thromboxane-a2 and dazmegrel

Previous open studies have suggested that thromboxane receptor antagonists or synthesis inhibitors lower airway hyperresponsiveness in human subjects. This would indicate a role of thromboxane A2 in the development or maintenance of hyperresponsiveness in asthma. Ten nonsmoking asthmatics (aged 23-64 yrs, 9 male) were included in a randomized, double-blind, placebo-controlled, cross-over study of the effect of one week of treatment with a potent selective thromboxane synthetase inhibitor (UK-38,485, 600 mg daily) on airway responsiveness. The study was preceded by a two week run-in period, and two weeks were used for wash-out between the two trial periods. Adequacy of dosage and patient compliance was confirmed by a reduction in the ex vivo formation of thromboxane B2 (median concentration 3.22 micrograms.ml-1 after placebo, 0.10 microgram.ml-1 after UK-38,485, p < 0.05). The mean forced expiratory volume in one second (FEV1) after UK-38,485 was 2.55 l, compared to 2.56 l after treatment with placebo (p = 0.74). The geometric mean provocative dose of methacholine producing a 20% fall in FEV1 (PD20) before and after UK-38,485 was 23.9 and 32.2 micrograms, respectively, compared to 25.1 and 26.3 micrograms respectively, before and after placebo (p = 0.31). The results of this study suggest that thromboxane A2 does not play an important role in the maintenance of increased airway responsiveness in moderately severe asthmatics treated with low doses of inhaled steroids.

Topics: Adult; Asthma; Bronchial Provocation Tests; Double-Blind Method; Female; Humans; Imidazoles; Male; Methacholine Chloride; Middle Aged; Thromboxane A2; Thromboxane-A Synthase; Time Factors

The pharmacokinetics of dazmegrel (UK-38,485), a novel selective thromboxane synthase inhibitor, and its effects on in vivo prostanoid formation were studied in a 2 weeks, multiple dose, placebo controlled, double blind trial in man. The drug was well tolerated. After dazmegrel 50-200 mg p.o. peak plasma levels of 0.7-3 mu/ml were reached within 1 hr. Elimination was of first order with a half life of 0.88 +/- 0.17 hr. Platelet count and bleeding time were unchanged by all regimes of dazmegrel used (100 and 200 mg b.i.d.; 50, 100 and 200 mg t.i.d.). Serum thromboxane (TXB2) was more than 95% suppressed one hour after all doses studied, but 200 mg t.i.d. were needed suppress circadian serum TXB2 profiles more than 90% at all times. Urinary excretion of 2,3-dinor-TXB2 (TXA2-M) fell by over 90%. An increase in the excretion of 2,3-dinor-6-keto-PGF1 alpha (PGI2-M), the major metabolite of prostacyclin, was largely transient and fell short of significance at all times. The ratio of TXA2-M to PGI2-M was lowered from about 5.0 to 0.2 and sustained throughout treatment. Dazmegrel selectively blocks in vivo and ex vivo TXA2 formation. Redirection of endoperoxides from total body TXA2 formation into prostacyclin formation is only minor under basal conditions.

Topics: Adult; Double-Blind Method; Epoprostenol; Humans; Imidazoles; Kinetics; Male; Metabolic Clearance Rate; Thromboxane A2; Thromboxane B2; Thromboxane-A Synthase

Thromboxane A2, a potent vasoconstrictor, is a major metabolite of arachidonic acid in the human kidney. To determine the role of thromboxanes in renal hemodynamics, we administered the new thromboxane inhibitor dazmegrel or placebo to 20 healthy volunteers for 14 days in a double-blind protocol. Dazmegrel reduced urinary thromboxane B2 by an average of 68% and serum thromboxane B2 by 79%, without affecting urinary excretion of the prostacyclin metabolite 6-ketoprostaglandin F 1 alpha. Neither p-aminohippurate clearance nor inulin clearance were altered by thromboxane inhibition. Thus it is unlikely that thromboxane A2 plays a major role in the regulation of glomerular function in healthy humans.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Double-Blind Method; Glomerular Filtration Rate; Humans; Imidazoles; Inulin; Kidney; Male; Oxidoreductases; p-Aminohippuric Acid; Thromboxane A2; Thromboxane B2; Thromboxane-A Synthase; Thromboxanes

Thromboxane A2 is a proaggregative vasoconstrictor that is synthesized and released in reperfusion injury. We aimed to investigate the effects of thromboxane synthase inhibitor, UK 38485, on endothelin-1,2 (ET) response of the renal endothelium and lipid peroxidation and protein oxidation in the early period of kidney transplantation. Four groups (n=8 in group IV and n=10 in the others) [corrected] of Sprague-Dawley rats were designed as Group I (sham nephrectomy), Group II (autotransplantation), Group III (allotransplantation) and Group IV (allotransplantation group in which the allografts were perfused with UK 38485. All subjects underwent right nephrectomy after transplantation. The grafts were flushed with 4 ml of ice-cold Ringer's lactate and in Group IV 10 microg of UK 38485 was added into the solution for each kidney. In allotransplantation groups, the kidneys were harvested from allogeneic white Wistar albino rats. The kidney grafts were allowed 120 min of reperfusion after 40 min of cold ischemic period. ET-1,2 plasma concentrations in the renal vein blood and diene conjugates (DC), hydroxyalkanals (HAA), hydroxyalkenals (HAE) and malondialdehyde (MDA) levels as the products of lipid peroxidation, protein carbonyls and protein sulfhydryls as the indicators of protein oxidation were analyzed in kidney tissue. Plasma ET-1,2 concentrations increased significantly in Group II and Group III (P<0.01) when compared to Group I but decreased in Group IV in comparison with Group III (P<0.05). DC, HAA, HAE and MDA levels increased in Groups II and III (P<0.001). Significant protein oxidation occurred only in Group III (P<0.01). Perfusion of the allografts with UK 38485 prevented lipid peroxidation and protein oxidation in Group IV. Histopathological changes were mild in the last group. We concluded that, in kidney transplantation, local administration of UK 38485 has cytopreservative effects on the allografts and this effect can be related to ET-1,2 concentrations.

Topics: Alkanes; Alkenes; Animals; Endothelin-1; Endothelin-2; Imidazoles; Kidney Transplantation; Male; Malondialdehyde; Oxidation-Reduction; Rats; Rats, Sprague-Dawley; Rats, Wistar; Reactive Oxygen Species; Renal Circulation; Reperfusion Injury; Sulfhydryl Compounds; Thromboxane A2; Thromboxane-A Synthase; Transplantation, Homologous; Vasodilator Agents

We determined the efficacy of continuous arteriovenous hemofiltration (CAVH) and a thromboxane synthetase inhibitor (TSI) on survival and their effect on TXA2, PGI2, TNF alpha, and IL-1beta production in rat endotoxemia. Thirty-six endotoxemic rats were randomized to one of 4 groups: (A) no TSI, sham CAVH; (B) no TSI, CAVH; (C) TSI, sham CAVH; and (D) TSI, CAVH. Either CAVH (Group B) or pretreatment with TSI (Group C) resulted in increased survival time. CAVH did not prevent the rise in TX (Group B). TNF alpha levels at 2 h after LPS infusion were higher in Group D compared to Group B (26.1 +/- 3.7 vs 13.2 +/- 4.3 ng/mL, P < 0.05) respectively. IL-1beta was detected earlier in Groups C,D when compared to Groups A,B (P < 0.02). TNF alpha and IL-1beta were not ultrafiltered. CAVH and the inhibition of TX synthesis independently improved survival in endotoxemia, however, their beneficial effects were not additive. While TSI may improve survival by blocking TXA2 production, the salutary effects of CAVH appear to be from removal of an undetermined TXA2 dependent mediator. TNF alpha and IL-1beta concentrations do not appear to influence survival times in this model.

Topics: Animals; Blood Pressure; Combined Modality Therapy; Enzyme Inhibitors; Epoprostenol; Heart Rate; Hemofiltration; Imidazoles; Inflammation Mediators; Interleukin-1; Male; Rats; Rats, Sprague-Dawley; Shock, Septic; Thromboxane A2; Thromboxane-A Synthase; Tumor Necrosis Factor-alpha

There is substantial evidence of increased platelet reactivity in vivo and in vitro during pregnancy. Previous in vitro studies suggest that platelets from pregnant women show increased sensitivity to agonists, the response to which has a thromboxane dependent component. The aim of this study was to determine whether this is due to increased activity of the thromboxane biosynthetic pathway or to increased platelet sensitivity to the effects of thromboxane. During pregnancy, platelets were more sensitive to the pro-aggregatory effects in vitro of the thromboxane mimetic U46619, in whole blood and in platelet rich plasma, compared to those from non-pregnant controls. The difference in extent of U46619-induced platelet aggregation between groups was abolished in the presence of a high concentration of the specific thromboxane antagonist ICI 192605, but not by prior incubation of blood with aspirin. Platelets from pregnant women were significantly less sensitive to inhibition of arachidonic acid induced activation by the thromboxane synthetase inhibitor dazmegrel, but there was no change in platelet cyclic AMP accumulation under these conditions. Arachidonic acid induced platelet thromboxane B2 production was similar in pregnant and non-pregnant subjects. In conclusion, platelets are more sensitive to the activating effects of thromboxane during pregnancy, but there is no change in the intrinsic reactivity of the thromboxane biosynthetic pathway.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Adolescent; Adult; Arachidonic Acid; Aspirin; Blood Platelets; Cross-Sectional Studies; Cyclic AMP; Dioxanes; Female; Humans; Imidazoles; Platelet Aggregation; Pregnancy; Prostaglandin Endoperoxides, Synthetic; Thromboxane A2; Thromboxane-A Synthase

The early phase of endotoxin-induced acute hemodynamic disturbances and hypoxemia is mediated by various factors, including eicosanoids and tumor necrosis factor-alpha (TNF alpha). Thromboxane A2 is the major mediator of the early pulmonary hypertension associated with endotoxemia, but the mechanisms underlying the prolonged hemodynamic disturbances observed in ongoing endotoxemia are not well understood. The authors used a chronically instrumental young piglet model to determine the roles of several eicosanoids and of TNF alpha in the prolonged endotoxin-induced pulmonary hypertension and other cardiovascular derangements. Animals were given 40 micrograms/kg endotoxin intravenously per hour for 30 minutes, followed by 20 micrograms/kg per hour. In all animals, persistent pulmonary hypertension, lowered cardiac output, any hypoxemia developed during endotoxin infusion. After 3 hours of endotoxin infusion, randomly ordered infusions of 1 mg/kg dazmegrel (a thromboxane A2 synthesis inhibitor), 5mg/kg nordihydroguaiaretic acid (a 5-lipoxygenase inhibitor), and 20 mg/kg pentoxifylline (A TNF alpha inhibitor) were given intravenously at 30-to-60-minute intervals. Dazmegrel and pentoxifylline lowered pulmonary arterial pressure and resistance and raised arterial oxygen tension. Cardiac output increased significantly after pentoxifylline. These hemodynamic effects persisted for 30-60 minutes, despite continued endotoxin infusion. The elevated plasma concentrations of thromboxane B2 and TNF alpha returned toward preendotoxin baseline values after dazmegrel and pentoxifylline treatment, respectively. No beneficial effects were noted after administration of nordihydroguaiaretic acid. Based on these results, both thromboxane A2 and TNF alpha, but not 5-lipoxygenase products, play active roles in prolonged endotoxin-induced pulmonary hypertension and hypoxemia in young piglets. Combined thromboxane A2 and TNF alpha blockade may be clinically useful in treatment of advanced sepsis in neonates.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Endotoxins; Female; Hemodynamics; Humans; Hypertension, Pulmonary; Imidazoles; Leukotriene Antagonists; Leukotrienes; Lipoxygenase; Masoprocol; Pentoxifylline; Sepsis; Swine; Thromboxane A2; Thromboxane B2; Thromboxane-A Synthase; Toxemia; Tumor Necrosis Factor-alpha

The production of 14CO2 from labelled glucose by isolated uterine strips from ovariectomized-diabetic rats has been studied. U46619, an analogue of TXA2 did not affect basal glucose metabolism; however, insulin-induced increment in CO2 production was completely blocked, both in ovariectomized (OVD) or ovariectomized-estrogenized (OVED) diabetic uterus. OKY064 as well as UK38485, both inhibitors of TXA2 synthesis, stimulated glucose metabolism (p < 0.05) similar to that of insulin in uterine tissue from OVD and OVED rats. Inhibition in the synthesis and release of TXB2 was detected (p < 0.01) by uterine radioconversion of 14C-arachidonic acid when adding OKY38485 to the incubation medium, and the production of other prostanoids such as 6-keto-PGF1 alpha, PGF2 alpha and PGE2 was enhanced. In summary, TXA2 inhibited insulin-induced glucose metabolism in diabetic animals.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Animals; Carbon Radioisotopes; Diabetes Mellitus, Experimental; Estrogens; Female; Glucose; Imidazoles; In Vitro Techniques; Insulin; Ovariectomy; Prostaglandin Endoperoxides, Synthetic; Prostaglandins; Rats; Rats, Wistar; Thromboxane A2; Thromboxane-A Synthase; Uterus

