INCREASED ANESTHETIC REQUIREMENTS FOR ISOFLURANE, HALOTHANE, ENFLURANE AND DESFLURANE IN OBESE ZUCKER RATS ARE ASSOCIATED WITH INSULIN-INDUCED STIMULATION OF PLASMA-MEMBRANE CA2-ATPASE()

A wide spectrum of structurally disparate inhalational anesthetics red uce brain synaptic plasma membrane Ca2+-ATPase (PMCA) activity, wherea s phospholipid methyltransferase I (PLMTI) is enhanced by anesthetics. Several rat models with incidental or disease-induced reduction of PM CA and enhancement of PLMTI activities manifest increased sensitivity to inhalational anesthetics. Because insulin is known to stimulate PMC A, anesthetic requirements in hyperinsulinemic obese Zucker rats (fa/f a) and in normoinsulinemic lean Zucker heterozygotes (fa/+) were exami ned, and brain synaptic PMCA and PLMTI activities were determined in b oth genotypes. Significantly higher partial pressures of halothane, en flurane, isoflurane, and desflurane were required to inhibit the pain response in obese rats compared to lean Zucker rats. Dose dependent st imulation of PMCA pumping was observed in synaptic membranes from both types, but insulin concentrations in extracts of diencephalon-mesence phalon, cerebellum, and medulla (but not cortex) were higher in obese than in lean Zucker rats. Microdialysis of three subcortical regions s howed marked increases in insulin levels with halothane exposure in ob ese rats, compared to lean controls. These observations in an anesthet ic resistant rat model lend further support to the hypothesis that the calcium pump plays a functional role in production of the anesthetic state.