Rutin present in Alibertia edulis extract acts on human platelet aggregation through inhibition of cyclooxygenase/thromboxane.

Alibertia edulis leaf extract is commonly used in folk medicine, with rutin caffeic and vanillic acids being its major compounds. The Alibertia edulis leaf extract was investigated for its pharmacological effects via platelet aggregation, calcium mobilization, cyclic nucleotides levels, vasodilator-stimulated phosphoprotein Ser157 and Ser239 and protein kinase Cß2 phosphorylation, thromboxane B2, cyclooxygenases 1 and 2, docking and molecular dynamics. Alibertia edulis leaf extract significantly inhibited (100-1000 µg mL-1) platelet aggregation induced by different agonists. Arachidonic acid increased levels of calcium and thromboxane B2, phosphorylation of vasodilator-stimulated phosphoprotein Ser157 and Ser239, and protein kinase Cß, which were significantly reduced by Alibertia edulis leaf extract, rutin, and caffeic acid as well mixtures of rutin/caffeic acid. Cyclooxygenase 1 activity was inhibited for Alibertia edulis leaf extract, rutin and caffeic acid. These inhibitions were firsrtly explored by specific stabilization of rutin and caffeic acid compared to diclofenac at the catalytic site from docking score and free-energy dissociation profiles. Then, simulations detailed the rutin interactions close to the heme group and Tyr385, responsible for catalyzing the conversion of arachidonic acid to its products. Our results reveal the antiplatelet aggregation properties of Alibertia edulis leaf extract, rutin and caffeic acid providing pharmacological information about its origin from cyclooxygenase 1 inhibition and its downstream pathway.

[Antiplatelet agents]. / Agents antiplaquettaires et athérothrombose.

Atherothrombosis is a major global public health problem. Chronic atherosclerotic disease is often clinically silent and coexists across multiple vascular beds but, when complicated by thrombosis, it can result in an acute coronary syndrome, stroke, transient ischemic attack, and critical limb ischemia. Platelets play a role in the development of chronic atherosclerotic disease and are a key mediator of clinical events in atherothrombosis. Numerous clinical trials have tested antiplatelet agents for primary and secondary prevention, and several new antiplatelet drugs are under development. There is evidence of clear benefit of single and, in some cases, dual antiplatelet therapy in the prevention of recurrent cardiovascular and cerebrovascular complications. Dual antiplatelet therapy has emerged as the standard of care for acute coronary syndromes, with aspirin typically being used in combination with clopidogrel or one of the newer more potent ADP receptor antagonists (ticagrelor or prasugrel). Conversely, in chronic stable coronary disease, no benefit of dual antiplatelet therapy has yet been convincingly demonstrated Evidence supporting routine use of aspirin or any other antiplatelet agent for primary prevention is mixed, and this strategy should only be considered for individual high-risk patients in whom the thrombotic risk outweighs the risk of major bleeding complications.

A novel prostacyclin agonist protects against airway hyperresponsiveness and remodeling in mice.

Airway remodeling in bronchial asthma results from chronic, persistent airway inflammation. The effects of the reversal of airway remodeling by drug interventions remain to be elucidated. We investigated the effects of ONO-1301, a novel prostacyclin agonist with thromboxane inhibitory activity, on the prevention and reversibility of airway remodeling in an experimental chronic asthma model. Mice sensitized and challenged to ovalbumin (OVA) three times a week for 5 consecutive weeks were administered ONO-1301 or vehicle twice a day from the fourth week of OVA challenges. Twenty-four hours after the final OVA challenge, airway hyperresponsiveness (AHR) was assessed, and bronchoalveolar lavage was performed. Lung specimens were excised for staining to detect goblet-cell metaplasia, airway smooth muscle, and submucosal fibrosis. Mice administered ONO-1301 showed limited increases in AHR compared with mice administered the vehicle. The histological findings of airway remodeling were improved in ONO-1301-treated mice compared with vehicle-treated mice. Presumably, these therapeutic effects of ONO-1301 are attributable to the up-regulation of production of hepatocyte growth factor (HGF) in lung tissue, because the neutralization of HGF by antibodies prevented the effects of ONO-1301 on AHR and airway remodeling. Mice administered ONO-1301 showed similar levels of AHR and airway remodeling as mice administered montelukast, a cysteinyl-leukotriene-1 receptor antagonist, and lower levels were observed in mice administered dexamethasone. These data suggest that ONO-1301 exerts the effect of reversing airway remodeling, at least in part through an elevation of HGF in the lungs, and may be effective as an anti-remodeling drug in the treatment of asthma.