Both tumor necrosis factor (TNF) and platelet-activating factor (PAF) are released during sepsis and are important mediators of septic lung injury. I investigated the interactions of TNF and PAF on vasoactive responses in the pulmonary circulation. In isolated rat lungs perfused with a cell- and plasma-free physiological salt solution, PAF (0.01- and 0.1-micrograms boluses) caused transient dose-dependent pulmonary arterial and venous constrictions. In vivo pretreatment of the rats with TNF (0.02 or 0.2 mg/kg i.v.) 1 h before lung isolation increased lung myeloperoxidase activity and markedly enhanced PAF-induced pulmonary vasoconstriction without affecting the pressor responses to angiotensin II or hypoxia. In contrast, pretreatment with lipopolysaccharide (10 mg/kg), which increased lung myeloperoxidase to the same extent as TNF, caused only a modest enhancement of PAF-induced vasoconstriction associated with reduced pressor responses to angiotensin II and hypoxia. Ex vivo perfusion of isolated lungs with TNF for 1 h did not affect PAF vasoconstriction. The TNF-induced potentiation of PAF vasoconstriction was not altered by depletion of circulating neutrophils with vinblastine but was blocked by Dazmegrel, a thromboxane synthase inhibitor. Thus, TNF potentiates PAF-induced pulmonary vasoconstriction by an in vivo mechanism that is neutrophil independent but thromboxane dependent. This TNF-PAF interaction likely contributes to the development of pulmonary hypertension during sepsis.

Topics: Animals; Blood Pressure; Drug Synergism; Imidazoles; In Vitro Techniques; Lipopolysaccharides; Male; Neutropenia; Neutrophils; Platelet Activating Factor; Pulmonary Circulation; Rats; Rats, Sprague-Dawley; Thromboxane A2; Thromboxane-A Synthase; Tumor Necrosis Factor-alpha; Vasoconstriction

Tumor necrosis factor alpha (TNF alpha) and thromboxane A2 (TXA2) are major products of the activated alveolar macrophage and serve as key mediators of lung injury. In order to determine if the synthesis of TXA2 and the release of TNF alpha are associated, the production of these inflammatory agents by the human alveolar macrophage (AM), as a result of activation by lipopolysaccharide (LPS), was assessed in the absence and presence of the thromboxane synthase inhibitors UK 38,485 (Dazmegrel) and OKY 046. UK 38,485 and OKY 046 inhibited both LPS-stimulated TXA2 production and TNF alpha release in a dose-dependent manner. Prostaglandin E2 (PGE2) production was not increased by UK 38,485 or OKY 046. Neither LPS nor UK 38,485 had any effect on LTB4 production by AM. Neither UK 38,485 or OKY 046 had any effect on LPS-stimulated interleukin-1 beta release. However, the TXA2 mimetic, U46619, did not stimulate TNF alpha release by AM either in the absence or presence of UK 38,485. These findings suggest that 1) UK 38,485 and OKY 046 are inhibitors of both TXA2 production and TNF alpha release by activated human AM, 2) UK 38,485 probably does not exert its inhibitory action on TNF alpha release through effects on eicosanoid production and 3) the possibility that TNF alpha- and TXA2-induced lung injury may be subject to amelioration by imidazole-based compounds should be further evaluated.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Adult; Cells, Cultured; Humans; Imidazoles; Kinetics; Lipopolysaccharides; Macrophage Activation; Macrophages, Alveolar; Male; Methacrylates; Middle Aged; Prostaglandin Endoperoxides, Synthetic; Thromboxane A2; Thromboxane-A Synthase; Tumor Necrosis Factor-alpha; Vasoconstrictor Agents

Anisodamine, an anticholinergic drug, is widely used in China for treatment of infants with septic shock and has been reported to inhibit thromboxane synthesis in cultured cells. Thromboxane A2 plays an important role in the early pulmonary hypertension in sepsis; however, the role of thromboxane A2 later in sepsis is unclear. We tested the hypothesis that thromboxane A2 synthesis inhibition with dazmegrel, and cholinergic blockade with anisodamine, would attenuate the later phase of pulmonary hypertension induced by 4 h of group B streptococcus (GBS) infusion. 1 mg/kg of dazmegrel reversed the pulmonary hypertension and slightly increased cardiac output; these hemodynamic improvements persisted for 30-60 min. Plasma thromboxane B2 levels returned toward pre-GBS baseline values after dazmegrel treatment. Thus, thromboxane A2 is still a major mediator of pulmonary hypertension in piglets after 4 h of continuous GBS infusion. 0.5 mg/kg of anisodamine had no significant hemodynamic effect. 2 and 4 mg/kg of anisodamine each caused transient, dose-related decreases in systemic artery pressure; cardiac output also fell after the highest anisodamine dose. Pulmonary hypertension was not alleviated by anisodamine. All hemodynamic changes induced by anisodamine were short-lived and returned to preanisodamine values within 10 min. Anisodamine did not ameliorate thromboxane-mediated pulmonary hypertension in this animal model, and therefore may not inhibit thromboxane synthesis in vivo. The results of this study do not support the use of anticholinergic therapy to improve hemodynamics in GBS sepsis, but do suggest that thromboxane synthesis inhibition may be a clinically useful therapy in advanced GBS sepsis.

Topics: Animals; Blood Gas Analysis; Dose-Response Relationship, Drug; Female; Hemodynamics; Hypertension, Pulmonary; Imidazoles; Parasympatholytics; Pulmonary Circulation; Solanaceous Alkaloids; Streptococcal Infections; Streptococcus agalactiae; Swine; Thromboxane A2; Thromboxane-A Synthase; Thromboxanes; Vasodilator Agents

The goal of this study was to determine the role of prostaglandin H2-thromboxane A2 (PGH2-TxA2) in altered responses of cerebral arterioles during chronic hypertension. Diameter of pial arterioles was measured during suffusion with ADP, acetylcholine, and nitroglycerin using intravital microscopy in Wistar-Kyoto (WKY) normotensive rats and spontaneously hypertensive rats (SHR) (8-10 mo old). ADP (100 microM) increased pial arteriolar diameter by 21 +/- 3% (means +/- SE) in WKY and only by 7 +/- 3% in SHR. Acetylcholine (10 microM) increased diameter 10 +/- 2% in WKY and, in contrast, reduced diameter 7 +/- 3% in SHR. Nitroglycerin produced similar vasodilatation in WKY and SHR. We then examined whether impaired dilatation of cerebral arterioles in SHR to ADP and acetylcholine may be related to activation of the PGH2-TxA2 receptor. SQ 29548, a specific PGH2-TxA2 receptor antagonist, restored vasodilatation in response to ADP in SHR toward that observed in WKY and reversed vasoconstriction to vasodilatation in response to acetylcholine in SHR. SQ 29548 did not alter responses in WKY. Thus these findings suggest that impaired responses of cerebral arterioles to ADP and acetylcholine during chronic hypertension may be related to the activation of the PGH2-TxA2 receptor.

Topics: Acetylcholine; Adenosine Diphosphate; Animals; Arterioles; Brain; Bridged Bicyclo Compounds, Heterocyclic; Chronic Disease; Fatty Acids, Unsaturated; Hydrazines; Hypertension; Imidazoles; Male; Nitroglycerin; Prostaglandin Endoperoxides, Synthetic; Prostaglandin H2; Prostaglandins H; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Thromboxane A2; Vasodilator Agents

Angiotensin II (A II) when given through the renal artery of the rabbit isolated perfused kidney elicited a concentration-dependent increase in perfusion pressure (PP) and urine flow (UF). Noradrenaline (NA) produced similar effect in PP but slightly not significantly increased UF. Addition of UK 38,485, a thromboxane A2 (TXA2)-synthetase inhibitor, to the bathing medium at the concentration of 10(-7) M caused a significant decrease in the pressor effect of A II but significantly enhanced UF. BM 13,177, a TXA2-receptor blocker, in the bathing medium (10(-6) M) produced identical effect in both PP and UF. The responses to NA were not significantly altered by both compounds. A II-induced enhancement of UF in presence of BM 13,177 was significantly lower than that obtained in presence of UK 38,485. These results were taken as an evidence that A II may increase the production of TXA2 in kidney probably originated from vascular bed or tubuli and part of the pressor effect of the peptide is due to this metabolite of arachidonic acid. Enhancement of UF following UK 38,485 is probably due to the shift of the synthesis toward E series of PGs. In addition this effect seems to be specific for A II since no such effect was seen with NA.

Topics: Angiotensin II; Animals; Female; Imidazoles; In Vitro Techniques; Kidney; Male; Norepinephrine; Perfusion; Rabbits; Sulfonamides; Thromboxane A2; Thromboxane-A Synthase; Urine

Cyclosporine (CsA), an immunosuppressive agent, is potentially nephrotoxic. We had previously observed that acute administration of CsA to Munich-Wistar rats induced a decrease in single nephron glomerular filtration rate, due to a decline in glomerular plasma flow, and in the glomerular ultrafiltration coefficient. Moreover, these alterations were prevented when an antagonist of platelet-activating factor (PAF) was administered. In the present study we examined whether the protective effect of the PAF blocker in CsA nephrotoxicity could have been mediated by thromboxane (TxA2). Our data show that the PAF effects were not mediated by TxA2, since administration of dazmegrel, a thromboxane synthetase inhibitor, did not ameliorate the acute renal failure caused by CsA. Thus, PAF appears to be a direct mediator of acute CsA nephrotoxicity, while TxA2 is not significantly involved in this process.

Topics: Animals; Blood Pressure; Cyclosporine; Glomerular Filtration Rate; Imidazoles; Kidney; Male; Platelet Activating Factor; Rats; Rats, Inbred Strains; Reference Values; Renal Circulation; Thromboxane A2; Thromboxane-A Synthase

Since we had found that angiotensin II (Ang II), but not phenylephrine (PE), increased the excretion of thromboxane (Tx) and raised mean arterial pressure (MAP) by a Tx-dependent mechanism, we tested the role of TxA2 in mediating Ang II-induced changes in renal hemodynamics. For series 1, groups of anesthetized rats received an i.v. infusion of Ang II (50 ng.kg-1.min-1). When infused with a vehicle, Ang II increased MAP, renal vascular resistance (RVR) and the excretion of TxB2 factored by GFR. A PGH2-TxA2 receptor antagonist, SQ-29,548, or three days of pretreatment with a TxA2 synthase inhibitor UK-38,485, which reduced excretion of TxB2 by 80%, blunted the rise in MAP and RVR induced by Ang II. In contrast, three days of pretreatment with indomethacin did not alter the renal vascular response to Ang II. For series 2, groups of rats received Ang II at a higher rate (500 ng.kg-1.min-1) while the RPP was stabilized at +11 to +15 mm Hg with a suprarenal aortic clamp. SQ-29,548 and UK-38,485 both prevented Ang II-induced reductions in GFR and blocked 80% of the increase in RVR. For series 3, infusions of phenylephrine at an equipressor dose to series 2 of 30 micrograms.kg-1.min-1 with control of RPP at +14 mm Hg also increased RVR but this was not blunted by SQ-29,548.. 1.) infusion of Ang II increases excretion of filtered TxB2, causes dose-dependent increases in RVR and, at high doses, reduces GFR.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Angiotensin II; Animals; Blood Pressure; Bridged Bicyclo Compounds, Heterocyclic; Fatty Acids, Unsaturated; Hemodynamics; Hydrazines; Imidazoles; Male; Rats; Rats, Inbred Strains; Receptors, Prostaglandin; Receptors, Thromboxane; Renal Circulation; Thromboxane A2; Thromboxane-A Synthase; Vascular Resistance

1. Biochemical mechanisms of ischaemia were investigated in rabbit skin flaps subjected to 2 h of primary ischaemia then, 24 h later, to 4 h of secondary ischaemia. During secondary ischaemia, flaps underwent either total ischaemia (arterial and venous blood supply occluded) or partial ischaemia (vein only occluded). Some of these flaps were treated at the time of reperfusion with the free-radical scavenger superoxide dismutase (EC 1.15.1.1) and/or the thromboxane synthetase inhibitor UK-38,485. 2. After 30 min of reperfusion, superoxide dismutase treatment significantly reduced blood thromboxane levels, elevated during ischaemia. Superoxide dismutase also reduced tissue levels of malonyldialdehyde and xanthine oxidase, indicators of free-radical damage, and restored the depleted tissue levels of superoxide dismutase. 3. UK-38,485 treatment failed to significantly alter any of these tissue free-radical parameters, although this agent significantly reduced blood thromboxane levels. 4. Combined superoxide dismutase plus UK-38,485 treatment was not significantly better than either treatment alone with respect to any parameter. 5. Partial ischaemia led to consistently higher levels of tissue free radicals and blood thromboxane than did total ischaemia. Thus partial ischaemia appears to result in greater free-radical damage than total ischaemia. 6. These results are consistent with the hypothesis that thromboxane acts as a mediator for free-radical damage in the ischaemic changes within the flap.

