Specific Thromboxane Synthetase Inhibitor Research Articles

Do prostacyclin and thromboxane play a role in endotoxic shock?

The role of prostacyclin and thromboxane during endotoxic shock is unknown. Using new radioimmunoassay techniques, we have studied the plasma levels of stable metabolites of prostacyclin (6-keto-PGF1 alpha) and thromboxane (TxB2) in a porcine model of endotoxic shock. TxB2 levels were markedly elevated but the production of prostacyclin appears to be impaired. Correction of this prostanoid imbalance by the infusion of prostacyclin or pre-treatment with a specific thromboxane synthetase inhibitor produces significant and beneficial effects on blood pressure and pre-kallikrein activation.

Protective effect of FK506 and thromboxane synthase inhibitor on ischemia-reperfusion injury in non-heart-beating donor in rat orthotopic liver transplantation.

The study investigated the possibility of pharmacologically modulating hepatic allograft function from non-heart-beating donors (NHBDs) using male Lewis rats. The donors were divided into 4 groups: Group 1 in which the vehicle was administered, Group 2 in which FK506 (tacrolimus; a powerful immunosuppressive agent) was administered, Group 3 in which OKY046 (a specific thromboxane synthetase inhibitor) was administered and Group 4 in which FK506 and OKY046 were administered. The recipients received orthotopic liver transplantation. The survival rates differed significantly between the recipients that had received liver transplantation from Groups 1 and 4. The serum liver enzyme and inflammatory cytokine concentrations of the recipients which had received liver transplantation from Groups 2, 3 and 4 were significantly lower than those of the recipients that had received liver transplantation from Group 1. Although there was no significant difference, all parameters were better in the recipients that had received transplantation from Group 4 than those that had received transplantation from Groups 2 and 3. The action mechanisms of FK506 and OKY046 are completely different. Therefore, concomitant use of FK506 and OKY046 might have additive effects on liver transplantation from NHBDs. In conclusion, we demonstrated that pretreatment of NHBDs using FK506 and OKY046 ameliorated graft viability.

Effects of dietary n-3 fatty acid supplementation versus thromboxane synthetase inhibition on gentamicin-induced nephrotoxicosis in healthy male dogs

Abstract Objective To evaluate the protective effects of dietary n-3 fatty acid supplementation versus treatment with a thromboxane synthetase inhibitor (TXSI) in dogs given high-dose gentamicin. Design Clinicopathologic and renal histopathologic changes induced by gentamicin (10 mg/kg of body weight, IM, q 8 h, for 8 days) were compared in dogs fed an n-3 fatty acid-supplemented diet containing a fatty acid ratio of 5.7:1 (n-6:n-3), dogs treated with CGS 12970 (a specific TXSI given at 30 mg/kg, PO, q 8 h, beginning 2 days prior to gentamicin administration), and control dogs. The TXSI-treated and control dogs were fed a diet with a fatty acid ratio of 51.5:1 (n-6:n-3). Both diets were fed beginning 42 days prior to and during the 8-day course of gentamicin administration. Animals Eighteen 6-month-old male Beagles, 6 in each group. Results After 8 days of gentamicin administration, differences existed among groups. Compared with n-3-supplemented and control dogs, TXSI-treated dogs had higher creatinine clearance. Both TXSI-treated and n-3-supplemented dogs had higher urinary prostaglandin E2 and E3 (PGE2/3) and 6-keto prostaglandin F1α (PGF1α) excretion, compared with control dogs. Urinary thromboxane B2 (TXB2) excretion was higher in n-3-supplemented and control dogs, compared with TXSI-treated dogs. Urine PGE2/3-to-TXB2 and PGF1α-to-TXB2 ratios were increased in TXSI-treated dogs, compared with n-3-supplemented and control dogs, and these ratios were increased in n-3-supplemented dogs, compared with control dogs. In addition, TXSI-treated and n-3-supplemented dogs had lower urinary protein excretion, compared with control dogs. Proximal tubular necrosis was less severe in TXSI-treated dogs, compared with control dogs. Conclusion Treatment with CGS 12970 prior to and during gentamicin administration prevented increases in urinary TXB2 excretion and reduced nephrotoxicosis. Clinical Relevance Increased renal production/excretion of thromboxane is important in the pathogenesis of gentamicin-induced nephrotoxicosis. (Am J Vet Res 1996;57:948–956)

Protective effect of thromboxane synthetase inhibitor on hypertensive renal damage in Dahl salt-sensitive rats.

