Selective Thromboxane Synthetase Inhibitor Research Articles

Thromboxane synthetase inhibition with CGS 13080 improves coronary blood flow after streptokinase-induced thrombolysis

The focus of this investigation was to examine the potential beneficial effects of the selective thromboxane synthetase inhibitor CGS 13080 (imidazo [1,5-a] pyridine-5-hexanoic acid) on coronary blood flow after streptokinase-induced thrombolysis. Thrombotic occlusion of the circumflex coronary artery was produced by electrolytic (100 μA anodal current) injury to the intimal surface of the circumflex coronary artery at the site of a noncircumferential stenosis in dogs anesthetized with pentobarbital to have open-chest surgery. Intracoronary streptokinase, 6000 IU/kg in 3 ml saline solution, was infused at 0.05 ml/min for 1 hour, beginning 30 minutes after the formation of an occlusive thrombus. The animals were assigned randomly to two groups. In group I (n = 10) the intravenous infusion of vehicle was begun simultaneously with the intracoronary administration of streptokinase and continued for 2 hours after thrombolysis had been achieved. The animals in group II (n = 10) received intravenous CGS 13080 (1 mg/kg/hr) along with intracoronary streptokinase. Infarct size was assessed by a dual perfusion technique with Evans blue and triphenyltetrazolium stains to demarcate the normally perfused myocardium from the area at risk and the infarct zone within the risk region. The two groups did not differ with respect to baseline coronary blood flow, time to the development of coronary artery thrombotic occlusion, or time to achieve thrombolysis. Oscillations in coronary blood flow were more frequent in group I than in group II (group I, 9 ± 2.2; group II, 4.4 ± 0.8 oscillation/min × 100, p < 0.05 [mean ± SEM]). Reocclusion was observed more frequently in group I than in group II (8 of 10 [80%] vs 2 of 10 [20%], p < 0.05). Infarct size expressed as a percent of the total left ventricular mass was similar ([IZLV] group I, 5% ± 2%; group II, 4% ± 1%), as was the percent of the left ventricle dependent on the blood flow distribution from the left circumflex coronary artery or the area at risk of infarction ([ARLV] 37% ± 2% vs 40% ± 3%, respectively). These results demonstrate that the thromboxane synthetase inhibitor CGS 13080, in combination with the thrombolytic agent streptokinase, is able to maintain patency of the injured coronary artery after thrombolysis and to decrease the frequency of oscillatory flow responses. The results suggest a possible role for thromboxane as a contributor to the process of thrombotic reocclusion after successful thrombolysis.

Effects of a selective thromboxane synthetase inhibitor (OKY-046) in patients with coronary artery disease during exercise.

We studied the levels of thromboxane B2 (TXB2), 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha), platelet aggregability, beta-thromboglobulin and platelet factor 4 in 30 coronary artery disease (CAD) patients and 21 normal subjects during exercise. During treadmill exercise, 13 of 30 CAD patients reported chest pain. We administered a selective thromboxane synthetase inhibitor (OKY-046) for 2 weeks to 10 CAD patients with exercise-induced chest pain and studied its effects. At rest, the plasma TXB2 levels and platelet aggregation were significantly lower in normal subjects than in CAD patients, and there was no difference between CAD patients with and without exercise-induced chest pain. On treadmill testing, plasma TXB2 levels and platelet aggregation increased significantly only in the CAD patients with exercise-induced chest pain. Plasma 6-keto-PGF1 alpha levels in normal subjects were significantly higher than those in CAD patients both at rest and during exercise. After administration of OKY-046, mean exercise time increased significantly from 7.5 to 8.6 min (p less than 0.001). Plasma TXB2 level and platelet aggregation decreased significantly after OKY-046 administration both at rest and during exercise. These results suggest that a marked increase in TXA2, with only a minimal change in PGI2, during exercise may contribute to exercise-induced myocardial ischemia, and that OKY-046 is useful in the treatment of CAD patients.

