Calcium channel blockers attenuate diclofenacinduced small intestinal ulceration

Abstract

BACKGROUND: Diclofenac (Voltaren ®) is a NSAID widely used for the treatment of arthritis. Endoscopic evaluations indicate bleeding or ulcers in > 70% of volunteers given therapeutic doses of diclofenac. Therefore, strategies are needed to minimize its enteropathic complications. Calcium channel blockers (CCBs) have been reported to exert beneficial effects against gastric ulcers in several animal studies, but not against intestinal ulcers caused by diclofenac. OBJECTIVE: Determine whether CCBs would attenuate diclofenac-indnced small intestinal ulcers and increases in intestinal permeability. EXPERIMENTAL DESIGN: At 1 hr prior to diclofenac treatment (50 mg/kg, po), adult male Sprague Dawley rats (4 months) were pretreated with structurally different CCBs: the phenylalkalamine; verapamil (40 mg/kg, ip); the benzothiazepine, diltiazem (90 mg/kg, ip), or the pharmacologically inactive stereoisomer, R verapamil (40 mg/kg, ip). Tissues were collected at 12 hrs after a single challenge of NSAID. To determine whether the protective effects of a CCB requires its continued bioavailability, diclofenac treated animals were examined at 24 hrs after a single (-1 hr) or two (at -1 hr and 12 hr) doses of verapamil. Gastrointestinal tracts were inspected for ulcers fresh and after fixation for the presence of ulcers and serum was analyzed for total protein and albumin as indices of permeability. RESULTS: By 12 hrs, diclofenac produced an average of 100 ulcers in the small intestine while less than 25 ulcers were found in animals pretreated with either CCB. No protection was evident in animals pretreated with R verapamil. At 24 hrs, a sustained protective effect against ulcers was found only in animals given two doses of verapamil. However, CCB pretreatment did not modify the effect of diclofenac on intestinal permeability as reflected by serum total protein or albumin. CONCLUSIONS: Our observations of ulcer protection by two structurally different CCBs but not by the inactive form of verapamil suggest that a common action of CCBs, such as calcium channel blockade, is involved in attenuation of diclofenac-induced intestinal ulceration. Our findings of sustained ulcer attenuation only with repeated CCB treatment suggests that CCBs could modulate a later stage of ulcerogenesis. (Supported by NIH DK 34806. R Verapamil was a kind gift from Dr. C. Romerdahl of BASF Pharmaceuticals).