1. The effects of OKY-046, a specific thromboxane (TX) synthetase inhibitor, on blood pressure, urinary excretion of TX and its release from blood platelets and renal papilla, and pathological change of glomeruli were evaluated in Dahl salt-sensitive rats. 2. Average daily intakes of OKY-046-treated rats were 0.93 mg/kg (low dose), 9.8 mg/kg (moderate dose), and 88 mg/kg (high dose). 3. Systolic blood pressure tended to decrease by 6.3, 11.4, and 10.9% in three OKY-treated groups. 4. OKY-046 suppressed the release of TX from platelets in a dose-dependent fashion. Both TX in urine and released from renal papilla decreased in OKY-treated groups with moderate and high dose. OKY-046 resulted no change in urinary excretion or release from renal papilla of prostaglandin E2 or 6-keto-prostaglandin F1alpha. 5. Glomerular sclerosis score decreased significantly in both groups treated with moderate and high doses of OKY-046. 6. An inhibition of renal TX synthesis by TX synthetase inhibitor has a protective effect on the development of hypertensive renal damage with minor antihypertensive effect in Dahl salt-sensitive rats.

Prostaglandins and diabetic nephropathy

Abnormalities of renal prostaglandins (PGs) contribute to the pathogenesis of diabetic nephropathy through changes in renal hemodynamics. Our recent studies have demonstrated that urinary excretion ratio of 6-keto-PGF 1 α (6KF) to TXB 2 is decreased in patients with non-insulin-dependent diabetes mellitus (NIDDM). In the present study, we evaluated the clinical effects of some drugs on renal PG metabolism and diabetic nephropathy. Ozagrel, a specific thromboxane synthetase inhibitor, reduced urinary TXB 2 excretion, resulting in the improvement of the decreased urinary 6KF/TXB 2 ratio in NIDDM patients. Urinary albumin excretion was decreased and creatinine clearance (Ccr) was increased during ozagrel administration. The similar beneficial effect was also found in the administration of cilostazol, a phosphodiesterase inhibitor, whereas a stable analogue of PGI 2, beraprost sodium, reduced urinary albumin excretion in relation to the reduction of platelet aggregation rate. In conclusion, the drugs modulating renal and platelet PG S metabolism with direction to an increase in 6KF/TXB 2 ratio and an inhibition against platelet function might be beneficial for the treatment of diabetic nephropathy.

Bacterial translocation after thermal injury.

To review the mechanisms responsible for bacterial translocation after thermal injury. Areas investigated were the rate of bacterial translocation, blood flow to the gastrointestinal tract, potential of reversibility of mesenteric vasoconstriction, specific vasomediators responsible for postburn mesenteric vasoconstriction, potential reversal of gut mucosal atrophy with decreased translocation, and evidence of gut mucosal damage after thermal injury. Using three different animal models consisting of rats, sheep, and minipigs, the objectives were defined. Using the sheep model, the relationship of decreased mesenteric blood flow after thermal injury was defined along with rates of translocation, and the potential reversibility of the postburn mesenteric vasoconstriction and its effect on translocation. The effect of smoke inhalation and the combination of thermal injury and inhalation injury on rates of translocation are explained. Using minipigs, the role that thromboxane A2 plays on the postburn mesenteric vasoconstriction was defined by blocking thromboxane A2 synthesis with OKY046, a specific thromboxane synthetase inhibitor. Evidence of gut mucosal injury was determined using ornithine decarboxylase as an indicator of gut mucosal damage and subsequent repair in the minipig model. The rat model was used to demonstrate gut mucosal atrophy after thermal injury and the potential for reversal of atrophy with the use of bombesin, a specific gut mucosal growth stimulator. After thermal injury, there were significant decreases in mesenteric blood flow. There was also an increase in bacterial translocation. Selective infusion of nitroprusside into the cephalic mesenteric artery prevented the post-burn mesenteric vasoconstriction and attenuated bacterial translocation. Smoke inhalation and smoke inhalation with thermal injury resulted in mesenteric vasoconstriction and increased rates of bacterial translocation. OKY046 infusion prevented the postburn increase in mesenteric vascular resistance. There were increased concentrations of ornithine decarboxylase within the colonic mucosa, indicating a previous injury and the presence of ongoing repair. Likewise, there was gut mucosal atrophy after thermal injury with bacterial translocation. Treating with bombesin attenuates the postburn mucosal atrophy and prevents bacterial translocation. Thermal injury is associated with mesenteric vasoconstriction. This postburn mesenteric vasoconstriction results in damage to gut mucosa and allows for increases in bacterial translocation. The postburn mesenteric ischemia can be ameliorated with nitroprusside infusion, thus preventing translocation. Thromboxane A2 appears to be a major mediator of the postburn decrease in mesenteric blood flow. Likewise, prevention of postburn gut mucosal atrophy with bombesin attenuates bacterial translocation.

