thromboxane-a2 and ridogrel

Aspirin, by nonselectively blocking cyclooxygenase both in platelets and in endothelial cells, not only inhibits the thromboxane A2 pathway of platelet activation but at the same time also the generation of vasodilating and platelet-inhibitory prostanoids, such as prostacyclin, by the endothelial cells. Ridogrel, by inhibiting thromboxane A2 synthase and blocking the thromboxane A2/prostaglandin endoperoxide receptors, is a more potent antiplatelet agent than aspirin and might offer an advantage over aspirin as an adjunct to thrombolysis. This study was performed to compare the efficacy and safety of ridogrel with that of aspirin as conjunctive therapy for thrombolysis in patients with acute myocardial infarction.. A total of 907 patients with acute myocardial infarction were randomized between aspirin and ridogrel given in addition to streptokinase (1.5 MU over a period of 1 hour). The primary end point was coronary patency (TIMI flow grades 2 and 3) at predischarge angiography to be performed between 7 and 14 days after admission. A patent infarct-related vessel was found in similar proportions of patients in the two treatment groups: 72.2% in the ridogrel and 75.5% in the aspirin group. The presence of clinical markers of reperfusion at 2 hours and the incidence of major clinical events during hospital stay were also similar in both groups. However, in a post hoc analysis, a lower incidence of new ischemic events (reinfarction, recurrent angina, ischemic stroke) was observed with ridogrel: 13% versus 19% in the aspirin group (a 32% reduction; P < .025). No excess of serious bleeding complications, including hemorrhagic stroke, was found.. Ridogrel is not superior to aspirin in enhancing the fibrinolytic efficacy of streptokinase but might be more effective in preventing new ischemic events.

Topics: Aged; Aspirin; Coronary Angiography; Female; Humans; Male; Middle Aged; Myocardial Infarction; Pentanoic Acids; Pyridines; Receptors, Prostaglandin; Receptors, Thromboxane; Thrombolytic Therapy; Thromboxane A2; Thromboxane B2; Thromboxane-A Synthase; Treatment Outcome; Vascular Patency

To determine the role of endothelium-derived contracting factor (EDCF) in the response to endothelin-1 in arteries with regenerated endothelium.. Rings of porcine coronary arteries, with and without endothelium of previously deendothelialized left anterior descending coronary arteries and native left circumflex coronary arteries, were suspended in conventional organ chambers for the measurement of isometric force.. In quiescent rings of the previously deendothelialized left anterior descending coronary artery treated with the NO-synthase inhibitor nitro-L-arginine, endothelin-1 caused contractions which were larger in rings with than that in those without endothelium. Under the same experimental conditions, in the left circumflex coronary artery, the contractions to endothelin-1 were augmented markedly by the removal of the endothelium. In rings with endothelium of the previously deendothelialized left anterior descending coronary artery, indometacin (inhibitor of cyclooxygenase) and ridogrel (thromboxane A2 receptor antagonist and inhibitor of thromboxane synthase) inhibited contractions to endothelin-1. Dazoxiben (inhibitor of thromboxane synthase) inhibited, to the same extent as indometacin and ridogel, the response to higher concentrations of endothelin-1. The endothelium-dependent component of the response to lower concentrations of endothelin-1 was inhibited by indometacin and ridogrel, but not by dazoxiben. In rings without endothelium of both previously deendothelialized left anterior descending and native left circumflex coronary arteries, indometacin and ridogrel did not affect the contractions to endothelin-1.. These findings suggest that in regenerated endothelium, high concentrations of endothelin-1 stimulate the release of thromboxane A2. Endoperoxides generated by activation of endothelial cyclooxygenase may be the endothelium-derived contracting factor(s) released in regenerated endothelium by lower concentrations of the peptide.

Topics: Animals; Coronary Vessels; Cyclooxygenase Inhibitors; Endothelin-1; Endothelium, Vascular; Imidazoles; Indomethacin; Male; Muscle Contraction; Muscle, Smooth, Vascular; Nitric Oxide Synthase; Nitric Oxide Synthase Type III; Nitroarginine; Pentanoic Acids; Pyridines; Swine; Thromboxane A2; Thromboxane-A Synthase

Inhibition of nitric oxide (NO) synthesis induces vasoconstriction and reduction of the blood flow in the brain, indicating that basal release of NO provides a resting vasorelaxant tone in the cerebral circulation. In the present study, the contractile effect of the NO synthase blocker NG-nitro-L-arginine (100 mumol/L) in isolated rat middle cerebral arteries was attenuated markedly in the presence of the cyclooxygenase inhibitor indomethacin (5 mumol/L), the thromboxane A2 synthase inhibitor ridogrel (10 mumol/L), or the thromboxane receptor antagonist ICI 192605 (100 mumol/L). These results indicate that removal of the endogenous NO stimulates the release of thromboxane A2 in cerebral vessels and basal NO production regulates the resting cerebrovascular tone, at least in part, by suppressing thromboxane A2.

