTPA clearance rates also occurred in the presence of a thromboxane receptor blocker (n = 4), even when blood levels of thromboxane were elevated. Changes in transalveolar DTPA clearance rates after balloon occlusion of pulmonary arteries seem to a significant extent to be thromboxane-mediated.

Do prostacyclin and thromboxane contribute to the "protective effect" of pregnancies with chronic hypertension? A preliminary prospective longitudinal study.

OBJECTIVE: The aim of this study was to assess prospectively the urinary excretion of renal and systemic metabolites of thromboxane and prostacyclin in normotensive and chronic hypertensive pregnancies. STUDY DESIGN: Pregnant hospital employees were invited to collect 24-hour urine samples weekly from the seventh week until delivery. Concentrations of renal metabolites (thromboxane B2, 6-keto-prostaglandin F1alpha) were measured by radioimmunoassay after extraction. Systemic metabolites (2,3-dinor-thromboxane B2, 2,3-dinor-6-keto-prostaglandin F1alpha) were assessed by enzyme immunoassay after extraction and high-pressure liquid chromatographic separation. RESULTS: Thromboxane B2 excretion was similar in normotensive and hypertensive pregnancies, whereas a twofold increase of 6-keto-prostaglandin F1alpha was observed in hypertensive compared with normotensive pregnancies (7537 +/- 349 vs 3857 +/- 202 pg/mg creatinine, p < 0.001). During pregnancy in both conditions measurements displayed uniform excretion of thromboxane B2 with progressively increased levels of 6-keto-prostaglandin F1alpha in chronic hypertension (R2 = 0.60, p < 0.005). Mean excretion of 2,3-dinor-thromboxane B2 averaged 1208 +/- 65 and 898 +/- 48 pg/mg creatinine in normotensive and hypertensive pregnancies (p < 0.001), mainly due to significant decreased concentrations in hypertension in the first half of pregnancy. Conversely, 2,3-dinor-6-keto-prostaglandin F1alpha levels were 845 +/- 39 and 1226 +/- 67 pg/mg creatinine in normotensive and hypertensive pregnancies (p < 0.001), mostly because of significantly increased production in hypertension from 22 weeks onward. Ratios of both renal and systemic metabolites favored increased prostacyclin production in chronic hypertension. CONCLUSION: In contrast to preeclampsia, uncomplicated mild to moderate chronic hypertensive pregnancies are characterized by an excess production of prostacyclin with unaltered or even lower thromboxane concentrations, which may contribute to the general favorable outcome of this hypertensive condition.

Tachykinin NK2 receptor antagonists decrease eicosanoid release in lung anaphylaxis.

Two tachykinin NK2 receptor antagonists, MEN 10.627 c(Met-Asp-Trp-Phe-Dap-Leu) and MEN 10.376 [(Tyr5,Trp6,8,9,Lys10]neurokinin A-(4-10), were used to investigate the role of tachykinins in in vitro guinea-pig lung anaphylaxis. Both antagonists dose-dependently decreased bronchoconstriction and the release of thromboxane and prostaglandin E2 induced by antigen challenge in perfused sensitized lungs, but neither had any effect on the basal release of either eicosanoid. The findings indicated that tachykinins released by sensory nerve fibers may contribute to anaphylactic reactions by increasing arachidonic acid metabolite release.

Leukotriene C4 regulation of splanchnic blood flow during ischemia.

The role of endogenous splanchnic eicosanoids in mediating splanchnic vasoconstriction induced by the leukotriene C4 (LTC4) was examined during mild hemorrhage/reperfusion injury. Male Sprague-Dawley rats were anesthetized and subjected to sham or acute hemorrhage for 30 minutes, to 30 mm Hg, followed by blood reperfusion (SK+R). The superior mesenteric artery was cannulated and removed with its end-organ intestine (SV+SI preparation) and perfused in vitro with oxygenated Krebs-Henseleit buffer. Perfusion pressure was constantly recorded. Net SV+SI release of 6-keto-PGF1 alpha, PGE2 and thromboxane B2 were analyzed by enzyme immunoassay after LTC4 stimulation. Leukotriene C4 increased perfusion pressure and decreased the ratio of 6-keto-PGF1 alpha to thromboxane release (but not PGE2 to thromboxane B2) in the sham group. Hemorrhage/reperfusion increased perfusion pressure and decreased the ratio of 6-keto-PGF1 alpha to thromboxane B2. Mild hemorrhage/reperfusion increased LTC4-induced splanchnic vasoconstriction in part by decreasing the release ratio of endogenous splanchnic PGI2 to thromboxane B2.