Potentiation of bradykinin-induced nociceptive response by arachidonate metabolites in dogs

Bradykinin was injected retrogradely into a branch of the splenic artery of lightly anesthetized dogs, and the reflex hypertensive response was used as an indicator of the nociception. The reflex hypertensive response to low doses of bradykinin (<1 nmol), but not to high doses (3–5 nmol), was markedly suppressed by infusion of indomethacin (0.54 μmol/min) into the splenic artery. During indomethacin infusion, The reflex hypertensive response to low doses of bradykinin was potentiated dose dependently by the following arachidonic acid metabolites (ED 50): prostaglandin (PG)I 2 (2.9 nmol) ≥ PGH 2 (4.4) > PGE 2 (14) = thromboxane (TX)A 2(15) > PGD 2(> 100). Leukotrienes B 4, C 4 and D 4 showed practically no activity. This potentiating effect lasted up to 20 min after injection, particularly with PGE 2. These results may not exclude the role of PGI 2 as a major candidate for involvement in bradykinin-induced nociception, although a selective TX synthetase inhibitor (OKY-046) showed a weak analgesic effect (only 1 30 that of indomethacin).

Effects of a thromboxane synthetase inhibitor (OKY-046) and a lipoxygenase inhibitor (AA-861) on bronchial responsiveness to acetylcholine in asthmatic subjects.

The effect of a selective thromboxane synthetase inhibitor, OKY-046, and a selective 5-lipoxygenase inhibitor, AA-861, on bronchial responsiveness to acetylcholine was studied in 23 asthmatic subjects. The provocative concentration of acetylcholine producing a 20% fall in forced expiratory volume in one second (PC20 FEV1) was measured before and after oral administration of OKY-046 (3000 mg over four days) and AA-861 (1100 mg over four days) and inhalation of OKY-046 (30 mg) in 10, 10, and nine asthmatic subjects respectively. Baseline values of FEV1 and forced vital capacity (FVC) were not altered by oral OKY-046, oral AA-861, or inhaled OKY-046. The geometric mean value of PC20 FEV1 increased significantly from 0.55 to 2.24 mg/ml after oral OKY-046, but was unchanged after inhalation of OKY-046 and after oral administration of AA-861. These results suggest that thromboxane A2 may play a part in bronchial hyperresponsiveness to acetylcholine.

The effect of the thromboxane synthetase inhibitor Dazmegrel (UK-38,485) on wound healing, dermal ink perfusion and skin blood flow measurements in deep partial thickness burns

A guinea-pig model was used to evaluate the effect of Dazmegrel (UK-38,485), a new highly selective inhibitor of thromboxane synthetase, on burn wound healing. Dazmegrel had a beneficial effect on wound healing when given systemically at a dosage of 3·4 mg kg −1day −1 but higher doses had no effect. There was no change in dermal perfusion measured by India ink injection or by 133Xe injection in any of the groups receiving parenteral Dazmegrel. Neither was the number of hair follicles in the healing burn wound significantly different between the treated and control animals. When Dazmegrel was applied topically, it inhibited wound healing. These findings are consistent with previous reports from different laboratories that prostaglandin inhibitors impair healing of the burn wound when applied topically but improve wound healing when given parenterally. The present study further suggested that the improvement in wound healing in this model was not mediated by improved dermal perfusion.

Effect of Dazmegrel (UK-38,485) on immune function in a burned guinea-pig model

We investigated the effects of Dazmegrel, a highly effective and selective thromboxane synthetase inhibitor, on the immune system in a bilateral 5 per cent total body surface area (TBSA) deep partial thickness scald in a guinea-pig model. The animals were randomized into two groups: one received Dazmegrel at 3·4mgkg 1 day 1 by i.m. injection; the other received the same volume of saline. Cell-mediated immunity was evaluated by the response to the hapten dinitrofluorobenzene (DNFB), as measured by ear swelling in response to cutaneous application. The ear swelling of the Dazmegrel-treated group was 52·8±3·8 per cent, compared to 41·4±2·4 per cent for the control group ( P<0.02). Neutrophil bactericidal function was determined on post-burn day (PBD) 7 and opsonic function on both post-burns days 7 and 22. The serum opsonic indices were nearly identical at both times, but the Dazmegrel-treated animals had a significantly improved neutrophil bactericidal index (1·15±0·05v. 1·68±0·17, P<0·01). Dazmegrel exerted a stimulating effect on the immune system in this burn model, improving neutrophil antibacterial function and cell-mediated immunity.

