It has been speculated that platelet activation may contribute to the evolution of vascular complications in patients with Type I diabetes mellitus. To address this hypothesis, we measured the plasma and urinary metabolites of thromboxane, presumably of platelet origin, and of prostacyclin, derived from endothelial cells, in addition to more conventional indexes of platelet function. Urinary excretion of the metabolites 2,3-dinor-thromboxane B2 and 2,3-dinor-6-keto-prostaglandin F1 alpha did not differ between diabetics with or without retinopathy and nondiabetic controls. Furthermore, measurement of platelet granule constituents, the aggregation responses to ADP or arachidonic acid, and levels of serum thromboxane B2 failed to discriminate between the groups. The institution of tight diabetic control with multiple daily injections of insulin failed to alter either urinary metabolite excretion or plasma levels of 11-dehydro-thromboxane B2. Conversely, insulin-induced hypoglycemia failed to alter the concentrations of plasma or urinary thromboxane metabolites in nondiabetic volunteers, despite a mean 60-fold increase in plasma epinephrine. These studies suggest that platelet activation does not precede the development of microvascular complications in patients with Type I diabetes who lack clinical evidence of macrovascular disease and have normal renal function. Furthermore, it is unlikely that platelet activation due to intermittent hypoglycemia contributes to the reportedly accelerated development of retinopathy in such patients, when they are subject to tight diabetic control.

6-Ketoprostaglandin F1 alpha↗

PubMed1988

Effects of low-dose aspirin on endogenous eicosanoid formation in normal and atherosclerotic men.

We have investigated the effects of a low-dose aspirin regimen (120 mg orally, then 20 mg twice daily) on the in vivo synthesis of prostacyclin, thromboxane and prostaglandin E in man by measurement of their urinary metabolites (PGI2-M, TxB2-M, PGE-M) using gas chromatography-mass spectrometry. A comparison was made between the selectivity of low-dose aspirin for thromboxane vs prostacyclin synthesis in patients with atherosclerosis, age-matched controls without vascular disease, and young healthy volunteers. After one week of treatment, aspirin reduced TxB2-M synthesis to a similar extent in the three groups (mean declines of 86, 84 and 78% respectively), while there was an unexpected difference in effect on PGI2-M, with only a 27% fall in the young volunteers but 53% and 54% declines in the patients with vascular disease and their age-matched controls. Serum TxB2 was reduced greater than 98% in all groups while PGE-M excretion was unchanged. These results indicate that bioselectivity for inhibition of Tx synthesis by aspirin is more difficult to achieve in older subjects than in the young volunteers previously studied and that very low, frequent dosing, or a sustained-release preparation of aspirin would be needed to achieve bioselectivity for Tx inhibition in patients with vascular disease.

Adult↗

PubMed1988

Effects of thromboxane synthase inhibitors on renal function.

In general the effects of thromboxane A2(TXA2) on renal function are opposite those produced by other prostanoids. TXA2 synthase inhibitors decrease the biosynthesis of TXA2 and may increase the production of other prostanoids by causing endoperoxide shunting. Therefore, in situations of increased kidney arachidonate mobilization, inhibition of renal TXA2 synthase might alter renal function by reducing TXA2 production and/or increasing prostaglandin (PG) biosynthesis. This hypothesis was tested by comparing the changes in renal function induced by suprarenal aortic constriction in anesthetized dogs pretreated with either a TXA2 synthase inhibitor (UK38,485; n = 7 or OKY1581; n = 7) or vehicle (0.1 M Na2CO3; n = 9). Several renal function parameters were compared in control versus treated animals by analysis of variance. Neither UK38,485 (1 mg/kg, i.v.) nor OKY1581 (10 mg/kg, i.v.) significantly altered renal artery hypotension-induced changes in mean arterial blood pressure, heart rate, renal blood flow, renal vascular resistance, glomerular filtration, filtration fraction, urine flow rate, sodium excretion rate, fractional sodium excretion, potassium excretion, or fractional potassium excretion. However, both UK38,485 and OKY1581 seemed to attenuate the increase in renal renin secretion rate induced by suprarenal aortic constriction. We conclude that acute administration of TXA2 synthase inhibitors does not modify acute renal artery hypotension-induced changes in either electrolyte excretion or renal hemodynamics. However, acute administration of TXA2 inhibitors attenuates suprarenal aortic constriction-induced increases in renin release in anesthetized dogs by unknown mechanisms.

