ࡱ> hjg%`bjbj"x"x 1@@zzzzzzzXXXX d g<|||||W W W  $h  9z" W W " " zz||! " z|z| " zz |p 0X " 70g > : z 4W  | d =W W W x W W W g" " " " XXzzzzzz THE ROLE OF PROSTAGLANDIN I2 IN MODIFYING ACUTE HEPATOTOXICITY OF ACETAMIONPHEN IN MICE Ivan avar (1), Tomislav Kelava (2), Tomislav Tabak (2), Filip ulo (2) (1) Department of Physiology, School of Medicine, Bijeli brijeg bb, Mostar, Bosnia and Herzegovina; (2) Department of Physiology, School of Medicine, `alata 3, Zagreb, Croatia Ivan avar ABSTRACT: Prostaglandins (PGs) are lipid compounds that mediate variety of physiological and pathological functions in almost all body tissues and organs. PGI2 (prostacyclin), which is synthesized by the vascular endothelium, is a potent vasodilator, inhibits the aggregation of platelets in vitro and has cytoprotective effect on gastrointestinal mucosa. The aim of this study was to determine whether PGI2 is playing a role in host defense to toxic effect of acetaminophen (APAP). This was investigated in mice which were intoxicated with single lethal or high sublethal dose of APAP. APAP was administered to mice by gastric lavage and PGI2 agonists or antagonists were given i.p. 30 minutes before or 2 hours after administration of APAP. The toxicity of APAP was determined by observing the survival of mice during 48 hours and by measuring the concentration of alanine-aminotransferase (ALT) in plasma 20-24 hours after APAP administration. Mice were given either pure PGI2 (PGI2 sodium salt), it's stable agonist (Iloprost) or inhibitor of IP-receptor (CAY-10441). The results have shown that PGI2 exhibits$  1 jrJMUh3hH h-%]6h-%] h^J h-%]^J h-%]\^JB D F 7$  7$ a strong hepatoprotective effect when it was given to mice either before or after APAP (both increase of survival of mice and decrease of serum ALT level were statistically significant). Iloprost shown a similar effect (although not statistically significant), and CAY-10441 increased toxic effect of APAP if given 2 hours after its administration. Presently, we are examining the possible mechanisms of protective action of PGI2, such are the effects on production of cAMP, synthesis of NO and platelet aggregation parameters. /1h;0. A!"#$% P@P Normal$*$1$A$a$CJ_HaJmH sH tHDAD Default Paragraph FontViV  Table Normal :V 44 la (k(No List JOJ Absatz-StandardschriftartFOF Default Paragraph Font1NO"N Heading x$CJOJPJQJ^JaJ6B@"6 Body Text x(/@!2( List^JJOBJ Caption1 xx $6CJ]^JaJ.OR. Index $^JXYST_`jo#o#o#o#o#o#o#o#o#o#o#o#o#o#XYST_`j080000000000000  8@0(  B S  ? -_-_s-_r-_-_ *urn:schemas-microsoft-com:office:smarttags PersonName  Filip ulo Ivan avar ProductIDTomislav Kelava    ^ciqrx~9?Y^  ]eu}HLu3YT`uF-%](qH\g3@$F4`` `@`0@UnknownGz