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.