The influence on platelet aggregation of drugs that affect the accumulation of adenosine 3′:5′-cyclic monophosphate in platelets

Mills, D. C. B.; Smith, J B

doi:10.1042/bj1210185

Cited by 419 publications

(117 citation statements)

References 25 publications

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“…The mechanism of its action on platelets is still uncertain. Although dipyridamole acts as a phosphodiesterase inhibitor (Mills & Smith, 1971), it elevates cyclic AMP in platelets only when used in combination with agents which stimulate adenyl cyclase, such as prostacyclin (Best et al, 1979). Prostacyclin is now thought not to circulate in the plasma in concentrations which are sufficient to inhibit platelet adhesion or aggregation (FitzGerald et al, 1981).…”

Section: Introductionmentioning

confidence: 99%

Dipyridamole: pharmacokinetics and effects on aspects of platelet function in man.

Gregov

Jenkins

Duncan

et al. 1987

Brit J Clinical Pharma

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1. The effect of dipyridamole on platelet function was measured in twelve normal subjects given 150 or 200 mg tablets as single and multiple doses, and in six subjects given single doses of 25, 50 and 100 mg and multiple doses of 50 mg 8 hourly. 2. Platelet aggregation was measured in response to ADP and collagen. In the subjects given 150/200 mg, the platelets were assayed for content of cyclic AMP and for formation of thromboxane after addition of collagen. The responses to ADP and collagen and the cyclic AMP content were assessed in both the presence and absence of added PGE1. The pharmacokinetics of dipyridamole were studied in all subjects. 3. One hour after 150/200 mg single doses of dipyridamole there was significant inhibition of platelet aggregation in response to both collagen and ADP. There was no detectable effect on aggregation at other time points or with lower doses of dipyridamole. The addition of PGE1 to platelets prior to testing did not enhance the effect of dipyridamole on platelet aggregation. 4. In multiple doses, dipyridamole (150/200 mg twice daily for 11 days) had no detectable effect on platelet aggregation. 5. Dipyridamole did not have any effect on platelet cyclic AMP content, whether or not PGE1 was added prior to assay. 6. Dipyridamole did not affect platelet thromboxane formation. 7. Plasma dipyridamole concentrations were maximal 1‐2 h after ingestion, at the same time that inhibition of platelet aggregation was detected. The concentrations declined in a biexponential fashion, with a terminal half life of 24.1 +/‐ 1.9 h (mean +/‐ s.e. mean). In six of the 17 subjects, the mean steady state plasma concentration was less than 75% of the value predicted from the single dose data.

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Section: Introductionmentioning

confidence: 99%

Dipyridamole: pharmacokinetics and effects on aspects of platelet function in man.

Gregov

Jenkins

Duncan

et al. 1987

Brit J Clinical Pharma

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“…Dipyridamole and phthalazinol inhibit cyclic AMP phosphodiesterase (13,19) aril accumulate cyclic AMP in platelets, being possibly involved in the inhibition of platelet aggregation (13). PGI2 increases the pro duction of cyclic AMP in arteries (20) and has antiaggregating (21) and vasodilator activities (22).…”

Section: Discussionmentioning

confidence: 99%

“…The present study was thus undertaken to determine the alteration by dipyridamole and phthalazinol of the relaxant response of isolated dog renal arteries to ANG II, possibly mediated via endogenous PG12, and the response to exogenously applied PGI2. Dipyridamole and phthalazinol inhibit the aggregation of platelets, possibly by an accumulation of cyclic AMP in the platelets (13,14). Interaction between dipyridamole and aspirin or indomethacin in the ANG induced relaxations was also studied.…”

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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“…The therapeutic effect of dipyridamole has been attributed to its action on platelets. 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).…”

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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The influence on platelet aggregation of drugs that affect the accumulation of adenosine 3′:5′-cyclic monophosphate in platelets

Cited by 419 publications

References 25 publications

Dipyridamole: pharmacokinetics and effects on aspects of platelet function in man.

Dipyridamole: pharmacokinetics and effects on aspects of platelet function in man.

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

Dipyridamole increases red cell deformability.

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