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PubMed1994

Arachidonic acid metabolism in alveolar macrophages from actively sensitized guinea-pigs: effects of sensitization and specific allergen.

Arachidonic acid (AA) metabolism, including mediator release and lipid turnover, was explored in [3H]AA-radiolabelled alveolar macrophages obtained from guinea-pigs actively sensitized to ovalbumin (sAM) and controls (cAM). The basal and allergen-induced AA metabolism of cAM and sAM were examined in the presence and absence of homologous serum obtained from the same control or sensitized animals. Basal AA metabolism of cAM and sAM involved the release of lipoxygenase and cyclooxygenase [3H]metabolites and free [3H]AA into the culture medium. However, in sAM, the production of free [3H]AA was significantly lower than in cAM. The allergen had no effect on the basal AA metabolism of cAM and sAM or on the metabolism of cAM and sAM cultured in the presence of control serum. In contrast, it increased the [3H]LTC4-D4 and free [3H]AA production of sAM cultured with sensitized serum but not those of cAM cultured with the same sensitized serum. In sAM, the allergen effect disappeared when the sensitized serum was heated for 1 h to 56 degrees C. Our results suggest that two factors, both induced by the active sensitization of guinea-pigs, one in the serum and one on the macrophages obtained from sensitized guinea-pigs, are required for the allergen to have an impact on the AA metabolism of alveolar macrophages in increasing the production of 5-lipoxygenase metabolites.

Allergens↗
PubMed1990

Diazepam sensitive mice: differential sensitivity to the depressant and anticonvulsant effects of diazepam.

A mouse line was developed by selecting for increased sensitivity to the hypnotic effect of diazepam. These "diazepam sensitive" mice showed a mean duration of loss of righting reflex (LORR) of approximately 150 min at a dose of 20 mg/kg diazepam, this dose failed to induce LORR in the control outbred mice. Rotarod treading times of the diazepam sensitive mice were significantly shorter than that of the control mice over the same dose range indicating that these mice are also more sensitive to the sedative/muscle relaxant effects of diazepam. On the contrary, the ability of diazepam to protect against pentylenetetrazole-induced convulsion was found to be the same in the sensitive and control mice. These observations strongly suggest that the heightened sensitivity to the sedative-hypnotic effects of diazepam in the sensitive mice is unlikely to be due entirely to changes in drug disposition.

Animals↗
PubMed1983

Convergence of signals from red-sensitive and green-sensitive cones onto L-type external horizontal cells of the goldfish retina.

The types of photoreceptors converging onto L-type external horizontal cells (LEHCs) were studied intracellularly in live, immobilized goldfish under dark-adapted conditions, and interactions between inputs from these photoreceptors were demonstrated. Our analysis of the color-dependence of response waveform, and the spectral sensitivity of LEHCs during various phases of their responses, suggests that LEHCs receive inputs not only from red-sensitive cones, but also from green-sensitive cones. Furthermore, inputs from red- and green-sensitive cones were found to interact so as to enhance LEHC responses. By presenting two successive flashes of different colors, the response enhancement was demonstrated only when green flashes preceded red flashes, indicating that responses to the input from green-sensitive cones affected the input from red-sensitive cones. A hypothetical model which incorporates reciprocal connections between green-sensitive cones and LEHCs is proposed, and shown to be consistent with most of the phenomena described in this paper, including the response enhancement.

Animals↗
PubMed1987

Isolation and cross-sensitivity of X-ray-sensitive mutants of V79-4 hamster cells.

The V79-4 Chinese hamster line was mutagenized and surviving clones screened for X-ray sensitivity using a replica microwell technique. One slightly sensitive clone and 3 clearly sensitive clones were isolated from approximately 5000 screened, and designated irs 1 to irs 4. The 3 more sensitive clones showed different responses to the genotoxic agents mitomycin C (MMC), ethyl methanesulphonate (EMS) and ultraviolet light (UV). irs 1 showed considerable sensitivity to all the agents tested, in the order MMC much greater than EMS greater than UV. irs 2 and irs 3 had similar sensitivities to EMS and to UV (EMS greater than UV) but irs 3 was more sensitive than irs 2 to MMC. None of these mutants is identical in phenotype to previously published mutants.