Topics: Animals; Cerebral Arteries; Cyclooxygenase Inhibitors; Dioxanes; Enzyme Inhibitors; Indomethacin; Male; Muscle Contraction; Nitric Oxide; Nitric Oxide Synthase; Nitroarginine; Pentanoic Acids; Pyridines; Rats; Rats, Wistar; Thromboxane A2; Thromboxane-A Synthase

Platelet aggregation at sites of vascular injury releases both peptide growth factors and vasoactive compounds. Although significant attention has been focused on peptide growth factors, very little is known about the mitogenic effect of vasoactive compounds. We evaluated the effect of serotonin (5-HT) and thromboxane A2 (TXA2) mimetic U46619 alone and in combination on aortic endothelial cells. Stimulation of endothelial cells by 5-HT resulted in an increase in tritiated thymidine uptake and an increase in cell number, whereas U46619 did not have any significant effect. However, when endothelial cells were exposed to both compounds, U46619 potentiated the mitogenic effect of 5-HT on endothelial cells. When endothelial cells were preincubated with LY281067 (a 5-HT2 receptor antagonist) or ridogrel (a combined TXA2 synthase inhibitor and receptor antagonist), LY281067 blocked the mitogenic effect of 5-HT and ridogrel blocked the potentiating effect of U46619 on 5-HT2-induced tritiated thymidine incorporation. When endothelial cells were preincubated with both antagonists, the effects of both 5-HT and U46619 were blocked. Recent studies have indicated that regenerating endothelial cells at sites of vascular injury may release growth factors for vascular smooth muscle cells, leading to smooth muscle cell proliferation and development of neointima. This study suggests that the combined use of 5-HT and TXA2 receptor antagonists may inhibit the growth of endothelial cells at sites of vascular injury and attenuate the formation of neointima.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Animals; Cell Division; Cells, Cultured; Disease Models, Animal; Endothelium, Vascular; Lysergic Acid; Male; Muscle, Smooth, Vascular; Pentanoic Acids; Platelet Aggregation; Pyridines; Rabbits; Serotonin; Serotonin Antagonists; Thromboxane A2; Thromboxane-A Synthase; Thymidine; Vasoconstrictor Agents

Ridogrel is a dual acting thromboxane synthase inhibitor/TP receptor antagonist. We examined the effects of single and multiple doses on systolic blood pressure in stroke-prone spontaneously hypertensive rats. Single doses of ridogrel (5 to 125 mg/kg) did not affect systolic blood pressure or furosemide-stimulated excretion rates of thromboxane B2 or 6-keto-prostaglandin F1alpha, although ex vivo serum thromboxane B2 was dose-dependently reduced up to 95%. In contrast, repeated dosing (7 days) with ridogrel (3 to 25 mg/kg/day), had an antihypertensive effect in 12-week-old stroke-prone spontaneously hypertensive rats. At 25 mg/kg/day, ridogrel reduced systolic blood pressure from 200+/-6.1 to 173+/-6.7 mmHg (n=12, P<0.01). Ridogrel dose-dependently reduced serum thromboxane B2 and increased plasma renin activity. Unlike single doses, repeated dosing reduced urinary thromboxane B2 excretion (from 103+/-7 ng/day to 49+/-10 ng/day, P<0.01) while preserving 6-keto-prostaglandin F1alpha excretion. Ketoprofen, a cyclo-oxygenase inhibitor, (10 mg/kg/day for 7 days), depressed urine 6-keto-prostaglandin F1alpha in addition to attenuating serum and urine thromboxane B2. Ketoprofen prevented the antihypertensive effects of ridogrel. Ridogrel did not lower systolic blood pressure in Sprague-Dawley rats. We conclude that the antihypertensive effect of ridogrel involves preserving renal prostaglandin synthesis during thromboxane attenuation.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Antihypertensive Agents; Blood Pressure; Dose-Response Relationship, Drug; Enzyme Inhibitors; Female; Hypertension; Male; Pentanoic Acids; Pyridines; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Rats, Sprague-Dawley; Receptors, Thromboxane; Systole; Thromboxane A2; Thromboxane-A Synthase

