INHIBITION OF HUMAN PLATELETS AND POLYMORPHONUCLEAR NEUTROPHILS BY THE POTENT AND METABOLICALLY STABLE PROSTAGLANDIN-D-2 ANALOG ZK-118.182

The actions of the novel metabolically stable and selective prostaglan din D-2 receptor agonist ZK 118.182 y-16,17,18,19,20-pentanor-3-oxa-5, 13-prostadienoic acid) were studied in human platelets and polymorphon uclear neutrophils in vitro and compared to the naturally occuring ago nist prostaglandin D-2. ZK 118.182 inhibited collagen and ADP induced platelet aggregation more potently than prostaglandin D-2 (IC50: 15 nM versus 60 nM) but was less effective than the stable prostacyclin mim etic iloprost (IC50: 3 nM). The same rank order of potencies was obser ved for the inhibition of collagen-induced platelet ATP secretion. A d ose-dependent activation of adenylate cyclase could be demonstrated by ZK 118.182 which was comparable to that of prostaglandin D-2 with res pect to the concentration needed for half maximal stimulation (ED(50)) maximal cAMP level achievable. ZK 118.182 also dose dependendly reduc ed the formyl-methionyl-leucyl-phenylalanine (FMLP) or platelet-activa ting factor (PAF) induced activation of polymorphonuclear neutrophils. Both, the oxygen burst resulting in the generation of superoxide anio ns and the degranulation of polymorphonuclear neutrophils accompanied by release of the lysosomal enzyme beta-glucuronidase, were significan tly and dose dependently inhibited. ZK 118.182 was more potent than pr ostaglandin D-2 in inhibiting polymorphonuclear neutrophil activation in all tests performed. In summary, ZK 118.182 is a prostaglandin D-2 mimetic exerting potent inhibitory effects on human platelets and poly morphonuclear neutrophils.