Animals↗
PubMed1994

Contact sensitivity of and cross-sensitivity between 2-(2'-hydroxy-5'-methylphenyl)benzotriazole (Tinuvin P) and 2-(2'-hydroxy-3'-tert-butyl-5'-methylphenyl)-5-chlorobenzotriazole (Tinuvin 326) evaluated by lymph node cell proliferation and ear swelling response in mice.

Contact sensitivity of and cross-sensitivity between 2-(2'-hydroxy-5'-methylphenyl)benzotriazole (Tinuvin P, TP) and 2-(2'-hydroxy-3'-tert-butyl-5'-methylphenyl)-5-chlorobenzotriazole (Tinuvin 326, T326) were investigated in BALB/c mice. Mice received an intradermal injection and subsequent topical application of the test chemical. Following final application, auricular lymph node cell (LNC) proliferation was measured. In another experiment, the appearance of contact sensitivity was assessed by increases in ear thickness following challenge of the test chemical. Application of TP to mice caused a significant increase in LNC proliferation. Challenge of these mice with TP resulted in an increase in ear thickness. However, TP-sensitized mice did not show an increase in ear thickness by challenge with T326. Under the same conditions, application of T326 failed to induce either LNC proliferation or ear swelling response. The induction of LNC proliferative response was closely related to the ear swelling response by challenge. Following intradermal injection of TP, topical application of T326 to mice did not induce LNC proliferation. A significant ear swelling response was not induced by first challenge with TP or T326 but induced by rechallenge with TP. Topical exposure of mice to TP following injection of T326 failed to induce LNC proliferation or any ear responses by challenge with T326 and TP. These data suggest that TP is a sensitizer, while T326 is not a sensitizer, and these chemicals do not cross-sensitize.

Administration, Topical↗
PubMed1990

Sensitivity to ether anesthesia and to gamma-rays in mutagen-sensitive strains of Drosophila melanogaster.

An ether-resistant strain of Drosophila melanogaster, Eth-29, has previously been found to be radiosensitive. Some mutagen-sensitive strains are known to be hypersensitive to X-rays in larvae. The correlation between sensitivities to ether anesthesia and to gamma-rays was examined in adult flies of 12 mutagen-sensitive strains and 6 control strains. A wide variation in sensitivities to ether anesthesia, gamma-ray knock-down and gamma-ray lethality was demonstrated. No correlation between DNA-repair capacity and ether sensitivity or gamma-ray knock-down sensitivity was shown. Only mei-9 and mus201, which are deficient in excision repair, as well as Eth-29 were found to be sensitive to gamma-ray lethality. These findings indicate that the targets for ether anesthesia, knock-down and lethality may be different. Lethality appears to be caused by DNA damage, while the other 2 endpoints appear not to be related to DNA damage.

Anesthetics↗
PubMed1990

X-ray sensitivity and single-strand DNA break repair in mutagen-sensitive mutants of Drosophila melanogaster.

Mutants of Drosophila melanogaster that are sensitive to chemical mutagens were analyzed for sensitivity to X-rays and for the capacity to repair single-strand DNA breaks induced by X-rays. Analysis of X-ray sensitivity demonstrated that 74% of the mutants assayed display some X-ray sensitivity, with 75% of the sensitive lines being extremely sensitive. Repair of single-strand breaks was assayed after both high and low doses of irradiation in order to permit detection of repair over a wide range of damage. The results of this investigation fail to show a correlation between X-ray sensitivity and this particular repair process. Repair of single-strand breaks is therefore mediated by repair processes unrelated to those that are disrupted in the current mutant collection.