Previous work suggests that cod liver oil helps to protect the microcirculation from the consequence of thromboembolic events. The possibility that altered synthesis of thromboxane A2 accounts for the protective effects seen with cod liver oil was investigated in the present study. This was done using the combined thromboxane A2 synthetase inhibitor and thromboxane A2-prostaglandin H2 receptor blocker R68070 (Ridogrel). A standardized microvascular injury was inflicted on the right iliac artery of the rat to generate emboli. The downstream cremaster muscle was used to visualize the passage of the ensuing emboli and to assess the effects of this arterial injury on capillary perfusion and arteriole diameters. The number of visible emboli was not changed by either cod liver oil diet or Ridogrel administration. However, capillary perfusion was preserved by using cod liver oil (n = 7) and was significantly increased by using Ridogrel (n = 7) in comparison with untreated controls (n = 7) in which capillary perfusion was decreased because of the emboli. The administration of Ridogrel to cod liver oil-treated animals (n = 7) provided no additive benefit. The percentage change in A-2 vessel diameters in cod liver oil-treated (n = 7) animals was no different from the control group (n = 7). Ridogrel (n = 7), on the other hand, produced a significant increase in A-3 vessel (n = 21) diameters, but its effects were comparatively less in the cod liver oil-treated animals (n = 7). The formation of platelet aggregates (emboli) appears relatively independent of thromboxane A2 in the rat. Ridogrel is very effective in protecting the microcirculation, and these effects appear to be mediated by A-3 vasodilatation, which, therefore, is at least partially thromboxane A2-dependent. The positive effects of cod liver oil may be mediated by a mechanism that reduces thromboxane A2 synthesis, but further studies are necessary.

Topics: Animals; Arterioles; Cod Liver Oil; Embolism; Enzyme Inhibitors; Iliac Artery; Male; Microcirculation; Muscle, Skeletal; Pentanoic Acids; Pyridines; Rats; Rats, Sprague-Dawley; Thromboxane A2; Thromboxane-A Synthase

To investigate the nature of the arachidonic acid metabolite involved in the altered reactivity of microvessels of two-kidney, one-clip hypertensive rats and the possible contribution of this product to the elevated blood pressure levels found in two-kidney, one-clip hypertension, mesenteric arterioles either perfused in vitro or studied in vivo were used along with blood pressure determinations. The decreased response to acetylcholine observed was normalized by ridogrel, a thromboxane A2 receptor antagonist, and dazoxiben, a thromboxane A2 synthase inhibitor. The smooth muscle response to nitric oxide, tested with sodium nitroprusside, was unaltered in two-kidney, one-clip hypertensive microvessels. Neither ridogrel nor dazoxiben modified the response to this vasodilator. In contrast, the potentiated response to noradrenaline was corrected by ridogrel and dazoxiben in vitro but not in vivo. Noradrenaline and acetylcholine increased the release of thromboxane A2 from the mesenteric microvessels of two-kidney, one-clip hypertensive rats. Ridogrel and dazoxiben decreased but did not normalize the elevated blood pressure of hypertensive rats. Based on these results, we concluded that: 1) the decreased responsiveness of smooth muscle to acetylcholine resulted from an increase in thromboxane A2 formation rather than a decrease in sensitivity to nitric oxide; 2) thromboxane A2 contributes to the increased noradrenaline response in mesenteric microvessels perfused in vitro while in in vivo other blood borne vasoactive agents may also be involved since the potentiated noradrenaline response was not corrected by inhibiting thromboxane A2 synthesis or receptors; 3) in addition to thromboxane A2, another as yet unidentified factor, may contribute to the elevated blood pressure in two-kidney, one-clip hypertension.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Animals; Arterioles; Enzyme Inhibitors; Hypertension, Renovascular; Imidazoles; Male; Mesentery; Microcirculation; Nitric Oxide; Nitroprusside; Pentanoic Acids; Perfusion; Pyridines; Rats; Rats, Wistar; Receptors, Prostaglandin; Receptors, Thromboxane; Receptors, Thromboxane A2, Prostaglandin H2; Renal Circulation; Thromboxane A2; Thromboxane-A Synthase; Vascular Resistance; Vasoconstrictor Agents

Platelets from familial hypercholesterolaemia type IIa patients are hyperreactive and produce increased amounts of thromboxane A2. These modifications of platelet function may play an important role in the occurrence of premature atherosclerosis. One approach to the prevention of the thromboembolic complications of atherosclerosis is the use of antiplatelet agents which depress platelet function. Ridogrel, a combined thromboxane synthase inhibitor and thromboxane A2/prostaglandin endoperoxide receptor blocker inhibits platelet aggregation. This study was designed to investigate the in vitro effect of ridogrel on platelet function in normocholesterolaemic and familial hypercholesterolaemia type IIa subjects. In citrated platelet rich plasma ridogrel significantly inhibited platelet aggregation and thromboxane A2 production in response to collagen, ADP and arachidonic acid stimulation. In washed platelets ridogrel significantly decreased aggregation and serotonin release. Ridogrel significantly increased cAMP levels in response to thrombin stimulation. In conclusion, ridogrel at low concentrations significantly inhibited the in vitro function of platelets in a dose dependant manner in both normocholesterolaemic subjects and familial hypercholesterolaemia IIa subjects.