Times New Roman5Symbol3& z ArialO& k9?Lucida Sans Unicode5& zaTahomaBh ʦ ʦ1Ȧ**!4d2HP?H2WTHE ROLE OF PROSTAGLANDIN I2 IN MODIFYING ACUTE HEPATOTOXICITY OF ACETAMIONPHEN IN MICE Filip uloMEFOh+'0{  ,< HT t   XTHE ROLE OF PROSTAGLANDIN I2 IN MODIFYING ACUTE HEPATOTOXICITY OF ACETAMIONPHEN IN MICE Filip uloNormalMEF2Microsoft Office Word@G@"_ @l}0@l}0*GyRt  <&" WMFC  d3dSl`gRt EMFdS!h   `g%  Rp@Times New RomanGz Times ew RomanwHI<HHJ H 2 IYII 7J HHHCH==H=8H=H=HI D >HI7 TN?2t@@NL`gxACETAMIONPHEN IN MICEHC==HZ HH8H=H IZC=TT@m2t@@@L`gP . TTN4zt@@NL`gP - T,N3t@@N%L`gIvan avar (1), Tomislav Kelava (2), 3,2C,2,!!2!=2N',3H,,2,!3!T4 t@@4L`gtTomislav Tabak (2), =2N',2=-2,2!2!T  t@@ L`ghFilip ulo (2)72C22!2!TT  t@@ L`gP - TTNzt@@NtL`gP - TTNzt@@NL`gP - TXN(qt@@NZWL`g(1) Department of Physiology, School of Medicine, Bijeli brijeg bb, Mostar, Bosnia and !2!H,3,!N,22!840'22308,2222!Y,2,3-B,2!-122Y2',!B2'2,,22 TpNsmt@@NL`gXHerzegH,!--1T8nst@@nRL`govina; (2) Department of Physiology, School of Medicine, `alata 3, Zagreb, Croatia222,!2!H,2-!N,22!830'22308,3222!Y,2,2,8,,,3<-2!,2C!3,,TTst@@L`gP . TTNzWt@@N@L`gP - TNYt@@N L`g`Ivan avar 3,2C,2,!TTY3t@@L`gP . TTNz=t@@N&L`gP - TN?st@@N L`g`ABSTRACT:HB8=CHC=TTt?t@@tL`gP - T@N|#t@@N SL`gProstaglandins (PGs) are lipid compounds that mediate variety of physiological and 8!2',1,222'!8H'!,!,22,2N22222'2,N,2,,2,!,02!240'231-,,22!`g"  TN% t@@NCL`gpathological functions in almost all body tissues and organs. PGI2 2,2221-,!22,22'2,N2',2230''2,'-222!2,2'8I 2T %t@@ L`g(prostacyclin), which is !2!2'--0-2!I2,2'!`g"  TN t@@N^L`gsynthesized by the vascular endothelium, is a potent vasodilator, inhibits the aggregation of (022,'-,2402,2,',2,!,2222,2N',22-22,'22,2!222'1,-21!-2,222!!`g"  % TN | t@@Ne L`g`platelets 2,,,'Rp@Times New Roman#1 0|ˮ0`1 0Gz Times ew Roman / 0pˮ030lN0(dv% T | t@@e L`g`in vitro 2,'2% T | t@@e 8L`gand has cytoprotective effect on gastrointestinal mucosa,222,'-022!2,,2,-!!-,221,'!22,'2,N2,2(,% TT | t@@ e L`gP.% T `| t@@ e L`gp The aim of this =2,,N2!2'!`g"  TTN~ m t@@N ,L`gstudy was to determine whether PGI2 is playi'230H,'22,,!N&" WMFC ddS2,I2,2,!8I 2'2.0Tn ~ i t@@n L`gtng a role in host de31,!2,222'2,Tj ~  t@@j L`gfense to toxic effect of !,2',233,,!!,,2!!`g"  TdN b t@@NK L`gTacet,,,T@ b t@@K SL`gaminophen (APAP). This was investigated in mice which were intoxicated with single Dd,N2222,2!H8H8!=2'H,'22,'1,,22N,,H2,2H-!,223,,,2H2'21,!`g"  TpNd  t@@N [L`glethal or high sublethal dose of APAP. APAP was administered to mice by gastric lavage and ,2,2!212'22,3,22',2!H8H8H8H8H,(,2N2',!,22N,,401,'!,,2-2,,22!`g"  TN H t@@N1 !L`gPGI2 agonists or antagonists were8I2-122''2!,2-123''H,!,T H t@@1 >L`g given i.p. 30 minutes before or 2 hours after administration 12,2222N22,'2,!2!,3!2222!'