ADO ATP⇔ADP⇔AMP
SAM⇔SAH
AK SAHase
Cell
(A)
ADO NT
ADO ATP⇒ADP⇒AMP
ATP⇒ADP⇒AMP
INO⇒Hx⇒XA INO
ADA
Cytosolic ADA 5’-Nuc Ecto
5’-Nuc
Cell
(B)
Figur e 1 Production and metabolism of adenosine in the nor mal (A) and adverse (B) condition.
ADA: adenosine dea minase, ADO: adenosine, ADP: adenosine diphosphat e, AK : adenosine kinase, AMP: adenosine monophosphate, ATP: adenosine triphosphate, Hx:
hypoxanthine, INO: inosine, 5’-N: 5’-nucleotidase, NT: nucleoside transport er, SAH : S-adenosylhomocyst eine, SAH: S-adenosylhomocyst eine hydrorase, SAM:
S-adenosylmet hionine, XA: xant hine.
Figur e 2 Chemical structur e of KF24345.
N
N N
O N
O N
O
O
N O
HCl
N
N N
O N
O N
O
O
N O
HCl
Figur e 3 Inhibitor y effects of KF24345 on adenosine uptake in mice ex vivo.
Mice were administ er ed intravenously wit h 0.3 (○), 1 (□) or 3 (◆) mg/ kg of KF24345.
Blood sa mples wer e collect ed the indicated times aft er the tr eatment and a mounts of adenosine uptake wer e measured as described in ‘Mat erials and Methods’. The values represent the mea ns ± S.E. of five animals.
A de n o sin e U pt ake In h ibit io n ( % )
0 30 60 90
Time after drug administration (min) -20
0 20 40 60 80 100
*
***
**
***
***
***
*
***
A de n o sin e U pt ake In h ibit io n ( % )
0 30 60 90
Time after drug administration (min) -20
0 20 40 60 80 100
*
***
**
***
***
***
*
***
Figur e 4 Effect of intravenous administration of KF24345 on the mortalit y in mice wit h CDE diet-induced acute pancreatit is.
Mice wer e exposed to CDE diet for 72 hours, and observed up to 144 hours after the onset of CDE diet. Treat ment of KF24345 (1.5 mg/ kg intravenously) was start ed wit h t he onset of CDE diet. KF24345 or the vehicle, as control, was administ ered 4 times ever y twelve hours ther eaft er. Values ar e percentages of t he survived out of 10-25 anima ls. ***
P < 0.001, compared wit h the control group.
0 20 40 60 80 100
0 50 100 150
Time after the onset of CDE diet (hours)
S u rv iv al r at e ( % )
Control Normal
1.5 mg/kg KF24345
***
0 20 40 60 80 100
0 50 100 150
Time after the onset of CDE diet (hours)
S u rv iv al r at e ( % )
Control Normal
1.5 mg/kg KF24345
***
Figur e 5 Sequent ial cha nges in serum paramet er s in mice with acute pancr eatitis induced by CDE diet.
Blood sa mples wer e collect ed the indicated times after the onset of nor mal (○) or CDE (●) diet. Serum lipase (A), GPT (B) and LDH (C) wer e measured as described i n
“Materials and Methods”. The va lues r epresent the mea ns ± S.E. of five anima ls.
0 200 400 600 800 1000
0 12 24 36 48
Time (hours)
Serum lipase (IU/L)
A
0 5000 10000 15000 20000 25000
0 12 24 36 48
Serum GPT (IU/L)
B
0 20000 40000 60000 80000
0 12 24 36 48
Serum LDH (IU/L)
C
Time (hours)
Time (hours) 0
200 400 600 800 1000
0 12 24 36 48
Time (hours)
Serum lipase (IU/L)
A
0 5000 10000 15000 20000 25000
0 12 24 36 48
Serum GPT (IU/L)
B
0 20000 40000 60000 80000
0 12 24 36 48
Serum LDH (IU/L)
C
Time (hours)
Time (hours)
Figur e 6 Sequent ial changes in tissue adenosine in mice with acute pancr eatitis induced by CDE diet.
