Dipyridamole inhibits human peritoneal mesothelial cell proliferation in vitro and attenuates rat peritoneal fibrosis in vivo.
BACKGROUND
Peritoneal fibrosis (PF) is one of the most serious complications after long-term continuous ambulatory peritoneal dialysis (CAPD). Proliferation of human peritoneal mesothelial cells (HPMC) and matrix over-production are regarded as the main processes predisposing to PF. Dipyridamole (DP) has been reported to have potential as an antiproliferative and antifibrotic agent. We thus investigated the effect of DP in inhibiting proliferation and collagen synthesis of HPMC. A rat model of peritonitis-induced PF was also established to demonstrate the in vivo preventive effect of DP.


METHODS
HPMC was cultured from human omentum by an enzyme digestion


METHODS
Cell proliferation was measured by the methyltetrazolium assay. Intracellular cAMP was measured using an enzyme immunoassay (EIA) kit. Total collagen synthesis was measured by (3)H-proline incorporation assay. Expression of collagen alpha1 (I) and collagen alpha 1 (III) mRNAs was determined by Northern blotting. The rat model of peritonitis-induced PF was developed by adding dextran microbeads (Cytodex, 8 mg/1 mL volume) to a standardized suspension (3 x 10(9)) of Staphylococcus aureus. DP was administrated via intravenous infusion (4 mg in 1 h) daily for seven days. Macroscopic grading of intraperitoneal adhesions and histological analyses of peritoneal thickness and collagen expression were performed.


RESULTS
Addition of DP to HPMC cultures suppressed serum-stimulated cell proliferation and collagen synthesis. The antimitogenic and antifibrotic effects of DP appear to be predominantly mediated through the cAMP pathway, as DP increased intracellular cAMP in a dose-dependent manner. The macroscopic grade of intraperitoneal adhesion and peritoneal thickness were both significantly increased in animals treated with Cytodex plus S. aureus; on the other hand, DP attenuated these fibrotic changes with statistical significance (P < 0.01). Analysis of gene expression of collagen alpha 1 (I) and alpha1 (III) in the peritoneal tissue of experimental animals yielded similar results.


CONCLUSIONS
This study suggests that dipyridamole may have therapeutic potential in treating peritoneal fibrosis.
Hung
K Y
KY
Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan, Republic of China.
Shyu
R S
RS
Fang
C C
CC
Tsai
C C
CC
Lee
P H
PH
Tsai
T J
TJ
Hsieh
B S
BS
D000818:Animals; D002448:Cell Adhesion / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D003094:Collagen / Q000235:genetics; D000242:Cyclic AMP / Q000378:metabolism; D004176:Dipyridamole / Q000494:pharmacology*; D004195:Disease Models, Animal; D004848:Epithelium; D005355:Fibrosis; D015870:Gene Expression / Q000502:physiology; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D009852:Omentum / Q000166:cytology; D010531:Peritoneal Dialysis, Continuous Ambulatory; D010537:Peritoneum / Q000187:drug effects* / Q000473:pathology*; D010538:Peritonitis / Q000188:drug therapy / Q000378:metabolism; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017208:Rats, Wistar
D010726:Phosphodiesterase Inhibitors; D012333:RNA, Messenger; D004176:Dipyridamole; D003094:Collagen; D000242:Cyclic AMP