RT Journal Article
SR Electronic
T1 Combination Therapy with an Angiotensin-Converting Enzyme Inhibitor and an Angiotensin II Receptor Blocker Synergistically Suppresses Chronic Pancreatitis in Rats
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 36
OP 45
DO 10.1124/jpet.104.077883
VO 313
IS 1
A1 Tamaki Yamada
A1 Atsushi Kuno
A1 Kumiko Ogawa
A1 Mingxi Tang
A1 Kazuhiko Masuda
A1 Soichi Nakamura
A1 Tomoaki Ando
A1 Tetsu Okamoto
A1 Hirotaka Ohara
A1 Tomoyuki Nomura
A1 Takashi Joh
A1 Tomoyuki Shirai
A1 Makoto Itoh
YR 2005
UL http://jpet.aspetjournals.org/content/313/1/36.abstract
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