Although myocardial damage caused by soman has been previously reported, its relation to brain damage is unclear. In order to clarify this relationship, we examined the histomorphogenesis of central nervous system (CNS) and myocardial lesions in Sprague-Dawley rats, given atropine methylnitrate (20 mg/kg) and HI-6 (125 mg/kg) ip 10 min before a single injection of 0 or 130 μg soman/kg (sc) and sacrificed 45 min and 1.5 hr, 3 hr, 24 hr, and 72 hr later. Bilaterally symmetrical CNS damage began with vacuolation of the neuropil and was followed by astrocytic degeneration and neuronal necrosis culminating in liquefaction necrosis and focal hemorrhage. The cerebral cortex, limbic system, thalamus, and substantia nigra were common target sites. Repair in affected sites was characterized by capillary endothelial cell proliferation, microgliosis, and reversal of microvacuolation. Myocardial damage began with myocytolysis and contraction bands and evolved into coagulative myocytolysis and replacement fibrosis with a transient recruitment of acute inflammatory cells. The left ventricle, especially its free wall and papillary muscles, was consistently affected. There was good correlation among seizures, CNS damage, and myocardial lesions at all times following treatment. The results support the view that CNS lesions are associated with protracted seizure activity and provide evidence that myocardial damage is neurogenic.
Anichkov SV and Vedeneyeva ZI (1961). Irritation of the sympathetic nerve as a cause of myocardial lesions. Acta Physiol. Hung. 19: 17-18.
2.
Anzueto A., Moore GT, White CD, Johnson D., Berdine GG, and Johanson WG (1986). Ventilatory support of nonhuman primates intoxicated with organophosphate compounds. In: Proc. 2nd Int. Symp. Protection Against Chemical Warfare Agents, Stockholm, Sweden, June 15-19, pp. 323-332.
3.
Ariens AT, Meeter E., and Wolthuis OL (1969). Reversible necrosis at the end-plate region in the striated muscles of the rat poisoned with cholinesterase inhibitors. Experientia25: 57-59.
4.
Atillo A., Soderfeldt B., Kalimo H., Olsson Y., and Siesjo BK (1983). Pathogenesis of brain lesions caused by experimental epilepsy. Light- and electron-microscopic changes in the rat hippocampus following bicuculline-induced status epilepticus. Acta Neuropathol. (Berlin)59: 11-24.
5.
Baroldi G. (1991). Morphologic forms of myocardial necrosis related to myocardial cell function. In: Cardiovascular Pathology, Vol. 1, MD Silver (ed). Churchill Livingstone, New York, pp. 643-670.
6.
Baze WB (1993). Soman-induced morphological changes-An overview in the non-human primate. J. Appl. Toxicol. 13: 173-177.
7.
Baze WB, Anderson DR, Harris LW, Lennox WJ, Bowersox SL, and Solana RP (1991). Soman-induced brain and heart lesions in the rat: Effects of antidotal and anticonvulsant therapy. In: Proceedings of the 1991 Medical Defense Bioscience Review. Aug 7-8, 1991.
8.
Braitman DJ and Sparenborg S. (1989). MK-801 protects against seizures induced by the cholinesterase inhibitor soman. Brain Res. Bull. 23: 145-148.
9.
Broomfield CA , Lenz DE, and Maciver B. (1986). The stability of soman and its stereoisomers in aqueous solution: Toxicological considerations . Arch. Toxicol. 59:261-265.
10.
Burch GE, Sun SC, Colcolough HC et al (1967). Acute myocardial lesions following experimentally-induced intracranial hemorrhage in mice: A histological and histochemical study. Arch. Pathol. 84: 517-521.
11.
Carpentier P., Lambrinidis M., and Blanchet G. (1991). Early dendritic changes in hippocampal pyramidal neurones (field CA1) of rats subjected to acute soman intoxication-A light microscopic study. Brain Res. 541:293-299.
12.
Chang FCT , Foster RE, Beers ET, Rickett DL, and Filbert MG (1990). Neurophysiological concomitants of soman-induced respiratory depression in awake, behaving guinea pigs. Toxicol. Appl. Pharmacol. 102: 233-250.
13.
Chappel CL, Rona G., and Balazs T. (1959). Comparison of cardiotoxic actions of certain sympathomimetic amines. Can. J. Biochem. Physiol. 37: 35-42.
14.
Churchill L. , Pazdernik TL, Jackson JL, Nelson SR, McDonough JH, and McLeod CG (1985). Soman induced brain lesions demonstrated by muscarinic receptor autoradiography . Neurotoxicology6: 81-90.
15.
