Inhibition of Prostaglandin Synthesis as a Mechanism of Action for Aspirin-like Drugs

Vane, John R.

doi:10.1038/newbio231232a0

Cited by 7,229 publications

(3,291 citation statements)

References 23 publications

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“…In the present study, indomethacin, which blocks cyclooxygenase and thereby eliminates the vascular PG production (Vane, 1971), had no effect on the contraction induced by 10-6 M PAF in BAs. Like wise, this contraction was unaffected by the Tx re ceptor antagonist AH23848 applied at a concentra tion sufficient to block contractions by both the TxA2-mimetic U46619 and PGF2a in this artery (U ski, 1988).…”

Section: T K Uski and P Reinstrup Discussioncontrasting

confidence: 71%

Actions of Platelet-Activating Factor on Isolated Feline and Human Cerebral Arteries

Uski

Reinstrup

1990

J Cereb Blood Flow Metab

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Summary:The effects of platelet-activating factor (PAF) were studied on isolated feline basilar arteries (BAs) and human pial arteries (PAs). PAF contracted the BAs by 67% of the contraction induced by 124 mM K + and the PAs by 80%. The contraction in BAs was unaffected by both indomethacin and the thromboxane receptor antag onist AH23848. PAF relaxed prostaglandin F2a-con tracted arteries. In BAs 10-6 M PAF reduced the conPlatelet-activating factor (PAF) is an active lipid released in response to different stimuli, for in stance, inflammation (Goldstein et aI., 1986). It is produced by a variety of cells such as platelets, leukocytes, and endothelial cells (Braquet et aI., 1987). PAF may contribute to the development of postischemic brain damage (Spinnewyn et aI., 1987), and PAF antagonists seem to increase CBF during the reperfusion period (Panetta et al., 1987). Armstead et al. (1988) have recently found PAF to be a potent constrictor of pial arterioles in vivo in newborn pigs. These observations suggest that PAF is mainly a cerebral vasoconstrictor, but the direct effects of PAF have not been studied in cerebral arteries.The present study was performed to examine the effects of PAF on isolated feline and human cere bral arteries. Since it has been suggested that the effects of PAF may be mediated by prostaglandins (PGs) and/or thromboxane (Tx) A2 (Braquet et aI., Received February 9, 1989; revised October 20, 1989; ac cepted October 23, 1989.Address correspondence and reprint requests to Dr. T. K. Uski at Department of Clinical Pharmacology, University Hos pital of Lund, S-221 85 Lund, Sweden.Abbreviations used: ANOV A, analysis of variance; BA, bas ilar artery; PA, pial artery; PAF, platelet-activating factor; PO, prostaglandin; Tx, thromboxane. 428traction by 17% and in PAs by 47%. The relaxant effects in both arteries were unaffected by indomethacin. In con clusion, P AF can act both as a constrictor and as a dilator of isolated feline and human cerebral arteries. The effects are seemingly unrelated to vascular prostanoid produc tion. Key Words: Feline basilar arteries-Human pial ar teries-Platelet-activating factor.1987), these possibilities were also addressed. For this purpose the cyclooxygenase inhibitor indo methacin and the Tx receptor antagonist AH23848 (Brittain et aI., 1985) were used. MATERIAL AND METHODSCats (2.2-2.8 kg) were exsanguinated during sodium pentobarbital (30 mg/kg i.p.) anesthesia. The brains were removed and the basilar artery (BA) was dissected free from the brainstem. Human pial arteries (PAs) were re moved together with adjacent parts of normal cortex in patients (16--69 years of age) undergoing frontal or tem poral lobectomies due to underlying gliomas. The speci mens were immersed in cold (-4°C) Krebs solution and the arteries were freed from brain tissues. All vessels were stored in cold Krebs solution for "",6 h.Ring segments, 1-1.5 (BA) or 2-3 (PA) mm in length, of the arteries were suspended between metal prongs in or gan baths containing 2.5 ml of a Krebs solution ...