Acrylates↗

PubMed1988

Cigarette smoking and hemostatic function.

Epidemiologic studies clearly link cigarette smoking with vasoocclusive cardiovascular disease. Postmortem studies provide evidence of accelerated atherogenesis in asymptomatic smokers. However, the rapid regression of cardiovascular risk within the first year of quitting smoking is difficult to explain solely in terms of vascular disease. Recent evidence indicates that plasma fibrinogen, which has been prospectively associated with the risk of ischemic heart disease, is elevated in smokers. Similarly, results from studies investigating thromboxane metabolite excretion in urine confirm those involving radiolabeled platelet turnover, suggesting that platelets are activated in the circulation of chronic smokers. Altered hemostatic function, either as a direct result of smoking or caused by smoking-induced vascular damage, may account for the more rapidly reversible component of cardiovascular risk observed in chronic smokers.

Cardiovascular Diseases↗

PubMed1988

Prostaglandins in Ascaris antigen.

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Animals↗

PubMed1988

Excretion of thromboxane A2 and prostacyclin metabolites during treadmill exercise in patients with intermittent claudication.

Platelet activation, with subsequent formation of thromboxane A2 (TxA2), is thought to play a role in the development of arterial occlusion. In patients with severe atherosclerosis of the lower limbs, characterized by leg ulcers and rest pain, the basal formation of TxA2 and prostacyclin (PGI2) is increased. Corresponding data in patients with more moderate atherosclerosis of the lower limbs have not been reported. Since the capacity to physical exercise is not blunted in such patients proper evaluation of their TxA2-PGI2 synthesis should comprise not only assessment of the basal formation, but also TxA2/PGI2 biosynthesis during conditions of elevated cardiovascular activity. To address this, we analysed these eicosanoids in patients with a history of intermittent claudication. Urinary dinor-metabolites of TxB2 and PGI2 (Tx-M and PGI-M, respectively) were estimated by gas chromatography/negative ion-chemical ionization mass spectrometry in samples collected prior to, during and immediately after 20 min of severe treadmill exertion. The basal excretion of Tx-M was 105 +/- 26 pg/mg creatinine. It was not changed during exercise, but increased to 176 +/- 48 pg/mg creatinine (P less than 0.05) during the recovery. The basal excretion of PGI-M was 142 +/- 25 pg/mg creatinine. The PGI-M response to exercise varied from no change at all to a 30-fold increase, without any obvious correlation to experienced leg pain, walking distance or other recorded variables. During the recovery period the outflow of PGI-M was significantly higher than at rest (482 +/- 145 pg/mg creatinine; P less than 0.01). We conclude that in patients with intermittent claudication due to atherosclerosis (1) platelet activation does not occur during the course of the exercise, and (2) vascular prostacyclin formation can be dissociated from of TxA2 synthesis. The observed increase in PGI-M in some of the patients is suggested to reflect tissue ischaemia induced by the lack of adequate hyperaemia during exercise.

6-Ketoprostaglandin F1 alpha↗

PubMed1988

Thromboxane receptor-mediated bronchial and hemodynamic responses in ovine endotoxemia.