Thromboxane Antagonism with terutroban in Peripheral Arterial Disease: the TAIPAD study.

BACKGROUND: Terutroban is a selective prostaglandin endoperoxide (TP) receptor antagonist with antithrombotic, antivasoconstrictive and antiatherosclerotic properties and is currently in development for long-term cardiovascular secondary prevention. OBJECTIVES: TAIPAD is an international, double-blind, randomized controlled study comparing the effects of five dosages of oral terutroban vs. aspirin and placebo on platelet aggregation in peripheral arterial disease (PAD) patients. PATIENTS/METHODS: After 10 day's placebo run-in, included patients (n = 435; ankle-brachial pressure index, 0.7 ± 0.1) were randomly allocated to aspirin 75 mg day(-1), terutroban 1, 2.5, 5, 10 or 30 mg day(-1) or placebo. On day 5, the placebo group was reallocated to one of the terutroban groups for the rest of the study (day 83). Ex vivo platelet aggregation induced by the thromboxane analog U46619 (7 µm) was measured 24 h after dosing, as well as platelet aggregation induced by arachidonic acid (AA), collagen and ADP. RESULTS: Terutroban dose-dependently inhibited U46619-induced platelet aggregation at days 5 and 83. At day 5, the inhibition was significant vs. placebo for all terutroban dosages (P < 0.001). Terutroban (5, 10 and 30 mg day(-1)) was at least as effective as aspirin in inhibiting platelet aggregation induced by arachidonic acid (AA), collagen and adenosine diphosphate (ADP). Terutroban was well tolerated, with a safety profile similar to aspirin. CONCLUSIONS: In PAD patients, terutroban dose-dependently inhibited platelet aggregation 24 h after dosing, and was at least as effective as aspirin at 5, 10 and 30 mg day(-1). Terutroban was well tolerated.

Pharmacological profile of a novel H(2)S-releasing aspirin.

The pharmacological profile of a new, safe, and effective hydrogen sulfide (H(2)S)-releasing derivative of aspirin (ACS14) is described. We report the synthesis of ACS14, and of its deacetylated metabolite (ACS21), the preliminary pharmacokinetics, and its in vivo metabolism, with the H(2)S plasma levels after intravenous administration in the rat. ACS14 maintains the thromboxane-suppressing activity of the parent compound, but seems to spare the gastric mucosa, by affecting redox imbalance through increased H(2)S/glutathione formation, heme oxygenase-1 promoter activity, and isoprostane suppression.

Incomplete inhibition of thromboxane biosynthesis by acetylsalicylic acid: determinants and effect on cardiovascular risk.

