Isoflurane and Whole Body Leucine, Glucose, and Fatty Acid Metabolism in Dogs

Horber, Fritz F.; Krayer, S.; Miles, John M.; Cryer, Philip E.; Rehder, Kai; Haymond, Morey W.

doi:10.1097/00000542-199007000-00013

Cited by 61 publications

(41 citation statements)

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“…This has been reported in a number of different systems, including intact animals (23)(24)(25), perfused organs (10,40,41), tissue slices in culture (15)(16)(17)(18), and cells in culture (3,6,8,21,35). Studies regarding effects of volatile anesthetics on protein synthesis in perfused rat liver, the system employed in the work reported here, demonstrate that halothane exposure produces a rapid and dose-dependent inhibition of translation initiation affecting synthesis of both secreted and retained proteins (10,12).…”

mentioning

confidence: 56%

Inhibition of mammalian translation initiation by volatile anesthetics

Palmer¹,

Rannels²,

Kimball³

et al. 2006

American Journal of Physiology-Endocrinology and Metabolism

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Volatile anesthetics are essential for modern medical practice, but sites and mechanisms of action for any of their numerous cellular effects remain largely unknown. Previous studies with yeast showed that volatile anesthetics induce nutrient-dependent inhibition of growth through mechanisms involving inhibition of mRNA translation. Studies herein show that the volatile anesthetic halothane inhibits protein synthesis in perfused rat liver at doses ranging from 2 to 6%. A marked disaggregation of polysomes occurs, indicating that inhibition of translation initiation plays a key role. Dose-and time-dependent alterations that decrease the function of a variety of translation initiation processes are observed. At 6% halothane, a rapid and persistent increase in phosphorylation of the ␣-subunit of eukaryotic translation initiation factor (eIF)2 occurs. This is accompanied by inhibition of activity of the guanine nucleotide exchange factor eIF2B that is responsible for GDP-GTP exchange on eIF2. At lower doses, neither eIF2␣ phosphorylation nor eIF2B activity is altered. After extended exposure to 6% halothane, alterations in two separate responses regulated by the target of rapamycin pathway occur: 1) redistribution of eIF4E from its translation-stimulatory association with eIF4G to its translation-inactive complex with eIF4E-binding protein-1; and 2) decreased phosphorylation of ribosomal protein S6 (rpS6) with a corresponding decrease in active forms of a kinase that phosphorylates rpS6 (p70 S6K1 ). Changes in the association of eIF4E and eIF4G are observed only after extended exposure to low anesthetic doses. Thus dose-and time-dependent alterations in multiple processes permit liver cells to adapt translation to variable degrees and duration of stress imposed by anesthetic exposure. halothane; eukaryotic translation initiation factor 2␣ phosphorylation; mammalian target of rapamycin pathway ALTHOUGH VOLATILE ANESTHETICS revolutionized medical practice when introduced in 1846, the mechanisms of action responsible for the physiological effects of these drugs remain essentially unknown. In addition to affecting cells of the central nervous system, these drugs affect all cells, tissues, and organisms examined (4,26,36). Molecular genetic studies with the small, relatively simple eukaryote Saccharomyces cerevisiae (yeast) provide an opportunity for gaining insight regarding physiologically relevant effects of these drugs (28) and generating hypotheses that are testable in more complex eukaryotes. Extensive similarities exist between the activity of these drugs in mammals and simpler eukaryotes, such as yeast, suggesting conservation of cellular mechanisms responsible for the responses (28,34,45). These similarities include rapid and reversible induction of responses, a sharp dose-response curve, correlation between the lipophilicity of various anesthetics and their potency for inducing responses (termed the Meyer-Overton relationship), additivity of doses of different anesthetics in producing effects, and lack of effec...