Topics: Animals; Free Radical Scavengers; Free Radicals; Imidazoles; Ischemia; Rabbits; Reperfusion Injury; Skin; Surgical Flaps; Thromboxane A2; Thromboxane B2; Thromboxane-A Synthase

Studies were designed to test the role of the endothelium and endogenous release of thromboxane (Tx) A2 in the contractile response of rat thoracic aortic rings to the TxA2/prostaglandin (PG) H2 mimetic, U-46,619. U-46,619 caused a dose-dependent contraction of rings with endothelium (mean ED50 = 6.54 +/- 3.02 x 10(-9) M; n = 13) which was abolished by the TxA2/PGH2 receptor antagonist, SQ-29,548. Removal of endothelium greatly potentiated (P less than .05) the contractile response to U-46,619 (ED50 = 4.78 +/- 2.14 x 10(-10) M; n = 14). On addition to the organ bath, oxyhemoglobin (10(-6) M), an inhibitor of endothelium-derived relaxing factor, increased vascular smooth muscle contraction in response to U-46,619 and abolished the difference in response between rings with endothelium (ED50 = 6.63 +/- 0.38 x 10(-11) M) and those without (ED50 = 5.13 +/- 0.18 x 10(-11) M). Vascular contraction with U-46,619 (10(-7] was associated with release of immunoreactive TxB2 and 6-keto PGF1 alpha as well as increased conversion of [14C]arachidonate to [14C]TxB2 and 6-keto-[14C]PGF1 alpha. To test the role of endogenous TxA2 in response to U-46,619, the TxA2 synthetase inhibitor UK-38,485 (10(-6) M) was added directly to the organ bath; this diminished (P less than .05) the contractile responses to U-46,619 of rings with and without endothelium.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Animals; Aorta, Thoracic; Endothelium, Vascular; Imidazoles; In Vitro Techniques; Male; Nitric Oxide; Prostaglandin Endoperoxides, Synthetic; Rats; Rats, Inbred Strains; Thromboxane A2; Thromboxane-A Synthase; Vasoconstriction

Previous studies have documented the phasic pulmonary vascular response to infused Escherichia coli endotoxin in unanesthetized sheep. Cyclooxygenase inhibition attenuates the initial vasoconstrictive phase (phase I) but not the late phase of increased microvascular permeability (phase II). We undertook to selectively inhibit thromboxane A2 synthesis and assess the pulmonary microvascular response to endotoxin. Twelve paired studies were carried out in six sheep prepared with chronic lung lymph fistulas and pressure monitoring catheters. Each sheep received E. coli endotoxin (0.5 microgram/kg) at time 0, both alone (control group) and 1 hr after pretreatment with a thromboxane synthetase inhibitor (UK-38485, 2 mg/kg). The animals were monitored for 1-2 hr prior to and 5 hr following endotoxin infusion to ensure a steady-state baseline and a complete late response. The pairs of studies were done in random order. In the presence of UK-38485, endotoxin caused significantly less pulmonary hypertension and shorter duration of leukopenia and lower lung lymph flow and lymph protein clearance rates than did endotoxin alone. The differences in lymph protein clearance were more pronounced in phase II. These data suggest that both the vasoconstrictive and permeability phases of the pulmonary vascular response to endotoxin may be modified on endogenous thromboxane A2.

Topics: Animals; Blood Pressure; Blood Proteins; Capillary Permeability; Endotoxins; Escherichia coli; Imidazoles; Leukocyte Count; Lung; Lymph; Metabolic Clearance Rate; Proteins; Pulmonary Artery; Sheep; Thromboxane A2; Thromboxane-A Synthase

Plasma thromboxane concentrations were found to be significantly elevated in acute necrotizing pancreatitis in rats, whereas prostaglandin I2 levels were not. The significance of these alterations was investigated. Pancreatitis was induced by injecting 5% sodium taurocholate into the pancreatic duct. Iloprost (ZK 36374, a stable analog of prostaglandin I2, 25 ng/kg body weight) decreased the mortality rate from 100% to 50%. When treatment with iloprost was combined with simultaneous administration of either Sibelium (flunarizine R 14,950, 0.2 mg/kg body weight) or dazmegrel (UK 38,485, 50 mg/kg body weight) an additional decrease in the mortality rate was recorded. Dazmegrel is a selective thromboxane A2 synthetase inhibitor and flunarizine (a calcium entry blocker) also inhibits the effects of elevated thromboxane A2 levels. With flunarizine and iloprost the mortality rate was 40% (P less than 0.05); with dazmegrel and iloprost it was 10% (P less than 0.01). The results of the present study suggest that thromboxane A2 and prostaglandin I2 play a role in the course of acute necrotizing pancreatitis.

Topics: Acute Disease; Animals; Epoprostenol; Flunarizine; Iloprost; Imidazoles; Male; Necrosis; Pancreas; Pancreatitis; Rats; Rats, Inbred Strains; Thromboxane A2; Vasodilator Agents

We studied the formation of cyclo-oxygenase products in a rat model of mesangial cell injury, in order to determine a possible role of prostaglandin E2 (PGE2), prostaglandin I2 (determined as 6-keto-PGF1 alpha and thromboxane A2 (TxA2) in immune-mediated glomerular disease. Selective immune-mediated mesangial cell injury was induced by i.v. administration of a rabbit anti-rat thymocyte antiserum (ATS). Intravenous ATS leads to immune deposits in the mesangium followed by mesangiolysis and the infiltration of polymorphonuclear granulocytes and monocytes. Glomerular TxB2 formation two hours (292 +/- 27 pg/mg/min) and 48 hours (396 +/- 69 pg/mg/min) following antibody was significantly (P less than 0.05) higher compared to animals receiving non-antibody rabbit IgG (TxB2: 2 hr 143 +/- 13; 48 hr 171 +/- 32 pg/mg/min). Treatment with cobra venom factor (CVF) and the reduction of glomerular monocyte infiltration inhibited the increase of glomerular TxB2 formation significantly. Depletion of granulocytes with a rabbit anti-rat granulocyte serum had no effect on glomerular prostanoid formation following ATS. Glomerular PGE2 and 6-keto PGF1 alpha production was not altered following ATS. Inulin clearance in rats with immune-mediated mesangial cell injury was significantly (P less than 0.001) lower at two hours (456 +/- 24 microliters/min/100 g body wt) and 48 hours (433 +/- 54 microliters/min/100 g body wt) compared to their corresponding control animals which were treated with non-antibody IgG (2 hr: 914 +/- 51; 48 hr: 694 +/- 79 microliters/min/100 g body wt).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Antilymphocyte Serum; Complement Activation; Dinoprostone; Epoprostenol; Glomerular Filtration Rate; Glomerular Mesangium; Glomerulonephritis; Imidazoles; Indomethacin; Male; Rats; Rats, Inbred Lew; Rats, Inbred Strains; T-Lymphocytes; Thromboxane A2; Thromboxane B2; Thromboxane-A Synthase

This study was designed to contrast the effects of prolonged treatment with a thromboxane (Tx) synthase inhibitor (UK 38485 or SC 41156) and a Tx receptor antagonist (SQ 29548) on the development of angiotensin II (Ang II)-salt-induced hypertension. Ang II infusion (125 ng/min i.p. for 12 days) in rats drinking 0.15 M NaCl resulted in severe hypertension accompanied by proteinuria, reduction of urinary creatinine excretion and augmentation of urinary TxB2 excretion and TxB2 release from aortic rings and renal cortex slices. In saline-drinking rats undergoing Ang II infusion, the concomitant administration by gavage of UK 38485 (100 mg/kg/day) or SC 41156 (25 mg/kg/day) reduced serum and urinary TxB2 and TxB2 release from aortic rings and/or renal cortex slices, but it was without effect on the development of hypertension. In contrast, concomitant infusion of SQ 29548 (4.2 mg/24 hr s.c.) significantly attenuated the increase of blood pressure produced by the infusion of Ang II in saline-drinking rats. This effect of SQ 29548 may be the consequence of blockade of the actions of one or more endogenous eicosanoids that increase blood pressure by a mechanism(s) involving interaction with TxA2 receptors. This implies that pressor eicosanoids play a contributory role in the development of severe Ang II-salt hypertension.

Topics: Angiotensin II; Animals; Blood Pressure; Bridged Bicyclo Compounds, Heterocyclic; Fatty Acids, Unsaturated; Hydrazines; Hypertension; Imidazoles; Male; Rats; Rats, Inbred Strains; Receptors, Prostaglandin; Receptors, Thromboxane; Sodium Chloride; Thromboxane A2; Thromboxane-A Synthase

To determine whether the increased renal biosynthesis of thromboxane A2 observed in young genetically hypertensive rats of the Lyon strain could be involved in the development of their hypertension, Lyon hypertensive female rats received either thromboxane synthetase inhibitors (Dazmegrel or OKY 046) or a thromboxane A2 receptor antagonist (AH 23848) during their prehypertensive stage. Treatment from 5 to 9 weeks of age with Dazmegrel failed to reduce systolic blood pressure. When given from 3 to 9 weeks of age, Dazmegrel and OKY 046 induced a similar progressive and specific reduction (60%) in the urinary excretion of thromboxane B2 that was associated with a transient decrease in blood pressure level with Dazmegrel and a longer lasting blood pressure-lowering effect with OKY 046. AH 23848, given according to the same schedule, normalized the blood pressure level. This effect persisted 1 week after the cessation of the treatment. Interestingly, active doses of thromboxane synthetase inhibitors or of thromboxane A2 receptor blocker required a 3-week delay to exhibit their antihypertensive properties. It is concluded that 1) the elevated production of thromboxane A2 observed in young Lyon hypertensive rats is likely to participate actively in their blood pressure regulation and 2) this effect may be independent of its direct vasoconstrictor properties.

Topics: Animals; Biphenyl Compounds; Female; Hypertension; Imidazoles; Methacrylates; Rats; Rats, Mutant Strains; Receptors, Prostaglandin; Receptors, Thromboxane; Thromboxane A2; Thromboxane-A Synthase

1. Administration of bradykinin caused dose-dependent vasoconstriction in rat isolated perfused mesenteric arteries precontracted with noradrenaline. 2. The vasoconstrictor response was not mediated by BK1-bradykinin receptors. 3. Inhibition of cyclo-oxygenase with indomethacin, aspirin or meclofenamate abolished the vasoconstrictor effect of bradykinin, showing that a member of the arachidonic acid cascade may be involved. 4. Inhibitors of thromboxane synthesis (imidazole and UK 38485) did not affect or only reduced the bradykinin-induced vasoconstriction. 5. The endoperoxide H2/thromboxane A2 receptor antagonist SQ 29548 significantly reduced the vasoconstrictor effect of bradykinin, but did not affect the vasoconstrictor response to noradrenaline, adrenaline, vasopressin, 5-hydroxytryptamine or prostaglandins. 6. The eicosanoid(s) that mediate bradykinin-induced vasoconstriction appear to be synthesized outside the arterial endothelium. 7. The data suggest that the vasoconstrictor effect of bradykinin in the rat isolated mesenteric artery is mediated by vasoconstrictor arachidonic acid metabolites including the cyclic endoperoxides and/or the thromboxanes.

