Testosterone Potentiation of Ionophore and ADP Induced Platelet Aggregation : Relationship to Arachidonic Acid Metabolism

Summary

The role of arachidonic acid oxygenated products in human platelet aggregation induced by the ionophore A23187 was investigated. The ionophore produced an increased release of both saturated and unsaturated fatty acids and a concomitant increased formation of TxA₂ and other arachidonate products. TxA₂ (and possibly other cyclo oxygenase products) appears to have a significant role in ionophore-induced aggregation only when low concentrations (<1 μM) of the ionophore are employed.

Testosterone added to rat or human platelet-rich plasma (PRP) was shown previously to potentiate platelet aggregation induced by ADP, adrenaline, collagen and arachidonic acid (1, 2). We show that testosterone also potentiates ionophore induced aggregation in washed platelets and in PRP. This potentiation was dose and time dependent and resulted from increased lipolysis and concomitant generation of TxA₂ and other prostaglandin products. The testosterone potentiating effect was abolished by preincubation of the platelets with indomethacin.

Keywords

Arachidonic acid - Platelets - Ionophore A23187 - Testosterone

• References

• 1 Johnson M, Ramey E, Ramwell PW. Androgen-mediated sensitivity in platelet aggregation. Am J Physiol 1977; 232 (04) H381-H385
• 2 Johnson M, Ramey E, Ramwell PW. Sex and age differences in human platelet aggregation. Nature 1975; 253: 355-357
• 3 Charo IF, Feinman RD, Detwiler TC. Interrelations of platelet aggregation and secretion. J Clin Invest 1977; 60: 866-873
• 4 Uzunova AD, Ramey ER, Ramwell PW. Arachidonate-induced thrombosis in mice: Effects of Gender or Testosterone and Estradiol administration. Prostaglandins 1977; 13: 995-1002
• 5 Johnson M, Maish T, Ramey E, Ramwell PW. Prostaglandin (PG)-mediated sensitivity in androgen treated platelets. Fed Proc 1975; 34: 304
• 6 Minkes M, Stanford N, Chi M, Roth GJ, Raz A, Needleman P, Majerus PW. Cyclic adenosine 3’:5’-monophosphate inhibits the availability of arachidonate to prostaglandin synthetase in human platelet suspensions. J Clin Invest 1977; 59: 449-454
• 7 Erman A, Raz A. Effects of bivalent cations on prostaglandin biosynthesis and phospholipase A₂activation in rabbit kidney medulla slices. Biochem J 1979; 182: 821-824
• 8 Bills TK, Smith JB, Silver MJ. Metabolism of ¹⁴C-arachidonic acid by human platelets. Biochim Biophys Acta 1976; 424: 303-314
• 9 Svensson J, Hamberg M, Samuelsoon B. Prostaglandin endoperoxides IX. Characterization of rabbit aorta contracting substance (RCS) from Guinea Pig lung and human platelets Acta Physiol Scand 1975; 94: 222-228
• 10 Schwarzmann M, Raz A. Prostaglandin generation in rabbit kidney: Hormone-activated selective lipolysis coupled to prostaglandin biosynthesis. Biochim Biophys Acta 1979; 472: 363-369
• 11 Pilo R, Raz A. Aspirin inhibits Ca²⁺-stimulated fatty acid release from human washed platelets. Prostaglandins Med. 1981 in press
• 12 White JG, Rao GH R, Gerrard JM. Effects of the Ionophore A23187 on blood platelets. Am J Pathol 1974; 77: 135-150
• 13 Feinstein MB, Fraser C. Human platelet secretion and aggregation induced by calcium Ionophores. J Gen Physiol 1975; 66: 561-581
• 14 Massini P, Lüscher EF. Some effects of ionophores for divalent cations on blood platelets. Biochim Biophys Acta 1974; 372:: 109-121
• 15 Pickett WC, Jesse RL, Cohen P. Initiation of phospholipase A₂activity in human platelets by the calcium ion ionophore A23187. Biochim Biophys Acta 1977; 486: 209-213
• 16 Lapetina EG, Chandrabose KA, Cuatrecasas P. Ionophore A23187 and thrombin-induced platelet aggregation: Independence from cyc-looxygenase products. Proc Natl Acad Sci USA 75: 818-822
• 17 Schoene WN, Iacono JM. The influence of phospholipase A₂on prostaglandin production in platelets. Adv Prostaglandin Thromboxane Res 1976; 2: 763-766
• 18 Rittenhouse SS, Deykin D. The Activation by Ca²⁺of platelet phospholipase A₂ . Biochim Biophys Acta 1978; 543: 409-422
• 19 Jesse RL, Franson RC. Modulation of purified phospholipase A₂activity from human platelets by calcium and indomethacin. Biochim Biophys Acta 1979; 575: 467-470
• 20 Derksen A, Cohen P. Patterns of fatty acid release from endogenous substrates by human platelet homogenates and membranes. J Biol Chem 1975; 250: 9342-9347
• 21 Jørgensen KA, Stoffersen E. On the inhibitory effect of albumin on platelet aggregation. Thromb Res 1980; 17: 13-18
• 22 Lagarde M, Velardo B, Blanc M, Dechavanne M. Fatty acids bound to serum albumin decrease the half-life of thromboxane A₂ . Prostaglandins 1980; 20: 275-283
• 23 Pearlman WH, Crepy O. Steroid-protein interaction with particular reference to testosterone binding by human serum. J Biol Chem 1967; 242: 182-189