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mentioning

confidence: 56%

Inhibition of mammalian translation initiation by volatile anesthetics

Palmer¹,

Rannels²,

Kimball³

et al. 2006

American Journal of Physiology-Endocrinology and Metabolism

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“…Olivecrona (4) found an ϳ10% escape of chylomicron fatty acids into plasma in rats, whereas our results and those of others (6,7) suggest that a higher figure is operative in humans. It is possible that the study of anesthetized animals influenced the results, since general anesthesia has a marked effect on FFA metabolism (20). However, the inconsistencies may relate more to species differences.…”

Section: Discussionmentioning

confidence: 99%

Systemic and Forearm Triglyceride Metabolism

et al. 2004

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Little is known about the fate of the lipolytic products produced by the action of lipoprotein lipase (LPL) on circulating triglyceride-rich lipoproteins in humans. We studied eight lean, healthy male subjects after an overnight fast. Subjects received infusions of lipid emulsions containing triolein labeled with 3 H on both the glycerol backbone and the fatty acid portion of the molecule; 14 C glycerol and 14 C oleate were coinfused to quantify the systemic and forearm release of 3 H glycerol and 3 H oleate resulting from LPL action. There was significant forearm uptake of both whole plasma triglyceride (presumed to represent primarily VLDL; extraction fraction 2.6 ؎ 0.6%, P < 0.005 vs. zero) and radiolabeled triglyceride derived from the lipid emulsion (a surrogate for chylomicrons; extraction fraction 31 ؎ 4%, P < 0.005 vs zero). Systemic clearance and forearm fractional extraction of glycerol was greater than that of oleate (P < 0.001 and P < 0.02, respectively). The systemic and forearm fractional release of LPL-generated glycerol were similar at 51 ؎ 4 and 59 ؎ 1%, respectively (NS). In contrast, the forearm fractional release of LPL-generated oleate was less than systemic fractional release (14 ؎ 2 vs. 36 ؎ 4%, P < 0.0001). These results indicate that there is escape, or spillover, of the lipolytic products of LPL action on triglyceride-rich lipoproteins in humans. They further suggest that LPL-mediated fatty acid uptake is an inefficient process, but may be more efficient in muscle than in adipose tissue. Diabetes 53:521-527, 2004 A lthough it is generally accepted that the action of hormone-sensitive lipase (HSL) in adipocytes is the primary source of plasma free fatty acids (FFAs) in normal postabsorptive individuals (1), the ubiquitous presence of lipoprotein lipase (LPL) (2) represents a potential additional source of plasma FFAs. Available evidence suggests that VLDL triglyceride is not an important source of plasma FFAs. Wolfe et al. (3) administered biosynthetic labeled VLDL to dogs and found that Ͼ95% of VLDL-triglyceride fatty acids were taken up directly into tissues without traversing the plasma FFA pool; in contrast, glycerol produced by the action of LPL on VLDL triglyceride was quantitatively released into the circulation.Chylomicrons, on the other hand, appear to be a significant source of FFAs during meal absorption. However, the magnitude of the chylomicron contribution to total FFA flux is controversial. Olivecrona et al. (4) gave chylomicrons labeled with 14 C glycerol and 3 H palmitate to rats, and found that ϳ90% of the administered 3 H was recovered in adipose tissue, whereas only trace amounts of 14 C could be found in adipose tissue. Recently, studies in which both chylomicrons and lipid emulsions containing labeled oleate were administered to mice found that 80 -90% of the label was recovered in plasma (5). Roust and Jensen (6) gave a meal containing radiolabeled triglyceride to human subjects and found that approximately one-third of dietary fatty acids were released into the sy...

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“…In contrast to propofol, high doses of opioids, 1 and neuraxial techniques, inhalational agents have been shown to accentuate the hyperglycemic response to surgery. 5,6 The administration of corticosteroids for the prevention of postoperative nausea and vomiting, even in small doses, further exacerbates hyperglycemia in non-diabetic patients. 7,8 Unexpectedly large numbers of patients show abnormal glucose homeostasis before surgery.…”

Section: Glucose Metabolismmentioning

confidence: 99%