Effects of low-dose aspirin and specific thromboxane synthetase inhibition on whole blood platelet aggregation and adenosine triphosphate secretion in healthy dogs

SUMMARY Platelet aggregation and adenosine triphosphate (atp) secretion in response to arachidonic acid (10 μM) or collagen (5 μg/ml) were compared in healthy, adult female Beagles treated with low-dosage aspirin (3.5 mg/kg of body weight, po, q 12 h for 7 treatments) or with CGS 12970, a specific thromboxane synthetase inhibitor (10 mg/kg, po, q 8 h for 10 treatments). Platelet aggregation was assessed in whole blood by use of an electrical impedance method. Baseline values obtained prior to treatment served as controls. Addition of arachidonic acid to blood from nontreated dogs resulted in significantly (P < 0.001) increased impedance, but had no effect in blood from dogs treated with either aspirin or CGS 12970. Treatment with CGS 12970 or aspirin significantly (P < 0.001) decreased platelet atp secretion in response to arachidonic acid, compared with baseline values; however atp secretion in aspirin-treated dogs was significantly (P < 0.01) less than atp secretion in CGS 12970-treated dogs. Differences in platelet aggregation were not observed between control dogs and aspirin- or CGS 12970-treated dogs in response to collagen as an aggregant, however, collagen-induced platelet atp secretion was significantly (P < 0.001) decreased in dogs treated with aspirin, compared with control values and values from dogs treated with CGS 12970. In dogs treated orally with 0.1, 0.2, 1.0, or 10 mg of CGS 12970/kg, dose-dependent inhibition of arachidonic acid-induced platelet aggregation was observed, with impedance changes not observed at the 10-mg/kg dosage and normal platelet aggregation associated with the 0.1-mg/kg dosage. After a single orally administered dosage of 10 mg of CGS 12970/kg, platelet aggregation was maximally inhibited at 1 hour, remained negligible through 12 hours, and returned to normal by 96 hours. Platelet numbers were not affected by treatment with CGS 12970. These results indicate that similar to low-dose aspirin administration, treatment with CGS 12970 decreases arachidonic acid-induced, but not collagen-induced, whole blood platelet aggregation in dogs. Low-dose aspirin administration, however, was more effective than CGS 12970 treatment in reducing arachidonic acid- and collagen-induced platelet atp secretion.

Effects of a specific thromboxane synthetase inhibitor (TXSI) UK 38,485 in experimental myocardial infarction

Effects of a specific thromboxane synthetase inhibitor (TXSI) UK 38,485 in experimental myocardial infarction

The role of thromboxane in allergen-induced asthmatic responses

In this study we evaluated the role of thromboxane in causing allergen-induced early and late asthmatic responses and airway hyperresponsiveness in asthmatic subjects. Twelve atopic subjects with stable asthma and documented early and late asthmatic responses to an inhaled allergen were treated with placebo or CGS 13080, a specific thromboxane synthetase inhibitor, given orally (200 mg four times daily) for two days before, the day of, and the day after allergen inhalation. Treatments were administered in a double-blind, placebo-controlled, crossover fashion. The effect of pretreatment with CGS 13080 was examined on serum TxB2 levels and the magnitude of the asthmatic responses after inhaled allergen. Serum TxB2 levels increased significantly from 96 ng.ml-1 (SEM 29) 3 h after diluent to 151 ng.ml-1 (SEM 27) 3 h after allergen (p = 0.008). CGS 13080 pretreatment markedly inhibited the levels of TxB2 at all time points before and after inhaled allergen (p = 0.0001) and had a small but significant effect on the magnitude of the early asthmatic responses after allergen (p = 0.0009). CGS 13080 did not alter either late asthmatic responses, baseline airway responsiveness, or the increase in histamine airway responsiveness after allergen. These results suggest that allergen-induced early asthmatic responses, but not late responses or allergen-induced airway hyperresponsiveness, are partly caused by thromboxane release.

