Combination therapy with an angiotensin-converting enzyme inhibitor and an angiotensin II receptor blocker synergistically suppresses chronic pancreatitis in rats.
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 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. 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 up-regulation of tumor necrosis factor-alpha, platelet-derived growth factor-receptor beta, and transforming growth factor-beta1 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-alpha, platelet-derived growth factor-receptor beta, and transforming growth factor-beta1 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.
Yamada
Tamaki
T
Okazaki City Medical Association, Public Health Center, 1-9-1 Tatsumi-nishi, Okazaki, Aichi, Japan, 444-0875. t-yamada@okazaki-med.or.jp
Kuno
Atsushi
A
Ogawa
Kumiko
K
Tang
Mingxi
M
Masuda
Kazuhiko
K
Nakamura
Soichi
S
Ando
Tomoaki
T
Okamoto
Tetsu
T
Ohara
Hirotaka
H
Nomura
Tomoyuki
T
Joh
Takashi
T
Shirai
Tomoyuki
T
Itoh
Makoto
M
D000199:Actins / Q000378:metabolism; D000450:Aldosterone / Q000097:blood; D000804:Angiotensin II / Q000097:blood; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology; D001713:Biphenyl Compounds; D001835:Body Weight / Q000187:drug effects; D002908:Chronic Disease; D016207:Cytokines / Q000096:biosynthesis; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D005355:Fibrosis; D011905:Genes, ras / Q000187:drug effects; D006909:Hydroxyproline / Q000378:metabolism; D007150:Immunohistochemistry; D017706:Lisinopril / Q000494:pharmacology; D008297:Male; D009929:Organ Size / Q000187:drug effects; D010195:Pancreatitis / Q000188:drug therapy* / Q000473:pathology; D007703:Peptidyl-Dipeptidase A / Q000097:blood; D009195:Peroxidase / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D017208:Rats, Wistar; D044140:Receptor, Angiotensin, Type 1; D013777:Tetrazoles / Q000494:pharmacology
D000199:Actins; D000806:Angiotensin-Converting Enzyme Inhibitors; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D016207:Cytokines; D012333:RNA, Messenger; D044140:Receptor, Angiotensin, Type 1; D013777:Tetrazoles; D000804:Angiotensin II; D000450:Aldosterone; D017706:Lisinopril; D009195:Peroxidase; D007703:Peptidyl-Dipeptidase A; D006909:Hydroxyproline; C081643:candesartan