Carbon monoxide(CO) inhibits human platelet aggregation triggered with threshold levels of agonists like arachidonate, ADP, collagen, thrombin, or the prostaglandin endoperoxide analogue U4661 9. This inhibition is counteracted by illumination with light above 400 nm indicating the involvement of a ferrous hemoprotein. An earlier suggestion that the mechanism of CO inhibition involves the cytochrome P450 protein thromboxane A2 synthase was ruled out as well as the involvement of the iron containing enzymes like cyclooxygenase or 12-lipoxygenase. In the pres-ence of GO, no arachidonate was released from phospholipids, no increase of intracellular calcium levels was observed, and phospholipase C was not activated suggesting that the transducing mechanisms from the receptors to phospholipase C was effected in the presence of CO. cAMP levels were also un-changed but cGMP levels showed an increase of about 30%. By comparison with the guanylate cyclase stimulator nitroprusside, it was shown that such levels could block aggregation. In a 10,000 x g supernatant, CO enhanced guanylate cyclase activity 4-fold, supporting the view that CO acts by increasing platelet cGMP levels. With respect to the mechanism of guanylate cyclase action, the binding of CO to the regulatory subunit of guanylate cyclase must be responsible for the observed activa-tion. It is concluded that cGMP is an importantfeedback regulator of the P1 response and that already a 25% increase in its steady state levels can cause inhibition of platelet aggregation.

Platelet aggregation is triggered by a variety of extracellular signals such as ADP, collagen, thrombin, or the synthetic prostaglandin endoperoxide analogue U46619. These agonists interact with a specific receptor which is coupled to a signal amplifying cascade known as the “P1 response”(1-4). Interac-tions with platelet receptors result in activation of phospholi-pase C, which by hydrolysis of phosphatidylinositol 4, 5-bisphosphate, leads to the formation of 1, 2 diacylglycerol and IP3 in a bifurcating pathway. IP3 releases[Ca2] from intracellular stores (5-7) and thus causes the physiological response of platelet aggregation. This so-called first wave of aggregation is followed by a second wave initiated by TxA2. This eicosanoid derivative is formed in a chain of events derived from the increase of intracellular[Ca2] which activates phospholipase A2 to liberate arachidonic acid. Free arachidonate is converted to the prostaglandin endoperoxides PGG2 and PGH2 and further transformed by TxA2 synthase(EC 5.3. 99.5) to TxA2 (8, 9). It had been considered that TxA2 is one of the most active agonists of platelet aggregation also responsible for the second