Topics: Adult; Blood Platelets; Enzyme Inhibitors; Humans; Hyperlipoproteinemia Type II; In Vitro Techniques; Middle Aged; Pentanoic Acids; Platelet Aggregation Inhibitors; Pyridines; Thromboxane A2; Thromboxane B2; Thromboxane-A Synthase

To investigate dilator effects of endothelins (ETs) on the pulmonary circulation and possible changes induced by chronic hypoxia, we examined vascular responses to ET-1 and ET-3 as well as ET binding to receptor subtypes ETA and ETB in the lungs from rats exposed to either room air (controls), hypoxia (10% O2) for 3 wk (3 WH), or 3 WH followed by recovery to room air (3 WH+R). In controls, both ETA and ETB receptor binding was present in smooth muscle of airways and vessels. Infusion of ET-1 or ET-3 (3-100 pM) to isolated perfused lungs preconstricted by U-46619 produced dose-dependent vasodilation with a greater potency of ET-3 (P < 0.01). The vasodilator responses to ET-1 and ET-3 were potentiated by the cyclooxygenase blocker meclofenamate (3 x 10(-6) M) or by the thromboxane synthetase inhibitor R-68070. In meclofenamate-treated lungs, the vasodilator responses to ET-1 and ET-3 remained unaffected by the inhibitor of nitric oxide synthesis, NG-monomethyl-L-arginine (5 x 10(-4) M) or by the guanylate cyclase inhibitor, methylene blue (10(-4) M). Conversely, the K+ channel blockers glibenclamide (10(-4) M) and tetraethylammonium (10(-4) M) attenuated the vasodilator responses to both ET-1 and ET-3. The selective ETA receptor antagonist BQ-123 did not alter ET-induced vasodilation, whereas it attenuated ET-induced vasoconstriction. Vasodilation to both ET-1 and ET-3 was abolished in lungs from 3 WH rats (P < 0.01) but was fully restored in lungs from 3 WH+R rats. Pulmonary vasodilation induced by the K+ channel opener pinacidil, which was suppressed by glibenclamide, did not differ between controls and 3 WH rat lungs. We found no change in ETA and ETB receptor binding from pulmonary vessels in H rat lungs compared with controls. In conclusion, endothelin-induced pulmonary vasodilation which may involve activation of K+ channels is abolished during chronic hypoxia. This abolition does not appear to be related to alterations in ET-receptor subtypes or to unresponsiveness of K+ channels in the pulmonary circulation.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Animals; Arginine; Autoradiography; Dose-Response Relationship, Drug; Endothelins; Glyburide; Guanidines; Hypoxia; In Vitro Techniques; Iodine Radioisotopes; Lung; Male; Meclofenamic Acid; Nitroarginine; Pentanoic Acids; Pinacidil; Potassium Channel Blockers; Prostaglandin Endoperoxides, Synthetic; Pulmonary Circulation; Pyridines; Rats; Rats, Wistar; Receptors, Endothelin; Tetraethylammonium; Tetraethylammonium Compounds; Thromboxane A2; Thromboxane-A Synthase; Vasoconstrictor Agents; Vasodilation; Vasodilator Agents

The effects of ridogrel, a dual thromboxane A2 (TXA2) synthase inhibitor and TXA2/prostaglandin (PG) endoperoxide receptor antagonist, on systemic and renal production of prostaglandins and on platelet TXA2/PG endoperoxide receptors was evaluated upon chronic administration (300 mg b.i.d. orally, for 8 and 29 days) to man. Such a medication with ridogrel inhibits the systemic as well as the renal production of TXA2 as measured by the urinary excretion of 2,3-dinor-TXB2 and TXB2 respectively without inducing significant changes in systemic or renal PGI2 production. Simultaneously with the latter effects, the production of TXB2 by spontaneously coagulated whole blood ex vivo is inhibited (greater than 99%) while that of PGE2 and PGF2 alpha is largely increased. Administration of ridogrel causes a three- to five-fold shift to the right of concentration-response curves for U46619 in eliciting platelet aggregation; no tachyphylaxis is observed after 29 days of treatment in this respect. Apart from a reduction of serum uric acid levels with a concomitant increase in urinary uric acid excretion during the first days of treatment, no clinically significant changes in hematological, biochemical, hemodynamic and coagulation parameters occur during the 8 days or 29 days study. The study demonstrates that ridogrel is a potent inhibitor of the systemic as well as renal TXA2 synthase and an antagonist of platelet TXA2/PG endoperoxide receptor in man, covering full activity during 24 h at steady-state plasma level conditions without tachyphylaxis during 29 days of medication. The compound is well tolerated, at least during 1 month of administration.

