Glucose-induced insulin secretion is impaired in chronic renal failure (CRF), and this abnormality is due to the elevation of cytosolic calcium [Ca2+]i and other derangements in pancreatic islet metabolism. Verapamil given to rats from day 1 of CRF prevented the rise in [Ca2+]i of islets and the impairment in insulin secretion. However, it is not known whether verapamil can reverse the abnormalities of islet function and metabolism in animals with preexisting renal failure. Such a documentation has important clinical implications for the treatment of carbohydrate intolerance in patients with CRF. The present study examined this question. After 6 weeks of CRF, rats were randomized into two subgroups and maintained for additional 6 weeks. One subgroup received intraperitoneal injections of verapamil (0.1 µg/kg body weight twice daily) and the other received vehicle only. At the time of randomization, there were no significant differences between the two subgroups in their body weight, plasma levels of calcium, phosphorus and creatinine, serum parathyroid hormone and creatinine clearance. Similarly, at the time of sacrifice (12 weeks), there were no significant differences in these parameters except for a modestly lower plasma level of creatinine and modestly higher creatinine clearance. The treatment of rats with preexisting CRF with verapamil (CRF-V) normalized glucose intolerance and reversed to normal or near normal the derangements in islet metabolism and function including [Ca2+]i (normal: 85 ± 1.5 nM; CRF: 135 ± 1.9 nM; CRF-V: 94 ± 2.9 nM), basal levels of ATP content (normal: 12.8 ± 1.11 pmol/islet; CRF: 7.8 ± 0.31 pmol/islet; CRF-V: 10.6 + 0.60 pmol/islet) and stimulated ATP content and ATP/ADP ratio, glucose-induced insulin secretion (normal: 2,380 ± 116.9 pg/islet-28 min; CRF: 842 ± 75.0 pg/islet-28 min; CRF-V: 1,929 ± 65.3 pg/islet-28 min) and the glucose-induced calcium signal (normal: 167 ± 11.1 nM;CRF: 136 ± 12.1 nM; CRF-V: 180 ± 13.5 nM). Vmax of Ca2+ ATPase and Na+-K+ ATPase of islets of CRF were also markedly and significantly improved by treatment with verapamil. These data demonstrate that the calcium channel blocker verapamil can reverse the functional and metabolic derangements of pancreatic islets that occur in CRF. The results provide the experimental basis for the clinical use of calcium channel blockers in the treatment of carbohydrate intoler