Clement JG and Broxup B. (1993). Efficacy of diazepam and avizafone against soman-induced neuropathology in brain of rats. Neurotoxicology14: 485-504.
16.
DeGroot DMG , Bierman EPB, and VanHuygenvoort AHBM ( 1990). Involvement of acetylcholine and glutamate in soman-induced brain damage. Micron Microsc. Acta21: 247-248.
17.
Duffy P. (1983). Functional implications of astrocyte metabolism . In: Astrocytes: Normal, Reactive and Neoplastic. Raven Press, New York, pp. 39-44.
18.
Ellman GL, Courtney KD, Andres V., and Feather-stone RM (1961). A new and rapid colorimetric determination of acetylcholinesterase activity. Biochem. Pharmacol . 7: 88-95.
19.
Filbert MG, Dochterman LW, Smith CD, Forster JS, Phann S., and Cann FJ (1993). Effect of mannitol treatment on soman-induced brain and heart lesions in the rat. Drug. Dev. Res. 30: 45-53.
20.
Fleckenstein A., Janke J., Doring HJ, and Leder O. (1974). Myocardial fibre necrosis due to intracellular calcium overload-A new principle in cardiac physiology . Rec. Adv. Struct. Metab. 4: 563-580.
21.
Glaum SR, Holzwarth JA, and Miller RJ (1990). Glutamate receptors activate Ca2+ mobilization and Ca2+ influx into astrocytes. Proc. Natl. Acad. Sci. USA87: 3454-3458.
22.
Goldman H., Berman RF, Hazlett J., and Murphy S. (1993). Cerebrovascular responses to soman: Time and dose dependent effects. Neurotoxicology14: 469-484.
23.
Greenhoot JH and Reichenbach DD (1969). Cardiac injury and subarachnoid hemorrhage. A clinical, pathological, and physiological correlation . J. Neurosurg. 30: 521-531.
24.
Gupta RC, McLean MJ, and Dettbarn WD (1987). Prophylaxis and treatment against the toxicity of organophosphate (op) compounds in rat by memantine and atropine. Toxicologist7: 276.
25.
Hansson E. (1988). Astroglia from defined regions as studied with primary cultures. Prog. Neurobiol. 30: 369-397.
26.
Hawkins WE and Clower BR (1971). Myocardial damage after head trauma and simulated intracranial hemorrhage in mice: The role of the autonomic nervous system . Cardiovasc. Res. 5: 524-529.
27.
Hayward IJ, Wall HG, Jaax NK, Wade JV, Marlow DD, and Nold JB (1990). Decreased brain pathology in organophosphate-exposed rhesus monkeys following benzodiazepine therapy. J. Neurol. Sci. 98: 99-106.
28.
Juhasz-Nagy A., Szentivanyi M., Ovary I., and Debreczeni L. (1965). Hypothalamic control of coronary circulation in the dog. Arch. Int. Physiol. Biochem. 73:798-816.
29.
Kadar T., Cohen G., Sahar R., Alkalai D., and Shapira S. (1992). Long-term study of brain lesions following soman, in comparison to DFP and metrazol poisoning. Hum. Exp. Toxicol . 11: 517-523.
30.
Kimelberg HK and Norenberg MD (1989). Astrocytes . Sci. Am. 26: 66-76.
31.
Kimelberg H. and Ransom B. (1986). Physiological and pathological aspects of astrocytic swelling. In: Astrocytes. Cell Biology and Pathology of Astrocytes , S Federeoff and A Vernadkis (ed). Academic Press, Orlando, FL, pp. 129-166.
32.
King JM, Roth L., and Haschek WM (1982). Myocardial necrosis secondary to neural lesions in domestic animals. J. Am. Vet. Med. Assoc. 180: 144-148.
33.
Kleinschmidt J., Zucker CL, and Yazulla S. (1986). Neurotoxic action of kainic acid in the isolated toad and goldfish retina: I. Description of effects . J. Comp. Neurol. 254: 184-185.
34.
Klouda MA and Brynjolfsson G. (1969). Cardiotoxic effects of electrical stimulation of the stellate ganglia. Ann. N.Y. Acad. Sci. 156: 271-280.
35.
Koyama Y., Baba A., and Iwata H. (1991). L-Glutamate-induced swelling of cultured astrocytes is dependent on extracellular Ca2+. Neurosci. Lett. 122: 210-212.
36.
Lallement G. , Carpentier P., Collet A., Baubichon D., Pernotmarino I., and Blanchet G. (1992). Extracellular acetylcholine changes in rat limbic structures during soman-induced seizures. Neurotoxicology13: 557-567.
37.