Animals↗
PubMed2003

A murine model for low molecular weight chemicals: differentiation of respiratory sensitizers (TMA) from contact sensitizers (DNFB).

Exposure to low molecular weight (LMW) chemicals contributes to both dermal and respiratory sensitization and is an important occupational health problem. Our goal was to establish an in vivo murine model for hazard identification of LMW chemicals that have the potential to induce respiratory hypersensitivity (RH). We used a dermal sensitization protocol followed by a respiratory challenge with the evaluation of endpoints typically associated with RH in human disease. Trimellitic anhydride (TMA) was used as a prototype respiratory sensitizer and was compared to the dermal sensitizer; 2,4-dinitrofluorobenzene (DNFB), along with vehicle controls. BALB/c mice were dermally sensitized using two exposure protocols. Mice in both protocols were dermally exposed on experimental days; D-18 and D-17 (abdomen), and D-13 (ear). On D 0 mice received an intratracheal (IT) challenge. The mice in Protocol 2 were abdominally exposed twice with the addition of exposures on D-25 and D-24. Results indicate that mice required the additional dermal sensitization and the IT challenge (Protocol 2) to significantly elevate total IgE in serum and bronchoalveolar lavage fluid (BALF). Additional responses suggestive of RH were seen following Protocol 2, including increases in BALF cell numbers and neutrophils post IT with TMA (but not DNFB). These data suggest that the dermal sensitization and IT challenge followed by evaluation of serum antibodies and lung parameters are a reasonable and logistically feasible approach towards the development of a model for RH responses to LMW chemicals.

Administration, Inhalation↗
PubMed1997

Local lymph node activation and IgE responses in brown Norway and Wistar rats after dermal application of sensitizing and non-sensitizing chemicals.

The local lymph node assay (LLNA) and the IgE test in the mouse are proposed models for predictive recognition of low molecular weight chemicals causing IgE-mediated allergic airway reactions in man. Since rats are commonly used in routine toxicity studies and a previous study (Arts et al. (1996) Food Chem. Toxicol. 34, 55-62) has shown that several rat strains were found appropriate for the LLNA, the suitability of the rat for the IgE test was examined in the present study. Serum IgE concentrations were examined following topical exposure of Brown Norway (BN) and Wistar rats to each of four chemicals with known diverse sensitization potential in humans: trimellitic anhydride (TMA), a dermal and respiratory sensitizer, dinitrochlorobenzene (DNCB), a dermal sensitizer with no or limited potential to cause respiratory allergy; formaldehyde (FA), a skin irritant and dermal sensitizer with equivocal evidence for respiratory sensitizing potential; methyl salicylate (MS), a skin irritant devoid of sensitizing properties. Of the four tested chemicals, only exposure to TMA resulted in a significant increase in serum IgE concentration and this response was only evoked in the high-IgE-responding BN rat. The latter two chemicals were also tested for lymph node activation, in casu the ear-draining lymph nodes. FA caused a dose-dependent activation of the draining lymph nodes whereas MS was inactive. The results as obtained with TMA, DNCB and MS in the rat are in agreement with human data. The results with FA though, indicate the need for further studies of chemicals that have both irritant and sensitizing properties at about similar concentrations or may act through non-IgE-mediated immune mechanisms.

Administration, Cutaneous↗
PubMed2001

L-Quisqualic acid transport into hippocampal neurons by a cystine-sensitive carrier is required for the induction of quisqualate sensitization.