BACKGROUND: Incomplete inhibition of platelet thromboxane generation, as measured by elevated urinary 11-dehydro thromboxane B(2) concentrations, has been associated with an increased risk of cardiovascular events. We aimed to determine the external validity of this association in aspirin-treated patients enrolled in the Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management and Avoidance (CHARISMA) trial and to determine whether there are any modifiable factors or interventions that lower urinary 11-dehydro thromboxane B(2) concentrations that could thereby reduce cardiovascular risk. METHODS AND RESULTS: Urinary 11-dehydro thromboxane B(2) concentrations were measured in 3261 aspirin-treated patients at least 1 month after they had been randomly assigned to placebo or clopidogrel. Baseline urinary 11-dehydro thromboxane B(2) concentrations in the highest quartile were associated with an increased risk of stroke, myocardial infarction, or cardiovascular death compared with the lowest quartile (adjusted hazard ratio 1.66, 95% CI 1.06 to 2.61, P=0.03). Increasing age, female sex, history of peripheral artery disease, current smoking, and oral hypoglycemic or angiotensin-converting enzyme inhibitor therapy were independently associated with higher urinary concentrations of 11-dehydro thromboxane B(2), whereas aspirin dose > or =150 mg/d, history of treatment with nonsteroidal antiinflammatory drugs, history of hypercholesterolemia, and statin treatment were associated with lower concentrations. Randomization to clopidogrel (versus placebo) did not reduce the hazard of cardiovascular events in patients in the highest quartile of urinary 11-dehydro thromboxane B(2) levels. CONCLUSIONS: In aspirin-treated patients, urinary concentrations of 11-dehydro thromboxane B(2) are an externally valid and potentially modifiable determinant of stroke, myocardial infarction, or cardiovascular death in patients at risk for atherothrombotic events.

Antithrombotic treatment for peripheral arterial disease.

CONTEXT: Patients with peripheral arterial disease (PAD) bear a substantial risk for vascular events in the coronary, cerebral and peripheral circulations. In addition, this disorder is associated with a systemic milieu characterised by ongoing platelet activation and heightened thrombogenesis. OBJECTIVE: To determine the optimal antithrombotic prophylaxis for patients with PAD. DATA SOURCES: Using terms related to PAD and antithrombotic agents, we searched the following databases for relevant articles: MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials, the Cochrane Database of Systematic Reviews, the National Institutes of Health Clinical Trials Database, Web of Science, and the International Pharmaceutical Abstracts Database (search dates: 1 January 1990 to 1 January 2007). Additional articles were identified from cardiovascular and vascular surgery conference proceedings, bibliographies of review articles, and personal files. STUDY SELECTION: We focused on randomised trials, systematic reviews and consensus guidelines of antithrombotic therapies for PAD. DATA EXTRACTION: Detailed study information was abstracted by each author working independently. RESULTS: Multiple studies show that patients with PAD manifest platelet hyperaggregability, increased levels of soluble platelet activation markers, enhanced thrombin generation and altered fibrinolytic potential. Many of these markers predict subsequent cardiovascular events. Available randomised trials and meta-analyses show that most available antithrombotic agents prevent major cardiovascular events and death in patients with PAD, including aspirin, aspirin/dipyridamole, clopidogrel, ticlopidine, picotamide and oral anticoagulants. CONCLUSIONS: Although the most favourable risk-benefit profile, cost-effectiveness and overall evidence base supports aspirin in this setting, we provide scenarios in which alternatives to aspirin should be considered.

Aspirin insensitive eicosanoid biosynthesis in cardiovascular disease.

Inhibition of platelet cyclooxygenase (COX)-1 is involved in aspirin cardioprotection observed in clinical trials, but, in some patients, aspirin is unable to protect from thrombotic complications. An incomplete suppression of platelet thromboxane (TX) A2 biosynthesis has been assumed to participate in the phenomenon of aspirin resistance, as a consequence of the following possible mechanisms: (i) COX-2 expression in newly formed platelets; (ii) pharmacodynamic interactions between aspirin and coadministered nonsteroidal antiinflammatory drugs (e.g. ibuprofen); (iii) expression of variant isoforms of COX-1 with reduced sensitivity to irreversible inactivation at Ser529. Furthermore, aspirin failure may be due to enhanced formation of vasoactive and/or proaggregatory eicosanoids despite an almost complete suppression of platelet TXA2 biosynthesis by aspirin. Thus, in a subset of patients with unstable angina treated with low-dose aspirin, to almost completely block platelet COX-1 activity, enhanced TXA2 biosynthesis in vivo has been demonstrated, presumably through an increased generation of COX-2-dependent PGH2 in plaque monocytes/macrophages or activated vascular cells. The concomitant increased formation of 8-iso-PGF2alpha, one of the most abundant F2-isoprostanes in humans, generated by free-radical catalyzed arachidonate peroxidation, may be involved in aspirin resistance because of its capacity to induce platelet and vascular smooth muscle cell activation through the interaction with thromboxane receptors (TPs). Finally, enhanced production of vasoactive cysteinyl leukotrienes (cys-LTs) occurs in unstable angina despite conventional antithrombotic and antianginal treatment. The use of selective pharmacological tools (i.e. highly selective COX-2 inhibitors, TP antagonists, cys-LT inhibitors and antagonists) will allow to ascertain the contribution of aspirin insensitive eicosanoid biosynthesis in aspirin cardioprotective failure.

