Calcium channel blockers - the effect on renal changes in clinical and experimental diabetes: an overview.

both dihydropyridine CCBs and non-dihydropyridine Introduction CCBs have been administered, with considerable differences in study duration and CCB dosage. Diabetic nephropathy is the most important cause of Several experimental studies have compared the end-stage renal failure in the Western world. It is efficacy of a dihydropyridine CCB and an ACEI preceded by increased urinary albumin excretion [6,11,15–17] in preventing the progression of diabetic ( UAE) in the microalbuminuric range (30–300 mg/ renal disease in normotensive [6,11,17] or spontan24 h, i.e. incipient nephropathy), often in association eously hypertensive rats (SHR) [15,16 ]. In none of with hypertension. Antihypertensive treatment with these studies was an effect achieved on UAE, glomerangiotensin-converting-enzyme inhibitors (ACEIs) is ular hypertrophy, or glomerulosclerosis in response to effective in preventing or postponing the development lacidipine [15–17] or nifedipine [6,11], in contrast to of overt nephropathy (i.e. UAE >300 mg/24 h) [1]. the effects with ACEI treatment. However, in one Other antihypertensive drugs, such as calcium channel study lacidipine treatment significantly reduced ocular blockers (CCBs), may also be effective in the treatment albumin vascular clearance [15], indicating a beneficial of diabetic kidney disease, but their preventive effect effect on diabetic retinal microvascular changes. In is controversial. In addition, it is still unknown whether dihydropyridine CCBs and non-dihydropyridine CCBs addition, one study reported lacidipine to abolish are equally effective. Further, the safety of CCB treatdiabetes-associated early renal hyperfiltration and hypment in diabetics has been debated, since increased erperfusion to the same degree as ACEI treatment on incidence of cardiovascular mortality has been reported short-term basis, while no long-term effect was during nisoldipine treatment in non-insulin-dependent observed on UAE or glomerulosclerosis [16 ]. Our diabetes mellitus (NIDDM). Thus, this paper will group reported nitrendipine to normalize UAE in present an updated review of experimental and clinical normotensive, diabetic rats and to reduce renal and data concerning the renoprotective effects of CCBs in glomerular hypertrophy when treatment was initiated patients with insulin-dependent diabetes mellitus right after diabetes induction [9,18]. Furthermore, (IDDM) and NIDDM, and briefly discuss safety connitrendipine treatment for 6 weeks, after a period of 3 siderations. The few studies examining the effect of months with untreated diabetes, reduced UAE, while CCBs in a mixture of IDDM and NIDDM patients no effects on manifest renal and glomerular enlargewill not be discussed in this review. ment were observed [10]. In diabetic SHR nitrendipine treatment failed to show any impact on the progression of diabetic, renal changes, which could be caused by a Animal models of diabetic nephropathy delayed reduction in systemic blood pressure [18]. In a long-term study with diltiazem, a nonExperimental models used for the study of diabetic dihydropyridine CCB, in alloxan-diabetic Beagle dogs nephropathy have been heterogeneous in terms of [13,14] CCB-treatment was found equally effective in animal species; some studies investigating rat strains comparison with the ACEI lisinopril, in preventing the with [2–6 ] or without [7–12] partial nephrectomy, and development of focal glomerulosclerosis and mesangial other studies using Beagle dogs [13,14]. Furthermore, volume expansion, and in normalizing UAE. When both treatments were combined an additional effect was observed [13,14]. This observation is in accordance Correspondence and offprint requests to: Birgitte Nielsen MD, with a study in streptozotocin-diabetic rats, where Medical Research Laboratory M (Diabetes and Endocrinology), diltiazem was found to normalize UAE concomitantly Institute of Experimental Clinical Research, Aarhus University with a reduction in systemic blood pressure and also Hospital, DK-8000 Aarhus C, Denmark. E-mail: BirgitteNielsen@dadlnet.dk. the preservation of heparan sulfate in the glomerular