A brief exposure of hippocampal slices to L-quisqualic acid sensitizes CA1 pyramidal neurons 30-250-fold to depolarization by two classes of excitatory amino acid analogues: (1) those whose depolarizing effects are rapidly terminated following washout, e.g. L-2-amino-4-phosphonobutanoic acid (L-AP4) and L-2-amino-6-phosphonohexanoic acid (L-AP6) and (2) those whose depolarizing effects persist following washout, e.g. L-aspartate-beta-hydroxamate (L-AbetaH). This process has been termed quisqualate sensitization. In this study we directly examine the role of amino acid transport systems in the induction of quisqualate sensitization. We report that L-quisqualate is a low-affinity substrate (K(M)=0.54 mM) for a high capacity (V(max)=0.9 nmol (mg protein)(-1) min(-1)) Na(+)-dependent transport system(s) and a high-affinity substrate (K(M)=0.033 mM) for a low-capacity (V(max)=0.051 nmol (mg protein)(-1) min(-1)) transporter with properties similar to the cystine/glutamate exchange carrier, System x(c-). We present evidence that suggests that System x(c-) participates in quisqualate sensitization. First, simultaneous application of L-quisqualate and inhibitors of System x(c-), but not inhibitors of Na(+)-dependent glutamate transporters, prevents the subsequent sensitization of hippocampal neurons to phosphonates or L-AbetaH. Second, L-quisqualic acid only sensitizes hippocampal neurons to other substrates of System x(c-), including cystine. Third, immunocytochemical analysis of L-quisqualate uptake demonstrates that only inhibitors of System x(c-) inhibit the highly concentrative uptake of L-quisqualate into a widely dispersed group of GABAergic hippocampal interneurons. We conclude that quisqualate sensitization is a direct consequence of the unique interaction of various excitatory amino acids, namely L-quisqualate, cystine, and phosphonates, with the exchange carrier, System x(c-). Therefore, the results of this study have important implications for the mechanism by which L-quisqualate, and other substrates of this transporter which are also excitatory amino acid agonists (such as glutamate and beta-N-oxalyl-L-alpha,beta-diaminopropionic acid, beta-L-ODAP) may trigger neurotoxicity.

Animals↗
PubMed1999

The isolation and genetic analysis of V79-derived etoposide sensitive Chinese hamster cell mutants: two new complementation groups of etoposide sensitive mutants.

Using a replica plating microwell method, three Chinese hamster V79-derived cell lines, designated ETO1, ETO2 and ETO3, which exhibit hypersensitivity to the non-intercalating topoisomerase II inhibitor etoposide have been isolated. Mutant lines ETO2 and ETO3 are cross-sensitive to the topoisomerase II inhibitors adriamycin and streptonigrin; however, neither mutant is sensitive to the topoisomerase I inhibitor camptothecin, the bifunctional alkylating agent mitomycin C, nor hydrogen peroxide. In contrast, ETO1 is cross-sensitive to camptothecin but displays only slight sensitivity to adriamycin, streptonigrin and hydrogen peroxide, and is not sensitive to mitomycin C. It has been established through extensive cell fusion studies that all three mutants are genetically distinct, and that ETO2 and ETO3 genetically complement all other known etoposide-sensitive Chinese hamster cell mutants (i.e., irs1, XR-1, xrs1, V3, BLM2, ADR1, ADR3, ADR4 and ADR5) thus defining two new complementation groups of etoposide sensitive mutants. Interestingly, the hybrids created by the fusion irs2TOR (thioguanine and ouabain resistant)xETO1 and the reciprocal cross ETO1TORxirs2 both exhibited a response to camptothecin intermediate with respect to V79 and ETO1. It has been hypothesised that this partial complementation may be the result of intragenic complementation and that both ETO1 and irs2 result from mutations in the gene XRCC8. This study indicates that cellular responses to topoisomerase II inhibitors are complex and hypersensitivity may result from mutations in many different genes.

Animals↗
PubMed1988

Noise annoyance with regard to neurophysiological sensitivity, subjective noise sensitivity and personality variables.

