Inhibition of platelet aggregation by carbon monoxide is mediated by activation of guanylate cyclase.
Carbon monoxide (CO) inhibits human platelet aggregation triggered with threshold levels of agonists like arachidonate, ADP, collagen, thrombin, or the prostaglandin endoperoxide analogue U46619. 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 presence of CO, 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 unchanged 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 activation. It is concluded that cGMP is an important feedback regulator of the Pl response and that already a 25% increase in its steady state levels can cause inhibition of platelet aggregation.
D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D000244:Adenosine Diphosphate / Q000378:metabolism; D016718:Arachidonic Acid; D001095:Arachidonic Acids / Q000494:pharmacology; D002248:Carbon Monoxide / Q000494:pharmacology*; D006152:Cyclic GMP / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D004837:Epinephrine / Q000494:pharmacology; D011464:Epoprostenol / Q000378:metabolism; D006162:Guanylate Cyclase / Q000378:metabolism*; D006801:Humans; D066298:In Vitro Techniques; D009599:Nitroprusside / Q000494:pharmacology; D010743:Phospholipids / Q000378:metabolism; D010974:Platelet Aggregation / Q000187:drug effects*; D011450:Prostaglandin Endoperoxides, Synthetic / Q000494:pharmacology; D013929:Thromboxane B2 / Q000378:metabolism
D001095:Arachidonic Acids; D010743:Phospholipids; D011450:Prostaglandin Endoperoxides, Synthetic; D009599:Nitroprusside; D016718:Arachidonic Acid; D013929:Thromboxane B2; D000244:Adenosine Diphosphate; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D002248:Carbon Monoxide; D011464:Epoprostenol; D006162:Guanylate Cyclase; D006152:Cyclic GMP; D004837:Epinephrine