The Effect of Intravenous Adenosine Diphosphate on the Number of Circulating Platelets in Experimental Animals: Inhibition by Prostaglandin E_1, Dipyridamole, SH-869 and VK-774

Summary

The number of circulating platelets was monitored in anaesthetized animals by a continuous flow technique, using a Technicon Autocounter®. Intravenous infusions of adenosine diphosphate (ADP) produced transient, dose-dependent falls in circulating platelet numbers in rabbits, dogs, rats, pigs and squirrel monkeys. The rat was the most sensitive of the species investigated.

In the rabbit, the effect of a submaximal dose of ADP was inhibited in a dose-dependent manner by intravenous infusions of prostaglandin E₁ (PGE₁), dipyridamole, and two derivatives of dipyridamole (SH-869 and VK-774). The dose-response curves for PGE_l, SH-869 and VK-774 were approximately parallel, whereas that for dipyridamole was considerably less steep. PGE₁ was the most potent inhibitor, but the duration of action was very short. Dipyridamole and SH-869 produced inhibition of long duration. The duration of action of VK-774 was intermediate.

All inhibitors produced marked and often long-lasting hypotension. The fact that no inhibition of ADP effects could be demonstrated with dibenzyline and hexamethonium, which also produced marked hypotension of long duration, indicated that inhibition of the ADP effect by the four antagonists studied was not due to changes in blood pressure.

• References

• 1 Born G.V.R, Cross M.J. Effect of adenosine diphosphate on the concentration of platelets in circulating blood. Nature, London 1963; 797: 974
• 2 Bousser M.-G, Lecrubier C. Effect of prostaglandin E₁ on experimental thrombosis and platelet aggregation in rabbits. Haemostasis 1973; 1: 294
• 3 Davey M.G, Lander H. Effect of adenosine diphosphate on circulating platelets in man. Nature, London 1964; 201: 1037
• 4 Deutsch E, Gasic S. Hemmung der ADP-induzierten Aggregation beim Meerschweinchen. Thrombosis Research 1973; 3: 103
• 5 Didisheim P. Inhibition by dipyridamole of arterial thrombosis in rats. Thrombosis et Diathesis Haemorrhagica 1968; 20: 256
• 6 Emmons P.R, Hampton J.R, Harrison M.J.G, Honour A.J, Mitchell J.R.A. Effect of prostaglandin E₁ on platelet behaviour in vitro and in vivo . British medical Journal 1967; 2: 468
• 7 Emmons P.R, Harrison M.J.G, Honour A.J, Mitchell J.R.A. Effect of a pyrimido-pyrimidine derivative on thrombus formation in the rabbit. Nature, London 1965; 208: 255
• 8 Ferreira S.H, Vane J.R. Prostaglandins: their disappearance from and release into the circulation. Nature, London 1967; 216: 868
• 9 Haarmann W, Kadatz R. SH-869, a new platelet active compound. IVth International Congress on Thrombosis and Haemostasis, Vienna, page 402, Abstract 1973; 367
• 10 Hampton J.R, Harrison M.J.G, Honour A.J, Mitchell J.R.A, Pritchard J.G. Assessment of antithrombotic agents: effects of dipyridamole analogues on platelet behaviour. Cardiovascular Research 1972; 6: 696
• 11 Harker L.A, Slichter S.J. Platelet and fibrinogen consumption in man. New England Journal of Medicine 1972; 287: 999
• 12 Horch V, Kadatz R, Kopitar Z. Pharmacology of dipyridamole and it derivatives. Thrombosis et Diathesis Haemorrhagica, Supplement 1970; 42: 253
• 13 Horton E.W. Prostaglandins . 1972. Springer-Verlag; Berlin, Heidelberg, New York:
• 14 Innocenti I.R, Poggi A, De Gaetano G. Platelet aggregation and haemolysis induced in rats by intravenous infusion of ADP – effect of potentially antithrombotic drugs. Scandinavian Journal of Haematology 1974; 13: 331
• 15 Kinlough-Rathbone R.L, Packham M.A, Mustard J.F. The effect of prostaglandin E₁ on platelet function in vitro and in vivo . British Journal of Haematology 1970; 19: 559
• 16 Kloeze J. Influence of prostaglandins on platelet adhesiveness and aggregation. Proceedings of the 2nd Nobel Platelet Symposium, Stockholm, June 1966, Almqvist and Wiksell, Stockholm 1967; p. 241
• 17 Kloeze J. Prostaglandins and platelet aggregation in vivo. I. Influence of PGE₁ and w-homo-PGE₁ on transient thrombocytopaenia and of PGE₁ on the LD50 of ADP. Thrombosis et Diathesis Haemorrhagica 1970; a 23: 286
• 18 Kloeze J. Prostaglandins and platelet aggregation in vivo. II. Influence of PGE₁ and PGF 2α on platelet thrombus formation induced by an electrical stimulus in veins on the rat brain surface. Thrombosis et Diathesis Haemorrhagica 1970; b 23: 293
• 19 Kobayashi I, Didisheim P. Systemic effects of ADP-induced platelet aggregation and their modification by aspirin and pyridinolcarbamate. Thrombosis et Diathesis Haemorrhagica 1973; 30: 179
• 20 MacKenzie R.D, Henderson J.G, Steinbach J.M. The evaluation of a method for adenosine diphosphate-induced platelet aggregation in the guinea-pig. Thrombosis et Diathesis Haemorrhagica 1971; 28: 30
• 21 Niewiarowski S, Lukasiewicz H, Nath N, Sha A.T. Inhibition of human platelet aggregation by dipyridamole and two related compounds and its modification by acid glycoproteins of human plasma. Journal of laboratory and clinical Medicine 1975; 86: 64
• 22 Philp R.B, Francy I, McElroy F. Effects of dipyridamole and five related agents on human platelet aggregation and adenosine uptake. Thrombosis Research 1973; 3: 35
• 23 Regoli D, Clark V. Effect of adenosine diphosphate on the concentration of platelets in circulating blood. Nature, London 1963; 200: 546
• 24 Silver M.D, Stehbens W.E, Silver M.M. Platelet reaction to adenosine diphosphate in vivo . Nature, London 1965; 205: 91
• 25 Smith G.M, Freuler F. The measurement of intravascular aggregation by continuous platelet counting. Bibliotheca Anatomica, Number 1973; 12: 229
• 26 Sullivan J.M, Harken D.E, Gorlin R. Pharmacologic control of thromboembolic complications of cardiac valve replacement. New England Journal of Medicine 1971; 284: 1391
• 27 Zbinden G. Lauric acid-induced thrombocytopenia and thrombosis in rabbits. Thrombosis et Diathesis Haemorrhagica 1968; 18: 57