Summary
The vascular and antiplatelet activities of a new, chemically stable carbacyclin derivative (ZK 36 374) were investigated and compared to PGI2.
ZK 36 374 dose-dependently relaxed bovine coronary artery strips in vitro but was without direct effects on strips of bovine coronary veins which were contracted by PGI2.
ZK 36 374 dose-dependently inhibited the ADP-, thrombin- and collagen-induced platelet aggregation in human platelet-rich plasma and disperded preformed platelet aggregates in whole blood of cats ex vivo. The IC50 was 0.2–1.1 (antigaggregation) and 13 (disaggregation) nM, respectively, and in the same range as PGI2.
The maximum antiplatelet dose of ZK 36 374 (resolution of platelet aggregates) in anaesthetized cats in vivo was 0.45 nmoles/kg x min, and could be increased up to 3 nmoles/kg x min, i.e. 6–7-fold without significant changes in arterial blood pressure and heart rate. This indicates an appreciable dissociation between antiplatelet and blood pressure-lowering activities of this compound, at least in this model.
It is concluded that ZK 36 374 is the first, chemically stable prostacyclin-mimetic agent that is equipotent to PGI2 in vitro and might be superior to PGI2 in vivo because of a reduced blood pressure-lowering activity.
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References
Aiken JW, Shebuski RJ (1980) Comparison in anaesthetized dogs of the anti-aggregatory and hemodynamic effects of prostacyclin and a chemically stable prostacyclin analog. 6α-carba-PGI2 (Carbacyclin). Prostaglandins 19:629–643
Ceserani R, Grossoni M, Longiave D, Mizzotti B, Pozzi O, Dembinska-Kiec A, Bianco S (1980) dl-9α-deoxy.-9α-methylene-PGI2 (A stable prostacyclin derivative): Preliminary pharmacological data. Prostaglandins Med 5:131–139
Fried J, Mitra DK, Nagarajan M, Mehrota MM (1980) 10,10-Difluoro-13-dehydroprostacyclin: A chemically and metabolically stabilized potent prostacyclin. J Med Chem 23:234–237
Johnson RA, Morton DR, Kinner JH, Gorman RR, McGuire JC, Sun FF, Whittaker N, Bunting S, Salmon JA, Moncada S, Vane JR (1976) The chemical characterization of prostaglandin X (prostacyclin). Prostaglandins 12:915–928
Langer SZ, Trendelenburg U (1969) The effect of a saturable uptake mechanism on the slopes of dose-response curves for sympathomimetic amines and on the shifts of dose-response curves produced by a competitive antagonist. J Pharmacol Exp Ther 167:117–143
Lefer AM, Ogletree ML, Smith JB, Silver MJ, Nicolaou KC, Barnette WE, Gasic CP (1978) Prostacyclin: A potentially valuable agent for preserving myocardial tissue in acute myocardial ischemia. Science 200:52–54
Lefer AM, Trachte GJ, Smith JB, Barnette W, Nicolaou KC (1979) Circulatory and platelet actions of 6,9-thiaprostacyclin (PGI2-S) in the cat. Life Sci 25:259–264
Levy JV (1978) Contractile responses to prostacyclin (PGI2) of isolated human saphenous and rat venous tissue. Prostaglandins 16:93–97
Moncada S, Vane JR (1979) Pharmacology and endogenous roles of prostaglandin endoperoxides, thromboxane A2 and prostacyclin. Pharmacol Rev 30:293–331
Morton DR, Bundy GL, Nishizawa EE (1979) Five-membered ringmodified prostacyclin analogs. In: Vane JR, Bergström S (eds) Prostacyclin. Raven Press, New York, p 31
Nicolaou KC, Barnette WE, Gasic CP, Magolda RL (1977) 6,9-Thiaprostacyclin. A stable and biologically potent analogue of prostacyclin (PGI2). J Am Chem Soc 99:7736–7738
Ohlendorf R, Perzborn E, Schrör K (1980) Prevention of infarctioninduced decrease in circulating platelet count by prostacyclin. Thromb Res 19:447–453
Quilley CP, McGiff JC, Lee WH, Sun FF, Wong PY-K (1980) 6-keto-PGE1: A possible metabolite of prostacyclin having platelet antiaggregatory effects. Hypertension 2:524–528
Radegran K, Papaconstantinou C (1980) Prostacyclin infusion during cardiopulmonary bypass in man. Thromb Res 19:267–270
Rosenkranz B, Fischer C, Reimann I, Weimer KE, Beck G, Frölich JC (1980) Identification of the major metabolite of prostacyclin and 6-keto-prostaglandin F1α in man. Biochim Biophys Acta 619:207–213
Schölkens BA, Bartmann W, Beck G, Lerch U, Konz E, Weithmann U (1980) Vasodilator and antiplatelet activities of prostacyclin with modified ω-side chain: In: Samuelsson B, Ramwell PW, Paoletti R (eds) Adv. in prostaglandin and thromboxane res. vol 6. Raven Press, New York, p 341
Schrör K (1979) The action of the dihydro derivatives of prostacyclin-(6R) PGI1 and (6S) PGI1 on the heart and the coronary vasculature. Naunyn-Schmiedeberg's Arch Pharmacol 306:213–217
Schrör K, Link H-B, Rösen R, Klaus W, Rösen P (1980) Prostacyclininduced coronary vasodilation. Interactions with adenosine, cyclic AMP and energy charge in the rat heart in vitro. Eur J Pharmacol 64:341–348
Schrör K, Moncada S (1979) Effects of prostacyclin on coronary circulation, heart rate and myocardial contractile force in isolated hearts of guinea pig and rabbit — comparison with prostaglandin E2 Prostaglandins 17:367–373
Sun FF, Taylor BM (1978) Metabolism of prostacyclin in rat. Biochemistry 17:4096–4101
Szczeklik A, Gryglewski RJ, Nizankowski R, Skawiński S, Gluszko P, Korbut R (1980) Prostacyclin therapy in peripheral arterial disease. Thromb Res 19:191–199
Webster J, Rees AJ, Lewis PJ, Hensby CN (1980) Prostacyclin deficiency in haemolytic-uraemic syndrome. Br Med J 281:271
Whittle BJR, Boughton-Smith NK (1979) 16-Phenoxy prostacyclin analogs — potent selective antiulcer compounds. In: Vane JR, Bergström S (eds), Prostacyclin. Raven Press, New York, p 159
Whittle BJR, Moncada S, Whiting F, Vane JR (1980) Carbacyclin a potent stable prostacyclin analogue for the inhibition of platelet aggregation. Prostaglandins 19:605–627
Wong PY-K, Sun FF, McGiff JC (1978) Metabolism of prostacyclin in blood vessels. J Biol Chem 253:5555–5557
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Schrör, K., Darius, H., Matzky, R. et al. The antiplatelet and cardiovascular actions of a new carbacyclin derivative (ZK 36 374) — Equipotent to PGI2 in vitro. Naunyn-Schmiedeberg's Arch. Pharmacol. 316, 252–255 (1981). https://doi.org/10.1007/BF00505658
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DOI: https://doi.org/10.1007/BF00505658