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

Abstract

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 ␣-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 ␣-smooth muscle actin-positive cells. Combination therapy suppressed up-regulation of tumor necrosis factor-␣, platelet-derived growth factor-receptor ␤, and transforming growth factor-␤1 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-␣, plateletderived growth factor-receptor ␤, and transforming growth factor-␤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.

Effect of icarisid II on diabetic rats with erectile dysfunction and its potential mechanism via assessment of AGEs, autophagy, mTOR and the NO–cGMP pathway

“…[13][14][15] The renin-angiotensin system plays an important role in causing SMC fibrosis, and angiotensin II type I receptor blockers and angiotensin-sconverting enzyme inhibitors can ameliorate SMC fibrosis and extend the life span of SMCs in animal models. [16][17][18][19] Tankyrase 1 also has a similar effect. 14,15 This study determined that a decrease in erectile function coincided with the downregulation of SMC proliferation and SMC/CF proportions in diabetic ED rats and that icarisid II could ameliorate these effects.…”

Effects of Medications on Post-Endoscopic Retrograde Cholangiopancreatography Pancreatitis

“…Animal studies, however, are not consistent with ARB-related damage. Studies have shown cardesartan suppresses inflammation and fibrosis in rats [22] and a combination of an ACE inhibitor and an ARB synergistically suppresses chronic pancreatitis [23]. The mechanisms by which pancreatitis is induced by ACE inhibitors or ARBs are unknown.…”

The pancreatic stellate cell: a star on the rise in pancreatic diseases

“…For example, blockade of the receptors for PDGF, TGF-β, and angiotensin II, as well as blockade of the intracellular signaling pathways downstream of these receptors, is likely to provide therapeutic benefit (17,51,76,108). In this regard, there are in vivo experiments showing the importance of the angiotensin II system in the development of pancreatic fibrosis (64,108).…”

“…In this regard, there are in vivo experiments showing the importance of the angiotensin II system in the development of pancreatic fibrosis (64,108). There are also several reports from in vitro experiments using PaSCs that show key roles in the activation and/or proliferation process for MAPK pathways, in particular, ERK1/2, p38 kinase, and JNK (50,52,53,66,109,110); PI3K and PKC (111); PPARγ (36,112); NADPH oxidases (our unpublished observations); and ethanol metabolism to acetaldehyde (18).…”

“…In the case of targeting fibrosis in pancreatic tumor models, antibodies to CTGF, which activate PaSCs through their α 5 β 1 integrin receptor (44), inhibited tumor growth and metastasis in a xenograft mouse pancreatic tumor model (116,117). Agents showing benefit in experimental chronic pancreatitis include inhibitors of angiotensin II-converting enzyme and antagonists of the angiotensin II receptor (50,108); vitamin E (118) and DA-9601 (119), which function as antioxidants; troglitazone and thiazolidinedione, which are PPARγ ligands (120,121); camostat, which is a serine protease inhibitor (62,122); the herbal preparation Saiko-keishito, which has antioxidant and antiinflammatory properties (123); and COX-2 inhibitors (124). In addition, strategies aimed at blocking TGF-β signaling pathways (113,125) have proved effective in reducing experimental pancreatic fibrosis in rodents.…”