Volatile Anesthetics Selectively Inhibit the Calcium sup 2+ -transporting ATPase in Neuronal and Erythrocyte Plasma Membranes

Fomitcheva, Ioulia; Kosk‐Kosicka, Danuta

doi:10.1097/00000542-199605000-00021

Cited by 14 publications

(4 citation statements)

References 28 publications

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“…By light microscopy, the preparation appears as microvascular segments, predominantly vascular smooth muscle, with occasional adherent pericytes. To validate functional viability, we measured steady-state Na+-K+ ATPase activity as previously described (Fomitcheva and Kosk-Kosicka, 1996). Enzyme activity was preserved in the microvascular preparation at 4.4 !Lm P/mg protein per hour.…”

Section: Methodsmentioning

confidence: 99%

Estrogen Increases cGMP in Selected Brain Regions and in Cerebral Microvessels

Palmon

Williams

Littleton-Kearney

et al. 1998

J Cereb Blood Flow Metab

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We have previously reported that exogenous and endogenous estrogen can amplify residual cerebral blood flow during experimental cerebral ischemia. Because estrogen has been linked to nitric oxide and cyclic guanosine monophosphate (cGMP) signaling in noncerebral tissue, we tested the hypothesis that long-term 17beta-estradiol treatment increases basal cGMP in brain homogenates and cerebral microvessels in female rabbits. We also determined whether there are important baseline gender-specific differences in regional cGMP. Adult female rabbits were implanted with 17beta-estradiol pellets, 10 mg (F10, n = 10) or 50 mg (F50, n = 13), and compared with untreated females (F, n = 19) and males with negligible estrogen (M, n = 19) (plasma 17beta-estradiol levels of 4+/-4 pg/mL in M, 7+/-5 pg/mL in F, 141+/-74 pg/mL in F10, and 289 +/-10 pg/mL in F50). Cyclic GMP was determined by radioimmunoassay in cerebellum, hypothalamus, caudate nucleus, hippocampus, and cortex. Cerebral microvessels were harvested from additional cohorts of untreated males and females or estradiol-implanted females (n = 6 per group). Basal cGMP was higher in F versus M only in cerebellum. Estrogen-induced increases in regional cGMP were prominent in hippocampus at all doses (M = 43+/-26, F = 43+/-21, F10 = 84+/-24, F50 = 117+/-55 fmol/mg protein) and in cortex at the high dose (M = 78+/-55, F = 88+/-51, F10 = 69+/-34, F50 = 143+/-52 fmol/mg protein). Similarly, microvascular cGMP increased only in females treated with the 50 mg dose (M = 77+/-13, F = 86+/-25, F10O = 106+/-35, F50 = 192+/-88 fmol/mg protein). Therefore, 17beta-estradiol increases cGMP content in parenchymal regions that are known physiologic targets for reproductive steroids but are also areas of selective vulnerability to ischemic insult. Further, high doses of estrogenic steroids could amplify cGMP signaling within the cerebral microvasculature.

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Section: Methodsmentioning

confidence: 99%

Estrogen Increases cGMP in Selected Brain Regions and in Cerebral Microvessels

Palmon

Williams

Littleton-Kearney

et al. 1998

J Cereb Blood Flow Metab

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“…It was hypothesized that the effects are based on an intracellular pH change due to interactions of increased free Ca 2+ -concentrations with the protonation of hemoglobin 20 , 21 . Further increasing the concentration to a MAC of approximately 3 was also shown to inhibit several types of ATPase like the Na + -K + -ATPase or the Mg 2+ -ATPase 19 . This may partially explain the underlying mechanisms behind the opponent effects on Hb-O 2 affinity when progressing the dose to rather high concentrations, as observed in our study.…”

Section: Discussionmentioning

confidence: 97%

“…Thus, the production of NAPDH was reduced, hence exposing the red blood cell to reactive oxygen species 18 . Fomitcheva et al showed that isoflurane in clinically relevant concentrations inhibits the activity of plasma membrane Ca 2+ -transporting adenosine triphosphatase (PMCA), thus increasing intracellular Ca 2+ concentrations 19 . This increase was linked to a right shift of the ODC and a lower affinity for oxygen.…”

Section: Discussionmentioning

confidence: 99%

The effect of desflurane, isoflurane and sevoflurane on the hemoglobin oxygen dissociation curve in human blood samples

Ronzani

Woyke

Mair

et al. 2022

Sci Rep

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Desflurane, isoflurane and sevoflurane, three halogenated ethers, are commonly used inhaled anesthetics, both in the operating room and in the intensive care unit (ICU). The potency and dosage of these drugs is expressed by the MAC value (minimum alveolar concentration). Their interaction with hemoglobin and its affinity for oxygen, best described by the oxygen dissociation curve (ODC), has already been investigated, with conflicting results. Altered by many factors, the ODC can be shifted to the left or to the right, therefore increasing or decreasing hemoglobin oxygen (Hb-O2) affinity. In venous blood samples of 22 healthy participants (11 female, 11 male) ODC were measured with a high-throughput method in vitro. Blood samples were either exposed to control or to three different concentrations of desflurane, isoflurane or sevoflurane prior to and during measurements (low, medium and high corresponding to MAC 0.5, MAC 1.0 and MAC 2.0). With increasing concentrations from control to medium, desflurane and isoflurane significantly decreased Hb-O2 affinity by shifting the ODC to the right (p = 0.016 and p < 0.001) but sevoflurane showed no effects. When further increasing concentrations from medium to high, all three inhaled anesthetics shifted the ODC back to the left (p < 0.001). Comparing only controls to high concentrations, a significant increase in Hb-O2 affinity for desflurane (p = 0.005) and sevoflurane (p < 0.001) was detected. Our study shows a varying effect at different doses of inhaled anesthetics on Hb-O2 affinity. While the underlying mechanisms remain unclear, these results show an effect which needs to be further investigated to determine if patients undergoing anesthesia may potentially benefit or get disadvantage from this slightly increased (e.g. impaired pulmonary oxygen uptake), or decreased Hb-O2 affinity (e.g. arterial vascular disease).Trial registration: This study is registered with clinicaltrials.gov (NCT04612270).