High plasma concentrations of human urotensin II do not alter local or systemic hemodynamics in man.

OBJECTIVE: Human urotensin II (hUII) is an endocrine hormone that acts as a potent arterial vasoconstrictor in both in vitro and in vivo studies in animals. We examined, for the first time, the local and systemic hemodynamic response to hUII in man in vivo. METHODS: Four healthy male volunteers took part in pilot studies and 11 in definitive studies. Forearm blood flow (FBF) was measured in response to intra-arterial infusion of authentic, biologically active hUII (incremental rates of 0.001-300 pmol min(-1)) and saline placebo using venous occlusion plethysmography. Blood pressure, heart rate, cardiac output and hUII plasma concentrations were also measured. Forearm studies were repeated in five subjects with inhibition of endothelial mediators using aspirin and a "nitric oxide clamp". Dorsal hand vein diameter was determined by a standard displacement technique in response to local administration of hUII (3-300 pmol min(-1)) with and without nitric oxide synthase inhibition. RESULTS: There was no significant change in FBF during brachial infusion of saline or hUII (dose range, 0.001 to 300 pmol min(-1)). A nitric oxide clamp did not unmask vasoactive effects of hUII. Human UII infusions (100 and 300 pmol min(-1)) significantly increased plasma hUII concentrations from baseline (12 +/- 3 pmol l(-1)) to 106 +/- 15 and 307 +/- 98 pmol l(-1), respectively. Despite high circulating hUII concentrations, no change was seen in systemic hemodynamics and ECGs were unchanged. Human UII had no effect on hand vein diameter (n=6). CONCLUSIONS: In contrast to our hypothesised role of hUII, we found no vasoactive responses to hUII in vivo, consistent with recent in vitro studies in human blood vessels, but in contrast to non-human primate studies in vivo. Our data do not support a key role for hUII in the regulation of vascular tone and resting blood pressure in man. However, studies with hUII receptor antagonists are also needed before firm conclusions can be drawn.

Ketoconazole and pulmonary failure after esophagectomy: a prospective clinical trial.

Thromboxane is a key mediator in pulmonary injury after esophageal resection. In this prospective trial we studied the clinical course and development of pulmonary alterations in patients undergoing esophagectomy and prophylactic treatment with a thromboxane synthase inhibitor. Thirty-eight consecutive patients undergoing esophageal resection were treated pre- and perioperatively with 3 x 200 mg ketoconazole. The clinical course was studied and pulmonary function was assessed according to the Murray score. A historical group of 118 patients undergoing esophagectomy for benign and malignant esophageal diseases served as controls. Patients in both groups were similar in terms of age, sex, and preoperative pulmonary function, as well as in the anesthetic and surgical procedures performed. However, in the ketoconazole group, more patients were at risk of pulmonary failure by receiving neoadjuvant radiochemotherapy (22/38) or undergoing thoracotomies (33/38) than control subjects (14/118 and 80/118, P < 0.05). Two out of 38 ketoconazole-treated patients developed acute lung injury after esophagectomy, as did 20/118 control patients (P < 0.05). This prospective non-randomized clinical study (in patients subjected to esophagectomy) provides further evidence that prophylactic thromboxane synthase inhibition by ketoconazole reduces the incidence of acute lung injury in patients at risk.

