Characterization of LY233569 on 5-lipoxygenase and reperfusion injury of ischemic myocardium.
LY233569 produced concentration-dependent inhibition of isolated guinea pig 5-lipoxygenase (5-LPO) and 5-LPO activity of human polymorphonuclear leukocytes in vitro; IC50 values were 0.4 and 0.1 microM, respectively. LY233569 also inhibited (IC50 approximately 1.8 microM) zymosan-stimulated production of leukotriene B4 in canine whole blood but had little or no concomitant effect on the production of thromboxane B2. Concentrations of LY233569 as high as 10 microM did not inhibit production or scavenge superoxide from activated human neutrophils. In normal anesthetized dogs, infusion of LY233569 (0.11 mg/kg/min, i.v.) for 6 hr produced persistent inhibition (approximately 80%) of leukotriene B4 production in blood challenged ex vivo with zymosan; the plasma concentration (approximately 4 microM) of LY233569 was consistent with in vitro data illustrating selective and maximal inhibition of 5-LPO. In subsequent experiments, myocardial infarct size was measured after 1 hr of occlusion of the circumflex coronary artery and 5 hr of reperfusion. Continuous infusion of LY233569 (0.11 mg/kg/min, i.v.) had little or no effect on base-line systolic arterial pressure, cardiac rate and the pressure rate product when compared with time-related changes observed in control dogs. LY233569 infusion also did not alter the degree of ST-segment deviation or the intensity and duration of cardiac arrhythmias associated with coronary artery occlusion and reperfusion. Resultant myocardial infarct sizes were 45 +/- 5% of the left ventricle placed at risk in control dogs and 43 +/- 4% in dogs given LY233569. Myeloperoxidase activity of infarcted myocardium did not differ between groups.(ABSTRACT TRUNCATED AT 250 WORDS)
Hahn
R A
RA
Lilly Research laboratories, Eli Lilly and Company, Indianapolis, Indiana.
MacDonald
B R
BR
Simpson
P J
PJ
Wang
L
L
Towner
R D
RD
Ho
P P
PP
Goodwin
M
M
Breau
A P
AP
Suarez
T
T
Mihelich
E D
ED
D000818:Animals; D002934:Cinnamates / Q000494:pharmacology*; D003331:Coronary Vessels / Q000502:physiology; D004285:Dogs; D006168:Guinea Pigs; D006801:Humans; D015289:Leukotrienes / Q000502:physiology; D016859:Lipoxygenase Inhibitors; D008297:Male; D009203:Myocardial Infarction / Q000517:prevention & control; D015428:Myocardial Reperfusion Injury / Q000188:drug therapy / Q000201:enzymology*; D009504:Neutrophils / Q000201:enzymology; D011897:Random Allocation; D013438:Sulfhydryl Compounds / Q000494:pharmacology*; D013440:Sulfides
D002934:Cinnamates; D015289:Leukotrienes; D016859:Lipoxygenase Inhibitors; D013438:Sulfhydryl Compounds; D013440:Sulfides; C066872:N-hydroxy-N-methyl-3-(2-(methylthio)phenyl)-2-propenamide