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“…Volatile anesthetics (VAs) inhibit the activity and Ca 2+ transport of the plasma membrane Ca 2+ ‐ATPase (PMCA) [1–3]. The two best studied activation pathways of the enzyme, proceeding through either calmodulin binding to PMCA monomers or enzyme dimerization, are inhibited in a dose‐dependent manner and with a similar I 50 by several VAs used in clinical practice, including halothane, isoflurane, and methoxyflurane [1,4].…”

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confidence: 99%

Effects of volatile anesthetic on the Ca²⁺‐ATPase activation by dimerization

López

Zelent

Kosk‐Kosicka

2000

European Journal of Biochemistry

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The phenomenological distance-dependent quenching (DDQ) model was employed to investigate the character of the interaction between volatile anesthetics (VAs) and the plasma membrane Ca 21 -ATPase (PMCA). The simultaneous analysis of the frequency-domain and steady-state data of tryptophan (Trp) fluorescence quenching by a VA points to a specific character of the apparent quenching effect of the VA, possibly arising from a significant contribution of static quenching. The apparent contributions of both static and dynamic quenching may be due to VA binding in the PMCA, which results in the modification of the conformational substates of the enzyme. To characterize further the molecular consequences of VA binding, we investigated its effects on the process of PMCA activation by self-association. VA shifted the equilibrium from enzyme dimers to monomers, as monitored by the loss of fluorescence energy transfer. The shift was apparently due to the VA-induced decrease in the affinity of PMCA molecules for self-association. Addition of a large molecular mass dextran to increase the proximity between enzyme monomers induced re-association of the VA-impaired PMCA, while the Ca 21 -ATPase activity was not recovered. The results are congruent with a dual VA effect on PMCA, a shift in the monomer/dimer equilibrium, and an inactivation of both monomers and dimers. -induced conformational change that PMCA undergoes in the initial step of its enzymatic cycle and the decrease in the intrinsic Trp fluorescence [4,5]. We have proposed that, upon binding to PMCA, the VAs disturb the sequence of conformational changes the enzyme normally undergoes in the process of catalytic activation, thus resulting in the inhibition of Ca 21 -ATPase activity [4,6]. Recently, we have shown that quenching of the total PMCA-intrinsic Trp fluorescence by halothane is dose-dependent, is saturable, and can be fitted to a binding curve [7].In this study we used two approaches to investigate the VA±PMCA interactions and their effects on enzyme activation. First, we employed the exponential distance-dependent quenching (DDQ) model (with parameters bimolecular rate constant of quenching k a , diffusion D and distances a and r e ) to analyze the Trp fluorescence quenching of PMCA by VA, which results in the loss of Ca 21 -ATPase activity. The DDQ model was developed to explain experimental frequency-domain and steady-state intensity decay data for which not only collisional but also through-space quenching was expected [8]. In using the DDQ model for our system we expanded our earlier spectroscopic studies [4] in which several characteristics of steady-state and preliminary frequency-domain data suggested that the PMCA±VA interaction is not just the result of mere collisional contacts. The frequency-domain data have been analyzed in more detail (see Materials and methods). Steadystate and frequency-domain Trp fluorescence intensity decays of the dimeric enzyme were measured under comparable experimental conditions at up to 5 mm isoflurane concentrations. S...

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Volatile Anesthetics Selectively Inhibit the Calcium sup 2+ -transporting ATPase in Neuronal and Erythrocyte Plasma Membranes

Cited by 14 publications

References 28 publications

Estrogen Increases cGMP in Selected Brain Regions and in Cerebral Microvessels

Estrogen Increases cGMP in Selected Brain Regions and in Cerebral Microvessels

The effect of desflurane, isoflurane and sevoflurane on the hemoglobin oxygen dissociation curve in human blood samples

Effects of volatile anesthetic on the Ca²⁺‐ATPase activation by dimerization

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Volatile Anesthetics Selectively Inhibit the Calcium sup 2+ -transporting ATPase in Neuronal and Erythrocyte Plasma Membranes

Cited by 14 publications

References 28 publications

Estrogen Increases cGMP in Selected Brain Regions and in Cerebral Microvessels

Estrogen Increases cGMP in Selected Brain Regions and in Cerebral Microvessels

The effect of desflurane, isoflurane and sevoflurane on the hemoglobin oxygen dissociation curve in human blood samples

Effects of volatile anesthetic on the Ca2+‐ATPase activation by dimerization

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Effects of volatile anesthetic on the Ca²⁺‐ATPase activation by dimerization