Topics: Adult; Blood Platelets; Drug Evaluation; Drug Tolerance; Humans; Kidney; Male; Middle Aged; Pentanoic Acids; Platelet Aggregation; Platelet Aggregation Inhibitors; Prostaglandins; Pyridines; Receptors, Prostaglandin; Receptors, Thromboxane; Safety; Thromboxane A2; Thromboxane-A Synthase

Arterial expanded polytetrafluoroethylene (ePTFE) grafts were interpositioned in the common carotid arteries of 20 adult sheep. This model was used to study the effect of a combined thromboxane receptor- and synthesis-antagonist, Ridogrel (R 68070), on acute graft patency and platelet, fibrinogen and leucocyte uptake. The animals were randomised to treatment (n = 10) or control groups (n = 10). Treatment was given as an intravenous injection with Ridogrel of 8 mg kg body weight-1. The flow in one of the two inserted grafts was restricted to 25 ml min-1. Autologous 111In-labelled platelets, 125I-labelled fibrinogen and 99m-Tc-labelled leucocytes were injected intravenously and the radioactivity over the vessels measured before and after graft insertion using the gamma scintillation technique. After graft insertion the measurements continued for 4 h at two separate points over the proximal and distal anastomosis areas. In the treatment group six out of 10 grafts with restricted flow remained patent compared with nine out of 10 grafts with flow reduction in the control group (N.S.). The median thrombus weights did not differ significantly. There was no difference in the platelet and fibrinogen activities at the proximal anastomosis but distally the animals receiving treatment had a significant reduction during the first 2 h of the experiment. The leucocyte activity in the treatment group compared to the control group did not differ proximally but distally the activity was significantly higher during the last 3 h of the experiment. In the group with unrestricted flow all grafts in both groups remained patent. The thrombus weight was significantly lower in the treatment group compared with the control group.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Blood Flow Velocity; Blood Vessel Prosthesis; Fibrinogen; Graft Occlusion, Vascular; Leukocyte Count; Pentanoic Acids; Platelet Adhesiveness; Polytetrafluoroethylene; Pyridines; Receptors, Prostaglandin; Receptors, Thromboxane; Thromboxane A2; Thromboxane-A Synthase; Vascular Patency

Ridogrel [(E)-5-[[[(3-pyridinyl)[3-(trifluoromethyl)phenyl] methylene]amino]oxy] pentanoic acid] is a potent inhibitor of the P450-dependent human platelet thromboxane A2 (TxA2) synthase. Fifty percent inhibition is already achieved at 5.0 +/- 0.37 nM. This IC50 value is close to half the P450 concentration used, i.e. 10.7 nM. Ridogrel binds to human platelet microsomal P450 as proven by the type II spectral changes induced by the addition of increasing concentrations of ridogrel to solubilized microsomes. The calculated half-maximal spectral change (SC50 value) is 3.78 +/- 1.79 nM. These results indicate that ridogrel binds stoichiometrically and suggest that inhibition of thromboxane synthesis may originate from liganding of its basic nitrogen to the haem-iron of P450 and from the attachment of the hydrophobic carboxylic side chain to or near the substrate binding place. Ridogrel is a selective inhibitor of the TxA2 synthase. At a high concentration (10 microM), ridogrel has a slight, if any, effect on the P450-mediated cholesterol synthesis in human liver and hepatoma cells and androgen synthesis from 17 alpha-hydroxy-20-dihydroprogesterone or pregnenolone in subcellular fractions from rat testes. These results indicate that ridogrel is a poor inhibitor of the P450-dependent 14 alpha-demethylase, 17 alpha-hydroxylase and 17,20-lyase. It has, up to 10 microM, no effect on the adrenal mitochondrial 11 beta-hydroxylase and cholesterol side-chain cleavage enzyme and does not inhibit aromatase activity in human placental microsomes. Ridogrel has no significant effect on the regio- and stereoselective P450-dependent oxidations of testosterone in liver microsomes from unpretreated or from 5-pregnen-3 beta-ol-20-one-16 alpha-carbonitrile-, phenobarbital- or 3-methylcholanthrene-pretreated male and female Sprague-Dawley rats. It does not interfere with the reduction of testosterone into 5 alpha-dihydrotestosterone and 5 alpha androstane 3 beta, 17 beta-diol.

