Dipyridamole and Other Phosphodiesterase Inhibitors Act as Antithrombotic Agents by Potentiating Endogenous Prostacyclin

Moncada, Salvador; Korbut, Ryszard

doi:10.1016/s0140-6736(78)91269-2

Cited by 381 publications

(85 citation statements)

References 19 publications

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“…ASA also potentiates the anti-thrombotic effect of dipyridamole (Giromini et al, 1972;Harker & Slichter, 1972;Moncada & Korbut, 1978). In our study, 2.6 or 5.7 mg/kg of ASA in combination with dipyridamole almost completely inhibited the platelet cyclo-oxygenase without changing the PGI2 formation.…”

Section: Discussion 5o0supporting

confidence: 61%

“…Our data, however, show that a single dose of dipyridamole (1.3 mg/kg) does not change the production of PGI2, as measured by PGI2 metabolite levels in serum. This does not exclude the possibility that dipyridamole acts as an anti-thrombotic agent by potentiating the effect of endogenous PGI2 (Moncada & Korbut, 1978).…”

Section: Discussion 5o0mentioning

confidence: 95%

“…Furthermore, it has been shown that ASA and dipyridamole have a synergistic anti-thrombotic effect in vivo (Harker & Slichter, 1970;Giromini. Bouvier, Dami, Denizot & Jeannet, 1972;Weiss, 1976) which effect, however, depends critically on the dose of ASA used (Moncada & Korbut, 1978 PGI2 and TxA2 production were studied indirectly by measuring the stable metabolites of these prostanoids, namely 6-keto-prostaglandin Fl2 (6-keto-PGF,,) and thromboxane B2 (TxB2), respectively (Hamberg et al, 1975;Johnson, Morton, Kinner, Gorman, McGuire, Sun, Whiltaker, Bunting, Salmon, Moncada & Vane, 1976). This was done with specific radioimmunoassays, the characteristics of which are given elsewhere .…”

Section: Introductionmentioning

confidence: 99%

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Effect of Various Doses of Acetylsalicylic Acid in Combination With Dipyridamole on the Balance Between Prostacyclin and Thromboxane in Human Serum

Viinikka

Ylikorkala

1981

British J Pharmacology

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I Thirty-six healthy human subjects were randomly divided into six groups which were treated with a single dose of 75 mg (1.3 mg/kg) of dipyridamole alone, or 75 mg of dipyridamole in combination with 30 mg (0.5 mg/kg), 50 mg (0.8 mg/kg), 160 mg (2.6 mg/kg) and 330 mg (5.7 mg/kg) of acetylsalicylic acid (ASA), or with placebo. 2 The concentrations of prostacyclin (PGI2) and thromboxane A2 (TxA2) metabolites, 6-keto-prostaglandin Fl, ) and TxB2 respectively, were measured in serum with specific radioimmunoassays before and 1 and 3 h after the ingestion of the test dose.3 The basal concentrations of 6-keto-PGF1, and TxB2 correlated significantly (r = 0.588, P < 0.001). 4 Dipyridamole alone did not change PGI2 or TxA2 production. 5 Dipyridamole-ASA combinations with ASA doses between 0.5 and 0.8 mg/kg inhibited TxB2 production by 48 to 74%, and with the ASA doses between 2.6 and 5.7 mg/kg by about 90%. None of these combinations changed PGI2 production. 6 The ratio of 6-keto-PGF1, to TxB2 increased 3.5 to 6 times with ASA doses of 0.5 to 0.8 mg/kg and 21 to 29 times with doses between 2.6 to 5.7 mg/kg. 7 These results suggest that the anti-thrombotic effect of dipyridamole in vivo is not mediated through direct changes in PGI2 and/or TxA2 production.