Topics: Animals; Aspirin; Bradykinin; Bridged Bicyclo Compounds, Heterocyclic; Cyclooxygenase Inhibitors; Eicosanoids; Endothelium, Vascular; Fatty Acids, Unsaturated; Hydrazines; Imidazoles; In Vitro Techniques; Indomethacin; Meclofenamic Acid; Mesenteric Arteries; Norepinephrine; Rats; Receptors, Prostaglandin; Receptors, Thromboxane; Thromboxane A2; Thromboxane-A Synthase; Vasoconstriction

Oxygenated metabolites of arachidonic acid (AA) are produced by the alveolar macrophage (AM) and have been shown to mediate inflammatory reactions. We therefore assessed the production of eicosanoids by AM harvested from the lungs of rats exposed to a bituminous coal dust for 2 wk in an inhalation chamber in order to determine if AA metabolism was altered in a manner that may promote an inflammatory response in the lung. Exposure to coal dust resulted in a 66% increase in the number of AM harvested, an increase in thromboxane A2 (TxA2) and leukotriene B4 (LTB4) production to 222% and 181% of control values, respectively, and a decrease in prostaglandin E2 (PGE2) production to 62% of control values. In AM harvested from rats allowed to breath clean air for 2 wk following coal dust exposure, PGE2 production returned to control levels but TxA2 and LTB4 production remained elevated. The TxA2 synthesis inhibitor UK 38,485 reduced TxA2 production in dust-exposed AM both immediately and 2 wk following exposure. Thus, exposure of rats to coal dust significantly alters the metabolism of AA in AM, with potentially important aspects of AA metabolism remaining altered even after a 2-wk recovery period. Based on the established role of eicosanoids in inflammatory and fibrotic processes, these results suggest that the alteration of AM eicosanoid production as a result of the inhalation of coal mine dust may be an important factor in the pathophysiology of coal workers' pneumoconiosis.

Topics: Animals; Arachidonic Acid; Arachidonic Acids; Chromatography, High Pressure Liquid; Coal; Dinoprostone; Dust; Eicosanoids; Female; Imidazoles; Leukocyte Count; Leukotriene B4; Macrophages; Pulmonary Alveoli; Rats; Thromboxane A2; Thromboxane-A Synthase

This study was designed to assess the contribution of thromboxane (Tx) A2 to the pathogenesis of renal dysfunction in rats with angiotensin II (Ang II)-salt hypertension. Hypertension was induced in rats drinking 0.15 mol/l NaCl by infusion of Ang II (125 ng/min, intraperitoneally) for 12 days. Relative to values in water- and saline-drinking rats without Ang II infusion, rats with Ang II-salt hypertension exhibited increased renal vascular resistance, decreased renal blood flow, and increased renal excretion and glomerular synthesis of TxB2. Treatment with an inhibitor of TxA2 synthesis, UK 38,485, had no effect on renal function in normotensive and hypertensive rats. Similarly, the TxA2 and prostaglandin endoperoxide antagonist SQ 29,548 did not affect renal function in normotensive rats. In contrast, in rats with Ang II-salt hypertension of 12 days' duration, SQ 29,548 caused a reduction in renal vascular resistance, allowing for maintenance of renal blood flow in the face of an accompanying reduction in blood pressure. A comparable reduction in renal perfusion pressure, produced by constriction of the abdominal aorta above the renal arteries, was not accompanied by a reduction in renal vascular resistance in Ang II-salt hypertensive rats. Therefore, the SQ 29,548-induced lowering of renal vascular resistance is attributable not to renal blood flow autoregulation, but to blockade of the renal vasoconstrictor actions of TxA2 and/or prostaglandin endoperoxides. This interpretation implies that pressor eicosanoids contribute to increase renal vascular resistance in rats with severe Ang II-salt hypertension.

Topics: Angiotensin II; Animals; Bridged Bicyclo Compounds, Heterocyclic; Fatty Acids, Unsaturated; Hydrazines; Hypertension; Imidazoles; Kidney; Male; Rats; Rats, Inbred Strains; Sodium, Dietary; Thromboxane A2; Thromboxane-A Synthase; Vascular Resistance

The effect of platelet activating factor (PAF) on the generation of cyclo-oxygenase-derived arachidonic acid metabolites was examined on purified eosinophils harvested from the peritoneal cavity of male guinea pigs. PAF produced a concentration-dependent increase in the amount of immunoreactive thromboxane B2 (TXB2) and PGE1/E2 released from these inflammatory cells at a relative molar ratio of 30:1. The EC50 of PAF was 20 to 40 nM and maximum stimulation (4.5-fold) of both prostanoids occurred at 1 microM PAF. The ability of PAF to generate TXA2 was rapid (t 1/2 = 9 s), transient (40 s), noncytotoxic, and noncompetitively antagonized by the PAF-receptor blocking drug, WEB 2086. On an equimolar (100 nM) basis, PAF was significantly more effective than C5a, fMLP, and PMA at stimulating TXB2 release but markedly less potent than the calcium ionophore, calcimycin. Pretreatment of eosinophils with the cyclo-oxygenase inhibitor flurbiprofen (8 microM for 5 min) abolished the ability of PAF to promote both TXB2 and PGE1/E2 release. Likewise, dazmegrel (50 microM for 5 min), a selective inhibitor of thromboxane synthetase, abolished PAF-stimulated TXB2 release but markedly augmented the elaboration of PGE1/E2. Inhibition of cyclo-oxygenase with flurbiprofen affected neither the ability of PAF to elevate the intracellular calcium ion concentration (measured by fura-2 fluorescence) nor its appetency to generate superoxide anions at any PAF concentration examined. It is concluded that activation of guinea pig eosinophils by PAF is receptor-mediated and independent of the concomitant generation of cyclo-oxygenase-derived excitatory prostanoids. Inasmuch as TXA2 may contribute to the pathogenesis of bronchial hyperreactivity, then these data implicate the eosinophil as a potential source of this lipid mediator.

Topics: Animals; Azepines; Calcimycin; Calcium; Complement C5a; Cyclooxygenase Inhibitors; Enzyme Activation; Eosinophils; Flurbiprofen; Guinea Pigs; Imidazoles; In Vitro Techniques; N-Formylmethionine Leucyl-Phenylalanine; Platelet Activating Factor; Platelet Membrane Glycoproteins; Prostaglandin-Endoperoxide Synthases; Prostaglandins E; Receptors, Cell Surface; Receptors, G-Protein-Coupled; Superoxides; Tetradecanoylphorbol Acetate; Thromboxane A2; Thromboxane B2; Thromboxane-A Synthase; Triazines; Triazoles

The role of thromboxane A2(Tx) in mediating the pressor response to angiotensin II (AII) was studied in anesthetized rats. Intravenous AII (500 ng/kg/min) increased mean arterial pressure (MAP) by 35 +/- 3 mm Hg and increased the excretion of prostaglandin PGE2, the metabolites of prostacyclin (6kPGF1 alpha) and Tx (TxB2) (P less than .05). A similar pressor infusion of the alpha 1-adrenoreceptor agonist phenylephrine (PE) increased the excretion of PGE2 and 6kPGF1 alpha but not TxB2. The increases in MAP and prostaglandin excretion produced by AII were reversed by the AII-receptor antagonist saralasin (10 micrograms/kg/min) while those produced by PE were reversed by the alpha-adrenoreceptor antagonist phenoxybenzamine (250 micrograms/kg). The Tx receptor antagonist, SQ-29,548 (8 mg/kg) attenuated (P less than .0001) the AII-induced rise in MAP (13 +/- 1 mm Hg) but did not modify the pressor response to PE. The Tx synthetase inhibitor, UK-38,485 (50 mg/kg/d) given for 3 days, reduced basal TxB2 excretion by 75% and also attenuated (P less than .001) the AII-induced rise in MAP (11 +/- 2 mm Hg). However, when given 40 min before the AII infusion, UK-38,485 did not attenuate the pressor response. In separate groups of rats, the log dose-response curve for bolus intravenous injection of AII was shifted to the right by SQ-29,548 while that for PE was unaffected.. 1) AII releases Tx; 2) Tx release is not secondary to hypertension; and 3) Tx can mediate up to two-thirds of the short-term pressor response to high-dose AII infusion.

Topics: Angiotensin II; Animals; Blood Pressure; Bridged Bicyclo Compounds, Heterocyclic; Dinoprostone; Dose-Response Relationship, Drug; Fatty Acids, Unsaturated; Hydrazines; Imidazoles; Infusions, Intravenous; Male; Phenoxybenzamine; Phenylephrine; Pressoreceptors; Rats; Rats, Inbred Strains; Saralasin; Thromboxane A2; Thromboxane-A Synthase; Thromboxanes; Urine

The endogenously produced cytokine, tumor necrosis factor-alpha (TNF-alpha), has been shown in adult animal models to be associated with many of the pathophysiologic effects of sepsis, including systemic hypotension and hemorrhagic necrosis. TNF-alpha can induce the release of various vasoactive arachidonic acid metabolites, suggesting that TNF-alpha may act either directly or via intermediary substances in producing its effects. The pathophysiologic role of TNF-alpha in neonatal sepsis, especially its potential effect on pulmonary vascular tone, is presently unknown. To assess the role of TNF-alpha in neonatal sepsis, 19 piglets (19 +/- 5 d old) were anesthetized, intubated, paralyzed, mechanically ventilated, and catheterized to assess pulmonary and systemic vascular hemodynamics and pulmonary gas exchange. The multiple inert gas elimination technique was used to assess ventilation perfusion matching. A 30-min infusion of human recombinant TNF-alpha (250 micrograms/kg total dose) was administered to animals pretreated with either 10 mg/kg dazmegrel, a thromboxane synthase inhibitor (n = 9) or placebo (n = 10). TNF-alpha alone induced a prompt and sustained rise in pulmonary arterial pressure and pulmonary vascular resistance that continued at least for 2 h after onset of the infusion. In contrast, the animals pretreated with dazmegrel demonstrated no rise in pulmonary vascular resistance until 2 h after the onset of the infusion. Neither group of animals demonstrated a significant decline in arterial PO2 or evidence from inert gas analysis of VA/Q mismatching or increase in intrapulmonary shunt.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Hemodynamics; Hypertension, Pulmonary; Imidazoles; Infusions, Intravenous; Premedication; Pulmonary Gas Exchange; Swine; Thromboxane A2; Thromboxane-A Synthase; Tumor Necrosis Factor-alpha

Urinary TXB2 excretion and the release of TXB2 from vascular and renal cortical tissues are increased in rats with severe AII-salt hypertension. Treatment with an inhibitor of TXA2 synthesis did not change the blood pressure of normotensive or of AII-salt hypertensive rats. Treatment with SQ29,548, a TXA2 receptor antagonist, caused reduction of blood pressure and renal vascular resistance in AII-salt hypertensive but not in normotensive rats. We conclude that the SQ29,548-induced lowering of blood pressure and renal vascular resistance in AII-salt hypertensive rats is the result of blockade of the vascular actions of one or more pressor eicosanoids including TXA2 and the prostaglandin endoperoxides. A corollary of this conclusion is that pressor eicosanoids may be contributory factors in the pathogenesis of severe AII-salt hypertension in rats.

Topics: Angiotensin II; Animals; Blood Pressure; Bridged Bicyclo Compounds, Heterocyclic; Fatty Acids, Unsaturated; Hydrazines; Hypertension; Imidazoles; In Vitro Techniques; Kidney; Kidney Cortex; Muscle, Smooth, Vascular; Rats; Reference Values; Sodium, Dietary; Thromboxane A2; Thromboxane B2; Thromboxane-A Synthase

The tubuloglomerular feedback (TGF) system is less sensitive after extracellular volume expansion (VE). In rats with partial ureteral obstruction, however, we have previously found increased TGF sensitivity during such expansion. Thromboxane A2 (TXA2) has been reported to be increased in the hydronephrotic kidney, and the present study was undertaken to investigate whether TXA2 might be responsible for these findings. The TGF characteristics were studied, by means of the stop-flow technique, in control and hydronephrotic rats before and after intravenous injection of either a thromboxane synthetase inhibitor or a thromboxane receptor antagonist during hydropenia. After VE, TGF was studied again. Proximal tubular stop-flow pressure (Psf) was measured during perfusion of the loop of Henle with a modified Ringer's solution, the maximal response (delta Psf) to an increased tubular flow rate was determined and the tubular perfusion rate which elicited a half-maximal decrease in Psf, designated the turning point, was recorded. In hydropenic control or hydronephrotic animals, TXA2 did not permanently change the TGF characteristics. During VE of the TXA2-blocked hydronephrotic animals, blocked both with synthetase inhibitor or receptor-antagonist, TGF was reset to a lower sensitivity like VE controls, as indicated by a high turning point and a low delta Psf. It was therefore concluded that thromboxane A2 inhibition does not influence the TGF system in hydropenia, but that the production of thromboxane A2 is responsible for the resetting of the TGF system during VE in hydronephrotic animals.

