A new prostacyclin analog, KP-10614, inhibits platelet-polymorphonuclear leukocyte interaction and limits experimental infarct size in rat heart.
A chemically stable prostacyclin analog, KP-10614 [(4Z,16S)-4, 5, 18, 18, 19, 19-hexadehydro-16,20-dimethyl-delta 6(9 alpha)-9(O)-methano-prostaglandin I1], was synthesized to increase the cytoprotective activity and to decrease the hypotensive activity. We have reported that KP-10614, infused i.v. at a dose of 3 ng/kg/min for 4 hr, inhibited platelet functions and reduced the experimental cardiac infarct size significantly, but did not change hemodynamic parameters and the ischemic area of the heart induced by ligation of the left descending coronary artery in rats. Accordingly, we thought that myocardial protective effects of KP-10614 might be based on the inhibition of platelet functions and cellular metabolism produced by platelets at the site of tissue injury. KP-10614 suppressed leukotriene B4 synthesis by N-formyl-methionyl-leucyl-phenylalanine-stimulated polymorphonuclear leukocytes, which was enhanced by thrombin-treated platelets in a concentration-dependent manner, even though KP-10614 did not suppress leukotriene B4 synthesis by N-formyl-methionyl-leucyl-phenylalanine-stimulated polymorphonuclear leukocytes separately in vitro. Moreover in in vivo studies, KP-10614, which was infused at a dose of 3 ng/kg/min for 4 hr, suppressed leukotriene B4 content, myeroperoxidase activity and polymorphonuclear leukocyte counts in myocardial tissues that were infarcted by ligation of the left descending coronary artery for 4 hr in rats. These data supported the hypothesis that KP-10614, a new prostacyclin analog, had protective effects on myocardial infarction in rats by suppressing the platelet-polymorphonuclear leukocyte interaction at the site of tissue injury in vivo.
Kanayama
T
T
Pharmaceuticals Laboratory, Research Center, Mitsubishi Kasei Corporation, Yokohama, Japan.
Kimura
Y
Y
Mizogami
S
S
D000818:Animals; D001792:Blood Platelets / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D002450:Cell Communication / Q000187:drug effects; D002478:Cells, Cultured; D004195:Disease Models, Animal; D011464:Epoprostenol / Q000031:analogs & derivatives* / Q000627:therapeutic use; D005343:Fibrinolytic Agents / Q000627:therapeutic use*; D016285:Iloprost / Q000627:therapeutic use; D007975:Leukotriene B4 / Q000096:biosynthesis; D008297:Male; D009203:Myocardial Infarction / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000494:pharmacology; D009504:Neutrophils / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D009195:Peroxidase / Q000378:metabolism; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley
D005343:Fibrinolytic Agents; C066682:KP 10614; D007975:Leukotriene B4; D009240:N-Formylmethionine Leucyl-Phenylalanine; D011464:Epoprostenol; D009195:Peroxidase; D016285:Iloprost