title: Preventive effects of the angiotensin-converting enzyme inhibitor, captopril, on the development of azoxymethane-induced colonic preneoplastic lesions in diabetic and hypertensive rats.
abstract: Metabolic syndrome (Mets), including diabetes and hypertension, increases the risk of colorectal cancer via the induction of chronic inflammation, acceleration of oxidative stress, and activation of the renin-angiotensin system. The present study examined the possible inhibitory effects of captopril, an angiotensin-converting enzyme (ACE) inhibitor and antihypertensive drug, on the development of azoxymethane (AOM)-induced colonic premalignant lesions, aberrant crypt foci (ACF), in SHRSP.Z-Leprfa/IzmDmcr (SHRSP-ZF) diabetic and hypertensive rats. Male 6-week-old SHRSP-ZF rats were administered two, weekly intraperitoneal injections of AOM (20 mg/kg body weight). Following the second injection, the rats received drinking water containing captopril (8 mg/kg/day) for two weeks. At sacrifice, captopril administration significantly lowered the blood pressure and reduced the total number and size of ACF compared with those observed in the untreated group. The serum levels of angiotensin-II and the expression levels ofACEand angiotensin-II type 1 receptor mRNA on the colonic mucosa decreased following captopril treatment. Captopril also reduced the urinary 8-hydroxy-2'-deoxyguanosine levels and the serum derivatives of reactive oxygen metabolites levels, both of which are oxidative stress markers, but increased the mRNA levels of catalase, an antioxidant enzyme, in the colonic epithelium. Moreover, the expression levels of tumor necrosis factor-α, interleukin-18, monocyte chemoattractant protein-1, inducible nitric oxide synthase, vascular endothelial growth factor and proliferating cell nuclear antigen mRNA in the colonic epithelium were decreased significantly following captopril administration. These observations suggested that captopril prevents the development of ACF by inhibiting renin-angiotensin system activation and attenuating inflammation and oxidative stress in SHRSP-ZF rats. Therefore, targeting Mets-related pathophysiological conditions, including renin-angiotensin system activation, may be an effective strategy to prevent colorectal carcinogenesis in patients with Mets, particularly those with hypertension.
authors: Department of Medicine/Gastroenterology, Gifu University Graduate School of Medicine, Gifu, Chūbu 501-1194, Japan.
authors: Takahiro
authors: T
authors: Kochi
authors: Department of Medicine/Gastroenterology, Gifu University Graduate School of Medicine, Gifu, Chūbu 501-1194, Japan.
authors: Masahito
authors: M
authors: Shimizu
authors: Department of Medicine/Gastroenterology, Gifu University Graduate School of Medicine, Gifu, Chūbu 501-1194, Japan.
authors: Tomohiko
authors: T
authors: Ohno
authors: Department of Medicine/Gastroenterology, Gifu University Graduate School of Medicine, Gifu, Chūbu 501-1194, Japan.
authors: Atsushi
authors: A
authors: Baba
authors: Department of Medicine/Gastroenterology, Gifu University Graduate School of Medicine, Gifu, Chūbu 501-1194, Japan.
authors: Takafumi
authors: T
authors: Sumi
authors: Department of Medicine/Gastroenterology, Gifu University Graduate School of Medicine, Gifu, Chūbu 501-1194, Japan.
authors: Masaya
authors: M
authors: Kubota
authors: Department of Medicine/Gastroenterology, Gifu University Graduate School of Medicine, Gifu, Chūbu 501-1194, Japan.
authors: Yohei
authors: Y
authors: Shirakami
authors: Department of Medicine/Gastroenterology, Gifu University Graduate School of Medicine, Gifu, Chūbu 501-1194, Japan.
authors: Hisashi
authors: H
authors: Tsurumi
authors: Department of Tumor Pathology, Gifu University Graduate School of Medicine, Gifu, Chūbu 501-1194, Japan.
authors: Takuji
authors: T
authors: Tanaka
authors: Department of Medicine/Gastroenterology, Gifu University Graduate School of Medicine, Gifu, Chūbu 501-1194, Japan.
authors: Hisataka
authors: H
authors: Moriwaki
keywords: angiotensin-converting enzyme inhibitor; colon carcinogenesis; hypertension; metabolic syndrome; renin-angiotensin system