Topics: Animals; Carbazoles; Extracellular Space; Feedback; Hydronephrosis; Imidazoles; Indomethacin; Kidney Glomerulus; Kidney Tubules; Rats; Rats, Inbred Strains; Thromboxane A2

Thromboxane A2 (TXA2) synthesis in rabbit and human platelet rich plasma (PRP) was inhibited in a dose-dependent manner by UK-38485 (dazmegrel) when the PRP was aggregated with collagen, arachidonic acid and ADP. The level of inhibition was time-dependent. That is, the dose-response curves shifted to lower concentrations with increasing incubation times with UK-38485 prior to addition of aggregation agents. Following bolus intravenous injections of UK-38485 in rabbits, the elimination from serum fitted a 3-exponential curve. The terminal elimination phase had a half-life of 69.8 +/- 3.8 min. Oral treatment of rabbits with UK-38485 for 2 weeks showed that animals with serum concentrations of 0.358 +/- 0.091 microgram/ml of the inhibitor had TXA2 synthesis inhibited in serum by 83.8 +/- 7.1%. This corresponded to animals which were treated with 20 mg/kg/day of the inhibitor.

Topics: Administration, Oral; Animals; Half-Life; Humans; Imidazoles; In Vitro Techniques; Indicators and Reagents; Injections, Intravenous; Male; Platelet Aggregation; Rabbits; Thromboxane A2; Thromboxane-A Synthase

The effect of the thromboxane synthesis inhibitor UK 38485 on glomerular filtration rate (GFR) and proteinuria was evaluated in a rat model of unilateral membranous nephropathy. Two and 24 hours following perfusion of kidneys with cationized human IgG and i.v. administration of anti-human IgG-antiserum (in situ ICGN), glomerular thromboxane B2 (TxB2) formation was significantly higher (2 hr: 448 +/- 116 pg/mg protein/min; 24 hr: 173 +/- 21 pg/mg protein/min) compared to control (C) kidneys (2 hr: 173 +/- 21 pg/mg protein/min, P less than 0.005; 24 hr: 154 +/- 17 pg/mg protein/min, P less than 0.025). Two and seven days after induction of ICGN these differences were no longer present. Pretreatment with the thromboxane synthesis inhibitor UK 38485 prevented the decrease in GFR, which occurred two hours after induction of the glomerular disease (without UK: 161 +/- 31; with UK 325 +/- 21 microliters/100 g body wt/min). This UK 38485 effect on GFR was no longer detectable at 24 hours, two days and seven days. Initiation of glomerular immune injury was followed by significant proteinuria which averaged 250 +/- 85 mg/24 hr at day two. UK 38485 treatment, which reduced TxB2 formation in isolated glomeruli by 90% did not influence proteinuria. These data demonstrate that induction of heterologous, in situ immune complex glomerulonephritis stimulates glomerular thromboxane B2 formation, an effect which partially modulates the decrease in GFR at two hours. Thromboxane, however, does not seem to play a role in the mediation of proteinuria in this animal model.

Topics: Animals; Glomerular Filtration Rate; Glomerulonephritis, Membranous; Imidazoles; Proteinuria; Rats; Thromboxane A2; Thromboxane B2; Thromboxane-A Synthase; Time Factors

Some studies have indicated that PGs can modulate the single nephron tubuloglomerular feedback (TGF) response. The aim of this study was to define the specific role of the vasoconstrictor PG, TX, by administration to rats of either vehicle (group 1; n = 20) or drugs that inhibit either cyclooxygenase (indomethacin [indo], 5 mg.kg-1, group 2, n = 17), TX synthetase (UK-38,485 [UK], 100 mg.kg-1, group 3, n = 19), or TX receptors (SQ-29,548 [SQ], 8 mg.kg-1, group 4, n = 14, or L-641,953 [L], 50 mg.kg-1, group 5, n = 8). Indo reduced excretion of the prostacyclin derivative 6-keto-PGF1 alpha and TXB2 and lowered whole kidney GFR and renal plasma flow, whereas UK lowered excretion of TXB2 only and did not change basal renal hemodynamics. The TGF response (assessed from reduction in proximal tubule stop-flow pressure (Psf, mmHg) during increases in perfusion of the loop of Henle (LH) from 0 to 40 nl.min-1) was unchanged after vehicle (9.8 +/- 0.5-10.9 +/- 1.0, NS) but blunted (P less than 0.001) by 40-65% in rats of groups 2-5 (indo, 11.1 +/- 1.0-4.4 +/- 0.7; UK, 9.0 +/- 0.8-4.8 +/- 0.7; SQ, 10.3 +/- 0.6-4.8 +/- 0.6; L, 10.7 +/- 0.5-6.7 +/- 1.3). This blunting was due to lower values for Psf at zero LH flow after indo, SQ, and L, and higher values of Psf at 40 nl.min-1 LH flow after indo and UK. The fall in single nephron GFR (SNGFR, nl.min-1) with increasing LH perfusion was unchanged after vehicle (10.9 +/- 2.8-11.2 +/- 0.8) but was blunted (P less than 0.05) by 45-55% in rats given indo (13.9 +/- 1.2-6.2 +/- 2.2) or UK (12.8 +/- 2.1-7.0 +/- 1.5). UK produced dose-dependent reductions in TXB2 excretion (IC50, 15 mg.kg-1) and inhibition of the TGF response (IC50: 30 mg.kg-1). After blockade of TX receptors by SQ, UK had no further affect on the TGF response. The fall in Psf at high LH flow was blunted (P less than 0.05) by indo and UK, whereas the rise in Psf at zero LH flow was blunted by indo, SQ, and L. In conclusion, endogenous TX generation can modulate the reductions in Psf and SNGFR during increased delivery of NaCl to the LH.

Topics: Analysis of Variance; Animals; Blood Pressure; Bridged Bicyclo Compounds, Heterocyclic; Cyclooxygenase Inhibitors; Dose-Response Relationship, Drug; Fatty Acids, Unsaturated; Glomerular Filtration Rate; Hydrazines; Hydrostatic Pressure; Imidazoles; Indomethacin; Kidney Glomerulus; Kidney Tubules; Male; Prostaglandins F; Rats; Rats, Inbred Strains; Receptors, Prostaglandin; Receptors, Thromboxane; Thromboxane A2; Thromboxane B2; Thromboxane-A Synthase

The aim of the present study was to explore the possible involvement of thromboxane A2(TxA2) in the development of cardiopulmonary dysfunction in experimental septic shock. Sepsis was induced in anesthetized cats by intravenous (i.v.) infusion of live Escherichia coli. One series (No. = 12) was pretreated with a specific TxA2 synthetase inhibitor, dazmegrel; another (No. = 8) served as a septic control series. In both series a systemic arterial hypotension developed after 2 hr; no differences in cardiac function were detected. After 2 hr bacteremia cardiac preload was increased by a rapid infusion of dextran. This showed that cardiac function was significantly more preserved in dazmegrel-pretreated cats compared with septic controls. Pretreatment with dazmegrel totally prevented the pulmonary vascular response to bacterial infusion. The pulmonary compliance decreased to 40% in controls but to only 75% in the dazmegrel series, and airway resistance increased to 300% and 140%, respectively. The ventilation-perfusion ratio was less impaired in the pretreated series. Pretreatment with dazmegrel abolished the increase in thromboxane B2 (TxB2), the stable metabolite of TxA2, seen in the untreated series. The rise in 6-keto-prostaglandin F1a (6-keto-PGF1a), the stable metabolite of prostaglandin I2PGI2, was evident in both series. We concluded that TxA2 is important for the impaired cardiac performance in septic shock. Furthermore, TxA2 is involved, but not as the only factor, in the development of pulmonary dysfunction.

Topics: Airway Resistance; Animals; Cats; Escherichia coli; Heart; Hemodynamics; Imidazoles; Lung; Lung Compliance; Shock, Septic; Thromboxane A2; Thromboxane B2; Thromboxane-A Synthase; Ventilation-Perfusion Ratio

A monoclonal antibody against thromboxane B2 which may be used in standard fluid phase radioimmunoassays with a detection limit of around 40 pg and a binding affinity of 1.98 X 10(9) M-1 is described. Limited crossreactivity could be observed only with structurally closely related compounds such as 2,3-dinor-thromboxane B2 (8.9%), thromboxane B1 (15.7%) and thromboxane B3 (39.7%). Detectable crossreactivity with 11-dehydro-thromboxane B2, omega-carboxy-thromboxane B2, omega-hydroxy-thromboxane B2, prostaglandins of the D-, E- and F-type as well as metabolites of prostacyclin was lacking. The monoclonal anti-thromboxane B2 antibody proved well suited for measuring the thromboxane B2 content in tissue culture supernatants as well as in human serum.

Topics: Animals; Antibodies, Monoclonal; Antibody Affinity; Antibody Specificity; Arachidonic Acid; Arachidonic Acids; Humans; Ibuprofen; Imidazoles; Immunoglobulin G; Indomethacin; Mice; Mice, Inbred BALB C; Platelet Aggregation; Radioimmunoassay; Thromboxane A2; Thromboxane B2

We tested the hypothesis that prostaglandins (PGs) and thromboxane (Tx) A2 are important mediators of the hemodynamic derangements occurring in a rabbit model of hyperdynamic endotoxicosis. Rabbits were injected with either normal saline (NS) or Escherichia coli lipopolysaccharide (LPS; 1-3 micrograms/kg) and studied 6 hr later. Cardiac index (CI) and regional blood flow were determined using thermodilution and radioactive microspheres, respectively. Systemic and regional hemodynamics were determined before and 40 min after administering indomethacin (cyclo-oxygenase inhibitor; 5 mg/kg), UK38485 (Tx synthetase inhibitor; 10 mg/kg), or NS. LPS increased CI (P = .0024) and decreased mean arterial pressure (P = .0031) and systemic vascular resistance index (P = .0001). LPS increased flow to the heart and small intestine and decreased flow to the hepatic artery and pancreas. The systemic and regional hemodynamic effects of indomethacin were similar in NS- and LPS-treated rabbits. UK38485 decreased perfusion of skeletal muscle and diaphragm in both endotoxemic and control animals. This agent increased splenic perfusion only in NS-treated rabbits. Plasma levels of 6-keto PGF1 alpha (PGI2 metabolite) were typically undetectable in both NS- and LPS-treated rabbits. These data do not support the hypothesis that PG's or TxA2 are major determinants of the hemodynamic perturbations that occur in this endotoxicosis model.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Cyclooxygenase Inhibitors; Disease Models, Animal; Endotoxins; Escherichia coli; Hemodynamics; Imidazoles; Indomethacin; Lipopolysaccharides; Male; Prostaglandins; Rabbits; Shock, Septic; Thromboxane A2; Thromboxane-A Synthase

This study was designed to assess the contribution of thromboxane A2 to high blood pressure in rats with angiotensin II (Ang II)-salt hypertension. Hypertension was induced in rats drinking 0.15 M NaCl by infusion of Ang II (125 ng/min i.p.) for 12 days. Relative to values in water-drinking rats without Ang II infusion, Ang II-salt hypertensive rats exhibited augmentation (p less than 0.05) of blood pressure (from 129 +/- 3 to 217 +/- 12 mm Hg), urinary thromboxane B2 excretion (from 5.4 +/- 0.9 to 25.4 +/- 2.1 ng/day), and thromboxane B2 release from renal cortex slices (from 71.3 +/- 6.7 to 121.1 +/- 14.4 pg/mg) and aortic rings (from 28.8 +/- 2.9 to 115.8 +/- 12.8 pg/mg). Treatment with an inhibitor of thromboxane A2 synthetase, UK 38485, had no effect on blood pressure in normotensive and Ang II-salt hypertensive rats. Treatment with a thromboxane A2 receptor blocker, SQ 29548, decreased blood pressure in Ang II-salt hypertensive rats from 191 +/- 9 to 152 +/- 9 mm Hg after 3 hours, but it had no effect on blood pressure in normotensive rats. Since SQ 29548 interfered with the pressor effects of the prostaglandin endoperoxide analogue U-46619, prostaglandin F2 alpha, and 9 alpha,11 beta-prostaglandin F2, we suggest that the SQ 29548-induced blood pressure reduction in Ang II-salt hypertensive rats is the manifestation of blockade of the vascular actions of one or more endogenous prostanoids including thromboxane A2 and prostaglandin endoperoxides. If so, pressor prostanoids may be contributory factors in the pathogenesis of severe Ang II-salt hypertension in rats.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Angiotensin II; Animals; Arteries; Bridged Bicyclo Compounds, Heterocyclic; Dinoprost; Fatty Acids, Unsaturated; Hydrazines; Hypertension; Imidazoles; Kidney Cortex; Male; Prostaglandin Endoperoxides; Prostaglandin Endoperoxides, Synthetic; Prostaglandins F; Rats; Rats, Inbred Strains; Sodium Chloride; Thromboxane A2; Thromboxane B2; Thromboxane-A Synthase

1. Increased local thromboxane (Tx) formation has been considered to be a contributing factor in digitalis-induced arrhythmias. 2. A potent Tx synthetase inhibitor (TxSI), UK 38,485 (0.1, 1.0 or 10.0 mg/kg per h, administered intravenously) and a Tx receptor antagonist (TxRA), ICI 185,282 (1, 2 or 10 mg/kg bolus and 1, 2 or 10 mg/kg per h, administered intravenously) were tested for their ability to reduce digoxin-induced arrhythmias in anaesthetized guinea-pigs. 3. Electrocardiograms, mean blood pressure, heart rate and arrhythmias were recorded, starting 30 min before digoxin administration and continued for 60 min afterwards. 4. ICI 185,282, at the doses used, significantly delayed the time of onset of arrhythmias, and reduced the incidence of ventricular fibrillation, mortality and arrhythmia score. In contrast, UK 38,485 was found to be effective on all measured variables only at the dose rate of 1.0 mg/kg per h, except for time required for the development of arrhythmias. These protective effects of both TxSI and TxRA were not found to be dose-dependent. 5. Arterial blood pressure and heart rate changes caused by either UK 38,485 or ICI 185,282 infusions did not have any marked effects on digoxin-induced arrhythmias. 6. These data suggest that endogenously released TxA2 and prostaglandin endoperoxides may play an important role in digoxin-induced arrhythmias in guinea-pigs.

