Coronary vascular occlusion mediated via thromboxane A2-prostaglandin endoperoxide receptor activation in vivo.

Fitzgerald, Desmond J.; Doran, Johniene; Jackson, Edwin K.; FitzGerald, Garret A.

doi:10.1172/jci112329

Cited by 85 publications

(27 citation statements)

References 23 publications

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“…The circumflex coronary artery was isolated through a left thoracotomy and all branches ligated down to the first obtuse marginal branch. A needle electrode was passed through the arterial wall such that 4-5 mm of exposed wire lay against the endothelium, as pre-viously described (27,28). The electrode consisted of 30-gauge Teflon coated silver wire onto the end ofwhich was crimped the tip (2 mm) of a 28-gauge hypodermic needle to aid passage through the vessel wall.…”

Section: Methodsmentioning

confidence: 99%

“…To determine if these mechanisms influence thrombogenesis in vivo, we have examined the interaction of a TXA2 synthase inhibitor and an antagonist ofthe shared TXA2/prostaglandin endoperoxide receptor in a canine model of coronary artery thrombosis (27,28). These studies demonstrate biochemical and functional evidence of a role for prostaglandin endoperoxides in modulating the response to TXA2 synthase inhibitors in vivo and identify an interaction of potential therapeutic importance between these classes of drugs.…”

Section: Introductionmentioning

confidence: 99%

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Prostaglandin endoperoxides modulate the response to thromboxane synthase inhibition during coronary thrombosis.

Fitzgerald¹,

J²,

FitzGerald³

1988

J. Clin. Invest.

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Prostaglandin endoperoxides (PGG2/PGH2), precursors of thromboxane (TX) A2 and prostaglandins, may accumulate sufficiently in the presence of a TXA2 synthase inhibitor to exert biological activity. To address whether this modulates the response to TXA2 synthase inhibition in the setting of thrombosis in vivo, we examined the interaction of a TXA2 synthase inhibitor (U63,557a) and a TXA2/prostaglandin endoperoxide receptor antagonist (L636,499) in a canine model of coronary thrombosis after electrically induced endothelial injury. U63,557a exerted little inhibitory effect in this model despite a marked reduction in serum TXB2 and urinary 2,3-dinor-TXB2, an index of TXA2 biosynthesis. Combination of the two drugs was more effective than either drug alone. The enhanced effect achieved upon addition of the TXA2/prostaglandin endoperoxide receptor antagonist to the TXA2 synthase inhibitor suggests that the response to the latter compound was limited by the proaggregatory effects of prostaglandin endoperoxides. The increased effect of the combination over the receptor antagonist alone may reflect metabolism of PGG2/PGH2 to platelet inhibitory prostaglandins. This is supported by the following findings: (a) urinary 2,3-dinor-6-keto-PGFia, an index of prostacyclin biosynthesis, increased after administration of the synthase inhibitor, an effect that was exaggerated in the presence of thrombosis; (b) inhibition of arachidonate-induced platelet aggregation by U63,557a was dependent on the formation of a platelet-inhibitory prostaglandin; and (c) pretreatment with aspirin abolished the synergism between these compounds. These studies demonstrate that prostaglandin endoperoxides modulate the response to TXA2 synthase inhibition in vivo and identify a drug combination of potential therapeutic efficacy in the prevention of thrombosis.

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Prostaglandin endoperoxides modulate the response to thromboxane synthase inhibition during coronary thrombosis.

Fitzgerald¹,

J²,

FitzGerald³

1988

J. Clin. Invest.

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“…We gratefully acknowledge gifts of (15S)-hydroxy-11,9-(epoxymethano)prostadienoic acid (U46619) from R. R. Gorman (Upjohn, Kalamazoo, MI), argatroban and t-PA (GR11044, Atlepase) from S. Bunting (Genentech, South San Francisco, CA), and {lr-[la(Z), 2(3, 3 (8, All animal studies were reviewed and approved by the Animal Care Committee at Vanderbilt University. In these studies we employed a chronic canine model of coronary thrombosis induced by electrical injury to the endothelium (20,21). Briefly, through a left thoracotomy, a needle electrode was implanted in the circumflex coronary artery distal to an ultrasonic flow probe (Crystal Biotech, Havistan, MA) in the anesthetized animal.…”

Section: Methodsmentioning

confidence: 99%

Role of thrombin and thromboxane A2 in reocclusion following coronary thrombolysis with tissue-type plasminogen activator.

Fitzgerald

FitzGerald

1989

Proc. Natl. Acad. Sci. U.S.A.