The role of thromboxane A2 in sheep endotoxemia, an animal model of the adult respiratory distress syndrome, was investigated by a combined biochemical and pharmacological approach. Endogenous thromboxane biosynthesis was assessed by gas chromatographic-mass spectrometric analysis of urinary (thromboxane B2, 2,3-dinor-thromboxane B2) and plasma (11-dehydrothromboxane B2) metabolites that demonstrated a significant stimulation by endotoxin. The functional relevance of thromboxane A2 was probed with a specific thromboxane-prostaglandin endoperoxide receptor antagonist, SQ 29548. The antagonist significantly blunted the increase in pulmonary arterial pressure, pulmonary vascular resistance, lung lymph flow, and lymph protein clearance induced by endotoxin. Whereas the reduction in lung compliance caused by endotoxin was abolished, the augmented airway resistance was unaffected. From the simultaneous increase in thromboxane biosynthesis and effects of receptor blockade, it was concluded that thromboxane A2 mediates the early pathophysiological changes of sheep endotoxemia. Thromboxane receptor antagonism may offer a potential therapeutic approach to patients at risk of the adult respiratory distress syndrome.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗

PubMed1988

Marked platelet activation in vivo after intravenous streptokinase in patients with acute myocardial infarction.

We assessed thromboxane biosynthesis as an index of platelet activation in 6 patients with acute myocardial infarction receiving intravenous streptokinase. Urinary 2,3-dinor-thromboxane B2 and plasma 11-dehydro-thromboxane B2, major enzymatic metabolites of thromboxane A2, were markedly increased after intravenous streptokinase (11,063 +/- 2758 pg/mg creatinine and 33 +/- 10 pg/ml, respectively) compared with levels in patients not receiving thrombolytic therapy (502 +/- 89 pg/mg creatinine and 3 +/- 0.7 pg/ml). Prostacyclin biosynthesis also increased markedly after streptokinase coincident with the increase in thromboxane A2 formation. Administration of aspirin between the time of onset of coronary thrombosis and reperfusion both in man and in a canine preparation demonstrated that this reflected thromboxane biosynthesis de novo and not metabolism of preformed inactive thromboxane B2 washed out from the coronary circulation. Since the platelet is the major source of thromboxane A2, these findings suggest that there is marked platelet activation after coronary thrombolysis with streptokinase. Studies in vitro demonstrated that streptokinase enhanced platelet activation in a dose-dependent manner, resulting in the secondary release of thromboxane A2. The increase in platelet activation and thromboxane A2 biosynthesis may limit the therapeutic effect of intravenous streptokinase in acute myocardial infarction.

Aspirin↗

PubMed1988

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

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-PGF1 alpha, 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.

6-Ketoprostaglandin F1 alpha↗

PubMed1988

Aspirin in cardiovascular disease.

Although other mechanisms may be contributory, the antithrombotic properties of aspirin derive predominantly from its platelet-inhibitory effects. These are mediated via irreversible acetylation of platelet cyclo-oxygenase with subsequent blockade of platelet thromboxane synthesis. Long term administration of doses of aspirin as low as 20mg daily depresses platelet thromboxane formation by more than 90%; however, higher doses appear to be necessary to prevent thromboxane-dependent platelet activation in vivo. While there is evidence of biochemical selectivity with low doses of aspirin, significant reduction of the platelet-inhibitory eicosenoid, prostacyclin, occurs even at dosages ranging from 20 to 40mg daily. The ability of aspirin to prevent the occurrence or recurrence of vaso-occlusion has been extensively investigated. In the secondary prevention of myocardial infarction 7 placebo-controlled trials involving more than 15,000 patients have been completed. The dose of aspirin varied from 300 to 1500mg daily. Although none of the individual trials produced statistically significant reductions in total or coronary mortality, taken together the results are highly suggestive of a beneficial effect of aspirin. Similarly, 2 recent studies in patients with unstable angina demonstrated a protective effect of aspirin against acute myocardial infarction and death. While each study employed widely different doses of aspirin (324mg and 1250mg daily) similar reductions in mortality were reported. The effects of aspirin on the prevention of coronary artery bypass graft occlusion have been evaluated in 9 trials. Aspirin in doses of 100 to 975mg daily was shown to be of benefit in preventing early (less than 6 months) graft occlusion, particularly when therapy was started within 24 hours of operation. In patients with prosthetic vascular grafts of the lower limbs, aspirin has been shown to reduce platelet deposition, however further controlled trials will be required to establish the patient population most likely to benefit and, as in all these studies, the optimum dose of aspirin to employ. In patients with prosthetic heart valves it is clear that aspirin alone is insufficient to prevent thromboembolic complications and when administered as an adjunct to anticoagulant therapy it is associated with a high incidence of bleeding. In contrast, there is convincing evidence from several studies for the efficacy of aspirin in doses of 990 to 1300mg daily in the prevention of stroke and death in patients with transient ischaemic attacks.(ABSTRACT TRUNCATED AT 400 WORDS)