To evaluate the relation between annoyance to environmental noise, general neurophysiological sensitivity, subjective noise sensitivity and other individual characteristics, experiments were undertaken in which 93 subjects assessed their subjective annoyance after exposure to noise under laboratory conditions. Evaluations were made of the discomfort threshold for pulsating sound, the light discomfort, and heat and cold discomfort. The heart rate and discomfort after exposure to a series of impulse noises was also determined. Subjective noise sensitivity, attitudes to noise, mood and personality characteristics of the subjects were evaluated using questionnaires. The results show that the annoyance after exposure to noise was not closely related to the general neurophysiological sensitivity, measured as discomfort threshold for noise, heat, cold and light; or to the heart rate reaction or discomfort after exposure to impulse noise. The annoyance was highly correlated with subjectively reported noise sensitivity and with the attitude to noise. There was also a relationship with neuroticism, measured with the EPI scale. It is suggested that the subjective noise sensitivity, attitude and neuroticism for the definition of noise sensitivity be defined in future studies of long term effects of noise exposure.

Adolescent↗
PubMed2003

It takes one to know one: interpersonal sensitivity is related to accurate assessments of others' interpersonal sensitivity.

Interpersonal sensitivity (emotional and social) is the ability to accurately assess others' abilities, states, and traits from nonverbal cues. The authors predicted that individuals' interpersonal sensitivity would be related to accurate judgments of friends' interpersonal sensitivity. Fifty participants were recruited, each bringing a friend to participate in performance-based, self-report, and other-rating measures of emotional and social sensitivity. Interpersonal sensitivity was related to accurate judgments of others' interpersonal sensitivity (the "it-takes-one-to-know-one effect"). Neither gender nor acquaintanceship was directly related to accurate judgments of interpersonal sensitivity, nor did either variable moderate the it-takes-one-to-know-one effect.

Adolescent↗
PubMed2003

Hepatic insulin sensitizing substance: a novel 'sensocrine' mechanism to increase insulin sensitivity in anaesthetized rats.

1. We recently described the sensory nitrergic nature of the hepatic insulin sensitizing substance (HISS) mechanism linked to postprandial activation of anterior hepatic plexus fibres in rabbits. This study is designed to assess the involvement of the sensory pathways in this mechanism. 2. Selective sensory denervation of the anterior hepatic plexus (AHP) was achieved by a 3-day perineurial treatment with 2% capsaicin solution in Wistar rats (230-250 g). After 1 week, hyperinsulinaemic (100 micro U kg(-1)) euglycaemic (5.5 mmol kg(-1)) glucose clamp studies were performed to estimate insulin sensitivity. 3. The rats with regional AHP sensory denervation exhibited a significantly decreased insulin sensitivity, that is, 9.1+/-1.0 mg kg(-1) min(-1) glucose reinstalled euglycaemia vs 13.3+/-1.9 mg kg(-1) min(-1) glucose (P<0.01) in control rats. 4. Acute partial hepatic denervation by AHP cut was without effect on insulin sensitivity, whereas chronic hepatic denervation induced insulin resistance was similar to that achieved by regional AHP capsaicin treatment. 5. Intraportal administration of L-NAME (10 mg kg(-1)) decreased, whereas capsaicin (0.3 mg kg(-1) min(-1)) increased insulin sensitivity. Neither atropine (1 mg kg(-1)) nor acetylcholine (1-10 micro g mg min(-1)) produced any significant effect. In animals with preceding regional capsaicin desensitization, none of the pharmacological manoeuvres modified the resulting insulin-resistant state. 6. Cysteamine (200 mg kg(-1) s.c.) is known to cause functional somatostatin depletion-induced insulin resistance similar to that produced by either chronic partial hepatic denervation or perineurial AHP capsaicin desensitization. Intraportal capsaicin (0.3 mg kg(-1) min(-1)) was unable to modify insulin resistance achieved by cysteamine. 7. We conclude that capsaicin-sensitive sensory fibres play a crucial role in neurogenic insulin sensitization known as the HISS mechanism without involvement of anatomical reflex-mediated circuits. The results also suggest that HISS is identical to somatostatin of AHP sensory neural origin.

Anesthetics, Intravenous↗
PubMed2000

Increased insulin sensitivity and decreased insulin secretion in offspring of insulin-sensitive type 2 diabetic patients.

