Abstract
K-MAP (p-Aminobenzoic acid-N-mannoside sodium salt) shows various pharmacological effects such as antihypertensive, antidiabetic and antiinflammatory actions in pathological states. The mechanism of the action of K-MAP is not elucidated yet, but it is thought that this compound acts to alter prostaglandin metabolism. In the present paper, firstly, the antiplatelet action of K-MAP was studied by using human platelets and rat arterial ring, in relation to the prostaglandin metabolism. Secondly, antithrombotic action of K-MAP was studied by using thrombosis models in vivo.
Platelet aggregation was inhibited in a dose dependent manner by pretreatment with K-MAP. Cyclic AMP level and cAMP-dependent protein kinase activity of intact human platelets were augmented by K-MAP in vitro. Phosphorylation of endogenous protein in 32Pi preloaded human platelets was also enhanced by this compound. But, the activation of cAMP metabolism by K-MAP was not significantly related to the direct action to adenylate cyclase or phosphodiesterase activity of platelet lysate, because these activities were not affected by K-MAP treatment. In washed platelets, K-MAP modulated the metabolism of arachidonic acid to stimulate the production of PGD2, which is a potent activator of adenylate cyclase activity. Thus platelet cAMP level was increased by K-MAP. Meanwhile, it was found that K-MAP stimulated the release of PGI2 in rat arterial ring. These results were compatible with the idea that K-MAP regulates cyclic nucleotides metabolism by modifying prostaglandin metabolism. Those metabolic changes might be concerned with multiple pharmacological effects of K-MAP and especially with antiplatelet action.
Furthermore, antithrombotic action of K-MAP was investigated by using three thrombosis models in which platelet aggregation was mainly involved. The models included β-aminopropionitrile-induced hyper-aggregation of platelets, ADP or collagen-induced acute pulmonary thromboembolism and bacterial endotoxin shock. K-MAP was effective in preventing platelet hyper-aggregation in β-aminopropionitrile-treated rats, ADP-or collagen-induced acute pulmonary thromboembolic death in mice and bacteria endotoxin shock in mice. All these results suggest the possibility of clinical application of K-MAP as an antithrombotic drug.
