. Local anesthetics worsen renal function after ischemia-reperfusion injury in rats. Am J Physiol Renal Physiol 286: F111-F119, 2004. First published September 30, 2003 10.1152 10. /ajprenal.00108.2003ics are widely used during the perioperative period, even in patients with preexisting renal disease. However, local anesthestics have been shown to cause cell death in multiple cell lines, including human kidney proximal tubule cells. We questioned whether local anesthetics potentiate renal dysfunction after ischemia-reperfusion (I/R) injury in vivo. Rats were implanted with subcutaneous miniosmotic pumps that continuously delivered lidocaine (2 mg⅐kg Ϫ1 ⅐h Ϫ1 ), bupivacaine (0.4 mg⅐kg Ϫ1 ⅐h Ϫ1 ), tetracaine (1 mg⅐kg Ϫ1 ⅐h Ϫ1 ), or saline vehicle, and 6 h later the rats were subjected to 30 min of renal ischemia or to sham operation. Renal function was assessed by measurement of plasma creatinine at 24 and 48 h after renal I/R injury in the presence or absence of chronic infusions of local anesthetics and correlated to histological changes indicative of necrosis. The degree of renal apoptosis was assessed by three methods: 1) DNA fragmentation detected by terminal deoxynucleotidyl transferase biotin-dUTP nickend labeling staining, 2) DNA laddering detected after agarose gel electrophoresis, and 3) morphological identification of apoptotic tubules at the corticomedullary junction. We also measured the expression of the proinflammatory markers ICAM-1 and TNF-␣. Continuous local anesthetic infusion with renal I/R injury resulted in an increased magnitude and duration of renal dysfunction compared with the saline-infused I/R group. Additionally, both apoptotic and necrotic renal cell death as well as inflammatory changes were significantly potentiated in local anesthetic-treated rat kidneys. Local anesthetic infusion alone without I/R injury had no effect on renal function. We conclude that local anesthetics potentiated renal injury after I/R by increasing necrosis, apoptosis, and inflammation. acute renal failure; apoptosis; bupivacaine; inflammation; lidocaine; necrosis; tetracaine ACUTE RENAL FAILURE (ARF) secondary to ischemia-reperfusion (I/R) injury continues to be a significant clinical problem Patients with impaired preoperative renal function undergoing aortovascular surgery are at greatest risk for developing perioperative ARF (26). Local anesthetics are widely used in clinical practice, even in patients with impaired preoperative renal function. Epidural infusions of local anesthetic are routinely used for intraoperative and postoperative analgesia (frequently lasting several days) in patients undergoing major abdominal and vascular procedures. During induction of general anesthesia for endotracheal intubation, intravenous lidocaine is given routinely to blunt the sympathetic reflex to direct laryngoscopy. Local anesthetics are used to provide surgical anesthesia and analgesia in peripheral and central nervous system nerve blocks (spinal and epidural anesthesia). In the intensive care unit, lidocaine is frequently used as an antiarrythmic agent. Several in vitro studies found that local anesthetics increase cell death via apoptosis in neuronal, lymphocytic, and osteoblastic cell lines MATERIALS AND METHODS Implantation of Miniosmotic Pumps and Renal I/R Injury All protocols were approved by the Institutional Animal Care and Use Committee of Columbia University. Adult male Sprague-Dawley rats (225-275 g, Harlan Sprague-Dawley, Indianapolis, IN) were used. They had free access to rodent chow and water. Rats were anesthetized with intraperitoneal (ip) pentobarbital sodium (50 mg/kg or to effect) and implanted with subcutaneous miniosmotic pumps (model 2ML1, Alzet) that continuously delivered 10 l/h of 5% lidocaine (2 mg⅐kg Ϫ1 ⅐h Ϫ1 ), 1% bupivacaine (0.4 mg⅐kg Ϫ1 ⅐h Ϫ1 ), 2.5% tetracaine (1 mg⅐kg Ϫ1 ⅐h Ϫ1 ), or saline vehicle. The doses of local anesthetics delivered mimicked clinically administered doses for continuous epidural infusion for a 70-kg person during and after abdominal and vascular surgical procedures. Some rats were infused with 0.5% bupivacaine instead of 1% bupivacaine. Six hours later (the time required for osmotic pump priming), rats were reanesthetized with pentobarbital sodium. After 500 U of heparin were given ip, rats were placed on an electric heating pad under a warming light. Body temperature was monitored with a rectal probe and maintained at 37°C. They were allowed to spontaneously breath room air. After a laparotomy, rats were subjected to 30-min left renal ischemia after right nephrectomy. The duration of ischemia was shown in pilot studies to produce reversible and moderate renal dysfunction in rats. Some rats were subjected to only sham operation (anesthesia, laparotomy, and right nephrectomy) and received vehicle (saline) infusion, and others received a sham operation plus local anestheti