To investigate the early defects of glucose metabolism in insulin-sensitive type 2 diabetes, we performed oral and frequently sampled intravenous glucose tolerance tests (OGTT and FSIGT) with minimal model analysis in 15 offspring of Japanese type 2 diabetics with normal insulin sensitivity (insulin resistance index of homeostasis model assessment [HOMA-R] < 2.0) and in 20 healthy control subjects without a family history of type 2 diabetes. The frequency of impaired glucose tolerance (IGT) was 40% (6 of 15) in the offspring and 0% (0 of 20) in the controls. Fasting plasma glucose (4.8 +/- 0.1 v4.6 +/- 0.1 mmol/L, P = .18) and immunoreactive insulin ([IRI] 29.9 +/- 2.5 v 28.3 +/- 2.5 pmol/L, P = .64) were comparable between the offspring and the controls. The rate of glucose disappearance (KG) was significantly lower in the offspring versus the control group (2.00 +/- 0.22 v 2.60 +/- 0.17 min(-1), P= .03). The insulin sensitivity index (Si) was significantly greater in the offspring versus the controls (2.68 +/- 0.41 v 1.71 +/- 0.17 x 10(-4) min(-1) x pmol/L , P = .02). First-phase insulin secretion (FPI) to intravenous glucose was significantly lower in the offspring versus the control group (886 +/- 110 v 2,296 +/- 267 min x pmol/L, P< .01). Glucose effectiveness (SG) was comparable between the offspring and control groups. The disposition index (Si x FPI) was significantly lower in the offspring versus the controls (2,106 +/- 256 v 3,652 +/- 490 x 10(-4), P = .02). When the offspring were subdivided into 2 groups by glucose tolerance status, both normal glucose tolerance (NGT) offspring and IGT offspring showed a significant decrease in FPI and increase in Si. Thus, although the offspring of insulin-sensitive type 2 diabetics had increased insulin sensitivity, the impairment in insulin secretion was more dominant. Our results suggest that the early metabolic abnormality in insulin-sensitive type 2 diabetes is an insulin secretory dysfunction despite increased insulin sensitivity.

Adult↗
PubMed1995

A wortmannin-sensitive phosphatidylinositol 4-kinase that regulates hormone-sensitive pools of inositolphospholipids.

The synthesis of phosphatidylinositol 4,5-bisphosphate [PtdIns(4,5)P2], the immediate precursor of intracellular signals generated by calcium-mobilizing hormones and growth factors, is initiated by the conversion of phosphatidylinositol to phosphatidylinositol 4-phosphate [PtdIns(4)P] by phosphatidylinositol 4-kinase (PtdIns 4-kinase). Although cells contain several PtdIns 4-kinases, the enzyme responsible for regulating the synthesis of hormone-sensitive PtdIns(4,5)P2 pools has not been identified. In this report we describe the inhibitory effect of micromolar concentrations of wortmannin (WT) on the synthesis of hormone-sensitive PtdIns(4)P and PtdIns(4,5)P2 pools in intact adrenal glomerulosa cells, and the presence of a WT-sensitive PtdIns 4-kinase in adrenocortical extracts. In addition to its sensitivity to the PtdIns 3-kinase inhibitor WT, this enzyme is distinguished from the recognized membrane-bound PtdIns 4-kinases by its molecular size and weak membrane association. Inhibition of this PtdIns 4-kinase by WT results in rapid loss of the hormone-sensitive PtdIns(4,5)P2 pool in angiotensin II-stimulated glomerulosa cells. Consequently, WT treatment inhibits the sustained but not the initial increases in inositol 1,4,5-trisphosphate and cytoplasmic [Ca2+] in a variety of agonist-stimulated cells, including adrenal glomerulosa cells, NIH 3T3 fibroblasts, and Jurkat lymphoblasts. These results indicate that a specific WT-sensitive PtdIns 4-kinase is critical for the maintenance of the agonist-sensitive polyphosphoinositide pool in several cell types.