Long-term safety and efficacy of picotamide, a dual-action antithromboxane agent, in diabetic patients with carotid atherosclerosis: a 6-year follow-up study.

In a controlled, randomized, 6-year trial the safety and efficacy of picotamide, a dual-action antithromboxane agent, were assessed in 50 patients with type 2 diabetes mellitus at increased risk of thrombotic vascular events. The patients were randomized to two groups of equal size and received 900 mg picotamide daily or placebo. After phase I (double-blind; years 1 - 2), patients receiving placebo were treated, if necessary, with antiplatelet drugs (aspirin, ticlopidine) while members of the other group continued to receive 600 mg picotamide daily. In the course of the study 21 vascular events occurred: 16 in the group receiving placebo (fatal myocardial infarction, n = 7; non-fatal stroke, n = 3) and five in the group receiving drug (fatal myocardial infarction, n = 2) (P < 0.005; Fisher's exact test). One patient (placebo group) died of malignant disease. During the initial double-blind phase a total of nine vascular events was observed (six and three in the groups receiving placebo and drug, respectively). Picotamide treatment was well tolerated and no major side-effects were observed during the study periods.

Postoperative adhesion prevention with low-dose aspirin: effect through the selective inhibition of thromboxane production.

The aim of the present study was to evaluate the efficacy of low-dose versus high-dose aspirin in the prevention of postoperative adhesion formation. Forty New Zealand White rabbits were randomized into three groups: low-dose aspirin (1.7 mg/kg per day for 5 days starting on the day of surgery), high-dose aspirin (28.0 mg/kg per day), and controls. The rabbits underwent a standardized surgical injury on the ovary, uterine horn and abdominal wall on one side at laparotomy. On postoperative day 21, a second-look laparotomy was performed for the evaluation of postoperative adhesions. In five animals in each group, peritoneal fluid samples were collected at initial surgery, then through an additional 2 cm incision performed on postoperative day 3, and at second-look laparotomy. The peritoneal concentrations of thromboxane B2 and 6-keto-prostaglandin F1alpha (the stable hydrolysis product of prostacyclin) were measured by radioimmunoassay. At second-look laparotomy, the adhesion formation rate was 46% in the low-dose aspirin group, 77% in the high-dose group, and 100% in the control group. The adhesion score in the low-dose group was significantly lower (P < 0.01) than in the high-dose and control groups. Peritoneal thromboxane decreased significantly during treatment in both low-dose and high-dose aspirin groups, whereas prostacyclin decreased only in the high-dose group. Postoperative adhesion reduction observed in this study with low-dose aspirin treatment could be due to the selective inhibition of thromboxane over prostacyclin production.

Airway responsiveness in transgenic mice overexpressing platelet-activating factor receptor. Roles of thromboxanes and leukotrienes.

Platelet-activating factor (PAF) is a potent proinflammatory compound potentially involved in the pathogenesis of inflammatory disorders, including bronchial asthma. To elucidate the pathophysiologic roles of PAF in bronchial asthma, we studied airway responsiveness in transgenic mice overexpressing PAF receptor. In the transgenic mice, PAF-induced airway smooth muscle contraction was demonstrated by physiologic and morphometric analyses, whereas there was no significant response in the littermate control group. The PAF-elicited bronchoconstriction in the transgenic mice was significantly reduced not only by a PAF receptor antagonist (WEB-2086) but also by a thromboxane synthesis inhibitor (indomethacin or ozagrel), an inhibitor of 5-lipoxygenase-activating protein (MK-886), or a cysteinyl leukotriene (LT) antagonist (pranlukast). LTB4 receptor antagonist (ONO-4057), however, had no effect on the PAF-induced responses. The transgenic mice showed a bronchial hyperreactivity to methacholine challenge, which was also inhibited by pretreatment with either thromboxane synthesis inhibitor or cysteinyl LT antagonist. These observations suggest that both thromboxane A2 and cysteinyl LTs (LTC4, LTD4, and LTE4) are involved in the bronchial responses to PAF or cholinergic stimulus in mice. The transgenic mice overexpressing PAF receptor may provide an appropriate model to study various PAF-related lung diseases, including bronchial asthma.