Effects of a specific thromboxane synthetase inhibitor on thromboxane generation and excretion in healthy dogs

SUMMARY A specific thromboxane synthetase inhibitor, 3-methyl- 2 (3-pyridyl)-l-indoleoctanoic acid (CGS 12970) was administered orally to 6 healthy adult Beagles at a dosage of 30 mg/kg of body weight. Blood generation of thromboxane B2 and urinary excretion of thromboxane B2 were measured before and after administration of CGS 12970. Although 97 ± 0.4% inhibition of thromboxane B2 generation was observed within 2 hours after a single dose of CGS 12970 was administered orally, an effect on urinary excretion of thromboxane B2 was not observed. Additionally, oral administration of 30 mg/kg every 12 hours resulted in 80 ± 14% inhibition of thromboxane B2 generation but had no effect on urinary thromboxane B2 excretion.

MODULATION OF EXPERIMENTAL CYCLOSPORINE NEPHROTOXICITY BY INHIBITION OF THROMBOXANE SYNTHESIS

The clinical usefulness of Cyclosporine is limited by its intrinsic nephrotoxicity. A potential mechanism of CsA-mediated renal injury may involve an alteration in the prostaglandin-thromboxane (PG-TX) cascade. In our studies, pharmacological manipulation of the PG-TX system in normal and nephrotoxic animals was conducted using a specific thromboxane synthetase inhibitor U63,557A, and the cyclooxygenase inhibitor indomethacin. Administration of CsA 50 mg/kg/day for 7 days to Sprague Dawley rats resulted in a 99% increase in urinary thromboxane B2 excretion compared with controls (48.2 +/- 3.1 vs. 24.2 +/- 2.6 ng/24 hr, P less than 0.001), while plasma levels remained unchanged. Glomerular and tubular function was significantly reduced at this time, with a 48% decrease in creatinine clearance (CCr), and a 25% reduction in the fractional excretion of sodium (FeNa) (P less than 0.001). Histological injury included cortical tubular vacuolization and necrosis. Administration of indomethacin 8 mg/kg/day to both normal and CsA-treated rats resulted in a significant reduction in prostanoid excretion. Indomethacin alone had no adverse effect on glomerular function; however, when coadministered with CsA an exaggerated decrease in renal function was observed. CCr in this group fell by a further 27% compared with the CsA-50 group, while FeNa decreased by 76% (P less than 0.001). Histologic injury intensified, with an increase in vacuolization and necrosis. In contrast, coadministration of U63,557A with CsA prevented the rise in urinary TXB2 excretion, improved CCr by 20% (P less than 0.05), and restored FeNa to control levels. The severity of CsA-induced vacuolization was significantly diminished. Selective inhibition of thromboxane production may therefore be valuable in mitigating the clinical nephrotoxicity of CsA.

Prostaglandin redirection by thromboxane synthetase inhibition. Attenuation of myocardial stunning in canine heart.

We have previously reported that inhibition of thromboxane synthesis results in an improvement in postischemic function in stunned myocardium of dogs. The purpose of the present study was to investigate further the mechanism by which thromboxane synthesis inhibition improves recovery of function in stunned myocardium (15 minutes of coronary occlusion and 3 hours of reperfusion) in barbital anesthetized dogs. The recovery of regional myocardial wall function (percent segment shortening, % SS) following treatment with two doses (0.5 and 10 mg/kg) of a thromboxane receptor blocker, BM 13.505, given prior to coronary occlusion, was not different from that of a control group (3-hour % SS of pretreatment control, PTC, 12 +/- 11) throughout reperfusion (3-hour % SS of PTC with BM 13.505: 0.5 mg/kg 14 +/- 10; 10 mg/kg, 27 +/- 9). In contrast, the specific thromboxane synthetase inhibitor, dazmegrel (3.0 mg/kg), significantly improved % SS throughout reperfusion (3-hour % SS of PTC, 66 +/- 8). In addition, while dazmegrel produced a marked decrease in thromboxane, 6-keto-PGF1 alpha was significantly increased in coronary venous blood throughout the occlusion and reperfusion period. The cyclooxygenase inhibitor, indomethacin, had no beneficial effect on functional recovery (3-hour % SS of PTC, 5 +/- 6), attenuated the dazmegrel induced shunting to prostacyclin, and completely prevented the beneficial effects of dazmegrel on functional recovery (3-hour % SS of PTC, 17 +/- 12). Thus, a redirection to endogenous cardioprotective prostanoids, such as prostacyclin, appears to be responsible for the beneficial effect of thromboxane synthesis inhibition on postischemic recovery in stunned myocardium whereas thromboxane does not appear to be an important mediator of the stunning phenomenon.