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150

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Reocclusion of the coronary artery occurs after thrombolytic therapy of acute myocardlal infarction despite routine use of the anticoagulant heparin. However, heparin is inhibited by platelet activation, which is greatly enhanced in this setting. Consequently, it is unclear whether thrombin induces acute reocclusion. To address this possibility, we examined the effect of argatroban {MCI9038, (2R,4R)--2-piperidinecarboxylic acid}, a specific thrombin inhibitor, on the response to tissue-type plasminogen activator in a dosed-chest canine model of coronary thrombosis. MCI9038 prolonged the thrombin time and shortened the time to reperfusion (28 + 2 min vs. 59 ± 7 min in controls; mean ± SEM, n = 5, P < 0.01). At the highest dose, 2.5 mg/kg per hr, complete reocclusion was prevented in four of the five experimental animals, whereas reocclusion occurred in all five controls. However, reperfusion was complicated by cycles of decreased flow, which were abolished by the thromboxane A2 antagonist, GR32191. GR32191 at 1 mg/kg combined with MCI9038 at 0.5 mg/kg per hr prevented reocclusion, whereas, at these doses, either drug alone was without effect. In addition, thromboxane A2 biosynthesis, determined as excretion of its metabolite 2,3-dinor-thromboxane B2, was increased after reperfusion at all doses of MC19038. These data demonstrate that thrombin impairs thrombolysis induced by tissue-type plasminogen activator in vivo and induces acute reocclusion. Furthermore, the response to thrombin inhibition may be impaired by continued formation of thromboxane A2.

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“…An intracoronary thrombus was induced by use of the technique initially described by Romson et a116 and subsequently used by us17 and others. 18 Briefly, the LAD was gently rubbed to disrupt the endothelium distal to the flow probe. A silver-coated copper wire with a 25-gauge needle tip (approximately 4 mm) bent 900 was inserted distal to the flow probe into the LAD and pulled back to ensure contact of the electrode with the intimal surface of the vessel.…”

Section: Coronary Artery Thrombosismentioning

confidence: 99%

Prostacyclin analogue iloprost decreases thrombolytic potential of tissue-type plasminogen activator in canine coronary thrombosis.

et al. 1990

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Platelets play an important role in the formation of a coronary thrombus and reocclusion after thrombolysis. Therefore, we examined the thrombolytic potential of concomitant intravenous administration of potent platelet inhibitor iloprost, a prostacyclin analogue, with tissue-type plasminogen activator (t-PA; n=8) and t-PA alone (n=9) in dogs with an electrically induced occlusive coronary artery thrombus. t-PA (0.75 mg/kg) was given over 20 minutes, and iloprost (4 ,ug/kg) was given over 40 minutes. Reperfusion rate was 63% (five of eight dogs) in the t-PA plus iloprost group and 67% (six of nine dogs) in the t-PA alone group (p=NS). The time to thrombolysis (or reperfusion) in the t-PA plus iloprost group was almost twice as great as in the t-PA alone group (33.0±13.3 vs. 18.5±6.7 minutes, mean±SD, p<0.02), and the duration of reperfusion was much shorter (3.4± 1.8 vs. 39.3+17.4 minutes,p<0.005). Peak coronary artery blood flow after reperfusion in the t-PA plus iloprost group was also less (20±+17 ml/min) than in the t-PA alone group (58±21 ml/min,p<0.005). Reocclusion occurred in all dogs given t-PA with iloprost despite potent synergistic platelet inhibitory effects of t-PA and iloprost, whereas four of six dogs given t-PA alone reoccluded. Neither regimen exerted a significant beneficial effect on regional myocardial shortening during coronary reperfusion. Plasma levels of t-PA were lower when iloprost was given with t-PA (1,022+360 vs. 1,459±f-270 ng/ml in t-PA alone group, p<0.05). The detrimental effects of iloprost identified in this study may relate to the reduction in plasma t-PA concentrations by its degradation in the liver caused by the prostacyclin analogue iloprost. (Circulation 1990;81:1115-1122 An occlusive thrombus in the atherosclerotic coronary artery is believed to be the precipitating factor in the genesis of unstable angina and acute myocardial infarction in a vast majority of patients. This is based on angiographic, angioscopic, and pathologic examination of the offending coronary artery.'-3 Accordingly, therapy of such patients includes use of thrombolytic agents, such as streptokinase or tissue-type plasminogen activator (t-PA).4-7 Because the occlusive thrombus consists

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Coronary vascular occlusion mediated via thromboxane A2-prostaglandin endoperoxide receptor activation in vivo.

Cited by 85 publications

References 23 publications

Prostaglandin endoperoxides modulate the response to thromboxane synthase inhibition during coronary thrombosis.

Prostaglandin endoperoxides modulate the response to thromboxane synthase inhibition during coronary thrombosis.

Role of thrombin and thromboxane A2 in reocclusion following coronary thrombolysis with tissue-type plasminogen activator.

Prostacyclin analogue iloprost decreases thrombolytic potential of tissue-type plasminogen activator in canine coronary thrombosis.

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