Pancr eas (A) and liver (B) samples wer e collected the indicat ed times after the onset of nor mal (○) or CDE (●) diet. Tissue adenosine was measur ed as described in “Mat erials and Methods”. The values repr esent the means ± S.E. of five animals. * p < 0.05 versus nor mal diet group.
0 5 10 15 20 25
0 12 24 36 48
Adenosine (pmol/mg dry tissue)
Time (hours)
A
0 5 10 15 20 25
0 12 24 36 48
Adenosine (pmol/mg dry tissue)
Time (hours)
B
*
0 5 10 15 20 25
0 12 24 36 48
Adenosine (pmol/mg dry tissue)
Time (hours)
A
0 5 10 15 20 25
0 12 24 36 48
Adenosine (pmol/mg dry tissue)
Time (hours)
B
*
Figur e 7 Changes in ATP metabolit e in mouse tissue wit h acute pancreatit is induced by CDE diet.
Pancr eas (A) and liver (B) sa mples wer e collected 24 hours after the onset of nor mal (□) or CDE (■) diet. Adenosine triphosphate (ATP), adenosine diphosphat e (ADP), adenosine monophosphate (AMP), inosine (INO) and hypoxantine (Hx) were measured as described in “Materials and Methods”. The va lues r epresent the mea ns ± S.E. of five anima ls.
A
0 2000 4000 6000 8000 10000 12000
ATP ADP AMP INO Hx
pmol/mg dry tissue
B
0 2000 4000 6000 8000 10000 12000
ATP ADP AMP INO Hx
pmol/mg dry tissue
A
0 2000 4000 6000 8000 10000 12000
ATP ADP AMP INO Hx
pmol/mg dry tissue
B
0 2000 4000 6000 8000 10000 12000
ATP ADP AMP INO Hx
pmol/mg dry tissue
Figur e 8 Sequent ial cha nges in plasma adenosine in mice wit h acute pancreatit is induced by CDE diet.
Plasma sa mples wer e collect ed the indicated times after the onset of nor mal (○) or CDE (●) diet. Plasma adenosine was measur ed as described in “Materials and Met hods”. The values represent the mea ns ± S.E. of six or seven anima ls.
0 500 1000 1500 2000
0 12 24 36 48
Plasma adenosine (nmol/L)
Time (hours) 0
500 1000 1500 2000
0 12 24 36 48
Plasma adenosine (nmol/L)
Time (hours)
Figur e 9 Effects of KF24345 on t issue adenosine in mice wit h acute pancreatitis induced by CDE diet.
KF24345 was administ ered intravenously 24 hours after the onset of nor mal (△) or CDE (▲) diet. Vehicle was administ ered intravenously 24 hours after the onset of nor mal (○) or CDE (●) diet. Pancreas (A) and liver (B) samples wer e collect ed t he indicated times aft er the administration. Tissue adenosine was measur ed as described in “Materials and Met hods”. The values repr esent the mea ns ± S.E. of five anima ls.
B
0 5 10 15 20 25 30
0 30 60 90
Adenosine (pmol/mg dry tissue)
Time (min)
A
0 10 20 30 40 50
0 30 60 90
Adenosine (pmol/mg dry tissue)
Time (min)
B
0 5 10 15 20 25 30
0 30 60 90
Adenosine (pmol/mg dry tissue)
Time (min)
A
0 10 20 30 40 50
0 30 60 90
Adenosine (pmol/mg dry tissue)
Time (min)
Figur e 10 Effects of KF24345 on hypoxantine in mouse tissue with acut e pancr eatitis induced by CDE diet.
KF24345 was administ ered intravenously 24 hours after the onset of nor mal (△) or CDE (▲) diet. Vehicle was administ ered intravenously 24 hours after the onset of nor mal (○) or CDE (●) diet. Pancreas (A) and liver (B) samples wer e collect ed t he indicated times aft er the administration. Tissue hypoxant ine was measured as described in “Materials and Met hods”. The values repr esent the mea ns ± S.E. of five anima ls.