Topics: Anesthesia; Animals; Arrhythmias, Cardiac; Blood Pressure; Digoxin; Dioxanes; Dioxins; Dose-Response Relationship, Drug; Electrocardiography; Female; Guinea Pigs; Imidazoles; Male; Thromboxane A2; Ventricular Fibrillation

The circulating prostaglandins have been implicated as mediators of microcirculatory derangements in skin and skin-muscle flaps. The study described here investigated the roles of thromboxane A2 and prostacyclin, measured as thromboxane B2 (TxB2) and prostaglandin 6-keto-F1a (PGF1a), in ischemic skin flaps, and the effects of thromboxane synthetase inhibition on flap blood flow and survival. A canine ventral island flap model was used to measure the appearance of TxB2 and PGF1a in the central arterial and venous plasma, and in the tissue and venous effluent of acutely raised flaps; with and without pretreatment with the specific thromboxane A2 synthetase inhibitor UK38485. Prostaglandin levels change significantly during flap elevation, and can be modified beneficially by thromboxane A2 synthetase inhibition, causing dramatic increases in flap blood flow and survival, as predicted by intravital dye penetration. The results presented in this article suggest that the manipulation of these compounds may provide a method of producing a pharmacological delay phenomenon and perhaps even allow effective intervention in the failing flap.

Topics: Animals; Dogs; Epoprostenol; Female; Imidazoles; Ischemia; Platelet Aggregation; Prostaglandins F; Skin; Surgical Flaps; Thromboxane A2; Thromboxane B2; Thromboxane-A Synthase

We have recently reported that infusion of stoichiometrically equal quantities of acid and base (neutral acid-base infusion) in the cat resulted in rapid, shallow breathing and in pulmonary hypertension (Orr et al., 1987). To investigate the mechanisms involved in these effects, we have measured in the anesthetized cat thromboxane (TX) B2 and 6-keto-prostaglandin (PG) F1 alpha, the stable metabolites of TXA2 and PGI2, in blood as well as cardiorespiratory parameters in response to neutral acid-base infusion. The first acid-base infusion prompted right ventricular blood pressure (Prv) to rise from 30 to a peak of about 55 mm Hg, with a concomitant rise in the right ventricular TXB2 level from below detection level to over 500 pg/ml. The second or third infusion evoked no (or small) rises in Prv and TXB2, individual values of Prv and TXB2 being tightly correlated. After blockade of TX synthesis by Dazmegrel, no changes were observed even at the first acid-base infusion in either Prv or TXB2. The TXA2 mimetic, U 46,619, caused Prv to rise with no change in TXB2, and this effect was repeatable. Increases were also observed in ventilation, particularly in respiratory rate. We conclude that acid exposure of blood stimulates TX synthesis and release from platelets, which in turn leads to pulmonary hypertension and to hyperventilation. The fact that these effects cannot be repeated within the same animal is due to a lack in TX release but not to a loss of responsiveness of the TX receptors in the lung.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; 6-Ketoprostaglandin F1 alpha; Animals; Blood Pressure; Cats; Female; Hydrochloric Acid; Imidazoles; Infusions, Intravenous; Male; Prostaglandin Endoperoxides, Synthetic; Pulmonary Circulation; Respiration; Thromboxane A2; Thromboxane B2; Thromboxane-A Synthase

The ontogeny of the renal response to continuous systemic infusion of atrial natriuretic peptide (ANP) was studied in chronically instrumented fetal, newborn, and adult nonpregnant sheep. Plasma immunoreactive ANP (ANPir) concentrations during low (0.025 microgram.kg-1.min-1) and high rate (0.1 microgram.kg-1.min-1) ANP infusion were similar between each group of animals. Decrease in renal blood flow velocity (RBFV) and rise in renal vascular resistance (RVR) were observed in fetal and newborn lambs during ANP infusion. The percent changes in RBFV and RVR were of significantly (P less than 0.05) greater magnitude during high ANP infusion rate in fetuses (-28.5 +/- 8.5 and 93 +/- 6.4%) than in adult sheep (-6.6 +/- 3.2 and -4.4 +/- 4.9%). ANP produced no changes in urine flow (V) in fetuses but increased V significantly in newborn lambs and adult sheep. Glomerular filtration rate increased significantly during ANP infusion in adult sheep but not in fetal and newborn lambs. Percentage changes in urinary excretion rate of Na (UNaV) during high ANP infusion rate were significantly higher in adult sheep (3,520 +/- 2,414%) than in newborn (157 +/- 106%) and fetal lambs (198 +/- 84%). These results suggest that the cardiovascular, renal hemodynamic, and possibly renal function responses to continuous ANP infusion increase during maturation, the overall response being larger in adult animals.

Topics: Animals; Homeostasis; Imidazoles; Indomethacin; Kidney Glomerulus; Kidney Tubules; Male; Masoprocol; Piroxicam; Prostaglandins; Prostaglandins, Synthetic; Rats; Rats, Inbred Strains; Thromboxane A2

Modification of the thromboxane: prostacyclin ratio alters the severity of reperfusion arrhythmias and postischemic damage in long-term, irreversibly injured myocardium. In this study, the effects of the thromboxane synthetase inhibitor dazmegrel and the thromboxane receptor antagonist BM 13.505 on myocardial postischemic functional recovery and preservation of tissue adenine nucleotides was examined after a 15-minute episode of ischemia followed by 3 hours of reperfusion (myocardial stunning). Dazmegrel (3 or 8 mg/kg) or BM 13.505 (10 mg/kg) was given 15 minutes before coronary occlusion and compared with a control group in barbital-anesthetized dogs. Regional segment shortening (percent segment shortening, sonomicrometry), regional myocardial blood flow (microspheres), and coronary venous eicosanoid and high-energy phosphate levels (biopsies after 3 hours of reperfusion) were measured. Areas at risk, regional myocardial blood flow, and regional segment shortening during coronary occlusion were similar in all groups. Dazmegrel (3 mg/kg) attenuated the decrease in endocardial and midmyocardial adenosine 5'-triphosphate, and both doses significantly improved regional segment shortening during reperfusion. Coronary venous thromboxane levels were significantly decreased throughout the experiment in both dazmegrel-treated groups, and thromboxane levels were significantly elevated in the control group 3 hours after reperfusion. Prostacyclin, measured in the form of its main metabolite, 6-keto-prostaglandin F1 alpha, did not change significantly in the control group throughout the experiment, but it was markedly increased in dazmegrel groups throughout reperfusion, particularly in the dazmegrel group receiving 3 mg/kg. BM 13.505 exerted no beneficial effects on postischemic function or metabolism. In conclusion, after a reversible ischemic insult, postischemic recovery of function and metabolic status was not enhanced by preocclusion treatment with a thromboxane receptor blocker, and thus, the beneficial effects of thromboxane synthesis inhibition on postischemic abnormalities was not due to a reduction in thromboxane but was the result of endoperoxide shunting and a subsequent increase in prostacyclin. Therefore, thromboxane does not appear to be an important mediator of reversible ischemia-reperfusion damage.

Topics: Animals; Coronary Circulation; Coronary Disease; Dogs; Energy Metabolism; Female; Heart; Hemodynamics; Imidazoles; Male; Myocardial Contraction; Phenylacetates; Phosphates; Prostaglandins; Sulfonamides; Thromboxane A2; Thromboxane-A Synthase

Thromboxane A2 is a prostanoid having potent platelet aggregatory and vasoconstrictor properties. To determine a possible role for thromboxane A2 in the development of severe hypertension and stroke, we chronically administered the selective thromboxane A2 synthase inhibitor UK-38,485 (Dazmegrel) to stroke-prone spontaneously hypertensive rats (SHRSP). Serum thromboxane B2 (the stable hydrolysis product of thromboxane A2) generation was significantly greater in incubates of whole blood from SHRSP than in those from normotensive control Wistar-Kyoto rats and was inhibited greater than 89% by UK-38,485 administered in vivo. In 10 male SHRSP fed a Japanese-style rat chow and given 1% NaCl in drinking water to accelerate the occurrence of stroke, treatment with 100 mg/kg/day UK-38,485 by gavage starting at 8.6 weeks of age diminished systolic blood pressure elevation at 10 (205 +/- 2 vs. 220 +/- 4 mm Hg, p less than 0.01) and 11 weeks of age (210 +/- 4 vs. 239 +/- 7 mm Hg, p less than 0.01) compared with 10 untreated SHRSP. The ultimate establishment of severe hypertension was not prevented by UK-38,485. Stroke-related mortality was 70% in both UK-38,485-treated and control SHRSP at 14 weeks of age. Histologic examination revealed cerebrovascular lesions consistent with the occurrence of stroke in both control and UK-38,485-treated SHRSP. Our results support a possible role for thromboxane A2 in the elevation of blood pressure in SHRSP but do not support a possible role for the prevention of stroke by thromboxane A2 synthase inhibition in these rats.

Topics: Animals; Blood Pressure; Brain; Cerebrovascular Disorders; Disease Susceptibility; Hypertension; Imidazoles; Male; Osmolar Concentration; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Thromboxane A2; Thromboxane B2

The effect of thromboxane A2 inhibitors and iloprost, a stable analogue of prostacyclin, on angiotensin II-induced oedema was studied in the isolated perfused rat lung. Angiotensin II, infused into the pulmonary artery, produced oedema of the lung, as evidenced by the increase in lung weight and in perfusion pressure. UK 38485, a thromboxane A2-synthetase inhibitor, and BM 13177, a thromboxane A2 receptor blocker, attenuated the oedema producing and vasoconstrictor effects of angiotensin II. A similar effect was obtained with iloprost at very low concentrations. Other agonists such as noradrenaline, phenylephrine and high K+ in the medium produced increases in perfusion pressure, but failed to elicit an increase in lung weight. Only serotonin, at relatively higher concentrations again increased lung weight, which was prevented by prior addition of UK 38485, BM 13177 and iloprost into the medium. These results were taken as an evidence indicating thromboxane A2 and prostacyclin-mediated effects of angiotensin II in the isolated perfused rat lung and the possible role of these unstable metabolites of arachidonic acid in the production of lung oedema.

Topics: Angiotensin II; Animals; Anti-Arrhythmia Agents; Blood Pressure; Catecholamines; Epoprostenol; Female; Iloprost; Imidazoles; In Vitro Techniques; Lung; Male; Organ Size; Pulmonary Edema; Rats; Serotonin; Thromboxane A2; Thromboxane-A Synthase

This study was undertaken to evaluate the efficacy of iloprost and UK 38485 in the prevention of gastric lesions due to restraint-cold stress, ethanol or indomethacin. Prior injection of iloprost to the rats significantly prevented the increase in ulcer index by restraint- cold stress or indomethacin but nonsignificantly reduced the ulcer index induced by ethanol. UK 38 485 at lower doses caused a highly significant decrease in the ulcer index induced by all noxious stimuli used in this study. UK 38 485 also reduced the increased 3H back diffusion due to restraint-cold stress. Higher doses of the compound, however, failed to decrease the mucosal damage due to restraint-cold stress. Combination of iloprost and UK 38 485 produced a further significant decrease in the ulcer index induced by all noxious stimuli and increased 3H back diffusion induced by restraint-cold stress. In relation to these results the importance of PGI2/TXA2 ratio in the production of gastric mucosal lesions is discussed.

