Angiotensin-converting enzyme (ACE) activity and vascular mass are both increased in the mesenteric arteries of diabetic rats. As vascular hypertrophy may result from smooth muscle growth following increased formation of angiotensin II, we have examined the histological nature of the increase in mesenteric arterial mass and the role of elevated ACE activity in diabetic vascular hypertrophy by administration of an ACE inhibitor (perindopril). Cross-sectional area of the media was measured in perfusion-fixed mesenteric vessels of diabetic rats 3 weeks after streptozotocin injection. The media was significantly larger (63%) in mesenteric vessels of diabetic rats compared to age-matched control animals. Medial hypertrophy in these vessels was not associated with increased blood pressure or plasma renin activity but there was evidence for increased hemodynamic load due to hyperphagia and intestinal enlargement. Increased mesenteric ACE activity was involved in this process as there was significant inhibition of medial hypertrophy by perindopril. Other markers of cardiovascular hypertrophy such as left ventricular weight and aortic medial area were less affected, but increased in the diabetic group when corrected for significant body weight effects, consistent with a systemic influence of diabetes on cardiovascular mass. These data provide new insights into the mechanisms of vascular complications of diabetes and may have implications for the use of ACE inhibitors in preventing or arresting diabetes-associated vascular pathology.