1-Phosphatidylinositol 4-Kinase↗
PubMed2000

Modulation of nucleotide sensitivity of ATP-sensitive potassium channels by phosphatidylinositol-4-phosphate 5-kinase.

ATP-sensitive potassium channels (K(ATP) channels) regulate cell excitability in response to metabolic changes. K(ATP) channels are formed as a complex of a sulfonylurea receptor (SURx), a member of the ATP-binding cassette protein family, and an inward rectifier K(+) channel subunit (Kir6.x). Membrane phospholipids, in particular phosphatidylinositol (PI) 4,5-bisphosphate (PIP(2)), activate K(ATP) channels and antagonize ATP inhibition of K(ATP) channels when applied to inside-out membrane patches. To examine the physiological relevance of this regulatory mechanism, we manipulated membrane PIP(2) levels by expressing either the wild-type or an inactive form of PI-4-phosphate 5-kinase (PIP5K) in COSm6 cells and examined the ATP sensitivity of coexpressed K(ATP) channels. Channels from cells expressing the wild-type PIP5K have a 6-fold lower ATP sensitivity (K(1/2), the half maximal inhibitory concentration, approximately 60 microM) than the sensitivities from control cells (K(1/2) approximately 10 microM). An inactive form of the PIP5K had little effect on the K(1/2) of wild-type channels but increased the ATP-sensitivity of a mutant K(ATP) channel that has an intrinsically lower ATP sensitivity (from K(1/2) approximately 450 microM to K(1/2) approximately 100 microM), suggesting a decrease in membrane PIP(2) levels as a consequence of a dominant-negative effect of the inactive PIP5K. These results show that PIP5K activity, which regulates PIP(2) and PI-3,4,5-P(3) levels, is a significant determinant of the physiological nucleotide sensitivity of K(ATP) channels.

Adenosine Triphosphate↗
PubMed2006

Impact of in vivo preconditioning by isoflurane on adenosine triphosphate-sensitive potassium channels in the rat heart: lasting modulation of nucleotide sensitivity during early memory period.

BACKGROUND: The early memory of anesthetic-induced preconditioning (APC) is a period when myocardial protection continues even after removal of the anesthetic. Because adenosine triphosphate-sensitive potassium (KATP) channels are important mediators of APC, the authors investigated the hypothesis that the memory involves channel priming by isoflurane via a long-term modulation of the sensitivity to intracellular adenosine nucleotides. METHODS: Ventricular cardiomyocytes were obtained from the rat hearts after 30 min in vivo APC with 1.4% isoflurane and from control non-APC rat hearts. Whole cell and excised inside-out patch clamp techniques were used to study the sarcolemmal KATP channel. Membrane expression of KATP channel proteins, the pore-forming inward rectifier Kir6.2, and the regulatory sulfonylurea receptor SUR2A were assessed in APC and non-APC hearts by Western blotting. RESULTS: Activation of whole cell KATP current by isoflurane was enhanced after in vivo APC. At the single-channel level, this was paralleled by a 12-fold decrease in adenosine 5'-triphosphate sensitivity and a 3-fold decrease in adenosine 5'-diphosphate sensitivity, without changing the probability of channel opening or single-channel conductance. The membrane expression of Kir6.2 and SUR2A subunits was not altered by in vivo APC. A direct in vitro application of isoflurane to excised membrane patches increased the channel open probability and produced a 4-fold decrease in adenosine 5'-triphosphate sensitivity only of channels in non-APC myocytes. CONCLUSIONS: In vivo APC by isoflurane decreases sensitivity of the sarcolemmal KATP channel to inhibition by adenosine 5'-triphosphate and decreases adenosine 5'-diphosphate sensitivity. These effects persist even after discontinuation of the anesthetic, suggesting a possible novel factor that may contribute to the mechanism of early memory of APC.

Adenosine Diphosphate↗