0 1000 2000 3000 4000
0 30 60 90
Time (min) after administration
pmol/mg dry tissue
0 1000 2000 3000 4000
0 30 60 90
Time (min) after administration
pmol/mg dry tissue
A
B
0 1000 2000 3000 4000
0 30 60 90
Time (min) after administration
pmol/mg dry tissue
0 1000 2000 3000 4000
0 30 60 90
Time (min) after administration
pmol/mg dry tissue
A
B
Figur e 11 Effects of KF24345 on plasma adenosine in mice with acut e pancreatit is induced by CDE diet.
KF24345 was administ ered intravenously 24 hours after the onset of nor mal (△) or CDE (▲) diet. Vehicle was administ ered intravenously 24 hours after the onset of nor mal (○) or CDE (●) diet. Plasma sa mples wer e collect ed the indicated times after the administration. Plasma adenosine was measured as described in “Materials and Methods”.
The values repr esent the mea ns ± S.E. of four or five animals. * p < 0.05 versus vehicl e group.
0 500 1000 1500 2000 2500
0 30 60 90
Time (min)
P la sm a ad eno si ne ( n mo l / L)
*
0 500 1000 1500 2000 2500
0 30 60 90
Time (min)
P la sm a ad eno si ne ( n mo l / L)
*
Figur e 12 Effects of adenosine and adenosine uptake inhibitors on fMLP-induced superoxide generation in PMN fractions.
Human PMN fractions wer e primed wit h 4 μg/ mL of cyt ocharacin B and then treated wit h the indicated concentration of adenosine (A) or wit h the indicated concentrations of KF24345 (B), dipyrida mole (C) and 0 (○) or 0.3 (●) μmol/L of adenosine. 5 min aft er the treat ment, lucigenin and fMLP wer e added and superoxide generation was measur ed as described in “Materials and Met hods”. R esults ar e shown as a percentage of the fMLP-induced superoxide generation (Control) observed in the absence of adenosine and the t est inhibit or. The values r epresent mean ± S.E. of six separate experiments, each perfor med in duplicate.
0 20 40 60 80 100 120
0 0.1 1 10
adenosine (µmol/L)
0 20 40 60 80 100 120
0 0.1 1
KF24345 (µmol/L)
0 20 40 60 80 100 120
0 0.1 1
dipyridamole (µmol/L)
A
B C
% of Control % of Control % of Control
0 20 40 60 80 100 120
0 0.1 1 10
adenosine (µmol/L)
0 20 40 60 80 100 120
0 0.1 1
KF24345 (µmol/L)
0 20 40 60 80 100 120
0 0.1 1
dipyridamole (µmol/L)
A
B C
% of Control % of Control % of Control
Figur e 13 Effects of adenosine and adenosine uptake inhibitors on fMLP-induced elastase release in PMN fractions.
Human PMN fractions wer e primed wit h 4 μg/ mL of cyt ocharacin B and then treated wit h
the indicated concentration of adenosine (A) or wit h the indicated concentrations of KF24345 (B), dipyrida mole (C) and 0 (○) or 0.3 (●) μmol/L of adenosine. 5 min aft er the treat ment, fMLP wer e added and the activity of r eleased elastase was measured as described in “Materials and Met hods”. R esults are shown as a percentage of the elastase activity (Control) obser ved in the absence of adenosine and the t est inhibit or. The values represent mean ± S.E. of five separate experiments, each perfor med in duplicat e.
0 20 40 60 80 100 120
0 0.1 1 10
% of Control
0 20 40 60 80 100 120
0 0.1 1
% of Control
0 20 40 60 80 100 120
0 0.1 1
% of Control
adenosine (µmol/L)
KF24345 (µmol/L) dipyridamole (µmol/L)
A
B C
0 20 40 60 80 100 120
0 0.1 1 10
% of Control
0 20 40 60 80 100 120
0 0.1 1
% of Control
0 20 40 60 80 100 120
0 0.1 1
% of Control
adenosine (µmol/L)
KF24345 (µmol/L) dipyridamole (µmol/L)
A
B C
Figur e 14 Effects of adenosine and adenosine uptake inhibitors on LPS-induced cytokine product ion in PBMC fractions.