The role of the endothelium in arterial thrombosis and the influence of antithrombotic therapy

AbstractThe nonthrombogenicity of vascular endothelium, a single layer of cells separating blood‐borne platelets and thrombogenic components of the underlying subendothelium, results from more than its provision of a physical barrier. These cells synthesize and secrete prostacyclin, plasminogen activator, and inhibitors of the coagulation system. They also catabolize proaggregatory agents such as ADP and serotonin (5‐HT). Damage to or removal of the endothelium is, of course, a potent thrombogenic stimulus. We have employed an acute canine model of coronary arterial thrombosis, which combines vessel narrowing and intimal injury as stimuli for repetitive, regular occlusive thrombus formation. Of all agents tested by us and others in this model, prostacyclin, selective thromboxane (TXA2) synthetase inhibitors, and 5‐HT antagonists consistently inhibit thrombus formation. Available data suggest that the antithrombotic actions of TXA2 synthetase inhibitors result in part from vascular metabolism of platelet‐derived endoperoxides, as well as endogenous PGI2 production. Serotonin, alone, exerts weak proaggregatory effects. However, it uniquely amplifies the proaggregatory effects of many physiologic proaggregatory mediators. Serotonin2 antagonists are more potent and consistently antithrombotic in this canine model than TXA2 synthetase inhibitors.The discordance between the marked antithrombotic effects of 5‐ht antagonists and txa2 synthetase inhibitors in vivo and their weak antiaggregatory and proaggregatory effects in vitro, respectively, underscores the danger of relying exclusively upon in vitro platelet aggregatory behavior to assess either the potential importance of a mediator or antithrombotic efficacy of a new drug. On the basis of results obtained from our laboratory and others that employ similar in vivo models of thrombosis, we conclude that (1) since platelet aggregation in vivo is stimulated by many physiologic agonists, in vivo and in vitro, models of aggregation and thrombosis should reflect this; (2) the most potent or efficacious proaggregatory agent in vitro may not necessarily be the most important mediator in vivo and vice versa. Future development of antithrombotic agents should continue; aspirin can be improved upon in several respects. Perhaps future antithrombotic agents will be targeted to specific platelet membrane (g1yco)proteins involved in platelet‐platelet )aggre‐ gation) and platelet‐vessel wall (adhesion) interactions.

Effects of flunixin meglumine, phenylbutazone and a selective thromboxane synthetase inhibitor (UK-38,485) on thromboxane and prostacyclin production in healthy horses

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.

トロンボキサン合成阻害剤OKY-046による冠動脈内血栓形成, 急性心筋梗塞発症予防に関する実験的検討

Effects of a thromboxane synthetase inhibitor was studied in an experimental model of acute myocardial infarction. Intracoronary thrombus was precipitated by a mock atheromatous plaque in 13 of 15 control dogs.Myocardial infarction was induced in 10 of them and sudden death in 2.There were 2 types of reduction of the coronary blood flow due to thrombus formation: a gradual decrease associated with the delayed appearance of abnormalities in myocardial contraction and the electrocardiogram in 7 of the 12 dogs with myocardial infarction or sudden death (Type A) and repetition of the alteration of reduction and sudden increase in coronary blood flow in the remaining (Type B). In either type, coronary blood flow decreased to induce myocardial infarction in 212±41 minutes.Thromboxane B2 and 6-keto-prostaglandin F1α were significantly elevated in the coronary venous blood during the reduction of the coronary blood flow.The model was utilized to investigate the effects of a selective thromboxane synthetase inhibitor, OKY-046, on an additional 10 dogs. OKY-046 could significantly interrupt the occurrence of myocardial infarction when administered intravenously during Type A or B reduction of the coronary blood flow (3/10 vs. 12/15, p<0.02). A significant reduction in thromboxane A2 appeared to be the major mechanism of the interruption of the thombus formation and completion of myocardial infarction.

