Anesthetic effects on the glycerol model of rhabdomyolysis-induced acute renal failure in rats

Abstract

Isoflurane, the most widely used inhalational anesthetic, releases inorganic fluoride during its metabolism by the cytochrome P450 system. Recent experimental data indicate that when cultured proximal tubular cells are exposed to inorganic fluoride, they become relatively resistant to myoglobin-and ATP depletion- mediated attack. The present study was undertaken to assess whether isoflurane anesthesia might confer in vivo cytoprotection, possibly by causing renal tubular inorganic fluoride exposure, thereby mitigating a combined myoglobin/ATP depletion model of acute renal failure (glycerol-induced ARF). Rats were injected with hypertonic glycerol (50%; 9 ml/kg, intramuscularly) while undergoing 4 h of isoflurane anesthesia. Glycerol-injected rats anesthetized with a virtually nondefluorinated inhalational anesthetic (desflurane) or with a nonfluorinated anesthetic (pentobarbital) served as controls. The severity of ARF was assessed 24 h later (blood urea nitrogen, plasma creatinine [Cr], and renal histology). Anesthetic effects on extrarenal injury (plasma creatine phosphokinase, lactate dehydrogenase, and hematocrit levels), acute intrarenal heme loading (cast formation), and BP during the initiation phase of renal injury (0 to 4 h after glycerol injection) were also assessed. Glycerol induced severe ARF under pentobarbital anesthesia (Cr, 2.8 ± 0.3 mg/dl; severe tubular necrosis). Somewhat worse azotemia, but comparable tubular necrosis, resulted with desflurane use. Conversely, glycerol plus isoflurane anesthesia induced only mild renal damage (Cr, 0.9 ± 0.1, minimal tubular necrosis; P < 0.01). This reduction apparently was not due to differences in degrees of muscle necrosis, hemolysis, acute renal heme loading, or BP during the initiation phase of ARF, suggesting that a direct renal mechanism was operative. These results: (1) underscore that differing anesthetics can profoundly alter the expression of experimental renal injury; (2) raise the intriguing possibility that isoflurane could potentially protect surgical/trauma patients from rhabdomyolysis-induced ARF; and (3) further support the concept that renal fluoride exposure may confer proximal tubular cytoprotective effects.