[Value of prostaglandins in a pre-eclampsia-equivalent animal model]. / Stellenwert der Prostaglandine in einem Präeklampsie-äquivalenten Tiermodell.

Pregnancy-induced hypertension is no uniform disease with one cause and one pathophysiologic course. On the contrary it seems to be a multifactorial event with a very different symptomatology and a variable damage of various organs. Because of the heterogeneity of the disease and the difficulty of differentiation these various kinds of courses clinical studies, mostly retrospectively done, have to be criticized. The aim of this study is to examine vasoactive regulation systems by means of a standardized animal model, using wistar rats. A systemic hypertension could be achieved only in pregnant animals with aid a infrarenal aortic stenosis. Non pregnant and simulated operated pregnant animals are the control group. In the normotensive pregnant rats there was an elevation of all renal prostanoids: PGI2, TxB2 and PGE2. On the contrary hypertensive pregnant rats showed a decrease of all eicosanoids, prononcigated of PGE2.

Platelet-activating factor potentiates protamine-induced lung edema. Role of eicosanoids.

Platelet-activating factor (PAF) is a cell membrane-derived ether lipid that plays an important role in acute lung vascular injury. We recently reported that PAF potentiates protamine-induced lung edema by enhancing pulmonary venoconstriction. As PAF is known to stimulate lung eicosanoid synthesis, we investigated the role of peptidoleukotrienes and other eicosanoids in this priming effect of PAF. Addition of PAF (1.6 nM), followed 10 min later by protamine (50 micrograms/ml), to perfusate of salt solution-perfused rat lungs resulted in marked arterial and venous constrictions and severe lung edema. Lung tissue thromboxane B2, 6-ketoprostaglandin F1 alpha and leukotriene C4 (LTC4) were markedly elevated 20 min after PAF/protamine. Pretreatment of the lungs with AA-861, a specific 5-lipoxygenase inhibitor, blocked PAF/protamine-induced leukotriene synthesis, arterial and venous constrictions, and lung edema. In addition, injection of LTC4 (1 microgram) markedly potentiated protamine-induced arterial and venous constrictions and caused lung edema similar to PAF/protamine. Indomethacin, a specific cyclooxygenase inhibitor, also reduced the vasoconstrictive and edemagenic responses to PAF/protamine. However, the pulmonary edema after LTC4/protamine was not blocked by indomethacin. In separate experiments, infusion of this "priming" dose of PAF into isolated perfused lungs induced LTC4 synthesis and augmented lung thromboxane A2 synthesis after arachidonic acid infusion. We conclude that both cyclooxygenase and lipoxygenase products of arachidonic acid metabolism are involved in PAF-induced potentiation of protamine lung edema.

[Role of arachidonic acid metabolites on development of ischemic cerebral edema in rat middle cerebral artery occlusion].

The products resulting from arachidonic acid metabolism of the both cyclo-oxygenase and lipoxygenase pathways possess strong physiological activities, such as vasoconstriction and the enhancement of vascular permeability. Therefore, it is likely that these metabolites are involved in cerebral circulatory disturbance and the formation of brain edema in cerebral ischemia. It is reported that intracerebral injection of leukotriene B4, C4, and E4 increased blood-brain barrier permeability. Thus, it is suggested that leukotrienes may induce vasogenic cerebral edema. We examined role of the products resulting from arachidonic acid of the cyclo-oxygenase and lipoxygenase pathways on the formation of ischemic cerebral edema in rats with focal cerebral ischemia. Focal cerebral ischemia was induced by the occlusion of right middle cerebral artery. Acyclo-oxygenase inhibitor, indomethacin (4mg/kg), was given intravenously 30 minutes before the occlusion of the middle cerebral artery. Also, azerastine hydrochloride (8mg/kg), which has an inhibitory effect on the production and release of leukotrienes from human neutrophil as well as an antagonistic action on leukotrienes and another inhibitory effect on the production of superoxide anion, was given intravenously 5 minutes prior to occlusion. Concentrations of prostaglandin E2 (PGE2), thromboxane B2 (TxB2), 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha) and leukotriene C4 (LTC4) measured by radioimmunoassay. The percent water content of a cerebral hemisphere was determined by the wet-dry weight method. In the occluded hemisphere, PGE2, 6-keto-PGF1 alpha, TxB2 and LTC4 significantly increased at 2, 6, 12 hours respectively, following the MCA occlusion as compared to the control levels.(ABSTRACT TRUNCATED AT 250 WORDS)