Specific mediator-directed therapy for gastrointestinal diseases.

A number of inflammatory mediators--such as proinflammatory cytokines, lipid derived eicosanoids and reactive oxygen metabolites--are elevated in chronic bowel inflammation. Existing drugs for Crohn's disease and ulcerative colitis, for example aminosalicylates and corticosteroids, work at many sites in the inflammatory cascade to control disease activity. These drugs may be associated with significant side-effects and do not always control the disease. Therefore there is an impetus to develop treatments which are safer and more specific for bowel inflammation. Specific inhibitors of inflammatory mediators have recently become available and some have been shown to be effective in animal models of bowel inflammation. Although far fewer data are currently available on specific mediator-directed therapy of intestinal inflammation in humans, early clinical trials in inflammatory bowel disease have given mixed results. It remains to be determined whether or not this strategy of specific mediator inhibition is an alternative to current therapy for chronic bowel inflammation in humans.

Antiplatelet drugs. A comparative review.

Antiplatelet therapy has become a useful means of preventing acute thromboembolic artery occlusions in cardiovascular diseases. The rationale for this is an enhanced activity of circulating platelets and release of platelet-derived vasoactive mediators, probably due to endothelial dysfunction. This review discusses the current status of 4 major classes of antiplatelet compounds: (i) aspirin and related drugs active via cyclo-oxygenase product formation; (ii) thienopyridines (ticlopidine and clopidogrel); (iii) direct thrombin inhibitors (e.g. hirudin); and (iv) GPIIb/IIIa receptor antagonists [e.g. abciximab (c7E3 Fab)]. It is concluded that aspirin is the drug of choice for long term oral treatment, specifically for secondary prevention of myocardial infarction, and is also a suitable basic but not maximally efficient drug in percutaneous transluminal coronary angioplasty (PTCA) and platelet activation during clot lysis. Ticlopidine has a similar indication and may be superior to aspirin in prevention of ischaemic stroke and peripheral arterial occlusion. Direct thrombin inhibitors and glycoprotein GPIIb/IIIa receptor antagonists need further investigation in clinical trials. To date, these compounds have a higher bleeding risk and currently they are available only for short term parenteral application. They are superior to aspirin in acute platelet-dependent ischaemic syndromes, such as unstable angina, and in connection with therapeutic PTCA because of their high potency in preventing platelet-dependent reocclusion. Future developments include more selective thromboxane inhibitors, i.e. combined-mode agents; nonpeptide clot-specific thrombin inhibitors with longer lasting action and nonpeptide fibrinogen receptor antagonists.

Studies on in vitro effect of picotamide on human platelet aggregation in platelet-rich plasma and whole blood.