Topics: Androgens; Animals; Blood Platelets; Cholesterol; Cytochrome P-450 Enzyme Inhibitors; Dose-Response Relationship, Drug; Female; Humans; Male; Microsomes; Pentanoic Acids; Pyridines; Rats; Rats, Inbred Strains; Spectrophotometry, Ultraviolet; Subcellular Fractions; Testosterone; Thromboxane A2; Thromboxane-A Synthase

When injected i.v. to guinea pigs, the granulocyte secretagog N-formyl-L-methionyl-L-leucyl-L-phenylalanine (fMLP) induces bronchoconstriction (BC), lung platelet sequestration and increased transendothelial albumin exchanges in lungs. We evaluated BC and the variations of the lung contents in radiolabeled platelets, erythrocytes and extravascular albumin, as measurements of platelet lung entrapment, reduction of lung blood volume and increase of transendothelial albumin exchanges, respectively. Trimetoquinol, a thromboxane A2 (TXA2)-endoperoxide receptor antagonist, inhibited BC and platelet entrapment by lungs induced by fMLP, but protection was nonspecific because it also suppressed BC by histamine. The specific TXA2 synthetase inhibitor/endoperoxide receptor antagonist ridogrel suppressed BC and reduced lung platelet entrapment, but failed to prevent the increase of extravascular albumin and the decrease of erythrocyte lung contents due to fMLP. Consequently, the fMLP-induced increase of vascular albumin exchanges and reduction of lung blood volume are TXA2-independent. Aspirin prevented BC, but failed to suppress lung platelet entrapment by fMLP, indicating that in vivo platelet activation is not TXA2-dependent, even though the levels of circulating TXB2, the stable metabolite of TXA2, were increased after fMLP concomitantly with that of 6-keto-prostaglandin (PG)F1 alpha, the stable metabolite of PGI2. The ridogrel-treated animals showed reduced blood level of TXB2 and increased levels of 6-keto-PGF1 alpha after fMLP challenge. Blocking the cyclooxygenase pathway with aspirin prevented ridogrel-induced protection against lung platelet sequestration after fMLP, supporting the concept that rechanneling of arachidonate metabolism toward protective prostaglandins accounts for protection by ridogrel.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; 6-Ketoprostaglandin F1 alpha; Animals; Arachidonic Acid; Blood Platelets; Bronchoconstriction; Guinea Pigs; Imidazoles; Lung; N-Formylmethionine Leucyl-Phenylalanine; Pentanoic Acids; Platelet Aggregation; Prostaglandin Endoperoxides, Synthetic; Pyridines; Radioimmunoassay; Serum Albumin; Suprofen; Thrombocytopenia; Thromboxane A2; Thromboxane B2; Thromboxane-A Synthase; Tretoquinol

The thromboxane A2 (TXA2) plasma level in kappa-carrageenin (KC)-induced acronecrosis in the rat tail has been studied. TXB2 as stable metabolite of TXA2 was determined by a radioimmunoassay (RIA). 30 min after KC i.v. injection, the increase in the plasma TXB2 level was highest in Barby:Wistar rats but not in Halle:Wistar rats. Lambda-carrageenin (LC) increased the TXB2 levels in both strains of Wistar rats, although it did not induce acronecrosis. Drugs inhibiting TXB2 formation, namely dexamethasone, acetylsalicylic acid, Hoe 944, R 68070 or chlorpromazine, had only a small effect on acronecrosis frequency. Heparin inhibited TXB2 formation and acronecrosis frequency while the serotonin antagonist cyproheptadine decreased only the acronecrosis frequency but caused no change in TXB2 plasma level. These data demonstrate that the kappa-carrageenin-induced acronecrosis is followed by an increased formation of TXA2 in rats.