Human PBMC fractions wer e tr eated with the indicated concentration of adenosine (A) or with t he indicated concentrations of KF24345 (B), dipyrida mole (C) and 0 (○) or 1 (●) μmol/L of adenosine. One hour after the t reatment, the fractions wer e treat ed wit h 10 μg/mL of LPS. The supernatants were collected six hours after the LPS-treat ment.
TNF-α in the supernatant was measured as described in “Materials and Methods”. Results are shown as a percentage of the TNF-α production (Control) observed in the absence of adenosine and the t est inhibit or. The values repr esent mean ± S.E. of eight separat e experiments, each perfor med in duplicate.
0 20 40 60 80 100 120
0 0.1 1 10
% of Control
0 20 40 60 80 100 120
0 0.1 1
% of Control
0 20 40 60 80 100 120
0 0.1 1
% of Control
adenosine (µmol/L)
KF24345 (µmol/L) dipyridamole (µmol/L)
A
B C
0 20 40 60 80 100 120
0 0.1 1 10
% of Control
0 20 40 60 80 100 120
0 0.1 1
% of Control
0 20 40 60 80 100 120
0 0.1 1
% of Control
adenosine (µmol/L)
KF24345 (µmol/L) dipyridamole (µmol/L)
A
B C
Figur e 15 Inhibitory effects of KF24345 on adenosine uptake in blood fractions.
Human PMN (A), PBMC (B) or eryt hrocyt e (C) fractions wer e tr eated wit h 0 (●), 0. 1 (△), 0.3 (□) or 1 (○) μmol/L of KF24345. Aft er the treat ment, the fractions wer e incubated wit h [3H] adenosine for the indicat ed time and a mounts of adenosine uptake wer e measured as described in ‘Mat erials and Met hods’. The values repr esent the mea ns of two det er minants.
0 5000 10000 15000 20000
0 30 60 90
ADO uptake (dpm)
0 2000 4000 6000 8000
0 30 60 90
0 10000 20000 30000 40000
0 30 60 90
Time (min)
ADO uptake (dpm)
Time (min)
ADO uptake (dpm)
Time (min)
A
B
C
0 5000 10000 15000 20000
0 30 60 90
ADO uptake (dpm)
0 2000 4000 6000 8000
0 30 60 90
0 10000 20000 30000 40000
0 30 60 90
Time (min)
ADO uptake (dpm)
Time (min)
ADO uptake (dpm)
Time (min)
A
B
C
Figur e 16 Effects of adenosine and adenosine uptake inhibitors on fMLP-induced elastase release in PMN and eryt hrocyt e fractions.
Human PMN and erythr ocyt e fractions wer e primed wit h 4 μg/ mL of cyt ocharacin B and then treated wit h the indicated concentration of adenosine (A) or with t he indicated concentrations of KF24345 (B), dilazep (C), dipyrida mole (D) and 0 (○) or 1 (●) μmol/L of adenosine. 5 min aft er the treat ment, fMLP wer e added and t he activity of
released elastase was measured as described in “Materials and Methods”. R esults ar e shown as a percentage of the elastase activit y (Control) observed in the absence of adenosine and t he t est inhibit or. The va lues represent mea n ± S.E. of four separat e experiments, each perfor med in duplicate.
