Endoperoxides and thromboxanes structural determinants for platelet aggregation and vasoconstriction

Structural requirements of prostaglandin endoperoxides for conversion to thromboxanes and for inducing platelet aggregation were compared utilizing five endoperoxides: prostaglandin H₂ which aggregates platelets and forms a potent vasoconstrictor thromboxane A₂; prostaglandin H₃ which does not aggregate but does form thromboxane A₃; prostaglandin H₁ which neither induces aggregation nor forms vasoactive thromboxane A₁; and two endoperoxides, one from fatty acid C_19:4 which induces aggregation but does not form a vasoactive thromboxane, and the other from fatty acid C_19:3 with actions similar to prostaglandin H₁. Utilizing these endoperoxides, receptor sites for aggregation and for thromboxane vasoconstriction have been distinguished by their structural requirements as well as their biological consequences. The aggregating receptor site requires an endoperoxide molecule with a c₆ or C₇ alkyl α-chain containing a double bond two carbons from the ring. An additional recognition factor involves the ω-chain since aggregation does not occur if this chain contains additional Unsaturation at C₁₇ (prostaglandin H₃). In contrast, the thromboxane synthetase enzyme can utilize an endoperoxide substrate molecule only if it contains a C₇ alkyl α-chain with a double bond two carbons from the ring. Additional unsaturation at n-3 (prostaglandin H₃) does not affect thromboxane formation. The results indicate that certain unique structural features of prostaglandin endoperoxides and not their conversion to thromboxanes are responsible for their pro-aggregatory activity. Thus thromboxane formation does not appear to be an essential process in endoperoxide-induced platelet aggregation. Finally the potent vasoconstrictor property of some thromboxanes can be dissociated from their capacity to cause platelet aggregation.