ABSTRACT-The inhibitory effect of manidipine, a long acting calcium channel blocker, on vascular smooth muscle cell proliferation was investigated in spontaneously diabetic GK rats with balloon catheter-induced denudation of the carotid artery. Treatment with manidipine at doses of 4.6 and 15.1 mg/kg/day inhibited thickening of the neo-intima in the balloon catheter-injured artery without any effect on blood pressure and lowered the ratio of intima to wall areas and wall to total vascular areas in a dose-dependent fashion. These results suggest that manidipine inhibits an abnormal proliferation of the intima in the carotid artery of spontaneously diabetic rats.Keywords: Manidipine, Neo-intima, Antimyoproliferative actionIt has been reported that calcium channel blockers suppress atherogenesis in cholesterol-fed animals (1-3) and the development of new occlusive lesions in pa tients with coronary atherosclerosis (4, 5). The possible mechanisms of this antiatherogenic effect are probably related to lowering of arterial pressure, prevention of dyslipidemic endothelial injury and inhibition of arterial smooth muscle cell (SMC) proliferation (6). In this paper, we examined the effects of manidipine, a long acting calcium channel blocker (7), on SMC prolifera tion after vascular injury induced by a balloon catheter in spontaneously diabetic Goto-Kakizaki (GK) rats (8), in which severe thickening of intima in the injured artery is observed.Male spontaneously diabetic GK rats were bred in our Laboratory Animal Unit. They were housed in in dividual wire cages and fed a commercial stock diet (CE-2, Clea Japan Inc., Tokyo) in a room with control led temperature (23 ± 1°C), humidity (55 ± 5%) and lighting (08:00-20:00).Thirteen-week-old, male GK rats were given a pow dered CE-2 diet with or without manidipine at a con centration (w/w) of 0.01 or 0.03% for 20 days. The concentrations were selected as those producing slight and mild antihypertensive effects in spontaneously hypertensive rats (9). The drug intake was calculated from the food intake and expressed as mg/kg/day. On day 6, these rats were anesthetized with pentobarbital (50 mg/kg, i.p.) and subjected to balloon catheter-in duced denudation of the left carotid artery according to the method described by Baumgartner (10). In brief, a 2F balloon catheter (Edwards Laboratories, Santa Ana, CA) was introduced into the left carotid artery via the left femoral artery. The balloon was then inflated with saline and drawn back and forth 3 times over a distance of 1 to 1.5 cm to remove the endothelium of the carotid artery. On day 20, the systolic blood pressure was measured by a tail pulse pick-up method in unanesthe tized rats. Thereafter, a catheter was inserted into the ascending aorta via the left ventricle under pentobarbi tal anesthesia. Phosphate-buffered saline with 4% form aldehyde (pH 7.4) was perfused under a pressure of 90 to 100 mmHg for 10 min to fix the carotid artery. Five frozen cross-sections (12 gum in thickness) from each injured artery were stained with ...