Lallement G. , Carpentier P., Collet A., Pemotmarino I., Baubichon D., and Blanchet G. (1991). Effects of soman-induced seizures on different extracellular amino acid levels and on glutamate uptake in rat hippocampus. Brain Res. 563: 234-240.
38.
Lallement G. , Carpentier P., Pemotmarino I., Baubichon D., Collet A., and Blanchet G. (1991). Involvement of the different rat hippocampal glutamatergic receptors in development of seizures induced by soman-An autoradiographic study. Neurotoxicology12:655-664.
39.
Lallement G. , Carpentier P., Pemotmarino I., Baubichon D., Collet A., and Blanchet G. (1993). Transient impairment of the gabaergic function during initiation of soman-induced seizures. Brain Res. 629:239-244.
40.
Lallement G. , Delamanche IS, Pemotmarino I., Baubichon D., Denoyer M., Carpentier P., and Blanchet G. (1993). Neuroprotective activity of glutamate receptor antagonists against soman-induced hippocampal damage-Quantification with an omega-3 site ligand. Brain Res. 618: 227-237.
41.
Lallement G. , Denoyer M., Collet A., Pernotmarino I., Baubichon D., Monmaur P., and Blanchet G. (1992). Changes in hippocampal acetylcholine and glutamate extracellular levels during soman-induced seizures- Influence of septal cholinoceptive cells. Neurosci. Lett. 139: 104-107.
42.
Lebeda FJ, Wierwille RC, Vanmeter WG, and Sikora-Vanmeter KC (1988). Acute ultrastructural alterations induced by soman and hypoxia in rat hippocampal CA3 pyramidal neurons. Neurotoxicology9: 9-22.
43.
Lemercier G. , Carpentier P., Sentenac-Roumanou H., and Morelis P. (1983). Histological and histochemical changes in the central nervous system of the rat poisoned by an irreversible anticholinesterase organophosphorus compound . Acta Neuropathol. (Berlin)61: 123-129.
44.
McDonough JH , Jaax NK, Crowley RA, Mays MZ, and Modrow HE (1989). Atropine and/or diazepam therapy protects against soman-induced neural and cardiac pathology. Fundam. Appl. Toxicol. 13: 256-276.
45.
McDonough JH , McLeod CG, and Nipwoda MT (1987). Direct microinjection of soman or vx into the amygdala produces repetitive limbic convulsions and neuropathology. Brain Res. 435: 123-137.
46.
McLeod CG (1985). Pathology of nerve agents: Perspectives on medical management. Fundam. Appl. Toxicol . 5: s10-s16.
47.
McLeod CG, Singer AW, and Harrington DG (1984). Acute neuropathology in soman poisoned rats. Neurotoxicology5: 53-58.
48.
McNair JL, Clower BR, and Sandford RA (1970). The effect of reserpine pretreatment on myocardial damage associated with simulated intracranial hemorrhage in mice. Eur. J. Pharmacol . 9: 1-6.
49.
Modrow HE and Jaax NK (1989). Effect of soman exposure on the acquisition of an operant alternation task. Pharmacol. Biochem. Behav. 32: 49-53.
50.
Montgomery DL (1994). Astrocytes: Form, functions, and roles in disease. A review. Vet. Pathol. 31: 145-167.
51.
Moreva E. (1980). Methods for producing experimental neurogenic lesions. In: Neurogenic Heart Lesions, IS Zavodskaya, EV Moreva, and NA Novikova (eds). Pergamon Press, Oxford, pp. 9-22.
52.
Neal MJ (1976). Minireview: Aminoacid transmitter substances in the vertebrate retina. Gen. Pharmacol. 7:321-332.
53.
Olney JW (1969). Glutamate-induced retinal degeneration in neonatal mice. Electron microscopy of the acutely evolving lesion. J. Neuropathol. Exp. Neurol. 28: 455-474.
54.
Oppenheimer S. (1992). The insular cortex and the pathophysiology of stroke-induced cardiac changes. Can. J. Neurol. Sci. 19: 208-211.
55.
Ransom B. and Carlini W. (1986). Electrophysiological properties of astrocytes . In: Astrocytes. Cell Biology and Pathology of Astrocytes , S Federoff and A. Vernadakis (eds). Academic Press, Orlando, FL, pp. 1-49.
56.
Rickett DL, Glenn JF, and Beers ET (1986). Central respiratory effects versus neuromuscular actions of nerve agents. Neurotoxicology7: 225-236.
57.
Robineau P. , Leclercq Y., Gerbi A., Berrebibertrand I., and Lelievre LG (1991). An organophosphorus compound, vx, selectively inhibits the rat cardiac Na+, K+-ATPase alpha-1 isoform - Biochemical basis of the cardiotoxicity of vx . FEBS Lett. 281: 145-148.
