Effects of Prostacyclin and of the Stable Prostacyclin Analogue ZK 36374 on Forearm Blood Flow and Blood Platelet Behaviour in Man

Summary

PGI₂ and ZK 36374 were each infused into volunteers and the effects on forearm blood flow and on platelet behaviour were determined. Infusions of PGI₂ or ZK 36374 did not alter resting forearm blood flow but both agents reduced the extent of the vasoconstriction that occurred in response to cold. ZK 36374 appeared to be a much more potent inhibitor of platelet behaviour than PGI₂ when blood was taken while the infusions were in progress, but the effects of both agents were no longer evident one hour after the infusions were terminated. There was an inverse relationship between the extent of cold-induced vasoconstriction and the concentration of sodium arachidonate that was needed to induce platelet aggregation for different individuals. Infusions of PGI₂ affected both parameters equally but ZK 36374 had a greater effect on platelet behaviour than on blood flow. It is possible that very low doses of ZK 36374 would result in inhibition of platelet behaviour without producing adverse haemodynamic effects.

Key words

Prostacyclin - ZK 36374 - Blood platelets - Blood vessels

• References

• 1 Moncada S, Higgs EA, Vane JR. Human arterial and venous tissues generate prostacyclin (prostaglandin X), a potent inhibitor of platelet aggregation. Lancet 1977; 1: 18-20
• 2 Armstrong JM, Lattimer N, Moncada S, Vane JR. Comparison of vasodepressor effects of prostacyclin and 6-oxo-prostaglandin F with those of prostaglandin E in rats and rabbits. Br J Pharmacol 1978; 62: 125-130
• 3 Lewis PG, Dollery CT. Clinical pharmacology and potential of prostacyclin. Br Med Bull 1983; 39: 281-284
• 4 Mitchell JR. Clinical aspects of the arachidonic acid-thromboxane pathway. Br Med Bull 1983; 39: 289-295
• 5 Schrör K, Darius H, Matzky R, Ohlendorf R. The anti-platelet and cardiovascular actions of a new carbacyclin derivative (ZK 36374) equipotent to PGI₂in vitro. Naunyn-Schmiedeberg’s Arch Pharmacol 1981; 316: 252-255
• 6 Menys VC, Davies JA. Inhibitory effects of ZK 36374, a stable prostacyclin analogue, on adhesion of rabbit platelets to damaged aorta and serotonin release by adherent platelets. Clin Sci 1983; 65: 149-153
• 7 Adaikan PG, Karim SM M, Lau LC, Tai MY, Kottegoda SR. Inhibition of platelet aggregation and antagonism of vasopressin- induced ECG changes in primates by a carboprostacyclin analogue, ZK 36374. Thromb Res 1984; 33: 333-340
• 8 Schrör K, Ohlendorf R, Darius H. Beneficial effects of a new carbacyclin derivative ZK 36374 in acute myocardial ischaemia. J Pharmacol Exp Ther 1981; 219: 243-249
• 9 Bergman G, Kiff PS, Atkinson L, Kerkez S, Jewitt DE. Dissociation of platelet aggregation and vasodilatation with Iloprost: a stable orally active, prostacyclin derivative. Circulation 1983; 68 (Suppl) (Suppl. 03) 398
• 10 Greenfield AD M, Whitney RI, Mowbray FR. Methods for the investigation of peripheral blood flow. Br Med Bull 1963; 19: 101-109
• 11 Burnham WR, Heptinstall S, Cockbill SR, Harrison S. Blood platelet behaviour during infusion of an Intralipid-based intravenous feeding mixture. Postgrad Med J 1982; 58: 152-155
• 12 Jones EW, Cockbill SR, Cowley AJ, Hanley SP, Heptinstall S. Effects of dazoxiben and low-dose aspirin on platelet behaviour in man. Br J Clin Pharmacol. 1983; 15: 39S-44S
• 13 Cowley AJ, Stainer K, Cockbill SR, Heptinstall S. Correlation between platelet behaviour and cold-induced vasoconstriction in man, and the effects of prostacyclin infusion. Clin Sci 1984; 67: 511-514
• 14 Dembienska-Kiec A, Zmuda A, Grodzinska L, Bieron K, Basista M, Kedzior A, Kostka-Trabka E, Telesz E, Zelazna T. Increased platelet activity after termination of prostacyclin infusion into man. Prostaglandins 1981; 21: 827-832
• 15 Reele SB, Miller OV, Spillers C, Gorman RR. The effects of continuous infusions of prostacyclin-Na (epoprostenol-sodium) on platelet counts, ADP-induced aggregation, and cyclic AMP levels in normal volunteers. Prostaglandins 1983; 26: 287-302
• 16 Yardumian DA, Mackie IJ, Bull H, Machin SJ. Platelet response observed during and after infusions of the prostacyclin analogue ZK 36374. Platelets, Prostaglandins and Cardiovascular System Symposium, Florence 1984; C 125 (Abstr.)