Inhibition of platelet thromboxane A2 synthase activity by sodium 5-(3′-pyridinylmethyl)benzofuran-2-carboxylate

doi:10.1016/0090-6980(83)90099-0

Prostaglandins

Volume 26, Issue 2, August 1983, Pages 325-342

Prostaglandins

https://doi.org/10.1016/0090-6980(83)90099-0 Get rights and content

Abstract

This report outlines the activity of a new thromboxane synthase inhibitor sodium, 5-(3-pyridinymethyl)-2-benzofurancarboxylate, (U-63557A). U-63557A is a potent inhibitor of the thromboxane synthase in human platelets $in$ $vitro$ , as well as in rhesus monkey platelets $ex vivo$ . A single oral dose of 3.0 mg/kg U-63557A inhibits the platelet thromboxane synthase in rhesus monkeys approximately 80% for at least 12 hrs. U-63557A has been administered to monkeys twice a day, (10 mg/kg) for 14 days, without evidence of drug tachyphylaxis or rebound. U-63557A does not inhibit thrombin-stimulated PGI₂ biosynthesis in human endothelial cells, the 5-lipoxygenase in human neutrophils, or the cyclo-oxygenase in a variety of test systems. In anesthetized dogs, U-63557A injected i.v. at 0.1 at 5 mg/kg prevented the blockage of stenosed coronary arteries caused platelet aggregation,. Similar effects were obtained by oral administration of 1–5 mg/kg. The thromboxane synthase inhibitor was more efficacious than cyclooxgenase inhibitors and equal to PGI₂ in efficacy. Under appropriate conditions the protective effects of U-63557A could be reversed by i.v. cylooxygenase inhibitors suggesting that its efficacy dependened in part of endogenous PGI₂ formation. Due to its specificity, oral activity, and extended duration of action, U-63557A is a promising compound for the evaluation of the role of thromboxane synthase in a variety of patho[hysiological states.