58.
Rockhold R. (1991). Cardiotoxicity of naturally occurring catecholamines . In: Principles of Cardiac Toxicology, SI Baskin (ed). CRC Press, Boca Raton, FL, pp. 347-417.
59.
Roth A., Zellinger I., Arad M., and Atsmon J. (1993). Organophosphates and the heart. Chest103: 576-582.
60.
Schenk EA and Moss AJ (1966). Cardiovascular effects of sustained norepinephrine infusions. II. Morphology. Circulation Res. 18: 605-615.
61.
Sellestrom A., Algers G., and Karlsson B. (1985). Soman intoxication and the blood brain barrier. Fundam. Appl. Toxicol. 5: s122-s126.
62.
Shih TM (1985). Time course effects of soman on acetylcholine and choline levels in six discrete areas of the rat brain. Psychopharmacology78: 170-175.
63.
Shih TM (1993). Comparison of several oximes on reactivation of soman-inhibited blood, brain and tissue cholinesterase activity in rats. Arch. Toxicol. 67: 637-646.
64.
Shih TM, Penetar DM, Mcdonough JH, Romano JA, and King JM (1990). Age-related differences in soman toxicity and in blood and brain regional cholinesterase activity. Brain Res. Bull. 24: 429-436.
65.
Shih TM and Scremin OU (1992). Cerebral blood flow and metabolism in soman-induced convulsions. Brain Res. Bull. 28: 735-742.
66.
Singer AW, Jaax NK, Graham JS, and McLeod CG (1987). Cardiomyopathy in soman and sarin intoxicated rats. Toxicol. Lett. 36: 243-249.
67.
Soderfeldt B., Kalimo H., Olsson Y., and Siesjo B. (1981). Pathogenesis of brain lesions caused by experimental epilepsy. Light- and electron-microscopic changes in the rat cerebral cortex following bicuculline-induced status epilepticus . Acta Neuropathol. (Berlin)54: 219-231.
68.
Tower D. (1988). Development of the knowledge of atrocytes since Virchow. In: Biochemical Pathology ofAstrocytes, MD Norenberg, L Hertz , and A Schousboe (eds). Alan R. Liss, New York, pp. 3-18.
69.
Tryphonas L. and Clement JG (1993). Soman-induced encephalopathy and cardiomyopathy in rats: A pharmacological study. In: United States Army 1993 Medical Defense Bioscience Review, May 10-13, Baltimore, MD, pp. 495-500.
70.
Tryphonas L. and Clement JG (1993). Dose and time related effects on the CNS and heart of rats exposed to a single dose of soman: A histopathological study. In: United States Army 1993 Medical Defense Bioscience Review, May 10-13, Baltimore, MD, pp. 685-694.
71.
Tryphonas L. and Iverson F. (1990). Neuropathology of excitatory neurotoxins: The domoic acid model. Toxicol. Pathol. 18: 165-169.
72.
Tryphonas L. , Truelove J., and Iverson F. (1990). Acute parenteral neurotoxicity of domoic acid in cynomolgus monkeys (M. fascicularis) . Toxicol. Pathol. 18: 297-303.
73.
Tryphonas L. , Truelove J., Nera E., and Iverson F. (1990). Acute neurotoxicity of domoic acid in the rat. Toxicol. Pathol . 18: 1-9.
74.
Vacca LL (1985). Laboratory Manual of Histochemistry. Raven Press, New York, pp. 161-377.
75.
Vanneste Y. and Lison D. (1993). Biochemical changes associated with muscle fibre necrosis after experimental organophosphate poisoning. Hum. Exp. Toxicol. 12: 365-370.
76.
Walz W. (1988). The role of potassium in cytotoxic brain edema . In: The Biochemical Pathology of Astrocytes, MD Norenberg, L Hertz , and A Schousboe (eds). Alan R. Liss, New York, pp. 315-326.
77.
Walz W. (1989). Role of the glial cells in the regulation of the brain micro-environment. Prog. Neurobiol. 33: 309-333.
78.
Walz W. and Hertz L. (1983). Functional interactions between neurons and astrocytes. II. Potassium homeostasis at the cellular level. Prog. Neurobiol . 20: 133-183.
79.
Weilder DJ (1974). Myocardial damage and cardiac arrhythmias after intracranial hemorrhage. A critical review. Stroke5: 759-764.
80.
Wolthuis OL and Meeter E. (1968). Cardiac failure in the rat caused by diisopropyl fluorosphosphate (dfp). Eur. J. Pharmacol. 2: 387-392.