0 20 40 60 80 100 120
0 0.01 0.1 1 10
adenosine (µmol/L)
% of Control
0 20 40 60 80 100 120
0 0.01 0.1 1
KF24345 (µmol/L)
% of Control
0 20 40 60 80 100 120
0 0.01 0.1 1
Dipyridamole (µmol/L)
% of Control
A B
D
0 20 40 60 80 100 120
0 0.01 0.1 1
% of Control
Dilazep (µmol/L)
C
0 20 40 60 80 100 120
0 0.01 0.1 1 10
adenosine (µmol/L)
% of Control
0 20 40 60 80 100 120
0 0.01 0.1 1
KF24345 (µmol/L)
% of Control
0 20 40 60 80 100 120
0 0.01 0.1 1
Dipyridamole (µmol/L)
% of Control
A B
D
0 20 40 60 80 100 120
0 0.01 0.1 1
% of Control
Dilazep (µmol/L)
C
Figur e 17 Effects of adenosine and adenosine uptake inhibitors on LPS-induced cytokine product ion in PBMC and erythrocyt e fractions.
Human PBMC and erythr ocyt e fractions wer e treat ed wit h the indicated concentrations of adenosine and 0 (●), 0.01 (□), 0.1 (△) or 1 (○) μmol/L of KF24345 (A), dilazep (B) or dipyrida mole (C). One hour after the treat ment, the fractions were treated with 10 μg/mL of LPS. The supernatants wer e collect ed six hours after the LPS-treat ment. TNF-α in the supernatant was measur ed as described in “Mat erials and Methods”. Results are shown as a percentage of the TNF-α production (Control) observed in the absence of adenosine and the test inhibit or. The values repr esent the mea ns of thr ee det er mina nts.
A
0 20 40 60 80 100 120
0 0.01 0.1 1 10
adenosine (µmol/L)
% of Control
B
0 20 40 60 80 100 120
0 0.01 0.1 1 10
adenosine (µmol/L)
C
0 20 40 60 80 100 120
0 0.01 0.1 1 10
adenosine (µmol/L)
% of Control
% of Control
A
0 20 40 60 80 100 120
0 0.01 0.1 1 10
adenosine (µmol/L)
% of Control
B
0 20 40 60 80 100 120
0 0.01 0.1 1 10
adenosine (µmol/L)
C
0 20 40 60 80 100 120
0 0.01 0.1 1 10
adenosine (µmol/L)
% of Control
% of Control
Figur e 18 Effects of adenosine dea minase (ADA) on the inhibit ions of LPS-induced TNF-α production by adenosine and adenosine uptake inhibitors in PBMC and eryt hrocyt e fractions.
Human PBMC and eryt hrocyt e fractions wer e treat ed wit h (■) or wit hout (□) ADA and 10 μmol/L of adenosine and 1 μmol/L of KF24345, dilazep or dipyrida mole. One hour aft er the tr eatment, the fractions wer e tr eated with 10 μg/ mL of LPS. The supernatant s wer e collect ed six hours after the LPS-treat ment . TNF-α in the supernatant was measured as described in “Mat erials and Met hods”. R esult s ar e shown as a percentage of the TNF-α product ion (Control) observed in the absence of adenosine, ADA and t he t est inhibit or.
The values r epresent mean ± S.E. of five separate exper iments, each perfor med in duplicat e.
0 20 40 60 80 100 120
KF24345 Dilazep Dipyridamole
% of C on trol
0 20 40 60 80 100 120
KF24345 Dilazep Dipyridamole
% of C on trol
Figur e 19 Mechanism of inhibitor y effects of KF24345 on acute pancr eatitis in mice.
Table 1 Effects of intravenous administration of KF24345 on the ser um para met ers in mice wit h CDE diet-induced acute pancr eatitis.
* P < 0.05, compar ed with the control group.
Normal Control KF24345
Amylase 5294 ± 132 15247 ± 2333 12088 ± 1253
Lipase 32 ± 10 1804 ± 390 1399 ± 184
GPT 12 ± 2 17200 ± 1203 12188 ± 914 GOT 177 ± 8 35798 ± 2392 26659 ± 1735 LDH 260 ± 44 43135 ± 3770 29278 ± 2876 (IU/L)
*
*
*
Normal Control KF24345
Amylase 5294 ± 132 15247 ± 2333 12088 ± 1253
Lipase 32 ± 10 1804 ± 390 1399 ± 184
GPT 12 ± 2 17200 ± 1203 12188 ± 914 GOT 177 ± 8 35798 ± 2392 26659 ± 1735 LDH 260 ± 44 43135 ± 3770 29278 ± 2876 (IU/L)
*
*
*
Table 2 Sequential Changes in adenosine metabolites in mouse pancreas and liver with acute pancreatitis induced by CDE diet.