Topics: Animals; Epoprostenol; Ethanol; Female; Gastric Mucosa; Iloprost; Imidazoles; Indomethacin; Male; Rats; Stomach Ulcer; Stress, Physiological; Thromboxane A2; Thromboxane-A Synthase

Topics: Angiotensin II; Animals; Dogs; Imidazoles; Kidney; Perfusion; Pressure; Renal Circulation; Thromboxane A2

The potential for endogenous prostaglandin production to modulate the renal vascular response to intrarenal infusions of angiotensin II (AII) was investigated in the canine kidney at varying renal perfusion pressures (RPP), using suprarenal aortic constriction to vary RPP. AII, infused to achieve increments in renal arterial plasma concentrations of 300 pg/ml, induced reductions in renal blood flow (RBF) and glomerular filtration rate (GFR) when RPP was 80 mm Hg or above. When RPP was reduced to 60 mm Hg, AII decreased RBF, but GFR failed to change. The vasoconstrictor response to AII was enhanced by indomethacin (8 mg/kg) at all perfusion pressures, but was not modified by the thromboxane (Tx) A2 synthase inhibitor, UK 38,485 (1 mg/kg). In contrast, the lack of change in GFR in response to AII at a RPP of 60 mm Hg was converted to a significant reduction by both indomethacin and UK 38,485. These observations are consistent with the hypothesis that the effect of AII on RBF is attenuated by renal release of vasodilator prostaglandins at all RPP. However, at low RPP, AII infusion also induces the release a factor that increases GFR. As this response can be prevented by both TxA2 synthase and cyclooxygenase inhibition, it is possible that this factor is TxA2.

Topics: Angiotensin II; Animals; Cyclooxygenase Inhibitors; Dogs; Female; Glomerular Filtration Rate; Imidazoles; Indomethacin; Kidney; Prostaglandins; Renal Circulation; Thromboxane A2; Thromboxane-A Synthase

Bacterial infusion in the cat, causing experimental septic shock, induces an early vascular response mainly characterized by pulmonary hypertension and intestinal vasoconstriction. Prostanoids are held to be important mediators of the pulmonary vascular reaction. This study was performed to explore the involvement of prostanoids in the central haemodynamics and the small intestinal vascular reactions in experimental septic shock. Aortic blood pressure was continuously monitored, as were aortic blood flow, the pressure in a. pulmonalis and the small intestinal venous outflow. All cats (n = 24) were given live E. coli (10(10) ml-1) as a continuous intravenous infusion. One series was pretreated with indomethacin, another with UK-38,485, a specific thromboxane A2 synthetase inhibitor, and a third series served as untreated control. The pulmonary hypertensive response was clearly attenuated in the two pretreated series, in fact abolished in the one given UK-38,485. The early intestinal vasoconstriction was eliminated in the two pretreated series. Later during bacteraemia, when untreated and indomethacin-pretreated cats showed intestinal vasoconstriction, UK-38-485-pretreated animals kept intestinal blood flow within the preseptic range. These data suggest that in the cat, thromboxane A2 is the prostanoid mediating the vascular reactions, not only in the lung but also in the small intestine.

Topics: Animals; Cats; Escherichia coli; Hemodynamics; Imidazoles; Indomethacin; Intestines; Shock, Septic; Thromboxane A2; Thromboxane-A Synthase; Vasoconstriction

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.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Endotoxins; Escherichia coli; Female; Horses; Imidazoles; Male; Thromboxane A2; Thromboxane B2; Thromboxane-A Synthase

The interaction between the renin-angiotensin (RA) system and thromboxane A2 (TXA2) was examined in dogs, before and during the renal artery pressure (RAP) was decreased. Intrarenal arterial administration of a small dose of angiotensin II (AII) reduced renal blood flow (RBF) and glomerular filtration rate (GFR) in non-treated dogs when RAP was maintained at the normal level. When mean RAP was decreased to 60 mmHg by means of an aortic clamp, AII reduced RBF, but increased GFR up to 122% of the control value. In dogs pretreated by captopril, GFR decreased when RAP was reduced to 60 mmHg, while RBF was well maintained. However, with the administration of AII, RBF decreased markedly. By indomethacin pretreatment, GFR and RBF decreased during reduced RAP, and their reduction rates were accelerated with the administration of AII into the renal artery. By pretreatment with the thromboxane A2 synthetase inhibitor UK38485, the changes of RBF and GFR following AII infusion were similar to nontreated dogs at normal RAP, but during reduced RAP, AII infusion into the renal artery decreased GFR to 80% of the control value. The thromboxane B2 (TXB2) production by the renal cortex during reduced RAP increased to 2.7-fold that at normal RAP, but TXB2 production did not increase during reduced RAP in captopril pretreated dogs. These results suggest that the RA system and prostanoids, especially TXA2, are important factors for maintaining GFR at low RAP.

Topics: Angiotensin II; Animals; Blood Pressure; Dogs; Glomerular Filtration Rate; Imidazoles; In Vitro Techniques; Perfusion; Renal Circulation; Renin-Angiotensin System; Thromboxane A2

The capacity of platelets to generate thromboxane A2, reflected by measurement of serum thromboxane B2 (TxB2), greatly exceeds the systemic production of thromboxane in vivo. Thus, it is possible that substantial but incomplete inhibition of thromboxane formation ex vivo would still allow marked augmentation of thromboxane production in vivo. To address this hypothesis, we administered aspirin 120 mg, a selective inhibitor of thromboxane synthase (TxSl), 3-(1H-imidazol-1-yl-methyl)-2-methyl-1H-indole-1-propanoic acid (UK-38, 485) 200 mg, and a combination of both drugs to 12 healthy volunteers and measured the effects on serum TxB2 and urinary 2,3-dinor-thromboxane B2 (Tx-M), an index of endogenous thromboxane biosynthesis. Although serum TxB2 was maximally inhibited by 94 +/- 1% after aspirin and 96 +/- 2% after the TxSl, maximal depression of Tx-M was only 28 +/- 8% and 37 +/- 9%, respectively. Combination of aspirin with the TxSl resulted in a small but significant increase in inhibition of thromboxane generation ex vivo (98 +/- 1% v 94 +/- 1%; P less than 0.05), but a disproportionately greater fall in thromboxane synthesis in vivo (58 +/- 7%; P less than 0.01). Consistent with further inhibition of platelet thromboxane synthesis, addition of the TxSl abolished the transient decline in prostacyclin formation after aspirin alone. Administration of a lower dose of aspirin (20 mg) to 6 healthy subjects caused a small reduction in Tx-M (12 +/- 4%; P less than 0.05) and inhibited serum TxB2 by 48 +/- 2%. The relationship between inhibition of platelet capacity to form thromboxane ex vivo (serum TxB2) and synthesis in vivo (Tx-M) departed markedly from the line of identity. When total blockade of the capacity of platelets to generate thromboxane is approached, minor decrements in capacity result in a disproportionate depression of actual thromboxane biosynthesis. These results imply that pharmacologic inhibition of serum TxB2 must be virtually complete before thromboxane-dependent platelet activation is influenced in vivo.

Topics: Adult; Aspirin; Blood Platelets; Humans; Imidazoles; Male; Metabolic Clearance Rate; Middle Aged; Platelet Count; Salicylates; Thromboxane A2; Thromboxane B2

We examined the possibility that glomerular prostaglandin E2 (PGE2) regulates the action of angiotensin II (ANG II) on mesangial contraction and filtration surface area. Using isolated rat glomeruli we indirectly assessed mesangial contraction and filtration surface area through measurements of glomerular planar surface area (GPSA) by image-analysis microscopy. ANG II reduced GPSA by approximately 20% in human and rat glomeruli, with threshold concentrations of 1 X 10(-13) M and maximum effect at 5 X 10(-11) M ANG II. Inhibition of glomerular PG synthesis with indomethacin or meclofenamate potentiated the threshold response of ANG II to reduce GPSA. Arachidonic acid (5 micrograms/ml) blunted both the threshold and the maximum responses of GPSA to ANG II. PGE2, 10(-8) and 10(-9) M, also decreased glomerular contraction to ANG II. Endoperoxide (EP) analogues decreased GPSA and EP 045, a thromboxane A2 (TXA2) receptor blocker, eliminated the contractile responses of glomeruli to the EP analogues. Authentic TXA2, synthesized from sheep platelet microsomes, also reduced GPSA. We conclude that glomerular products of arachidonate cyclooxygenation may either relax or contract the mesangium, thereby preserving or reducing filtration surface area. PGE2 exerts protective actions to reduce the mesangial contraction of ANG II, primarily through postreceptor effects. TXA2 may decrease glomerular filtration rate in certain diseases through direct actions on the mesangium.

Topics: Angiotensin II; Animals; Arachidonic Acid; Arachidonic Acids; Blood Platelets; Cyclooxygenase Inhibitors; Dinoprostone; Eicosanoic Acids; Humans; Imidazoles; Kidney Glomerulus; Methacrylates; Microsomes; Prostaglandins E; Rats; Receptors, Prostaglandin; Receptors, Thromboxane; Thromboxane A2; Thromboxane B2

Thromboxane A2 was generated by infusing arachidonic acid (2.5 micrograms ml-1) into an extra-corporeal circuit of blood withdrawn from anaesthetized dogs, and assayed on a blood-bathed bioassay cascade of porcine and bovine coronary artery strips, chick rectum and rat stomach strip. All tissues except chick rectum were treated with phentolamine and propranolol to abolish direct effects of catecholamines. The arachidonate-induced contractions of artery strips were abolished by a thromboxane synthetase inhibitor UK-38485 (3 mg kg-1, i.v.), but were not altered by the 5-hydroxytryptamine antagonist ketanserin (10 microM) administered over the tissues. Intravenous infusion of adrenaline (0.2 and 0.4 micrograms kg-1 min-1) reversibly potentiated the coronary contractions produced by arachidonate, but did not alter contractions when applied directly over the bioassay tissues. Intra-aortic infusion of nicotine (5 or 10 micrograms kg-1 min-1) also increased the arachidonate-induced contractions of the bioassay tissues but only on those experiments where nicotine caused appreciable adrenaline release, as indicated by relaxation of chick rectum. Phenoxybenzamine (2 mg kg-1, i.v.) blocked the potentiation effect of adrenaline and nicotine on coronary contractions. The specific alpha 2-adrenoceptor antagonist, idazoxan (1 mg kg-1, i.v.), also blocked nicotine-induced potentiation of the contractions. These findings suggest that the ability of nicotine to potentiate thromboxane release from circulating platelets and blood cells is dependent upon the release of adrenaline, and probably involves an action on alpha-adrenoceptors of the circulating blood elements.

Topics: Animals; Arachidonic Acid; Arachidonic Acids; Blood Pressure; Catecholamines; Dioxanes; Dogs; Epinephrine; Female; Heart Rate; Idazoxan; Imidazoles; In Vitro Techniques; Ketanserin; Male; Nicotine; Phenoxybenzamine; Piperidines; Thromboxane A2; Vasoconstriction

This study was designed to establish the influence of the recipient's thrombotic potential on the patency of small-caliber prostheses and to evaluate the subsequent improvement of graft performance by medicinally altering the prostaglandin balance in subjects predisposed to graft occlusion. Mongrel dogs were pretested and classified as low and high responders according to their thrombotic potential, measured as prostaglandin metabolite balance and platelet aggregability. High responders were randomly divided into two groups. Those assigned to serve as the medicated subjects were pretreated 1 week before surgery with a single oral daily administration of combined dazmegrel (UK-38,485) and aspirin in equal dosages of 3 mg/kg. Medication was continued throughout the experiment. Dacron grafts were implanted bilaterally in the carotid artery site in all subjects. Following a 3-week implantation period, the patency rate for the group with low thrombotic potential was 100%. In the animals with high thrombotic potential the patency rate was 10% for nonmedicated subjects and 100% for medicated subjects. These data support the concept that the thrombotic potential largely determines the capacity of the recipient's blood to thrombose small-caliber prostheses. Effective medicinal alteration of prostaglandin balance results in exceptionally increased patency of synthetic grafts.