CGS 12970: a novel, long acting thromboxane synthetase inhibitor

CGS 12970 is a potent selective inhibitor of human platelet thromboxane synthetase in vitro (IC50 = 12 nM). It is four orders of magnitude less potent as an inhibitor of sheep seminal vesicle cyclooxygenase, bovine aorta prostacyclin synthetase and human leucocyte 15-lipoxygenase. The compound inhibited collagen-induced thromboxane B2 production by human platelets in vitro without an effect on the accompanying platelet aggregation induced by collagen, ADP, platelet activating factor, thrombin, arachidonic acid or the prostaglandin mimetic, U 46619. Administration of CGS 12970 to rats inhibited collagen-induced thromboxane B2 production but had no effect on platelet aggregation ex vivo. It also had no effect on platelet aggregation induced by thrombin or on plasma clotting times. A single oral dose of 1 or 3 mg kg-1 to rabbits inhibited thromboxane B2 production in clotting blood ex vivo for 12 or 24 h respectively. CGS 12970 inhibited thromboxane B2 production in vivo induced by intravenous administration of collagen to rats or calcium ionophore to guinea-pigs. In both cases there was a concomitant elevation of immunoreactive 6-keto-prostaglandin F1 alpha but no effect on the induced thrombocytopenia. As with other thromboxane synthetase inhibitors, CGS 12970 prolonged tail bleeding time in the rat. However, CGS 12970 was not as potent as other thromboxane synthetase inhibitors in this test. In addition to these usual effects of thromboxane synthetase inhibitors, CGS 12970 inhibited the thrombocytopenia induced by the Forssman reaction or ADP administration. In these tests the effect of the compound was of short duration. 8 CGS 12970 had no effect on the thrombocytopenia associated with the Arthus reaction which distinguishes it from cyclo-oxygenase inhibitors. It also had no effect on thrombus formation on a cotton thread in an arteriovenous shunt in the rat.

Effects of OKY-046, a selective thromboxane synthetase inhibitor, on endotoxin-induced lung injury in unanesthetized sheep.

We tested the effects of OKY-046, a selective thromboxane synthetase inhibitor, on endotoxin-induced lung injury in unanesthetized sheep in order to evaluate the role of thromboxane (Tx) in this injury. Escherichia coli endotoxin (1 microgram/kg) infusion produced a biphasic response. The early period (Phase 1) was a transient pulmonary hypertension. The late period (Phase 2) was a more prolonged period characterized by a marked high flow of lung lymph with a high concentration of protein, suggesting increased pulmonary vascular permeability. During Phase 1, there were remarkable increases in TxB2 and 6-keto-PGF1 alpha concentrations in lung lymph and in plasma samples obtained from the pulmonary artery (PA) and the left atrium (LA). The increase in plasma TxB2 level of the LA was greater than that of the PA. During Phase 2, TxB2 levels returned to the baseline values, whereas 6-keto-PGF1 alpha levels remained elevated. Pretreatment with OKY-046 prevented the pulmonary hypertension and increases in TxB2 levels during Phase 1. However, OKY-046 had little effect on lung lymph balance during Phase 2. We conclude that the early pulmonary hypertension induced by endotoxin is mediated mainly by release of TxA2 from the lungs, and TxA2 is not attributed to the increased pulmonary permeability during the late period.

A new approach to antithrombotic therapy--evaluation of combined therapy of thromboxane synthetase inhibitor and very low dose of aspirin.

