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Biomedical subjects

G A FitzGerald

Publications and source records attributed to G A FitzGerald.

At least 181 records · Page 10Linked to original sources
PubMed1987

Radioimmunoassay of 11-dehydrothromboxane B2 in human plasma and urine.

Because of the discrepancy between the capacity of platelets to synthesize thromboxane B2 ex vivo and the actual synthetic rate in vivo, measurement of thromboxane B2 in plasma is highly influenced by sampling-related artifacts. We have developed and validated a radioimmunoassay for a major enzymatic derivative of thromboxane B2 with an extended plasma half-life, i.e., 11-dehydrothromboxane B2. The binding of the tracer is displaced by as low as 1 pg/ml of the homologous ligand, with a high degree of specificity for the open ring structure as well as for the omega side-chain. This method can detect changes in the plasma concentration and urinary excretion of 11-dehydrothromboxane B2 associated with stimulated short-term increases of thromboxane B2 secretion in the human circulation.

Adult↗
PubMed1987

Prostacyclin as neuromodulator in the sympathetically stimulated rabbit heart.

Prostaglandin E2 (PGE2) has previously been shown to inhibit sympathetic neurotransmission in different organs and species. Based on this inhibitory effect and on its reversal by cyclo-oxygenase inhibitors, PGE2 has been claimed to be a physiological modulator of in vivo release of norepinephrine (NE) from sympathetic nerves. It is now recognized that prostacyclin (PGI2) is the main cyclo-oxygenase product in the heart. We therefore addressed the question whether PGI2, within the same preparation, is formed in increased amounts during sympathetic nerve stimulation and has neuromodulatory activity. The effluent from isolated rabbit hearts subjected to sympathetic nerve stimulation or to infusion of NE or adenosine (ADO) was collected, and its content of PGE2 and 6-keto-PGF1 alpha (dehydration product of PGI2) was analyzed using gas chromatography/mass spectrometry, operated in the negative ion/chemical ionization mode. Other hearts were infused with PGI2 and nerve stimulation induced outflow of endogenous NE into the effluent was analyzed using HPLC with electrochemical detection. Nerve stimulation at 5 or 10 Hz (before but not after adrenergic receptor blockade), as well as infusion of NE (10(-6)-10(-5)M) or ADO (10(-4)M) increased the cardiac outflow of 6-keto-PGF1 alpha. Basal and nerve stimulation induced efflux of 6-keto-PGF1 alpha was approximately 5 times higher than the corresponding efflux of PGE2. PGI2 dose-dependently inhibited the outflow of NE from sympathetically stimulated hearts, the inhibition at 10(-6)M being approximately 40%. On the basis of these observations we propose that PGI2 is a more likely candidate than PGE2 as a potential modulator of neurotransmission in cardiac tissue in vivo.

6-Ketoprostaglandin F1 alpha↗
PubMed1987

Increased thromboxane biosynthesis in normal pregnancy is mainly derived from platelets.

Thromboxane biosynthesis was determined in normal pregnant subjects by measurement of its major urinary and plasma metabolites, 2,3-dinor-thromboxane B2 and 11-dehydro-thromboxane B2. Urinary 2,3-dinor-thromboxane B2 increased early in pregnancy (731 +/- 124 pg/mg creatinine) compared with nonpregnancy (less than 350 pg/mg creatinine; p less than 0.001) and the postpartum period (155 +/- 42 pg/mg creatinine, p = 0.015) and remained elevated throughout gestation. Similarly, plasma and urinary 11-dehydro-thromboxane B2 were increased in pregnancy. To determine the cellular origin of the increase in thromboxane biosynthesis in pregnancy, platelet cyclooxygenase was selectively inhibited with aspirin in a dose of 120 mg orally followed by 20 mg twice daily for 7 days (n = 4). Selectivity was confirmed by measurement of urinary 2,3-dinor-6-keto-prostaglandin F1 alpha, an index of prostacyclin biosynthesis. Coincident with a 97% inhibition of serum thromboxane B2, urinary 2,3-dinor-thromboxane B2 was almost completely inhibited and paralleled the recovery of platelet cyclooxygenase after withdrawal of aspirin. This study demonstrates that thromboxane biosynthesis is increased in pregnancy. The increase is mainly platelet derived and is consistent with increased platelet activation throughout pregnancy.

Blood Platelets↗
PubMed1987

Decreased prostacyclin biosynthesis preceding the clinical manifestation of pregnancy-induced hypertension.