Pancreas
Time (h) ATP ADP AMP INO Hx
0 Pre 9435 ± 220 1281 ± 183 429 ± 50 14.2 ± 1.1 33 ± 3.0
16 Normal diet 9853 ± 256 1064 ± 71 344 ± 10 14.6 ± 1.5 20 ± 0.4
CDE diet 7440 ± 244 790 ± 26 259 ± 17 11.3 ± 0.4 1998 ± 146
24 Normal diet 8467 ± 435 1098 ± 63 366 ± 53 12.8 ± 1.9 23 ± 1.9
CDE diet 7381 ± 162 725 ± 22 244 ± 13 9.1 1871 ± 127
48 Normal diet 8162 ± 459 1291 ± 122 456 ± 54 10.2 ± 0.9 22 ± 1.4
CDE diet 7489 ± 362 1419 ± 169 548 ± 76 19.0 ± 1.9 1017 ± 96
(pmol/mg dry tissue) Liver
Time (h) ATP ADP AMP INO Hx
0 Pre 6434 ± 613 2676 ± 302 1570 ± 566 3.3 41 ± 4.4
16 Normal diet 7820 ± 225 1654 ± 114 605 ± 78 11.0 ± 3.4 19 ± 1.3
CDE diet 6062 ± 198 1259 ± 76 499 ± 83 6.0 ± 0.5 1917 ± 325
24 Normal diet 9446 ± 360 2074 ± 147 787 ± 89 5.4 ± 1.8 26 ± 2.1
CDE diet 6940 ± 499 1760 ± 37 817 ± 35 5.4 ± 0.5 3125 ± 617
48 Normal diet 9967 ± 252 1808 ± 74 631 ± 36 3.4 N.D. *
CDE diet 4029 ± 738 1014 ± 101 505 ± 46 7.5 ± 1.6 106 ± 35
(pmol/mg dry tissue)
* N.D.; Not detected Pancreas
Time (h) ATP ADP AMP INO Hx
0 Pre 9435 ± 220 1281 ± 183 429 ± 50 14.2 ± 1.1 33 ± 3.0
16 Normal diet 9853 ± 256 1064 ± 71 344 ± 10 14.6 ± 1.5 20 ± 0.4
CDE diet 7440 ± 244 790 ± 26 259 ± 17 11.3 ± 0.4 1998 ± 146
24 Normal diet 8467 ± 435 1098 ± 63 366 ± 53 12.8 ± 1.9 23 ± 1.9
CDE diet 7381 ± 162 725 ± 22 244 ± 13 9.1 1871 ± 127
48 Normal diet 8162 ± 459 1291 ± 122 456 ± 54 10.2 ± 0.9 22 ± 1.4
CDE diet 7489 ± 362 1419 ± 169 548 ± 76 19.0 ± 1.9 1017 ± 96
(pmol/mg dry tissue) Liver
Time (h) ATP ADP AMP INO Hx
0 Pre 6434 ± 613 2676 ± 302 1570 ± 566 3.3 41 ± 4.4
16 Normal diet 7820 ± 225 1654 ± 114 605 ± 78 11.0 ± 3.4 19 ± 1.3
CDE diet 6062 ± 198 1259 ± 76 499 ± 83 6.0 ± 0.5 1917 ± 325
24 Normal diet 9446 ± 360 2074 ± 147 787 ± 89 5.4 ± 1.8 26 ± 2.1
CDE diet 6940 ± 499 1760 ± 37 817 ± 35 5.4 ± 0.5 3125 ± 617
48 Normal diet 9967 ± 252 1808 ± 74 631 ± 36 3.4 N.D. *
CDE diet 4029 ± 738 1014 ± 101 505 ± 46 7.5 ± 1.6 106 ± 35
(pmol/mg dry tissue)
* N.D.; Not detected
Table 3 Effects of KF24345 on adenosine metabolites in mouse pancreas and liver with acute pancreatitis induced by CDE diet.
