Inhibition of human platelets and polymorphonuclear neutrophils by the potent and metabolically stable prostaglandin D2 analog ZK 118.182.
The actions of the novel metabolically stable and selective prostaglandin D2 receptor agonist ZK 118.182 ((5Z,13E)-(9R,11R,15S)-9-chloro-15-cyclohexyl-15- hydroxy-16,17,18,19,20-pentanor-3-oxa-5,13-prostadienoic acid) were studied in human platelets and polymorphonuclear neutrophils in vitro and compared to the naturally occurring agonist prostaglandin D2. ZK 118.182 inhibited collagen and ADP induced platelet aggregation more potently than prostaglandin D2 (IC50: 15 nM versus 60 nM) but was less effective than the stable prostacyclin mimetic iloprost (IC50: 3 nM). The same rank order of potencies was observed for the inhibition of collagen-induced platelet ATP secretion. A dose-dependent activation of adenylate cyclase could be demonstrated by ZK 118.182 which was comparable to that of prostaglandin D2 with respect to the concentration needed for half maximal stimulation (ED50) maximal cAMP level achievable. ZK 118.182 also dose dependently reduced the formyl-methionyl-leucyl-phenylalanine (FMLP) or platelet-activating factor (PAF) induced activation of polymorphonuclear neutrophils. Both, the oxygen burst resulting in the generation of superoxide anions and the degranulation of polymorphonuclear neutrophils accompanied by release of the lysosomal enzyme beta-glucuronidase, were significantly and dose dependently inhibited. ZK 118.182 was more potent than prostaglandin D2 in inhibiting polymorphonuclear neutrophil activation in all tests performed. In summary, ZK 118.182 is a prostaglandin D2 mimetic exerting potent inhibitory effects on human platelets and polymorphonuclear neutrophils.
Darius
H
H
Department of Medicine II, Johannes Gutenberg-Universität, Mainz, Germany.
Michael-Hepp
J
J
Thierauch
K H
KH
Fisch
A
A
D000255:Adenosine Triphosphate / Q000378:metabolism; D000262:Adenylyl Cyclases / Q000378:metabolism; D001665:Binding Sites; D001792:Blood Platelets / Q000187:drug effects* / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism; D015237:Dinoprost / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D004789:Enzyme Activation; D005966:Glucuronidase / Q000378:metabolism; D006801:Humans; D016285:Iloprost / Q000494:pharmacology; D066298:In Vitro Techniques; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000494:pharmacology; D009504:Neutrophils / Q000187:drug effects* / Q000378:metabolism; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000378:metabolism / Q000494:pharmacology*; D015230:Prostaglandin D2 / Q000494:pharmacology; D011971:Receptors, Immunologic; D011982:Receptors, Prostaglandin / Q000187:drug effects / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism
D010975:Platelet Aggregation Inhibitors; D011971:Receptors, Immunologic; D011982:Receptors, Prostaglandin; D013481:Superoxides; C067426:ZK 118182; D009240:N-Formylmethionine Leucyl-Phenylalanine; D000255:Adenosine Triphosphate; D015237:Dinoprost; D000242:Cyclic AMP; D005966:Glucuronidase; D000262:Adenylyl Cyclases; D016285:Iloprost; D015230:Prostaglandin D2; C036293:prostaglandin D2 receptor