Patients who develop pregnancy-induced hypertension exhibit a lesser increment in prostacyclin biosynthesis than healthy pregnant subjects. Whether this precedes the development of clinical disease and therefore may be important in the pathogenesis of pregnancy-induced hypertension or is a secondary event is unknown. We prospectively determined prostacyclin biosynthesis in pregnant subjects at risk of developing pregnancy-induced hypertension by use of noninvasive approach, measurement of the urinary metabolite 2,3-dinor-6-keto-prostaglandin F1 alpha. Patients were recruited at less than 20 weeks gestation. After delivery, patients were retrospectively allocated by use of preset criteria, to one of four groups: pregnancy-induced hypertension (n = 12), hypertension in labor (n = 22), chronic hypertension (n = 9), and normotension (n = 24). There was a significant increase in prostacyclin biosynthesis in all study groups during gestation. However, patients who developed pregnancy-induced hypertension exhibited a lesser increment and this difference persisted throughout gestation. These results are consistent with a pathophysiologic role for altered prostacyclin biosynthesis in women with pregnancy-induced hypertension. In addition, decreased prostacyclin formation identifies a population at risk of developing pregnancy-induced hypertension. Such information would assist the design of clinical trials of drugs, such as aspirin, that might prevent the development of this disease.

6-Ketoprostaglandin F1 alpha↗
PubMed1987

Biochemical evidence of a chronic abnormality in platelet and vascular function in healthy individuals who smoke cigarettes.

Cigarette smoking is associated with increased mortality from cardiovascular disease that declines after cessation. This study extends the evidence regarding the effects of chronic smoking on platelets and the vessel wall in vivo. Excretion of a major urinary thromboxane metabolite, 2,3-dinor-thromboxane B2, is significantly (p less than .01) elevated in apparently healthy chronic smokers (20 cigarettes daily) compared with that in nonsmoking control subjects. This difference in excretion of 2,3-dinor-thromboxane B2 was abolished by the administration of 20 mg aspirin twice daily, a dose shown to selectively inhibit platelet cyclooxygenase. After aspirin, the return of the excretion of 2,3-dinor-thromboxane B2 to pretreatment levels paralleled the recovery of platelet cyclooxygenase. These findings indicate that excessive thromboxane A2 generation in chronic smokers predominantly derives from platelets. The urinary excretion of the prostacyclin metabolite 2,3-dinor-6-keto-prostaglandin F1 alpha also is increased during chronic cigarette smoking, as is the case with other diseases associated with accelerated interaction of platelets with the vessel wall. We have found evidence of platelet and vascular dysfunction in vivo in chronic cigarette smokers before the manifestation of overt cardiovascular disease. The results would also be consistent with the hypothesis that in chronic smokers, the platelet defect is largely reflective of smoking-induced vascular injury.

Adult↗
PubMed1987

Thromboxane biosynthesis and antagonism in humans.

Despite the evanescence of TXA2 in biological fluids, recent developments promise to considerably enhance our insight into the role of this molecule in vivo. Clinical trials already suggest that it plays an important role in certain human diseases, such as unstable angina. Combined administration of TX antagonists and TX synthase inhibitors offers a theoretical advantage over aspirin which may ultimately justify their place in the therapy of vascular disease in humans.

Blood Platelets↗
PubMed1987

Thromboxane A2 biosynthesis in human disease.

Thromboxane A2 (TxA2), the predominant cyclooxygenase product of human platelets, is a potent vasoconstrictor and platelet agonist. Although its biological properties are readily appreciable in vitro, it has been difficult to define its biological importance in vivo. To a large extent this reflected the problems associated with efforts to monitor biosynthesis of this eicosanoid and the lack of selective pharmacological probes that prevented the synthesis of TxA2 or antagonized its biological action in vivo. Recently the analysis of urinary metabolites of TxB2 has become simplified so that the methodology is readily applicable to clinical studies. This provides a noninvasive, time-integrated index of Tx biosynthesis. Although one cannot definitively establish a tissue of origin for metabolites measured in urine, indirect evidence suggests that urinary TxB2 derives primarily from the kidney whereas its dinor metabolite predominantly reflects platelet biosynthesis under physiological conditions. Although plasma concentrations of TxB2 are readily confounded by platelet activation ex vivo, the enzymatic metabolites formed from TxB2 have recently been identified and appear to bypass this problem. Combined analysis of long-lived (e.g., 11-dehydro-TxB2) and short-lived (e.g., 2,3-dinor-TxB2) metabolites in plasma promise to more accurately localize phasic increases in the biosynthesis of TxA2 and have been paralleled by the development of antagonists of the TxA2/prostaglandin endoperoxide receptor and their study of humans. The use of such specific probes in conditions characterized by abnormal biosynthesis of TxA2 promises to define the biological role of this mediator for humans.

Arachidonic Acid↗
PubMed1987

Inhibition of thromboxane formation in vivo and ex vivo: implications for therapy with platelet inhibitory drugs.