Effects of OKY-046, a selective thromboxane synthetase inhibitor, on blood pressure and thromboxane synthesis in spontaneously hypertensive rats

The effects of OKY-046, a specific thromboxane (TX) synthetase inhibitor, on blood pressure, urinary TX excretion, TX synthesis in blood platelets, kidney slices and aortic strips, were evaluated in adult spontaneously hypertensive rats (SHR). OKY-046 was dissolved in drinking water at concentrations of 1, 10, 100 mg/dl. The average intakes of OKY-046 were 1.4 ± 0.1, 13.0 ± 1.1, and 147 ± 12 mg/kg/day, in rats who took 1, 10, 100 mg/dl of OKY-046 solutions for drinking water, respectively. The systolic blood pressure was significantly decreased by 34 mmHg only with the high dose of OKY-046 (147 mg/kg/day). OKY-046 suppressed the platelet aggregability to ADP and the release of TX B 2, a stable metabolite of TX A 2, from blood platelets in a dose-dependent fashion. Urinary excretion of TX B 2 decreased significantly in both groups treated with moderate (13.0 mg;/kg/day) and high doses of OKY-046 (147 mg/kg/day). The release of TX B 2 from kidney slices was decreased only by the high dose of OKY-046, while the release of TX B 2 from aortic strips was not changed even by the high dose of OKY-046. OKY-046 had no effect on urinary excretion of 6-keto-prostaglandin F 1α, a stable metabolite of prostacyclin, or, on its release from the kidney slices and aortic strips. These results suggest that the effect of OKY-046 on TX synthesis has organ specificity and that the antihypertensive effect of this drug in SHR is related to reduced renal TX synthesis.

OKY-046 inhibits thromboxane synthesis with no effect on brain edema and neurological status in head traumatized rats

Head trauma (HT) was induced in the left hemisphere of rats by a weight drop device. Edema was maximal 24 h after HT in the injured zone, and PGE 2, TXB 2 and 6-keto-PGF 1α were elevated in both the injured and remote areas. The effect of a specific thromboxane synthetase inhibitor, OKY-046, on the outcome of HT was studied. OKY-046, 100 mg/kg, was given to rats immediately and 8 h after HT. The neurological severity score (NSS) was evaluated at 1 h after HT, and at 24 h, just prior to sacrifice. Specific gravity (SG) of both hemispheres was measured after decapitation. Prostaglandins (PGs) were extracted from the site of injury and from the frontal lobes, remote from the injury, and assayed by RIA. Basal levels of PGE 2 and 6-keto-PGF 1α were not reduced by the drug while basal TXB 2 levels were lowered. However, the increased production due to HT of all PGs, was inhibited by OKY-046, especially that of TXB 2. The ratio of TXB 2 6 -keto-PGF 1α , known to affect vascular tone, was reduced by OKY-046 treatment as a result of TXA 2 synthesis inhibition. Still, no effect was found on the neurological outcome (as evaluated by the NSS), or on edema formation (expressed by reduced SG). Thus, based on the present findings increased TXA 2 synthesis cannot be implicated in the pathophysiology of cerebral edema or dysfunction following HT.

Effects of a specific thromboxane synthetase inhibitor on development of experimental Dirofilaria immitis immune complex glomerulonephritis in the dog.