Topics: Animals; Aspirin; Blood Cell Count; Blood Vessel Prosthesis; Carotid Arteries; Dogs; Drug Therapy, Combination; Epoprostenol; Graft Occlusion, Vascular; Imidazoles; Male; Malondialdehyde; Platelet Aggregation; Prostaglandins; Thrombosis; Thromboxane A2; Thromboxane-A Synthase

The efficacy of three agents which alter the metabolism of arachidonic acid was investigated in normal, conscious horses. A dose response evaluation was made of flunixin meglumine and phenylbutazone, two cyclo-oxygenase inhibitors, and of a selective thromboxane synthetase inhibitor, UK-38,485. Radioimmunoassay of thromboxane B2 (TxB2) and 6-keto prostaglandin F1 alpha (PGF1 alpha) was used to assess the concentrations of thromboxane A2 (TxA2) and prostacyclin (PGI2) respectively, in serum. Flunixin was the most potent inhibitor of serum TxB2 and 6-keto PGF1 alpha production. UK-38,485 also decreased serum TxB2 generation while significantly increasing serum 6-keto PGF1 alpha levels, thus confirming its selectivity as a thromboxane synthetase inhibitor.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Clonixin; Epoprostenol; Horses; Imidazoles; Male; Nicotinic Acids; Orchiectomy; Phenylbutazone; Thromboxane A2; Thromboxane B2; Thromboxane-A Synthase

The purpose of this study was to determine the role of thromboxane and prostacyclin in modulating pulmonary hemodynamics during maximal cardiopulmonary stress in the healthy lung. We studied 11 yearling sheep in paired studies during progressive maximal treadmill exercise with and without meclofenamate (n = 5), ibuprofen (n = 6), or UK38485 (n = 2). We also studied five sheep during hypoxia and hypoxic exercise, and six sheep during prolonged steady-state treadmill exercise for 45-60 min with and without drug treatment. We measured the metabolites of thromboxane A2 (thromboxane B2, TxB2) and prostacyclin (6-ketoprostaglandin F1 alpha, 6-keto-PGF1 alpha) in blood plasma and lung lymph in each protocol. We found that progressive exercise significantly reduced pulmonary vascular resistance but that cyclooxygenase or thromboxane synthesis blockade did not alter the change. Plasma TxB2 rose minimally but significantly during maximal exercise, but 6-keto-PGF1 alpha did not change. During continuous hypoxia, exercise reduced pulmonary vascular resistance nearly to base-line levels, but the degree of reduction was also unchanged by drug treatment. There were also no significant changes in lymph or plasma TxB2 or 6-keto-PGF1 alpha during 45-60 min of continuous moderate exercise. We conclude that neither TxB2 nor prostacyclin modulate pulmonary hemodynamics in the normal lung during maximal exercise, prolonged moderate exercise, or exercise-induced reductions in vascular resistance during hypoxia.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Blood Pressure; Cardiac Output; Epoprostenol; Hemodynamics; Hypoxia; Ibuprofen; Imidazoles; Lung; Lymph; Meclofenamic Acid; Physical Exertion; Pulmonary Artery; Sheep; Thromboxane A2; Vascular Resistance

As platelet and renal thromboxane (TX)A2 synthesis are increased in spontaneously hypertensive rats (SHR), we tested the hypothesis that increased renal TXA2 synthesis may cause the reduction in glomerular filtration rate (GFR), renal plasma flow (RPF), and the increase in arterial pressure in SHR of the Okamoto-Aoki strain. A selective inhibitor of TXA2 synthetase (UK 38485) was given acutely, with or without a TXA2 receptor antagonist (EP-092), to 6- to 8-wk-old SHR and age-matched Wistar-Kyoto rats (WKY) and chronically for 5.5 wk to 3.5-wk-old SHR. Inhibition of TXA2, measured by the stable metabolite TXB2, in the acute experiments was greater than 95% in serum and greater than 80% in glomeruli; in the chronic studies, it was greater than 65% in glomeruli. There was no endoperoxide shunting to vasodilatory and natriuretic prostaglandins (PGE2, PGI2) in glomeruli after TXA2 inhibition. Before drug administration, GFR and RPF were reduced and renal vascular resistance (RVR) was increased in SHR. During acute blockade of renal TXA2 synthesis, with or without a TXA2 receptor antagonist, there was no significant change in GFR, RPF, or RVR in WKY and SHR. Inhibition of TXA2 did not affect urine flow or sodium excretion in anesthetized or conscious WKY or SHR. Mean arterial pressure did not fall in treated SHR and WKY. Chronic TXA2 synthesis inhibition did not improve GFR or RPF in SHR, and systolic arterial pressure was not altered. These findings show that enhanced serum and glomerular TXA2 synthesis do not significantly contribute to the reduction in renal function and are not essential for the development of hypertension in young SHR.

Topics: Animals; Blood Pressure; Glomerular Filtration Rate; Hypertension; Imidazoles; Kidney; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Renal Circulation; Thromboxane A2; Time Factors; Vascular Resistance

This study was performed to examine potential protective effects of UK 38.485, an inhibitor of thromboxane synthetase, in canine myocardium stressed by transient ischemia. On anesthetized open-chest mongrel-dogs (n = 9) repeated ischemia (3 min) was produced by proximal, intermittent occlusion of the left anterior descending artery. A total of 18 occlusions after 3 mg UK 38.485/kg body wt. and 12 occlusions after 5 mg UK 38.485/kg body wt. were compared to a total of 24 occlusions under control conditions. In each experiment, 2-3 control occlusions and 3-4 therapy occlusions were performed. The drug was applied i.v. in a dose of 3 or 5 mg/body wt. 30 min before the first therapy occlusion. In both groups, hemodynamics and energetics did not significantly change as compared to control. The efficiency of the drug in protecting ischemically stressed myocardium was examined by (a) quantification of oxygen debt and oxygen repayment in the occlusion and reperfusion periods and (b) the amounts of inorganic phosphate, lactate, and potassium released in the first minute of reperfusion. Compared to control occlusions, premedication with either 3 or 5 mg UK 38.485 led to a significantly reduced oxygen debt combined with a significant decrease of the release of inorganic phosphate, lactate, and potassium. The protective effect is suggested to be mainly due to enhanced flow to ischemic areas. Data obtained in this study suggest protective effects of the compound in the preservation of myocardium in transient ischemia and attest to the concept that thromboxane A2 may aggravate the metabolic and energetic situation of myocardium in circumstances with reduced oxygen supply.

Topics: Animals; Coronary Circulation; Coronary Disease; Dogs; Energy Metabolism; Hemodynamics; Imidazoles; Myocardium; Oxygen Consumption; Thromboxane A2; Thromboxane-A Synthase

Eicosanoid metabolites may play a role in the pathophysiology of nephrotoxic serum nephritis (NSN), a model of immune renal disease. Our purpose was to determine the relative importance of vasoconstrictor [thromboxane A2 (TX)A2] and vasodilator [prostaglandin E2 (PG)E2] eicosanoids as mediators of hemodynamic and renal functional changes. Glomerular filtration rate (GFR; inulin clearance), and renal plasma flow (RPF; para-aminohippurate clearance/extraction) were measured in rats on day 1 and day 14 of NSN. Specific inhibitors of TXA2 synthesis and receptor binding, and cyclooxygenase inhibitors were used to determine the relative roles of TXA2 and PGE2. In vitro glomerular production of radioimmunoassayable PGE2 and TXB2 were measured after clearances. At 1 day GFR is decreased compared to control, 1.9 +/- 0.2 vs. 2.6 +/- 0.2 ml/min. RPF is numerically increased, 10.0 +/- 1.0 vs. 7.0 +/- 0.6 ml/min. By 14 days GFR is normal, 2.2 +/- 0.2 ml/min, as a consequence of significantly increased RPF, 11.7 +/- 1.0 ml/min. Glomerular production of PGE2 and TXB2 was increased 11- and 15-fold respectively at both 1 and 14 days. Pretreatment with OKY-1581, or acute treatment with UK-38,485, both inhibitors of TXA2 synthesis, had no effect on GFR or RPF in NSN rats. Addition of EP 092, a TXA2 receptor antagonist was similarly without effect. In contrast, acute treatment with the cyclooxygenase inhibitors meclofenamate or indomethacin resulted in a 50% decrease in both RPF and GFR; these inhibitors had no effect in control rats. We conclude that PGE2 (vasodilator) is of greater relative significance than TXA2 (vasoconstrictor) with respect to renal function in the NSN rat at 1 and 14 days.

Topics: Animals; Dinoprostone; Glomerular Filtration Rate; Glomerulonephritis; Hemodynamics; Imidazoles; Kidney; Male; Methacrylates; Prostaglandins E; Rabbits; Rats; Rats, Inbred Strains; Renal Circulation; Thromboxane A2; Thromboxanes

Whereas numerous studies have investigated the role of prostacyclin and thromboxane A2 in the maintenance of coronary blood flow, most of these have focused on normal vessels. In the present investigation, we examined the prostaglandin- and thromboxane-synthesizing capacity of isolated coronary artery segments obtained from the site of a critical coronary artery stenosis. Cyclic flow variations were produced by placing a hard cylindrical constrictor on the proximal left anterior descending coronary artery in open-chest, anesthetized dogs. Cyclic flow variations are characterized by progressive declines in coronary blood flow, interrupted by sudden spontaneous restorations of flow. After cyclic flow variations had been induced, the hearts were removed, and the left anterior descending and circumflex coronary arteries were dissected. The vessels were cut into segments and incubated in the presence of increasing concentrations of arachidonic acid (10(-4)-10(-6) M). The synthesis of prostaglandin E2, thromboxane B2, and 6-keto prostaglandin F1 alpha by the coronary segments was measured by radioimmunoassay. When incubated in the presence of 10(-5) M arachidonic acid, coronary artery segments obtained from the left anterior descending coronary artery undergoing cyclic flow variations produced substantially more thromboxane B2 (142 +/- 27 vs. 29 +/- 3 pg/mg P less than 0.01) and less 6-keto prostaglandin F1alpha (125 +/- 12 vs. 350 +/- 30 pg/mg, P less than 0.01) than control circumflex coronary artery segments. Circumflex coronary vessels in which the endothelium was removed ex vivo produced 6-keto prostaglandin F1alpha levels comparable to those found in the left anterior descending coronary artery (147 +/- 17 pg/mg), but did not synthesize thromboxane B2 (23 +/- 2.6 pg/mg).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Aortic Valve Stenosis; Arachidonic Acid; Arachidonic Acids; Chromatography, High Pressure Liquid; Coronary Circulation; Coronary Vessels; Dinoprost; Dinoprostone; Dogs; Epoprostenol; Imidazoles; Male; Platelet Aggregation; Prostaglandins E; Prostaglandins F; Regional Blood Flow; Thromboxane A2; Thromboxane B2; Thromboxanes

This study tested the hypothesis that aggregation of platelets and release of thromboxane A2 at the site of a coronary arterial stenosis may contribute to myocardial ischemia by impairing flow regulation of the distal coronary bed. Measurements of hemodynamics, flow (microspheres), lactate metabolism, and prostaglandin (PG) metabolites (thromboxane B2 and 6-keto-PGF1 alpha) were made in closed-chest anesthetized pigs instrumented with a stenosis (65% diam reduction) in the left anterior descending (LAD) coronary artery. Data were acquired prior to stenosis insertion (control) and 5 and 15 min after insertion, during which time thrombotic occlusion of the device was occurring. Heart rate was controlled by atrial pacing. Distal LAD zone endocardial flow (ml X min-1 X g-1) declined versus control (1.15 +/- 0.20, mean +/- SD) at 5 min (0.89 +/- 0.40, P less than 0.05) and 15 min (0.41 +/- 0.36, P less than 0.01) of occlusion. Distal endocardial resistance (mmHg X ml-1 X min X g), however, did not change versus control (72 +/- 12) at 5 (66 +/- 12) or 15 min (61 +/- 38). Distal epicardial resistance (mmHg X ml-1 X min X g) declined versus control (90 +/- 17) at 5 (66 +/- 35, P less than 0.05) and 15 min (43 +/- 26, P less than 0.01) postinsertion. Finally, lactate extraction (%) at control (42 +/- 19) changed to production 15 min postinsertion (-36 +/- 93, P less than 0.05) and arterial-anterior interventricular vein thromboxane B2 difference (pg/0.1 ml) changed from 13.1 +/- 17.8 pre to -15.8 +/- 30.0 at 5 min post (P less than 0.05). Thus platelet aggregation and release at a spontaneously thrombosing stenosis contribute to ischemia not only by reduction of stenosis diameter but also by impairment of flow regulation in endocardial layers distal to it.

Topics: Animals; Arterial Occlusive Diseases; Aspirin; Coronary Circulation; Heart Rate; Hemodynamics; Imidazoles; Lactates; Lactic Acid; Prostaglandin Endoperoxides, Synthetic; Regional Blood Flow; Swine; Thrombosis; Thromboxane A2; Vascular Resistance; Vasodilation