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Central bombesin activates adrenal adrenaline- and noradrenaline-containing cells via brain thromboxane A<inf>2</inf> in rats
2009, Autonomic Neuroscience: Basic and Clinical
The sympathetic nervous system regulates peripheral organs via the adrenal chromaffin cells containing adrenaline (A-cells) or noradrenaline (NA-cells) and the sympathetic ganglia. We examined the effect of intracerebroventricularly administered bombesin on neuronal activities of adrenal A-cells and NA-cells and several kinds of sympathetic ganglia (superior cervical, stellate and celiac ganglia) using c-Fos (a marker for neuronal activation), with regard to brain prostanoid, in anesthetized rats. Bombesin induced c-Fos in both adrenal A-cells and NA-cells, but not in any of the sympathetic ganglia. Central pretreatment with either indomethacin (a cyclooxygenase inhibitor) or furegrelate (a thromboxane A₂ synthase inhibitor) abolished all bombesin-induced responses. These results suggest that bombesin centrally activates adrenal A-cells and NA-cells by brain thromboxane A₂-mediated mechanisms in rats.
Centrally administered neuromedin U elevates plasma adrenaline by brain prostanoid TP receptor-mediated mechanisms in rats
2008, European Journal of Pharmacology
Neuromedin U is a hypothalamic peptide involved in energy homeostasis and stress responses. The peptide, when administered intracerebroventricularly (i.c.v.), decreases food intake and body weight while increasing body temperature and heat production. We examined the effect of i.c.v. administered neuromedin U on plasma catecholamines with regard to the brain prostanoid using anesthetized rats. Neuromedin U (0.1, 0.5 and 1 nmol/animal, i.c.v.) effectively elevated plasma adrenaline (a maximal response was obtained at 0.5 nmol/animal), but had little effect on plasma noradrenaline. However, intravenously administered neuromedin U (0.5 nmol/animal) had no effect on plasma catecholamines. Neuromedin U (0.5 nmol/animal, i.c.v.)-induced elevation of plasma adrenaline was effectively reduced by intracerebroventricular pretreatments with indomethacin (an inhibitor of cyclooxygenase) (0.6 and 1.2 µmol/animal), furegrelate (an inhibitor of thromboxane A₂ synthase) (0.9 and 1.8 µmol/animal) and (+)-S-145 (a blocker of prostanoid TP receptors) (250 and 625 nmol/animal), respectively. The neuromedin U-induced adrenaline response was also abolished by acute bilateral adrenalectomy. These results suggest that centrally administered neuromedin U evokes the secretion of adrenaline from the adrenal medulla by brain prostanoid TP receptor-mediated mechanisms in rats.
Centrally administered N-methyl-d-aspartate evokes the adrenal secretion of noradrenaline and adrenaline by brain thromboxane A<inf>2</inf>-mediated mechanisms in rats
2008, European Journal of Pharmacology
Plasma adrenaline mainly originated from adrenaline-containing cells in the adrenal medulla, while plasma noradrenaline reflects the release from sympathetic nerves in addition to the secretion from noradrenaline-containing cells in the adrenal medulla. The present study was undertaken to characterize the source of plasma catecholamines induced by centrally administered N-methyl-d-aspartate with regard to the brain prostanoid, using urethane-anesthetized rats. Intracerebroventricularly (i.c.v.) administered N-methyl-d-aspartate (1.0, 5.0, 10.0 nmol/animal) dose-dependently elevated plasma levels of noradrenaline and adrenaline. The N-methyl-d-aspartate (5.0 nmol/animal, i.c.v.)-induced elevation of both catecholamines was reduced by dizocilpine maleate (5 nmol/animal, i.c.v.), a non-competitive N-methyl-d-aspartate receptor antagonist. Indomethacin (0.6 and 1.2 μmol/animal, i.c.v.), an inhibitor of cyclooxygenase, dose-dependently reduced the N-methyl-d-aspartate (5.0 nmol/animal, i.c.v.)-induced elevation of both catecholamines. The N-methyl-d-aspartate-induced response was dose-dependently attenuated by furegrelate (0.9 and 1.8 μmol/animal, i.c.v.), an inhibitor of thromboxane A₂ synthase. Furthermore, the acute bilateral adrenalectomy abolished the N-methyl-d-aspartate-induced responses, indicating that the source of increase in plasma noradrenaline evoked by N-methyl-d-aspartate is due to secretion from the adrenal gland and not due to release from sympathetic nerve terminals. These results suggest that centrally administered N-methyl-d-aspartate induces the secretion of noradrenaline and adrenaline from adrenal medulla by the brain thromboxane A₂-mediated mechanisms in rats.
Adrenal adrenaline- and noradrenaline-containing cells and celiac sympathetic ganglia are differentially controlled by centrally administered corticotropin-releasing factor and arginine-vasopressin in rats
2007, European Journal of Pharmacology
Citation Excerpt :
The present results are well consistent with those of our previous report in which central pretreatment with indomethacin abolished the centrally administered CRF- and AVP-induced elevation of plasma catecholamines in rats (Yokotani et al., 2001; Okada et al., 2003a). Finally, we examined the effects of furegrelate, a selective inhibitor of thromboxane A2 synthase (Gorman et al., 1983), on the centrally administered CRF- and AVP-induced cFos expression. Central pretreatment with furegrelate abolished the CRF-induced cFos expression in the adrenal A-cells (but not noradrenergic neurons in the celiac ganglia), and also abolished the AVP-induced all cFos expression in the adrenal A-cells and NA-cells.