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Section: T K Uski and P Reinstrup Discussioncontrasting

confidence: 71%

Actions of Platelet-Activating Factor on Isolated Feline and Human Cerebral Arteries

Uski

Reinstrup

1990

J Cereb Blood Flow Metab

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“…1 In 1967, the antiplatelet actions of aspirin were found. 2 In 1971, Smith and Willis 3 and Vane 4 independently proposed that the action mechanism of aspirin involves inhibition of cyclooxygenase 1 (COX-1). In addition, in 1991, Funk et al 5 found aspirin-related acetylation and inactivation of the active site of COX-1, Ser at position 529.…”

Section: Introductionmentioning

confidence: 99%

Exploratory aspirin resistance trial in healthy Japanese volunteers (J-ART) using platelet aggregation as a measure of thrombogenicity

et al. 2007

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“…According to Ekstrand et al [5] the therapeutic plasma levels of indomethacin are in the range of 0.3 to 3.0 nmol/ml, thus slightly lower than those reached in the patients of group 2 and very likely similar to those reached in the patients of group 1. Moreover, indomethacin not only inhibits cyclo-oxygenase activity and prostaglandin synthesis [32], but also reduces the activity of some enzymes involved in degradation of prostaglandins [24], as well as that of phosphodiesterase [6], the latter effect leading to increased intracellular concentrations of cyclic AMP. The dose-effect relationship for these various actions of indomethacin in vivo remains to be determined.…”

Section: Discussionmentioning

confidence: 99%

Failure of indomethacin to affect arginine-induced C-peptide and glucagon release in insulin-treated diabetics

Luyckx

Lefèbvre

1981

Diabetologia

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Summary. Fourteen insulin-treated diabetics were submitted to an arginine infusion test performed with either 11.7 or 5.85mgkg -t min -1 arginine monohydrochloride infused during 40 rain with or without previous oral administration of a low (75 + 50 mg) or a high (75 mg + 3 mg/kg) dose of indomethacin. Blood glucose, plasma non-esterified fatty acids, insulin, C-peptide and glucagon were determined at regular intervals before, during and after the arginine infusion. These parameters were totally unaffected by the two doses of indomethacin both in the basal state and during the arginine infusions at the two loads tested. Eight subjects had a basal C-peptide level above 0.07 pmol/ml and a mean (_+ SEM) maximal rise of 0.21 + 0.04 pmol/ml during the arginine infusion, whereas the remaining six patients had virtually zero values throughout the tests. The arginineinduced plasma glucagon rise was similar for the two rates of arginine infusion; the sum of the increments in plasma glucagon averaged 877 + 120 and 647 + 92pg/ml (p > 0.1) for the high and low rates of arginine infusion, respectively. The magnitude of the blood glucose rise appeared independent of the amount of arginine infused. Confirming previous reports, we found that the blood glucose rise after arginine was three to four times higher in subjects without C-peptide than in subjects with C-peptide. The mean glucagon response did not differ significantly between subjects with or without C-peptide. Thus, residual B cell function determines the magnitude of the blood glucose rise but not the glucagon response after intravenous arginine.Key words: Insulin-treated diabetics, intravenous arginine, insulin, glucagon, C-peptide, indomethacin, prostaglandins.Exogenous prostaglandins stimulate glucagon secretion in vitro [13,25] and in vivoin animals [27] andin man [8]. Moreover, previous studies from our laboratory using isolated guinea-pig islets incubated in vitro support the view that intra-insular synthesis of prostaglandins is involved in the stimulus-secretion coupling of pancreatic A cells [17][18][19][20][21].Since suppression of glucagon secretion may be considered as a therapeutic goal of diabetic management, at least under certain conditions [14], it is of interest to investigate the possible effect of inhibitors of prostaglandin synthesis in diabetic subjects. The present work was therefore designed to investigate arginine-induced glucagon secretion in insulin-treated diabetic subjects before and after the administration of moderate or high doses of indomethacin. The influence of indomethacin on residual insulin secretion was also assessed by measuring C-peptide plasma levels during the arginine infusions. Indeed, Robertson and his group [2,22,26] have reported that blocking the synthesis of prostaglandins by sodium salicylate intravenous infusion improved the insulin response to glucose in Type 2 (insulin independent) diabetics. In addition we attempted to correlate the magnitude of the blood glucose rise induced by arginine infusion with the insulin-...

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Inhibition of Prostaglandin Synthesis as a Mechanism of Action for Aspirin-like Drugs

Cited by 7,229 publications

References 23 publications

Actions of Platelet-Activating Factor on Isolated Feline and Human Cerebral Arteries

Actions of Platelet-Activating Factor on Isolated Feline and Human Cerebral Arteries

Exploratory aspirin resistance trial in healthy Japanese volunteers (J-ART) using platelet aggregation as a measure of thrombogenicity

Failure of indomethacin to affect arginine-induced C-peptide and glucagon release in insulin-treated diabetics

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