Abstract
Effects of prior hypoxia acclimation (14-day at 380 mm Hg) on soman (pinacolyl methylphosphonofluoridate) induced brain neuronal RNA and acetylcholinesterase (AChE) depletion and lethality were monitored in rats following their return to ambient oxygenation. Quantitative cytochemical techniques were used to measure RNA and AChE changes in individual cerebrocortical (Layer III) and striatal (caudate plus putamen) neurons. In ambient PO 2 controls, soman eventuated in a moderate diminution of neuronal RNA in both brain regions and severe, dosedependent suppression of AChE activity. Hypoxia acclimation per se induced RNA alterations as manifested in cortical RNA depletion and increased variability of striatal neuron RNA contents. In hypoxia acclimated rats, the extent of neuronal RNA depletion following soman injection was attenuated in both brain regions, yet there were no discernible differences in saline control AChE levels or in the extent of soman-induced AChE inhibition in ambient control versus hypoxia acclimated treatment groups. Hypoxia acclimated rats, however, were found to be even more susceptible to lethal actions of soman as assessed using 24- and 48-hour survival following a three-point treatment regimen. These data indicate that while compensatory systemic and central metabolic adjustments associated with 14d acclimation to reduced oxygen availability may retard soman-induced neuronal RNA depletion, resistance to lethal or near-lethal soman exposure is not enhanced. It is postulated that hypoxia acclimation is associated with complex adaptive and maladaptive neurophysiological alterations influencing CNS responsiveness to soman toxication, and that detrimental consequences exceed protection afforded by metabolic adaptation.
Similar content being viewed by others
References
Adams, G. K., Yamamura, H. I., andO'Leary, J. F. 1976. Recovery of central respiratory function following anticholinesterase intoxication. Eur. J. Pharmacol. 38:101–112.
Alberghina, M., Viola, M., andGiuffrida, A. M. 1982. Changes in enzyme activities of glycerolipid metabolism of guinea-pig cerebral hemispheres during experimental hypoxia. J. Neurosci. Res. 7:147–154.
Anthony, A., Bocan, T., Doebler, J., Penman, J. andHollis, T. M. 1981. Ribonucleic acid changes in medial cells in Evans blue positive regions of the dog aorta. Exp. Mol. Pathol. 35:347–358.
Anthony, A., Doebler, J. A., Bocan, T. M. A., andShih, T.-M. 1983. Scanning integrating microdensitometric analyses of brain neuronal RNA and acetylcholinestease in acute soman treated rats. Cell Biochem. Funct. 1:30–36.
Anthony, A., andKreider, J. 1961. Blood volume changes in rodents exposed to simulated high altitude. Am. J. Physiol. 200:523–526.
Benzi, G., Arrigoni, E., Pastoris, O., Villa, R. F., Dossena, M., Agnoli, A., andGiuffrida, A. M. 1982. Drug action on the metabolic changes induced by acute hypoxia on synaptosomes from the cerebral cortex. J. Cereb. Blood Flow Metab. 2:229–239.
Benzi, G., Pastoris, O., andDossena, M. 1982. Relationships between gamma-aminobutyrate and succinate cycles during and after cerebral ischemia. J. Neurosci. Res. 7:193–201.
Bignami, G., Rosic, N., Michalek, H., Milosevic, M., andGhatti, G. L. 1975. Behavioral toxicity of anticholinesterase agents: Methodological, neurochemical, and neuropsychological aspects. Pages 155–215,in Weiss, B., andLaties, V. G. (eds.), Behavioral Toxicology, Plenum Press, New York.
Bartholini, A., Bartholini, R., andDomino, E. F. 1973. Effects of physostigmine on brain acetylcholine content and release. Neuropharmacology 12:15–25.
Blayo, M. C., Marc-Vergnes, J. P., andPocidalo, J. J. 1973. pH,\(P_{CO_2 } \), and\(P_{O_2 } \) of cisternal cerebrospinal fluid in high altitude natives. Resp. Physiol. 19:298–311.
Brimblecombe, R. W. 1974. Drug Actions on Cholinergic Systems, Page 1–227, University Park Press, Baltimore.
Cohen, P. J., Alexander, S. C., Smith, T. C., Reivich, M., andWollman, H. 1967. Effects of hypoxia and normocarbia on cerebral blood flow and metabolism in conscious man. J. Appl. Physiol. 23:183–189.
Davis, J. N. 1975. Adaptation of brain monoamine synthesis to hypoxia in the rat. J. Appl. Phsiol. 39:215–220.
De Candole, C. A., Douglas, W. W., Evans, C. L., Holmes, R., Spencer, K. E. V. Torrence, R. W., andWilson, K. M. 1953. The failure of respiration in death by anticholinesterase poisoning. Brit. J. Pharmacol. 8:466–475.
Doebler, J. A., Bocan, T. M. A., Moore, R. A., Shih, T.-M., andAnthony, A. 1983. Brain neuronal RNA metabolism during acute soman toxication: Effects of antidotal pretreatments. Neurochem. Res. 8:997–1011.
Fonnum, F., andSterri, S. H. 1981. Factors modifying the toxicity of organophosphorous compounds including soman and sarin. Fund. Appl. Toxicol. 1:143–147.
Gibson, G. E. andBlass, J. P. 1976. Impaired synthesis of acetylcholine in brain accompanying mild hypoxia and hypoglycemia. J. Neurochem. 27:37–42.
Gibson, G. E., andDuffy, T. E. 1981. Impaired synthesis of acetylcholine by mild hypoxic hypoxia or nitrous oxide. J. Neurochem. 36:28–33.
