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Possible generation of potent vasocontracting substance from prostaglandin endoperoxide analogs, human platelets
Abstract:
The mixture of human platelets and prostaglandin (PG) endoperoxide analogs (U46619 and U44069) at threshold concentrations caused a marked enhanced vasocontraction of rabbit aortae and bovine coronary arteries. THe configuration of the mixture-induced contraction was a sustained and tonic form. On the other hand, the thromboxane A2-like substance which was generated during the incubation of arachidonic acid with human platelets caused a transient and phasic contraction, and the amplitude of this contraction was much less than that of the mixture. Even after exposure to high temperature for various time periods, the mixture was still able to cause the enhanced vasocontraction. However, this mixture lost the activity of vasocontraction after an incubation in strong acid (pH 1) or alkali (pH 12) for 10 min. Serotonin and alpha adrenoceptor antagonists had no effect on the mixture-induced contraction. When tissues were incubated in Ca-free medium for a few minutes, the mixture failed to cause vasocontraction, whereas the contractile responses to histamine, norepinephrine and serotonin were not affected. When tissues were pretreated with imidazole (10(-5) M), which is a thromboxane synthetase inhibitor, the vasocontration induced by the mixture was potentiated rather than inhibited, whereas the thromboxane A2-like substance-induced contraction was inhibited. When either the tissue was pretreated with or platelets were incubated with indomethacin, the mixture failed to cause the enhanced vasocontraction. The new synthetic arginine derivatives (T1189 and T1233) nearly abolished the vasocontractile response to the mixture. However, both derivatives failed to inhibit the vasocontractions of PGE2 and PGF2 alpha, arachidonic acid and KCl. These results suggest the possibility that during the incubation of endoperoxides with human platelets a potent vasocontractile substance could be generated and such a substance does not resemble thromboxane A2 or any of the PGs tested.