Pancreas Normal diet
Time (min) ATP ADP AMP INO Hx
0 Pre 7405 ± 112 1229 ± 60 256 ± 17 22.2 ± 2.9 19.1 ± 1.7
10 vehicle 7767 ± 269 1305 ± 63 266 ± 28 20.3 ± 1.9 18.4 ± 2.4
KF 7775 ± 368 1257 ± 47 235 ± 12 20.0 ± 0.9 17.2 ± 1.8
30 vehicle 7998 ± 289 1350 ± 34 269 ± 15 17.6 ± 2.7 17.3
KF 7993 ± 245 1313 ± 72 295 ± 15 19.4 ± 1.3 13.6
90 vehicle 8077 ± 234 1396 ± 52 295 ± 29 18.6 ± 1.4 39.5 ± 26.6
KF 8344 ± 296 1453 ± 92 327 ± 24 19.2 ± 1.2 14.6
(pmol/mg dry tissue) Pancreas CDE diet
Time (min) ATP ADP AMP INO Hx
0 Pre 11789 ± 552 1129 ± 45 366 ± 20 11.6 ± 0.5 2371 ± 244
10 vehicle 10778 ± 609 1102 ± 44 273 ± 8 11.4 ± 1.1 2262 ± 195
KF 11237 ± 723 1298 ± 107 358 ± 37 13.4 ± 2.8 2600 ± 108
30 vehicle 10261 ± 204 1373 ± 125 399 ± 60 33.6 ± 22.7 2712 ± 330
KF 9833 ± 459 1040 ± 85 286 ± 38 13.0 ± 1.4 2325 ± 199
90 vehicle 10323 ± 717 1095 ± 69 267 ± 15 3.3 1810 ± 347
KF 6669 ± 329 1077 ± 95 194 ± 29 17.9 ± 1.1 1496 ± 143
(pmol/mg dry tissue) Pancreas Normal diet
Time (min) ATP ADP AMP INO Hx
0 Pre 7405 ± 112 1229 ± 60 256 ± 17 22.2 ± 2.9 19.1 ± 1.7
10 vehicle 7767 ± 269 1305 ± 63 266 ± 28 20.3 ± 1.9 18.4 ± 2.4
KF 7775 ± 368 1257 ± 47 235 ± 12 20.0 ± 0.9 17.2 ± 1.8
30 vehicle 7998 ± 289 1350 ± 34 269 ± 15 17.6 ± 2.7 17.3
KF 7993 ± 245 1313 ± 72 295 ± 15 19.4 ± 1.3 13.6
90 vehicle 8077 ± 234 1396 ± 52 295 ± 29 18.6 ± 1.4 39.5 ± 26.6
KF 8344 ± 296 1453 ± 92 327 ± 24 19.2 ± 1.2 14.6
(pmol/mg dry tissue) Pancreas CDE diet
Time (min) ATP ADP AMP INO Hx
0 Pre 11789 ± 552 1129 ± 45 366 ± 20 11.6 ± 0.5 2371 ± 244
10 vehicle 10778 ± 609 1102 ± 44 273 ± 8 11.4 ± 1.1 2262 ± 195
KF 11237 ± 723 1298 ± 107 358 ± 37 13.4 ± 2.8 2600 ± 108
30 vehicle 10261 ± 204 1373 ± 125 399 ± 60 33.6 ± 22.7 2712 ± 330
KF 9833 ± 459 1040 ± 85 286 ± 38 13.0 ± 1.4 2325 ± 199
90 vehicle 10323 ± 717 1095 ± 69 267 ± 15 3.3 1810 ± 347
KF 6669 ± 329 1077 ± 95 194 ± 29 17.9 ± 1.1 1496 ± 143
(pmol/mg dry tissue)