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Section: Discussion 5o0supporting

confidence: 61%

Section: Discussion 5o0mentioning

confidence: 95%

Section: Introductionmentioning

confidence: 99%

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Effect of Various Doses of Acetylsalicylic Acid in Combination With Dipyridamole on the Balance Between Prostacyclin and Thromboxane in Human Serum

Viinikka

Ylikorkala

1981

British J Pharmacology

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“…Dipyridamole is known to inhibit phosphodiesterase (Mills & Smith, 1971) leading to elevation of cyclic AMP levels and inhibition of platelet aggregation. It has been suggested that dipyridamole may require endogenous epoprostenol (PGI2) to be fully effective (Moncada & Korbut, 1978;Masotti et al, 1979) and PGI2 is itself a potent stimulator of adenylcyclase (Gorman et al, 1977). As well as being important in platelet aggregation, cyclic nucleotides may also be involved in the regulation of red cell shape and flexibility (Yawata et al, 1976) and PGI2 also increases filterability of red cells (Kovacs & O'Grady 1984).…”

Section: Introductionmentioning

confidence: 99%

Dipyridamole increases red cell deformability.

So¹,

Kovács²,

Pickles³

et al. 1983

Brit J Clinical Pharma

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The effects of dipyridamole on red cell filterability both in vitro and ex vivo were measured. In a balanced, randomised and double‐blind trial, six healthy male and female volunteers (22‐37 years) were given dipyridamole 400 mg/day or matching placebo in four divided doses for 3 days, and heparinised venous blood samples were taken 1 h after the ingestion of the last dose. Filterability of red cells was increased significantly (P less than 0.05 paired t‐test) when the subjects were on dipyridamole compared with placebo. In separate experiments, 15 min incubation with 2 or 20 micrograms/ml dipyridamole in vitro was found to have no effect on the filterability of freshly prepared red cell suspensions. After 24 h storage at 4 degrees C, the filterability of red cells was significantly decreased (P less than 0.01) and this could be partially prevented by adding dipyridamole to the stored cells (P less than 0.05). These results suggest that dipyridamole has an effect on the behaviour of the red cell membrane to increase the deformability of the cells. This may contribute to its therapeutic effect.

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“…Combined treatment with dipyridamole and aspirin reduced coronary mortality (6). These antithrombotic agents have different and additive modes of action (7). However, attention has not been paid to the action of dipyridamole on an aspirin induced inhibition of the PGI2 synthesis.…”

mentioning

confidence: 99%

Modification of angiotensin II-induced relaxation by dipyridamole, phthalazinol and aspirin in isolated dog renal arteries.

Toda

Yamamoto

1983

Jpn.J.Pharmacol

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Abstract-Angiotensin(ANG) II-induced relaxations in isolated dog renal and cerebral arteries are postulated to be mediated by the release of prostaglandin (PG) 12 from the arterial wall. In helical strips of dog renal arteries treated with dipyridamole, relaxations induced by ANG II (10-7 M) and exogenously applied PG12 (10-8 M) were potentiated; the potentiation was appreciably greater in the ANG-induced relaxation. Treatment with phthalazinol did not alter the response to ANG II, but significantly potentiated the relaxation induced by PGI2. The ANG-induced relaxations were suppressed or reversed to contractions by aspirin or indomethacin. Combined treatment of dipyridamole with aspirin or indomethacin restored the relaxant response to ANG II, while phthalazinol in combination with aspirin did not restore the response. It may be concluded that the potentiation of responses to ANG II by dipyridamole is associated with increments in the release of PGI2 from the arterial wall and potentiations of the response of arterial smooth muscle to PG12. Dipyridamole appears to increase the production of PGI2 even in the presence of PG synthesis inhibition by aspirin or indomethacin.

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Dipyridamole and Other Phosphodiesterase Inhibitors Act as Antithrombotic Agents by Potentiating Endogenous Prostacyclin

Cited by 381 publications

References 19 publications

Effect of Various Doses of Acetylsalicylic Acid in Combination With Dipyridamole on the Balance Between Prostacyclin and Thromboxane in Human Serum

Effect of Various Doses of Acetylsalicylic Acid in Combination With Dipyridamole on the Balance Between Prostacyclin and Thromboxane in Human Serum

Dipyridamole increases red cell deformability.

Modification of angiotensin II-induced relaxation by dipyridamole, phthalazinol and aspirin in isolated dog renal arteries.

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