Picotamide is a new antiaggregating agent influencing the platelet prostaglandin pathway through an inhibition of thromboxane A2 (TXA2) synthesis and a competitive antagonism of platelet TXA2 receptors. In the present study, we investigated the in vitro effect of this drug on human platelet aggregation induced by different agents (adenosine 5'-diphosphate [ADP], collagen, Na arachidonate) both in platelet-rich plasma (PRP; Born's method) and whole blood (WB; impedance method). For each aggregating agent, ED50 value (agonist concentration necessary to induce a maximal aggregation of 50%) was determined in control samples and following addition of different picotamide concentrations on the basis of dose-response curves. Picotamide decreased the response to each aggregating agent in both WB and PRP samples. In WB, 25 microM picotamide was able to induce a highly significant enhancement of ED50 values for ADP (from 6.6 +/- 1 microM to 12.7 +/- 1.7 microM, p < 0.01), Na arachidonate (from 740 +/- 240 microM to 1,080 +/- 280 microM, p < 0.01) and collagen (from 2.4 +/- 0.3 micrograms/ml to 3.8 +/- 0.15 micrograms/ml, p < 0.01). In PRP, the same picotamide concentration significantly enhanced ED50 for each aggregating agent (from 2.0 +/- 0.1 microM to 3.1 +/- 0.3 microM for ADP, p < 0.01; from 960 +/- 80 microM to 1,850 +/- 260 microM for Na arachidonate, p < 0.001; from 3.0 +/- 0.3 microgram/ml to 5.0 +/- 0.8 micrograms/ml for collagen, p < 0.01). Present results show that picotamide effect on platelet response is present also in WB. Data might support the use of picotamide as antiaggregating agent in vascular diseases.

Eliminating the strong pulmonary vasoconstriction caused by Euro-Collins solution.

Single-flush perfusion with Euro-Collins solution (ECS), after pretreatment with prostaglandin E1 or prostacyclin, is at most centers the standard procedure for preservation of lungs for transplantation. In a previous study, we showed that the high potassium content of ECS causes strong pulmonary vasoconstriction at temperatures higher than 20 degrees C. In the present study, five drugs used as pretreatment and added to the perfusate were compared for their ability to counteract ECS-induced constriction of porcine pulmonary arteries: papaverine reduced the vasoconstrictive effect by 92% +/- 4%; nifedipine, by 62% +/- 6%; the thromboxane A2 receptor antagonist daltroban, by 15% +/- 4%; and prostaglandin E1, by 12% +/- 4%. On the other hand, prostacyclin not only failed to reduce ECS-induced vasoconstriction but at the highest concentration tested, enhanced it by 37% +/- 7%. The combination of papaverine (10(-4) mol/L) and nifedipine (10(-6.5) mol/L) was the only pretreatment to abolish ECS-induced vasoconstriction; moreover, it has no adverse effect on endothelial function. Neither prostaglandin E1 nor prostacyclin effectively counteracts ECS-induced vasoconstriction, though they may have other beneficial effects.

Early hemodynamic and renal effects of tumor necrosis factor alpha: role of thromboxane.

TNF alpha is an early mediator of endotoxemic shock. Its acute effect on renal hemodynamics is not known. In this study, the early hemodynamic and renal effects of TNF alpha were investigated in a rabbit model of shock, in which the measurement of the aortic blood flow before the bifurcation of the renal arteries allows one to differentiate between prerenal factors and hemodynamic renal response. Six groups of rabbits were studied, receiving either: (1) endotoxin, (2) endotoxin + thromboxane inhibitor Dazmegrel, (3) TNF alpha, (4) TNF alpha + Dazmegrel, (5) TNF alpha+indomethacin, or (6) placebo. Between 60 min and 3 hr after the injection, endotoxin induced a mean fall in arterial pressure of 32% (P < 0.01) and TNF alpha of 16% (P < 0.01). After endotoxin, the aortic blood flow decreased by 27% (P < 0.01) and after TNF alpha by 18% (P < 0.001). Both specific thromboxane inhibition and indomethacin abolished the TNF alpha central hemodynamic effect. The renal blood flow (-53%), the renal fraction of the aortic blood flow (-38%), and the glomerular filtration rate (-47%, P < 0.05) decreased 1 hr after endotoxin injection. In contrast, TNF alpha induced only a slight fall of the renal fraction of the aortic blood flow (-19%) after 2.5 hr. Glomerular filtration was not modified after TNF alpha injection most likely because of a 17% mean increase of filtration fraction in this group (P < 0.001). These data indicate that TNF alpha is implicated in the early hemodynamic changes of endotoxemic shock.(ABSTRACT TRUNCATED AT 250 WORDS)