Aspirin↗

PubMed1988

Differential prostacyclin production by human umbilical vasculature.

Using the avidin-biotin immunohistochemical technique with rabbit antihuman 6-keto-prostaglandin (PG)-F1 alpha (6KPGF), we studied the distribution of the stable prostacyclin metabolite, 6KPGF, in 14 formaldehyde-fixed human umbilical cords. All umbilical veins demonstrated intense endothelial cell staining. None of the arteries stained. To corroborate the immunohistochemical findings, three fresh umbilical cords were dissected to separate arteries from veins and then were incubated in oxygenated tissue baths containing Ringer's lactate (37 degrees C) for 30 minutes. Cumulative 6KPGF production as measured by radioimmunoassay of tissue effluents was markedly different between arteries and veins with the umbilical vein producing the largest quantity of 6KPGF. Thus, immunohistochemistry and ex vivo capacitance studies suggest that there is a differential distribution of 6KPGF in human umbilical arteries and veins.

6-Ketoprostaglandin F1 alpha↗

PubMed1987

Two polymorphisms in the human lipoprotein lipase (LPL) gene.

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Chromosomes, Human, Pair 8↗

PubMed1987

Paired analysis of urinary thromboxane B2 metabolites in humans.

11-Dehydro-TxB2 and 2,3-dinor-TxB2 are products of the two major pathways of thromboxane metabolism in man. In this study we compared urinary excretion of 2,3-dinor-TxB2 and 11-dehydro-TxB2 as indices of Tx biosynthesis in vivo. We performed three studies to assess i) the relative abundance of these two metabolites in the urine of healthy subjects, ii) their cellular origin under physiological conditions and iii) their relative formation during platelet activation. In healthy normal volunteers urinary 11-dehydro-TxB2 is more abundant than 2,3-dinor-TxB2 (792 +/- 119 pg/mg creatinine vs 106 +/- 21 pg/mg creatinine). Administration of a dose of aspirin selective for platelet cyclooxygenase (20 mg/day for 10 days) caused substantial and comparable suppression of both 11-dehydro-TxB2 (mean 82 +/- 4.9%) and 2,3-dinor-TxB2 (mean 79 +/- 6.9%). recovery of excretion of both metabolites after a nonselective aspirin regimen (325 mg BID for 3 days) corresponded to platelet life-span. Furthermore, excretion of both metabolites was increased in patients with severe atherosclerosis consistent with the known increase in platelet activation in this setting. Quantitative analysis of both urinary 11-dehydro-TxB2 and 2,3-dinor-TxB2 by GC-MS established that, in contrast to previous assumptions, 11-dehydro-TxB2 is the most abundant urinary metabolite of TxB2. The aspirin study demonstrates that platelets are the major source of both metabolites in urine, consistent with their increased excretion in severe atherosclerosis. Combined analysis of both metabolites will distinguish altered metabolism from increased biosynthesis of thromboxane A2.

Adult↗

PubMed1987

Dipyridamole.

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Blood Platelets↗