The effect of a selective thromboxane (TX) synthetase inhibitor (OKY-046), alone and in combination with a very low dose of aspirin, on the platelet function was studied in healthy and diseased subjects. A single dose of 100 mg OKY-046 was orally administered to patients with ischemic cerebrovascular disease (CVD) and healthy volunteers. TXB2 generation and platelet aggregation were measured before and at 1, 4, 6 and 8hr after dosing. In addition, after the administration of a very low dose of aspirin (0.1-0.25 mg/kg/day) for at least one month, a single dose of OKY-046 was given to CVD patients. TXB2 generation and platelet aggregation were measured in the same manner as OKY-046 alone. The effect of OKY-046 on platelet aggregation induced by arachidonic acid (AA) was different in each subject whereas platelet TXB2 generation was almost completely inhibited in all of the patients and healthy volunteers. OKY-046 had a slight inhibitory effect on collagen induced aggregation. A combination of OKY-046 with a very low dose of aspirin, on the other hand, produced additional inhibition of the platelet aggregation induced by both AA and collagen. The present results suggest that the accumulation and metabolism of cyclooxygenase products that accumulate when TX synthetase is blocked, differ in each subject, additional inhibition is caused by the combined use of TX synthetase inhibitor and a very low dose of aspirin because the very low dose of aspirin partially reduces the proaggregatory cyclooxygenase products that accumulate when TX synthetase is blocked.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration of Dazoxiben, a Selective Thromboxane Synthetase Inhibitor, in the Adult Respiratory Distress Syndrome

Experimental studies suggest that thromboxane A2 could play a role in the pulmonary hypertension of the adult respiratory distress syndrome (ARDS). We therefore investigated the hemodynamic and gasometric effects of dazoxiben, a selective thromboxane synthetase inhibitor, in seven patients who had developed ARDS. The patients were studied for 120 minutes after a single intravenous bolus of 1.5 mg of dazoxiben per kilogram of body weight. During this period, there was no change in pulmonary hemodynamics, a moderate increase in arterial oxygen pressure, and a slight decrease in venous admixture. Therefore, administration of dazoxiben in patients with ARDS does not decrease pulmonary hypertension. This study does not support the role of thromboxane A2 as an important mediator in pulmonary hypertension in human ARDS, at least once the syndrome has been recognized.

Effect of imidazole and indomethacin on hemodynamics of the obstructed canine kidney

In the anesthetized dog renal blood flow (RBF) and its intrarenal distribution were investigated by the radioactive microsphere technique 24 hr after bilateral (BUL) and unilateral (UUL) ureteral ligation. In the control series indomethacin (IM) led to a decrease in RBF with outward shifting of zonal perfusions; imidazole (IA) did not cause significant changes in renal hemodynamics. In the BUL series there was a sharp drop in RBF with a proportional decrease in outer (OC) and inner (IC) cortical perfusion; IM treatment resulted in a further decrease in overall and zonal perfusions. IA, a selective inhibitor of thromboxane synthetase, relieved IC vasoconstriction. In the ligated kidney of the UUL preparations decrease in RBF was due to OC vasoconstriction, while IC perfusion equalled controls. IM led to an overall vasoconstriction in all cortical layers; IA did not influence either total RBF or its distribution. It was concluded that BUL "unmasked" TXA2 production in the IC layers, while IM treatment, by inhibiting the production of PGE2, PGI2, and TXA2, resulted in an overall vasoconstriction both in controls and the BUL and UUL preparations.

Protective action of a thromboxane synthetase inhibitor in preventing extension of infarct size in acute myocardial infarction

U-63,557A, a new selective thromboxane synthetase inhibitor, was evaluated for its ability to prevent the extension of myocardial infarct size. Left coronary arteries of male Sprague-Dawley rats (230 – 270 g) were acutely ligated, producing a consistent model of myocardial infarction NO in rats analyzed 48 hours later. Left ventricular free wall (LVFW), creatine kinase (CK) activity,, and amino-nitrogen concentrations were assayed as indices of infarct size. U-63,557A was administered intravenously in two doses (4 and 8 mg/kg) with a split schedule (2 min post-ischemia and either 4 or 24 hrs later). Administration of the thromboxane synthetase inhibitor significantly reduced both myocardial CK and amino-nitrogen loss at a dose of 8 mg/kg, but it was only slightly effective at 4 mg/kg. Drug treatment significantly increased the percent LVFW spared; 27 ± 39% (vehicle) vs 43 ± 796 and 52 ± 796 (8 mg/kg). U-63,557A is an effective agent in myocardial ischemia for limiting the extension of infarct size after acute coronary artery ligation. Previous studies of other thromboxane synthetase inhibitors showed effectiveness in the early stages of MI. This study shows an effect on true infarct size 48 hours post-ligation, and suggests that inhibition of thromboxane A 2 plays an important role in the pathogenesis of ischemic damage in the myocardium.

