The lining of blood vessels releases relaxing factors including nitric oxide that not only cause smooth muscle cells of the blood vessels to relax but, by diffusion into the blood stream, nitric oxide can cause reduction in the ease with which platelets stick to each other. We investigated whether this phenomenon occurs in the human heart and peripheral circulation. The study demonstrated that infusion of acetylcholine, a drug that promotes release of nitric oxide from the lining of blood vessels, caused increase in the platelet level of cyclic GMP, a compound that inhibits platelets sticking to each other. This effect was diminished in patients who had hardening (atherosclerosis) of the blood vessels in the heart or in the leg circulation. The study thus provides evidence in favor of the ability of nitric oxide to inhibit platelets from aggregating and thus reducing the incidence of clot formation inside blood vessels. It also demonstrates that dysfunction of the lining of blood vessels that accompanies coronary artery disease, might predispose to the ease with which clotting occurs.