-!,!,2N2'!,22!`g"  TdNJ  t@@N YL`gof APAP. The toxicity of APAP was determined by observing the survival of mice during 48 2!H8H8=2,23,/2"H8H8H,'2,,!N2,23022'-!2213,'2!22,2!N,,22!3122!`g"  TN } . t@@N 3L`ghours and by measuring the concentration of alanine222!',2240N,,'2!312,,22-,2!,222!,-22,TT~ . t@@~  L`gP-!T  . t@@  #L`gaminotransferase (ALT) in plasma 20,N22!,2'",!,(,!I==!22,'N,22TT . t@@ L`gP-!T` . t@@ L`gT24 22!`g"  TN0  t@@N L`ghhours after AP222!',!,!H8T0  t@@ ML`gAP administration. Mice were given either pure PGI2 (PGI2 sodium salt), it's H8,2N2'!,22Y,,H,",12,3,2,!22!,8J 2!8I 2'222N',!'!`g"  TTN  t@@N ,L`gstable agonist (Iloprost) or inhibitor of IP',2,-122'" 22!2'!2!2222!2!8TT  t@@ L`gP-t"T 5  t@@ L`ghreceptor (CAY!,-,23!!CHHTT6 V  t@@6 L`gP-!T$W  t@@W $L`g10441). The results have shown that 22222!=3,",'2'2,2,'22H22,!`g"  TlN 9 t@@Np L`gXPGI2 8I2T|: w t@@:p L`g\exhibits,322'T@x  t@@xp SL`g a strong hepatoprotective effect when it was given to mice either before or after ,'!2212-2,22!2,,2,-!!-,H2-2H,'12,22N,,,2,!2,!3!,2!,!-!!`g"  TN  t@@N L`g|APAP (both increase of H8H8!2222,!,,',3!T| a t@@ L`g\survival(2!22,Tb  t@@b <L`g of mice and decrease of serum ALT level were statistically 2!N,,,223,,"-,',2!'-!2NI<=,2,H,!,',',,0!`g"  T8N bmt@@NVRL`gsignificant). Iloprost shown a similar effect (although not statistically signific'12!,,2! &WMFCddS 22!2''22H2,'N,!,!",,",2221222',',,0'12!,Tdc mt@@cVL`gTant),2!TT mt@@VL`gP,T| mt@@VL`g\ and CAY,22CIHTT mt@@VL`gP-"!`g"  TNo t@@N<L`g10441 increased toxic effect of APAP if given 2 hours after 222222,!,,(,223,,!",,2!H8H8!12,22322!',!,!T` o t@@ L`gTits'T ot@@ L`g administration. Presently, we ,2N2'!,228!,',20I,!`g"  TtNSt@@N<\L`gare examining the possible mechanisms of protective action of PGI2, such are the effects on ,!,,3,N2212,22''3,N,,2,2'N'2!2!2-,2,,,222!8I 2'2,2,!,2,,!",,'22!`g"  T<NU t@@N(L`gproduction of cAMP, synthesis of NO and 2!222,222!,HY8)032,''2!HH,22T U} t@@ L`glplatelet aggrega2,,,,22!-1,T} U t@@} L`gltion parameters222-!,N,-!'TT Ut@@ L`gP.TTU/t@@L`gP .!`g"  TTNz9t@@N"L`gP - TTN;zt@@NL`gP - TTNzt@@NL`gP -% 6g6`g6`66f6_f6_66e6^e6^66d6]d6]66c6\c6\66b6[b6[66a6Za6Z66`6Y`6Y66_6X_6X6 6 ^6W^6W 6  6 ]6V]6V 6  6 \6U\6U 6  6 [6T[6T 6  6 Z6SZ6S 6 6Y6RY6R66X6QX6Q66W6PW6P66V6OV6O66U6NU6N6  d."System-@Times New Roman- n2 m_BdTHE ROLE OF PROSTAGLANDIN I2 IN MODIFYING ACUTE HEPATOTOXICITY OF               +2 _dACETAMIONPHEN IN MICEf    2 *d W 2 _d WC2 _%dIvan avar (1), Tomislav Kelava (2), n    )2 QdTomislav Tabak (2),    2 dFilip ulo (2)   2 1d W 2 _d W 2 _d W2 _Wd(1) Department of Physiology, School of