The effect of a thromboxane synthetase inhibitor, OKY-046, on urinary excretion of immunoreactive thromboxane B2 and 6-keto-prostaglandin F1 alpha in patients with ischemic cerebrovascular disease.

Thromboxane synthetase activity is selectively inhibited by (E)-3-[4-(1-imidazolylmethyl)phenyl]-2-propenoic acid hydrochloride monohydrate (OKY-046). A single dose of 100 mg OKY-046 was orally administered to patients with ischemic cerebrovascular disease and healthy volunteers. Platelet aggregation and thromboxane B2 (TXB2) generation of intact and homogenised platelets induced by 1.0 mM sodium arachidonate were measured before and at 1, 4, 6 and 8 h after dosing. OKY-046 inhibited arachidonate-induced aggregation in platelet rich plasma from some, but not all, individuals, whereas platelet TXB2 generation was almost completely inhibited by a single dose of 100 mg OKY-046, in all of the patients and healthy volunteers. Endogenous TXA2 and prostacyclin (PGI2) biosynthesis were assessed by measurement of urinary immunoreactive TXB2 (i-TXB2) and 6-keto-PGF1 alpha (i-6-keto-PGF1 alpha) before and at 0-3, 3-6, 6-9 h after dosing. OKY-046 increased the urinary i-6-keto-PGF1 alpha coincidently with a decrease of urinary i-TXB2, both in patients and healthy volunteers. These effects of a selective thromboxane synthetase inhibitor will improve a disturbed balance between TXA2 and PGI2, associated with the development of ischemic cerebrovascular disease.

Pharmacological interventions and myocardial infarct size in rat

Infarction was produced in male albino rats by left coronary artery ligation and infarct size was measured using NBT staining. Imidazole significantly decreased the myocardial infarct. The effect did not appear to be mediated through the thromboxane synthetase inhibitory property of imidazole because dazoxiben (a selective thromboxane synthetase inhibitor) failed to produce a similar effect. Propranolol pretreatment decreased the infarct size but treatment after coronary ligation increased it. Reserpine treatment did not alter the infarct size significantly.

Controlled double-blind trial of dazoxiben and nifedipine in the treatment of Raynaud's phenomenon

The prostaglandin thromboxane A 2 causes platelet aggregation and vasoconstriction and may be important in the pathogenesis of Raynaud's phenomenon. Therefore, a randomized, double-blind, placebo-controlled trial was conducted to assess the effectiveness of dazoxiben, a selective thromboxane synthetase inhibitor, in the treatment of Raynaud's phenomenon and to compare it with nifedipine, a calcium channel blocker. Twenty-two subjects who had at least one episode of Raynaud's phenomenon per day entered the study. Three patients withdrew from the study because of side effects while taking nifedipine. There was no difference among the subjects' subjective evaluation of the three treatments. Seven of 19 (44 percent) reported a moderate to marked improvement while taking placebo compared with 12 of 19 (63 percent) taking nifedipine and five of 19 (26 percent) taking dazoxiben (p = NS). Similarly, there was no difference in the mean two-week episode rate among the three treatments: placebo 30.4 ± 4.5, nifedipine 24.7 ± 5.6, dazoxiben 32.0 ± 4.9 (p = NS). Twelve of 22 subjects experienced side effects while taking nifedipine as compared with two of 21 taking placebo and eight of 21 taking dazoxiben (p <0.005). These data show that dazoxiben is not effective in the treatment of Raynaud's phenomenon and suggest that thromboxane does not cause the vasoconstriction that characterizes this disorder.

Sodium 5-(3'-pyridinylmethyl)benzofuran-2-carboxylate (U-63557A) potentiates protective effect of intravenous eicosapentaenoic acid on impaired CBF in ischemic gerbils.