Topics: Animals; Aspirin; Carrageenan; Chlorpromazine; Dexamethasone; Heparin; Imidazoles; Naphthalenes; Necrosis; Pentanoic Acids; Pyridines; Radioimmunoassay; Rats; Rats, Inbred Strains; Thromboxane A2; Thromboxane B2

Perfusion of isolated rabbit lungs with hydrogen peroxide (H2O2, 3 x 10(-5) M) raised the overflow of thromboxane B2 (TXB2) and the perfusion pressure. H2O2 induced oedema formation and endothelial distress, as evidenced by an increased production of 6-oxo-prostaglandin F1 alpha (6-oxo-PGF1 alpha). Endothelial cell death did not occur since there was no release of lactate dehydrogenase. The thromboxane A2 (TXA2)-synthase inhibitor/receptor antagonist ridogrel (R68070) further enhanced 6-oxo-PGF1 alpha output, while inhibiting TXB2 release. Ridogrel prevented the rise in pulmonary artery pressure and oedema formation. These data indicate that TXA2 is probably involved in the acute pulmonary pressor response and concomitant oedema formation induced by H2O2. In order to assess the functional activity of the pulmonary endothelium, the uptake of 5-hydroxytryptamine (5-HT) was measured before and 15 min after exposure to H2O2. As the H2O2-induced effects were not associated with any change in the uptake of 5-hydroxytryptamine (5-HT), we conclude that the endothelial injury was reversible or that the 5-HT uptake was not sensitive enough to evaluate the integrity of the pulmonary endothelium during oxidant-induced injury.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Blood Pressure; Cell Death; Endothelium, Vascular; Female; Hydrogen Peroxide; L-Lactate Dehydrogenase; Lung; Pentanoic Acids; Pulmonary Edema; Pyridines; Rabbits; Serotonin; Thromboxane A2; Thromboxane-A Synthase

In open-chest dogs, cyclic flow reductions (CFRs, 5.1-6.6/hr in controls; n = 24) caused by platelet deposition/dislodgment at sites of endothelial cell injury in critically stenosed left anterior descending coronary arteries (59% flow reduction) were attenuated to the same extent either by single thromboxane A2 (TXA2) synthase inhibition (0.31 mg/kg i.v. ridogrel; CFR, 0.16 +/- 0.16/hr; n = 6; p less than 0.05) or by a comparatively modest degree of TXA2/prostaglandin endoperoxide receptor antagonism on top of TXA2 synthase inhibition (5 mg/kg i.v. ridogrel; CFR, 0.22 +/- 0.1/hr; n = 10; p less than 0.05). By contrast, occlusive thrombosis on deep vascular damage elicited by intraluminal stimulation (150-microA anodal constant current) in nonpreconstricted canine coronary arteries (time to occlusion, 237.1 +/- 13.9 minutes; n = 7; incidence of occlusion within 300 minutes, six of seven experiments) was not affected by platelet cyclooxygenase inhibition (5 mg/kg i.v. acetylsalicylic acid; n = 7), single TXA2 synthase inhibition (1.25 mg/kg i.v. ridogrel; n = 7), or single TXA2/prostaglandin endoperoxide receptor antagonism (10 mg/kg + 10 mg/kg/hr i.v. sulotroban for 300 minutes; n = 5). However, such an occlusive thrombus formation was significantly reduced by combined TXA2 synthase/prostaglandin endoperoxide receptor inhibition (5 mg/kg i.v. ridogrel; time to occlusion greater than 300 minutes, n = 7; incidence of occlusion within 300 minutes, one of seven experiments; p less than 0.05). This study reveals 1) a differential efficacy of TXA2 synthase inhibition, singly or combined with TXA2/prostaglandin endoperoxide receptor antagonism, depending on the extent of the vessel wall lesion triggering thrombosis and the size of the thrombus required to obstruct the vascular lumen and 2) a significant synergism in preventing occlusive thrombosis of extensively damaged coronary arteries between strong TXA2 synthase inhibition and comparatively modest TXA2/prostaglandin endoperoxide receptor antagonism with ridogrel.

Topics: Animals; Coronary Thrombosis; Coronary Vessels; Dogs; Endothelium, Vascular; Female; Hemodynamics; In Vitro Techniques; Male; Pentanoic Acids; Pyridines; Receptors, Prostaglandin; Receptors, Thromboxane; Sulfonamides; Thromboxane A2; Thromboxane-A Synthase

Two ventral skin flaps were raised in each of 60 rats and viability was assessed 48 h after operation. Twenty animals served as controls and immediately preoperatively 20 received an intraperitoneal injection of either 5 mg/kg body weight ridogrel, a combined thromboxane synthesis inhibitor and receptor blocker, or 4 mg/kg forskolin, a cAMP stimulator. The mean total and surviving flap areas measured 14.3 +/- 1.4 and 10.1 +/- 3.2 cm2 respectively for the control group. In the treated groups it was 16.4 +/- 1.3 cm2 and 15.6 +/- 2.6 cm2 for ridogrel and 17.8 +/- 1.1 cm2 and 15.8 +/- 4.3 cm2 for forskolin respectively. The differences between the areas of each treated group and the control group were statistically significant (p less than 0.0001). It can be concluded that both ridogrel and forskolin afford protection against skin necrosis probably because of improved conditions in the microcirculation due to reduced platelet aggregation in the vasculature of the distal part of the flap.