Pulmonary hypertensive response to rabbit blood components in goats: role of thromboxane.

Transfusion of small quantities of heterologous blood may cause severe pulmonary hypertensive response in certain species. To determine the responsible component in the donor blood and the main mediator, we studied the responses of goats to small quantities of rabbit blood components and observed the effects of several pharmacologic agents on these responses. In anesthetized goats, a bolus injection of 0.004 ml/kg rabbit blood caused the pulmonary arterial pressure to increase from 25.3 +/- 2.8 to 57.1 +/- 11.6 cm H2O within 45 to 90 s, and the aortic thromboxane concentration rose from 44 +/- 38 to 238 +/- 104 pg/ml. Pulmonary vascular resistance increased more than 4-fold, whereas systemic vascular resistance increased moderately (50%). The erythrocyte stroma, mainly cell membranes, caused similar responses; other blood components were all ineffective. By blocking the production of thromboxane, indomethacin and U63557A (thromboxane synthetase inhibitor) abolished nearly all of the hemodynamic responses to rabbit blood. Isoproterenol also largely attenuated the responses to rabbit blood by blocking thromboxane production without interfering with the responses to the thromboxane mimic U46619. Nitrendipine (calcium-channel blocker) equally attenuated rabbit blood and U46619-induced hemodynamic responses but did not block thromboxane production. Chlorpheniramine (H1-receptor antagonist) partially blocked the hemodynamic responses to rabbit blood without affecting thromboxane production or U46619-induced responses. We conclude that the erythrocyte membrane is the responsible component in the donor blood and thromboxane is the predominant mediator. The main action of isoproterenol is to reduce thromboxane production and histamine participates by possible interaction with cyclooxygenase products.

The role of prostaglandins in obstetrical disorders.

All pregnancy-associated tissues are capable of producing prostaglandins including PGI2 and TXA2. In normal pregnancy there is a dominance of PGI2 over TXA2 which may contribute to the maternal circulatory adaptation to pregnancy. Furthermore, both fetoplacental PGI2 and TXA2 production are important regulators of the fetal blood supply. It has been clearly established that in pre-eclampsia PGI2 production decreases in the fetoplacental tissues and quite probably also in the maternal tissues. The effect of this change may be further exaggerated by the simultaneous stimulation in pre-eclampsia of TXA2 production. The reason for PGI2 deficiency is not known. Other vasoactive agents, such as endothelin, may act in concert with prostaglandins. Relative PGI2 deficiency is likely to exist also in IUGR and lupus anticoagulant syndrome of pregnancy. In the latter, lupus anticoagulant may directly inhibit the synthesis of PGI2. One study suggests PGI2 deficiency also in early pregnancies of women with a history of repeated abortions. Prostaglandin production increases during full-term labour, and similar but smaller changes also occur in preterm labour. A silent bacterial infection may trigger the onset of preterm labour through cytokine-stimulated increase of prostaglandin production. No data were found on prostaglandin production in post-term pregnancies. That oligo-polyhydramnios is possibly prostaglandin mediated is suggested by the control of polyhydramnios by indomethacin treatment. Smoking decreases the production of PGI2 and possibly increases that of TXA2, which may lead to decreased blood flow and IUGR. Which constituent of cigarette smoke exerts this effect is not known. Ethanol consumption causes aberrations in prostaglandin metabolism which cannot be directly connected with fetal alcohol effects.