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Journal of Pharmacology And Experimental Therapeutics Fast Forward
First published on December 17, 2004; DOI: 10.1124/jpet.104.077883

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Received for publication September 15, 2004.
Revised December 7, 2004.
Accepted for publication December 13, 2004.

Combination Therapy with an Angiotensin-Converting Enzyme Inhibitor and an Angiotensin II Receptor Blocker synergistically suppresses Chronic Pancreatitis in Rats

Tamaki Yamada 1*, Atsushi Kuno 2, Kumiko Ogawa 2, Mingxi Tang 2, Kazuhiko Masuda 2, Soichi Nakamura 2, Tomoaki Ando 2, Tetsu Okamoto 2, Hirotaka Ohara 2, Tomoyuki Nomura 2, Takashi Joh 2, Tomoyuki Shirai 2, Makoto Itoh 2

1 Okazaki City Medical Association, Public Health Center, Japan 2 Nagoya City University Graduate School of Medical Sciences, Japan

* Address correspondence to: E-mail: t-yamada{at}okazaki-med.or.jp

Abstract

Background & Aims: We recently demonstrated that both lisinopril and candesartan, respectively an angiotensin-converting enzyme inhibitor and angiotensin II type 1 receptor blocker, attenuate pancreatic inflammation and fibrosis in male 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. Methods: Lisinopril, candesartan, or a combination of both in drinking water were administered to 10-week-old male WBN/Kob rats for 10 weeks. Parameters of inflammation and fibrosis, positive immunostaining for {alpha}-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. Results: 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 {alpha}-smooth muscle actin positive cells. Combination therapy suppressed upregulation of tumor necrosis factor-{alpha}, platelet-derived growth factor-receptor {beta}, and transforming growth factor-{beta}1 mRNA in the pancreas. Dose-dependence of combination therapy was recognized with reference to improvement in these parameters. Conclusion: Combination therapy synergistically alleviated pancreatic inflammation and fibrosis in male WBN/Kob rats. This effect may be related to suppression of tumor necrosis factor-{alpha}, platelet-derived growth factor-receptor {beta}, transforming growth factor-{beta}1 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.


Key words: Angiotensin II Receptor Blocker, Angiotensin-Converting Enzyme Inhibitor, Chronic Pancreatitis, Fibrosis, Renin-Angiotensin System, WBN/Kob rat




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