The adrenal glands and sympathetic celiac ganglia are innervated mainly by the greater splanchnic nerves, which contain preganglionic sympathetic nerves that originated from the thoracic spinal cord. The adrenal medulla has two separate populations of chromaffin cells, adrenaline-containing cells (A-cells) and noradrenaline-containing cells (NA-cells), which have been shown to be differentially innervated by separate groups of the preganglionic sympathetic neurons. The present study was designed to characterize the centrally activating mechanisms of the adrenal A-cells, NA-cells and celiac sympathetic ganglia with expression of cFos (a marker for neural excitation), in regard to the brain prostanoids, in anesthetized rats. Intracerebroventricularly (i.c.v.) administered corticotropin-releasing factor (CRF) induced cFos expression in the adrenal A-cells, but not NA-cells, and celiac ganglia. On the other hand, i.c.v. administered arginine–vasopressin (AVP) resulted in cFos induction in both A-cells and NA-cells in the adrenal medulla, but not in the celiac ganglia. Intracerebroventricular pretreatment with indomethacin (an inhibitor of cyclooxygenase) abolished the CRF- and AVP-induced cFos expression in all regions described above. On the other hand, intracerebroventricular pretreatment with furegrelate (an inhibitor of thromboxane A₂ synthase) abolished the CRF-induced cFos expression in the adrenal A-cells, but not in the celiac ganglia, and also abolished the AVP-induced cFos expression in both A-cells and NA-cells in the adrenal medulla. These results suggest that centrally administered CRF activates adrenal A-cells and celiac sympathetic ganglia by brain thromboxane A₂-mediated and other prostanoid than thromboxane A₂ (probably prostaglandin E₂)-mediated mechanisms, respectively. On the other hand, centrally administered AVP activates adrenal A-cells and NA-cells by brain thromboxane A₂-mediated mechanisms in rats.
Centrally administered histamine evokes the adrenal secretion of noradrenaline and adrenaline by brain cyclooxygenase-1- and thromboxane A<inf>2</inf>-mediated mechanisms in rats
2006, European Journal of Pharmacology
Plasma adrenaline is originated from adrenal medulla, while plasma noradrenaline reflects the release from sympathetic nerves in addition to the secretion from adrenal medulla. The present study was designed to characterize the source of plasma catecholamines induced by centrally administered histamine, with regard to the brain prostanoids. Intracerebroventricularly (i.c.v.) administered histamine (1, 5 and 10 μg/animal) elevated plasma noradrenaline and adrenaline (noradrenaline < adrenaline) in a dose-dependent manner. Ketoprofen (a selective inhibitor of cyclooxygenase-1) (100, 250 and 500 μg/animal, i.c.v.) dose-dependently reduced the histamine (5 μg/animal, i.c.v.)-induced elevation of both catecholamines, while NS-398 (a selective inhibitor of cyclooxygenase-2) (250 and 500 μg/animal, i.c.v.) had no effect. The histamine-induced response was dose-dependently attenuated by furegurelate (an inhibitor of thromboxane A₂ synthase) (250 and 500 μg/animal, i.c.v.), and abolished by acute bilateral adrenalectomy. These results suggest that centrally administered histamine evokes plasma noradrenaline and adrenaline from adrenal medulla by brain cyclooxygenase-1- and thromboxane A₂-mediated mechanisms in rats.
Brain prostanoid TP receptor-mediated adrenal noradrenaline secretion and EP<inf>3</inf> receptor-mediated sympathetic noradrenaline release in rats
2005, European Journal of Pharmacology
Sympathetic nerves release noradrenaline, whereas adrenal medullary chromaffin cells secrete noradrenaline and adrenaline. Therefore, plasma noradrenaline reflects the secretion from adrenal medulla in addition to the release from sympathetic nerves, however the exact mechanisms of adrenal noradrenaline secretion remain to be elucidated. The present study was designated to characterize the source of plasma noradrenaline induced by intracerebroventricularly (i.c.v.) administered bombesin and prostaglandin E₂ in urethane-anesthetized rats. Bombesin (1.0 nmol/animal, i.c.v.) elevated plasma noradrenaline and adrenaline, while prostaglandin E₂ (0.3 nmol/animal, i.c.v.) elevated only plasma noradrenaline. The bombesin-induced elevations of both catecholamines were attenuated by pretreatments with furegrelate (an inhibitor of thromboxane A₂ synthase) [250 and 500 μg (0.9 and 1.8 μmol)/animal, i.c.v.)] and [(+)-S-145] [(+)-(1R,2R,3S,4S)-(5Z)-7-(3-[4-³H]-phenylsulphonyl-aminobicyclo[2.2.1]hept-2-yl)hept-5-enoic acid sodium salt] (an antagonist of prostanoid TP receptors) [100 and 250 μg (250 and 625 nmol)/animal)], and abolished by acute bilateral adrenalectomy. On the other hand, the prostaglandin E₂-induced elevation of plasma noradrenaline was not influenced by acute bilateral adrenalectomy. These results suggest that adrenal noradrenaline secretion and sympathetic noradrenaline release are mediated by differential central mechanisms; brain prostanoid TP receptors activated by bombesin are involved in the adrenal noradrenaline secretion, while brain prostanoid EP (probably EP₃) receptors activated by prostaglandin E₂ are involved in the sympathetic noradrenaline release in rats. Brain prostanoid TP receptors activated by bombesin are also involved in the adrenal adrenaline secretion.

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Inhibition of platelet thromboxane A2 synthase activity by sodium 5-(3′-pyridinylmethyl)benzofuran-2-carboxylate

Abstract

Lancet

Prostaglandins

J. Biol. Chem.

Analytical Biochem.

Prostaglandins

Prostaglandins

Thromboxanes: A New Group of Biologically Active Compounds Derived from Prostaglandin Endoperoxidases

Application of Imidazole as a Selective Inhibitor of Thromboxane Synthetase in Human Platelets

Inhibition of platelet thromboxane A₂ synthase activity by sodium 5-(3′-pyridinylmethyl)benzofuran-2-carboxylate