Twelve Beagle dogs were immunized with aqueous-soluble Dirofilaria immitis antigens, and subsequent to at least fivefold increases in serum antibody titer, 6 mg of homologous antigen was infused into the left renal artery. Six dogs were treated once daily starting the day of infusion with 0.75 mg/kg of 1-benzylimidazole (1-BIM) in saline. Six control dogs were given saline only. Light, immunofluorescent, and transmission electron microscopic examinations of renal tissue from control dogs, 10 days after antigen infusion, showed a mesangioproliferative glomerulonephritis in the left kidney with polymorphonuclear leukocyte (PMNL) infiltration and fibrin deposition. Immunoglobulin (Ig) G, M, C3, and Dirofilaria antigen deposits were observed in a segmental granular pattern. Mesangial, subendothelial, and intramembranous electron dense deposits were observed, and anti-Dirofilaria antibodies were demonstrated in kidney eluates from each dog. Administration of 1-BIM had no significant effect on IgG, IgM, C3, or antigen deposits, electron dense deposits, or concentration of antibody in kidney eluates. However, 1-BIM-treated dogs had less glomerular cell proliferation, periodic acid-Schiff (PAS) positive glomerular staining, PMNL infiltration, and fibrin deposition. These data suggest that thromboxane is an important mediator in the development of immune complex glomerulonephritis, and that in certain circumstances, inhibition of thromboxane synthesis may be an effective therapy for immune complex glomerulonephritis in the dog.

The association of in vitro arachidonic acid responsiveness and plasma thromboxane levels with early platelet deposition on the luminal surface of small-diameter grafts

The response of canine platelets to arachidonic acid (AA) stimulation was studied as a predictor of thrombotic potential. Fifty mongrel dogs underwent in vitro platelet aggregation studies with adenosine diphosphate (ADP), collagen, and AA used as inducing agents. Thirty-two dogs were selected on the basis of their response to AA stimulation. Platelet aggregation in response to AA stimulation occurred in 16 (responders) and 16 showed no aggregatory response (nonresponders). The animals were divided into four groups. Group I received no antiplatelet agents (control); group II received U-63,557A, a specific thromboxane synthetase inhibitor (TSI); group III received aspirin; and group IV received aspirin and TSI. Polytetrafluoroethylene grafts were implanted in the carotid and femoral arteries of the dogs in all four groups. Plasma thromboxane (TxB2) levels were drawn before drug treatment and 4 weeks after surgery. Platelet deposition on the luminal surface of the implanted grafts was studied in vivo with a technique that uses both 111In-labeled platelets and 99mTc-labeled red blood cells and was expressed as percentage of indium excess (%IE). Group I (control) dogs whose platelets aggregated in response to AA stimulation had significantly higher 24-hour platelet deposition (%IE) on the luminal surface of implanted grafts (p < 0.02), lower 4-week graft patency (p < 0.002), and higher plasma TxB2 levels (p < 0.01) than those dogs whose platelets did not aggregate. In contrast to the results of AA stimulation, neither ADP nor collagen responsiveness was discriminatory for the thrombotic potential of canine arteries as measured by 24-hour platelet deposition (%IE), 4-week graft patency, or plasma TxB2 levels. Pharmacologic platelet inhibition by use of aspirin (groups III and IV) effectively transformed AA responders into AA nonresponders as manifested by lowering the 24-hour platelet deposition (%IE) and increasing the 4-week patency to a value similar to AA nonresponders. This study confirms that the in vitro platelet response to AA stimulation is the best method for determining the endogenous thrombotic potential of canine arteries and correlates well with plasma TxB2 levels and 24-hour in vivo platelet deposition studies.

Renal vascular effects of leukotriene C4 in the isolated perfused kidney of the rat.

1 The vascular effects of leukotriene C4 (LTC4) were investigated in the isolated perfused kidney of the rat. 2 LTC4 (6.4 X 10(-10) to 3.2 X 10(-8) mol kg-1 min-1 given over 5 min) resulted in a prompt, dose-dependent increase in renal vascular resistance in a recirculating system, which lasted for more than 60 min. 3 LTC4 was 10 to 20 fold and 1000 to 2000 fold, respectively, less active on a molar basis than noradrenaline and angiotensin II in eliciting renal vasoconstriction. 4 The vascular response to LTC4 was blocked dose-dependently by FPL 55712, an antagonist of slow reacting substance of anaphylaxis. OKY 1581, a specific thromboxane synthetase inhibitor, and indomethacin, a cyclo-oxygenase inhibitor, did not influence the LTC4 response. 5 LTC4 given in a single-pass perfusion system resulted in a short lasting response with baseline values for renal vascular resistance reached after 4 min. 6 These results show that LTC4 is a short acting renal vasoconstrictor with less potency than noradrenaline and angiotensin II. Its pressor effects seem to be mediated by specific leukotriene receptors and independent of cyclo-oxygenase products. The long-lasting effect in the recirculating arrangement, in contrast to the single pass system, is compatible with formation of active metabolite(s).

