PT  - JOURNAL ARTICLE
AU  - Tamaki Yamada
AU  - Atsushi Kuno
AU  - Kumiko Ogawa
AU  - Mingxi Tang
AU  - Kazuhiko Masuda
AU  - Soichi Nakamura
AU  - Tomoaki Ando
AU  - Tetsu Okamoto
AU  - Hirotaka Ohara
AU  - Tomoyuki Nomura
AU  - Takashi Joh
AU  - Tomoyuki Shirai
AU  - Makoto Itoh
TI  - Combination Therapy with an Angiotensin-Converting Enzyme Inhibitor and an Angiotensin II Receptor Blocker Synergistically Suppresses Chronic Pancreatitis in Rats
AID  - 10.1124/jpet.104.077883
DP  - 2005 Apr 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 36--45
VI  - 313
IP  - 1
4099  - http://jpet.aspetjournals.org/content/313/1/36.short
4100  - http://jpet.aspetjournals.org/content/313/1/36.full
SO  - J Pharmacol Exp Ther2005 Apr 01; 313
AB  - We recently demonstrated that both lisinopril and candesartan, an angiotensin-converting enzyme inhibitor and angiotensin II type 1 receptor blocker, respectively, attenuate pancreatic inflammation and fibrosis in male Wistar Bonn/Kobori (WBN/Kob) rats. The purpose of the present study was to assess whether combination therapy with low doses of both, ineffective when given alone, might synergistically exert protective effects. Lisinopril, candesartan, or a combination of both in drinking water was administered to 10-week-old male WBN/Kob rats for 10 weeks. Parameters of inflammation and fibrosis, positive immunostaining for α-smooth muscle actin, and gene expression of cytokine and growth factors were assessed, as well as circulating renin-angiotensin system components. Dose-dependent effects of combination therapy were also investigated. Only combination therapy attenuated gross alterations in the pancreas, as quantitatively confirmed by increases in pancreatic weights and decreases in myeloperoxidase activity, hydroxyproline content, histologic scores, relative fibrosis area, and relative area of α-smooth muscle actin-positive cells. Combination therapy suppressed up-regulation of tumor necrosis factor-α, platelet-derived growth factor-receptor β, and transforming growth factor-β1 mRNA in the pancreas. Dose dependence of combination therapy was recognized with reference to improvement in these parameters. The conclusions are that combination therapy synergistically alleviated pancreatic inflammation and fibrosis in male WBN/Kob rats. This effect may be related to suppression of tumor necrosis factor-α, platelet-derived growth factor-receptor β, and transforming growth factor-β1 mRNA. Compared with the either therapy alone, combination therapy with an angiotensin-converting enzyme inhibitor and an angiotensin II type 1 receptor blocker may be more beneficial for treating chronic pancreatitis. The American Society for Pharmacology and Experimental Therapeutics