Groff, W. A., Kaminskis, A., andEllin, R. I. 1976. Interconversion of cholinesterase enzyme activity units by the manual ΔpH method and a recommended automated method. Clin. Toxicol. 9:353–358.
Heath, D. F. 1961. Organophosphorous Poisons. Page 1–331 Pergamon Press, New York.
Jovic, R., Bachalard, H. S., Clark, A. G., andNicholas, P. C. 1971. Effects of soman and DFP in vivo and in vitro on cerebral metabolism in the rat. Biochem. Pharmacol. 20:519–527.
Jovic, R., andMilosevic, M. 1970. Inhibitory actions of soman and some cholinolytics on the uptake of oxygen in the brain of rats and mice. Eur. J. Pharmacol. 19:304–310.
Karnovsky, M. J., andRoots, L. 1964. A “direct coloring” thiocholine method for cholinesterases. J. Histochem. 12:219–221.
Klausen, K. 1966. Cardiac output in man in rest and work during and after acclimatization to 3800 m. J. Appl. Physiol. 21:609–616.
Lipp, J. A., andDola, T. J. 1978. Effect of atropine upon the cerebrovascular system during soman-induced respiratory despression. Arch. Int. Pharmacodyn. 235:211–218.
Mabe, H., Blomqvist, P., andSiesjo, B. K. 1983. Intracellular pH in the brain following transient ischemia. J. Cereb. Blood Flow Metab. 3:109–114.
Maher, J. T., Goodman, A. L., Bowers, W. D., Hartley, L. H., andAngelakos, E. T. 1972. Myocardial function and ultrastructure in chronically hypoxic rats. Am. J. Physiol. 223:1029–1033.
Meeter, E., andWolthuis, O. L. 1968. The spontaneous recovery of respiration and neuromuscular transmission in the rat after anticholinesterase poisoning. Eur. J. Pharmacol. 2:377–386.
Nelson, S. R., Doull, J., Tockman, B. A., Cristiano, P. J., andSamson, R. E. 1978. Regional brain metabolism changes induced by acetylcholinesterase inhibitors. Brain Res. 157:186–190.
Ott, L. 1977. An Introduction to Statistical methods and Data Analysis. Page 1–730, Duxbury Press, North Scituate, Massachusetts.
Ou, L. C., andTenney, S. M. 1970. Properties, of mitochondria from hearts of cattle acclimatized to high altitude. Resp. Physiol. 8:151–159.
Piwonka, R. W., andBarnes, C. D. 1970. Spinal reflex activity during acute hypoxia in normal and chronic altitude-exposed cats. J. Appl. Physiol. 29:96–102.
Serra, I., Alberghina, M., Viola, M., andGiuffrida, A. M. 1981. Effect of hypoxia on nucleic acid and protein synthesis in different brain regions. Neurochem. Res. 6:595–605.
Serra, I., Alberghina, M., Viola, M., Mistretta, A., andGiuffrida, A. M. 1981. Effect of CDP-choline on the biosynthesis of nucleic acids and proteins in brain regions during hypoxia. Neurochem. Res. 6:607–618.
Shea, J. R. 1970. A method for in situ cytophotometric estimation of absolute amount of RNA using azure B. J. Histochem. Cytochem. 18:143–152.
Shimada, M. 1981. Glucose uptake in mouse brain regions under hypoxic hypoxia. Neurochem. Res. 6:993–1003.
Smialek, M., andHamberger, A. 1970. The effect of moderate hypoxia and ischemia on cytochrome oxidase activity and protein synthesis in brain mitochondria. Brain Res. 17:369–371.
Sorensen, S. C., Lassen, N. A., Severinghaus, J. W., Coudert, J., andZamora, M. P. 1974. Cerebral glucose metabolism and cerebral blood flow in high-altitude residents. J. Appl. Physiol. 37:305–310.
Taylor, P. 1980. Anticholinesterase agents. Pages 110–119,in Gilman, A. G., Goodman, L. S., andGilman, A. (eds.), The Pharmacological Basis of Therapeutics, MacMillan, New York.
Tenney, S. M., andOu, L. C. 1970. Physiological evidence for increased tissue capillarity in rats acclimatized to high altitude. Resp. Physiol. 8:137–150.
Van Liere, E. J., andStickney, J. C. 1963. Hypoxia. Pages 1–381 Univ. Chicago Press, Chicago.
Welsh, F. A., O'Conner, M. J., Marcy, V. R., Spatacco, A. J., andJohns, R. L. 1982. Factors limiting regeneration of ATP following temporary ischemia in cat brain. Stroke 13:234–242.
Wing, M. E., Woolley, D. E., andTimiras, P. S. 1967. Electrical activity of the rhinencephalon during high-altitude acclimatization. Am. J. Physiol. 212:135–141.
Wood, J. D. 1967. A possible role for gamma-aminobutyric acid in the homeostatic control of brain metabolism under conditions of hypoxia. Exp. Brain Res. 4:81–84.
Woolley, D. E., Herrero, S. M. andTimiras, P. S. 1963. CNS excitability changes during altitude acclimatization and deacclimatization in rats. Am. J. Physiol. 205:727–732.
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Doebler, J.A., Wall, T.J., Moore, R.A. et al. Soman toxication in hypoxia acclimated rats: Alterations in brain neuronal RNA and survival. Neurochem Res 9, 1239–1252 (1984). https://doi.org/10.1007/BF00973037
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/BF00973037