Effects of a specific thromboxane synthetase inhibitor in equine endotoxaemia

Thromboxane A2 may play a major role in circulatory shock. In some species, thromboxane synthetase inhibitors have a beneficial effect on shock induced by endotoxin, trauma, sepsis and administration of arachidonate. In some shock models, however, results with thromboxane synthetase inhibitors have been conflicting. The effect of UK-38,485, a selective thromboxane inhibitor, was evaluated in ponies injected with endotoxin intraperitoneally. Four groups of ponies were used to compare the effects of endotoxin alone, UK-38,485 alone, treatment with UK-38,485 before endotoxin challenge and treatment with UK-38,485 after endotoxin challenge. Haematological, metabolic, eicosanoid and clinical responses in each group were evaluated. The results indicated that UK-38,485 is an effective inhibitor of thromboxane A2 generation following endotoxin challenge. Prostacyclin values were elevated compared with baseline in ponies administered UK-38,485 and endotoxin. However, prostacyclin values were not significantly different from those of ponies receiving endotoxin alone. Furthermore, UK-38,485 failed to attenuate the haematological, metabolic and clinical manifestations commonly seen in the pony after endotoxin challenge.

The role of thromboxane in cuprophan–induced pulmonary hypertension

Previous studies demonstrated that acute infusion of cuprophan activated plasma into experimental animals produce cardiopulmonary changes which included severe pulmonary hypertension. It was further suggested that these changes were mediated by complement activation products. The current study examined the role of arachidonic acid metabolites in the pathogenesis of cuprophan-induced pulmonary hypertension in the swine. Plasma thromboxane concentrations and pulmonary arterial pressure rose concomitantly with cuprophan-activated plasma infusion; both could be inhibited by the specific thromboxane synthetase inhibitor, OKY1581. Likewise, this inhibitor also blocked the increment in plasma thromboxane concentrations and pulmonary arterial pressure induced by zymosan-activated plasma. In vitro incubation of cuprophan-activated plasma with porcine lung fragments produced significantly higher thromboxane concentrations in the medium than incubation with other porcine tissues examined. It is postulated that the complement activation products formed in the plasma during cuprophan exposure subsequently stimulated release of thromboxane from the lungs and other tissues upon infusion of the plasma into animals. The thromboxane, in turn, triggers the pulmonary hypertension.

肺循環とプロスタノイド 特に低酸素性肺血管収縮におけるプロスタノイドの関与

Hypoxic pulmonary vasoconstriction (HPV) is known to be an important physiological response to preserve an appropriate ventilation-perfusion ratio in the lung. The precise mechanism of HPV remains to be controversial, but recently the role of prostaglandins for mediating and/or modulating HPV has been emphasized. From this viewpoint, we studied the effect of PAF on HPV in anesthetized, open chest mongrel dogs. HPV was assessed by the change of total pulmonary resistance (TPR, PPA-PLA/QAO) . After the stable condition was established, 15-min exposure to 10% O2 followed by 15-min exposure to 100% O2 was repeated 6 times.In control group (N=5), spontaneous potentiation of HPV was observed during the 1st to the 5th hypoxic exposures, but an attenuation was occurred in the 6th hypoxic exposure.In PAF treatment group (N=5), the 6th hypoxic exposure was performed during continuous infusion of PAF at the dose of 33 ng/kg/min for 30 min (totally 1μg/kg) . This group showed no attenuation but potentiation of HPV in the 6th hypoxic exposure.Pretreatment with CV-3988 (10mg/kg), a specific antagonist of PAF, blocked the potentiating effect on HPV induced by PAF but pretreatment with OKY-046 (10mg/kg), a specific thromboxane synthetase inhibitor, did not block the effect of PAF.It is suggested that PAF, at the dose of 1μg/kg, acts as vasoconstrictor even in the condition of elevated pulmonary vascular tone induced by HPV in mongrel dogs.