Topics: Animals; Colforsin; Graft Survival; Male; Microcirculation; Pentanoic Acids; Pyridines; Rats; Rats, Inbred Strains; Receptors, Prostaglandin; Receptors, Thromboxane; Skin; Surgical Flaps; Thromboxane A2; Valerates

The purpose of this study was to test the hypothesis that combined thromboxane A2 synthetase inhibition and receptor blockade is superior to either action alone in preventing cyclic flow variations in stenosed and endothelially injured canine coronary arteries. Forty-five dogs developed coronary cyclic flow variations after a plastic constrictor was placed around the left anterior descending coronary artery at the site where the endothelium was injured and received different interventions. In Group I, 17 dogs were treated with SQ 29,548, a thromboxane A2-prostaglandin H2 receptor antagonist. In Group II, 11 dogs received dazoxiben, a thromboxane A2 synthetase inhibitor. In Group III, R 68,070, a dual thromboxane A2 synthetase inhibitor and thromboxane A2-prostaglandin H2 receptor antagonist, was administered to 11 dogs. Group IV comprised six dogs that received aspirin before receiving R 68,070. Complete abolition of cyclic flow variations was achieved in 71% of dogs in Group I, 82% in Group II, 100% in Group III (p = 0.06 compared with Group I) and 50% in Group IV (p = 0.03 compared with Group III). Epinephrine was infused into dogs with abolished cyclic flow variations: all dogs in Group I had cyclic flow variations restored, 44% in Group II (p = 0.01 compared with Group I) and 64% in Group III (p = 0.04 compared with Group I). The plasma epinephrine levels required to restore cyclic flow variations were 2.2 +/- 0.5 ng/ml (control 0.04 +/- 0.01) in Group I, 8.7 +/- 4.5 ng/ml (control 0.05 +/- 0.02) in Group II and 7.4 +/- 2.6 ng/ml (control 0.07 +/- 0.02) in Group III.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Aspirin; Bridged Bicyclo Compounds, Heterocyclic; Coronary Circulation; Coronary Disease; Dogs; Epinephrine; Epoprostenol; Ergolines; Fatty Acids, Unsaturated; Female; Hydrazines; Imidazoles; Male; Pentanoic Acids; Pyridines; Receptors, Prostaglandin; Receptors, Thromboxane; Serotonin Antagonists; Thromboxane A2; Thromboxane-A Synthase

Topics: Animals; Arachidonic Acid; Arachidonic Acids; Blood Platelets; Humans; In Vitro Techniques; Pentanoic Acids; Platelet Aggregation; Prostaglandin Endoperoxides; Pyridines; Rats; Receptors, Prostaglandin; Receptors, Thromboxane; Thromboxane A2; Thromboxane-A Synthase; Valerates

The effects of R-68070 were studied in a well-characterized model of drum-induced traumatic shock in rats. R-68070 is a combination thromboxane A2 (TxA2) synthetase inhibitor-TxA2 receptor antagonist. Pentobarbital-anesthetized (50 mg/kg) rats subjected to Noble-Collip drum trauma developed a lethal circulatory shock state characterized by a marked decrease in mean arterial blood pressure (MABP) to about 75 mmHg, resulting in a survival time of 1.58 +/- 0.18 h. This compares with MABP of 120 +/- 4 mmHg 5 h after anesthetization in rats subjected to a sham traumatic shock protocol. Administration of R-68070 (1.5 mg/kg) significantly attenuated the plasma accumulation of the lysosomal protease, cathepsin D (p less than 0.05), as well as free amino-nitrogen concentration (p less than 0.05) and myocardial depressant factor activity (p less than 0.02). Additionally, R-68070 significantly prolonged survival time to 2.85 +/- 0.48 h (p less than 0.015) compared with traumatized rats given only the vehicle. These results suggest that TxA2 may be an important mediator in traumatic shock, and that R-68070 may prove to be a useful therapeutic agent in this situation if given early in the course of the shock state.

Topics: Animals; Cathepsin D; Male; Myocardial Depressant Factor; Pentanoic Acids; Pyridines; Rats; Rats, Inbred Strains; Receptors, Prostaglandin; Receptors, Thromboxane; Shock, Traumatic; Thromboxane A2; Thromboxane-A Synthase; Valerates