The capacity of platelets to generate thromboxane A2, reflected by measurement of serum thromboxane B2 (TxB2), greatly exceeds the systemic production of thromboxane in vivo. Thus, it is possible that substantial but incomplete inhibition of thromboxane formation ex vivo would still allow marked augmentation of thromboxane production in vivo. To address this hypothesis, we administered aspirin 120 mg, a selective inhibitor of thromboxane synthase (TxSl), 3-(1H-imidazol-1-yl-methyl)-2-methyl-1H-indole-1-propanoic acid (UK-38, 485) 200 mg, and a combination of both drugs to 12 healthy volunteers and measured the effects on serum TxB2 and urinary 2,3-dinor-thromboxane B2 (Tx-M), an index of endogenous thromboxane biosynthesis. Although serum TxB2 was maximally inhibited by 94 +/- 1% after aspirin and 96 +/- 2% after the TxSl, maximal depression of Tx-M was only 28 +/- 8% and 37 +/- 9%, respectively. Combination of aspirin with the TxSl resulted in a small but significant increase in inhibition of thromboxane generation ex vivo (98 +/- 1% v 94 +/- 1%; P less than 0.05), but a disproportionately greater fall in thromboxane synthesis in vivo (58 +/- 7%; P less than 0.01). Consistent with further inhibition of platelet thromboxane synthesis, addition of the TxSl abolished the transient decline in prostacyclin formation after aspirin alone. Administration of a lower dose of aspirin (20 mg) to 6 healthy subjects caused a small reduction in Tx-M (12 +/- 4%; P less than 0.05) and inhibited serum TxB2 by 48 +/- 2%. The relationship between inhibition of platelet capacity to form thromboxane ex vivo (serum TxB2) and synthesis in vivo (Tx-M) departed markedly from the line of identity. When total blockade of the capacity of platelets to generate thromboxane is approached, minor decrements in capacity result in a disproportionate depression of actual thromboxane biosynthesis. These results imply that pharmacologic inhibition of serum TxB2 must be virtually complete before thromboxane-dependent platelet activation is influenced in vivo.

Adult↗
PubMed1986

Platelet activation in unstable coronary disease.

Pathological and clinical studies have suggested that platelets have a role in the pathogenesis of unstable angina and myocardial infarction. However, the relation of platelet activation to episodic ischemia in patients with unstable angina is unknown. We assessed the biosynthesis of thromboxane and prostacyclin as indexes of platelet activation in patients with stable and unstable coronary disease by physicochemical analysis of metabolites in plasma and urine. Prostacyclin biosynthesis was markedly elevated in patients with acute myocardial infarction and correlated with plasma creatine kinase (r = 0.795; P less than 0.001). The largest rise in thromboxane synthesis was observed in patients with unstable angina, in whom 84 percent of the episodes of chest pain were associated with phasic increases in the excretion of thromboxane and prostacyclin metabolites. However, 50 percent of such increases were not associated with chest pain, possibly reflecting silent myocardial ischemia. These data indicate that platelet activation occurs during spontaneous ischemia in patients with unstable angina. The increment in prostacyclin biosynthesis during such episodes may be a compensatory response of vascular endothelium that limits the degree or effects of platelet activation. If so, biochemically selective inhibition of the synthesis or action of thromboxane A2 would be desirable in the treatment of unstable angina. In contrast, thromboxane inhibitors or antagonists would not be expected to be effective in patients with chronic stable angina, in whom there was no increase in the formation of thromboxane A2.

6-Ketoprostaglandin F1 alpha↗
PubMed1986

In vivo indexes of platelet and vascular function during fish-oil administration in patients with atherosclerosis.

Populations that consume a diet rich in marine lipids may have a lower risk of atherosclerotic disease. Fish oil contains the N-3 polyunsaturated fatty acid eicosapentaenoate, and the biosynthesis of thromboxanes and prostacyclins from eicosapentaenoate (thromboxane A3 and prostaglandin I3), rather than from the usual precursor arachidonate (thromboxane A2 and prostaglandin I2), may help to reduce the risk. To examine this hypothesis, we studied the effect of eicosapentaenoate supplementation (10 g per day) for one month on the synthesis of thromboxanes and prostacyclins, as assessed by urinary metabolite excretion, in six patients with peripheral vascular disease and seven normal controls. Supplementation markedly increased the eicosapentaenoate content of phospholipids from red cells and platelets. Synthesis of the platelet agonist thromboxane A2, which was elevated in the patients at base line, declined by 58 percent during supplementation but did not reach normal values. The decline in thromboxane A2, which is synthesized from arachidonate, coincided with the formation of the inactive thromboxane A3, which is synthesized from eicosapentaenoate. A lower dose of eicosapentaenoate (1 g per day) was not sufficient to maintain the changes in thromboxane A2 synthesis. Platelet function was only moderately inhibited during eicosapentaenoate supplementation, consistent with incomplete suppression of thromboxane A2 synthesis. These studies show that a high dose of eicosapentaenoate alters the pattern of synthesis of thromboxanes and prostacyclins. However, effects comparable to those of aspirin require long-term administration in high doses. Whether other properties of fish oil might render it a more attractive antithrombotic therapy remains to be determined.

6-Ketoprostaglandin F1 alpha↗