Eicosapentaenoic acid (EPA) has been reported to improve postischemic cerebral blood flow (CBF). The present study was designed to determine whether sodium 5-(3'-pyridinylmethyl)benzofuran-2-carboxylate (U-63557A), a selective thromboxane synthetase inhibitor, could potentiate the effects of EPA on CBF in ischemic gerbils. Ischemia was produced by bilateral carotid artery occlusion for 15 minutes followed by reperfusion for 2 hours. Immediately after ischemia, gerbils were given either an intravenous bolus of 0.167 mg of EPA followed by a continuous infusion of EPA at 1 mg/hr, or U-63557A (10 mg/kg intraperitoneally), or U-63557A and EPA, or a saline infusion. Regional CBF was measured by the hydrogen clearance method, and brain water by the specific gravity technique. Brain prostaglandins were measured by radioimmunoassay. Preischemic CBF's ranged from 27.4 to 29.5 ml/100 gm/min for the four animal groups. After ischemia and 2 hours of reperfusion, CBF in the saline-infused gerbils was significantly decreased to 19.2 ml/100 gm/min. Gerbils treated with either EPA or U-63557A alone had a CBF of 23.7 and 21.6 ml/100 gm/min, respectively. Postischemic CBF in animals treated with both U-63557A and EPA was 30.0 ml/100 gm/min, significantly higher than in saline-infused gerbils. Brain levels of 6-keto prostaglandin (PG)F1 alpha (the metabolite of PGI2) were significantly higher in gerbils treated with U-63557A and EPA compared to gerbils given EPA alone. This study indicates that U-63557A potentiates the effects of EPA on postischemic CBF. This is probably due to the ability of U-63557A to increase prostacyclin formation in the vessel wall.

Effects of the selective thromboxane synthetase inhibitor dazoxiben on variations in cyclic blood flow in stenosed canine coronary arteries.

Recent studies suggest that platelet activation and subsequent thromboxane (TX) A2 release play important roles in certain coronary syndromes. To further test this possibility, we examined the ability of a selective TXA2-synthetase inhibitor, dazoxiben (UK-37-248), to abolish cyclic flow reductions (CFRs) that occur in experimentally stenosed canine coronary arteries. CFRs, which are characterized by progressive declines in coronary blood flow and interrupted by sudden and usually spontaneous restorations of flow, were produced by placing hard plastic cylindrical constrictors (5 mm long X 4.5 mm outer diameter) on the proximal left anterior descending or circumflex coronary artery in open-chest, anesthetized dogs. Coronary blood flow was measured with pulsed Doppler flow probes placed proximal to the constrictors and regional myocardial blood flow with 15 micron radiolabeled microspheres. CFRs were observed for 1 hr, during which coronary blood flow was monitored continuously. Regional myocardial blood flow was measured before constriction, when coronary blood flow appeared to be at its nadir, and after spontaneous restorations of flow. After 1 hr dazoxiben (2.5 mg/kg iv) or an equal volume of saline was given and coronary blood flow was monitored for another hour. Dazoxiben abolished CFRs completely in 18 of 28 dogs and significantly reduced their frequency in the dogs receiving the drug (10.1 +/- 0.8 vs 3.2 +/- 1.0 per hour [+/- SE]; p less than .001, n = 28). The frequency and magnitude of variations in cyclic blood flow were unchanged after saline (8.8 +/- 0.8 vs 9.0 +/- 1.0 per hour; p = NS, n = 13). The lowest levels of coronary blood flow before and after dazoxiben were 8.6 +/- 2.2% and 48.8 +/- 5.4% of control, respectively (p less than .001, n = 28), whereas this parameter remained unchanged after saline (18.7 +/- 5.7% vs 13.4 +/- 4.1%, respectively; n = 13). The levels of TXB2 and 6-keto-prostaglandin (PG) F1 alpha (stable breakdown products of TXA2 and prostacyclin, respectively) were measured in blood collected from aortic and distal coronary arterial catheters before coronary constriction (control), during CFRs, and after administration of dazoxiben. TXB2 levels measured distal to the stenosis were increased fivefold during CFRs (352 +/- 126 vs 71 +/- 18 pg/ml plasma; p less than .03) and were reduced to preconstriction (control) levels by dazoxiben (57 +/- 12 pg/ml). Aortic TXB2 levels almost doubled with CFRs and also returned to control levels after dazoxiben.(ABSTRACT TRUNCATED AT 400 WORDS)