Medicine, Bijeli brijeg bb, Mostar, Bosnia and       2 _dHerzeg 2 Rdovina; (2) Department of Physiology, School of Medicine, alata 3, Zagreb, Croatia         2 d W 2 _d W2 _ dIvan avar  2 d W 2 %_d W2 8_ dABSTRACT:  2 8d W2 J_SdProstaglandins (PGs) are lipid compounds that mediate variety of physiological and    ,d'p2 \_Cdpathological functions in almost all body tissues and organs. PGI2    12 \ d(prostacyclin), which is  ,d'2 o_^dsynthesized by the vascular endothelium, is a potent vasodilator, inhibits the aggregation of    ,d'-2 _ dplatelets @Times New Roman-2  din vitro -_2 8dand has cytoprotective effect on gastrointestinal mucosa - 2 3d.W-%2 7d The aim of this )  ,d'M2 _,dstudy was to determine whether PGI2 is playi     )2 dng a role in host de12 dfense to toxic effect of ,d'2 _dacet2 xSdaminophen (APAP). This was investigated in mice which were intoxicated with single          ,d'2 _[dlethal or high sublethal dose of APAP. APAP was administered to mice by gastric lavage and o     ,d'=2 _!dPGI2 agonists or antagonists were   h2 :>d given i.p. 30 minutes before or 2 hours after administration   ,d'2 _Ydof APAP. The toxicity of APAP was determined by observing the survival of mice during 48 d       ,d'X2 _3dhours and by measuring the concentration of alanineu    2 d-W@2 #daminotransferase (ALT) in plasma 20    2 d-W2 d24 ,d' 2 _dhours after AP 2 MdAP administration. Mice were given either pure PGI2 (PGI2 sodium salt), it's         ,d'M2 _,dstable agonist (Iloprost) or inhibitor of IP 2 gd-W2 m dreceptor (CAY 2 d-WA2 $d10441). The results have shown that   ,d'2 '_dPGI2 g 2 'dexhibits2 'Sd a strong hepatoprotective effect when it was given to mice either before or after     ,d'.2 :_dAPAP (both increase of 2 :dsurvivale2 :/<d of mice and decrease of serum ALT level were statistically     ,d'2 L_Rdsignificant). Iloprost shown a similar effect (although not statistically signific  2 LOdant) 2 Lhd,W2 Lld and CAY 2 Ld-W,d'e2 ^_<d10441 increased toxic effect of APAP if given 2 hours after  2 ^dits:2 ^d administration. Presently, we    ,d'2 q_\dare examining the possible mechanisms of protective action of PGI2, such are the effects on      ,d'G2 _(dproduction of cAMP, synthesis of NO and     #2 rdplatelet aggrega"2 dtion parametersa  2 <d.W 2 @d W,d' 2 _d W 2 _d W 2 _d W-ddddddccccccccccccccbbbbbbbbbbbbaaaaaa՜.+,0@ hp|  ' XTHE ROLE OF PROSTAGLANDIN I2 IN MODIFYING ACUTE HEPATOTOXICITY OF ACETAMIONPHEN IN MICE Title  "#$%&'()*+,-./0123456789:;<=>?@ABCDEFGHIJKLMNOPQRSTUVWXYZ[\]^`abcdefiRoot Entry FP0kData 1TableWordDocument1SummaryInformation(!{DocumentSummaryInformation8_CompObjq  FMicrosoft Office Word Document MSWordDocWord.Document.89q