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Cyanide-Induced Cytochrome A,A3 Oxidation-Reduction Responses in Rat Brain in Vivo

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Cyanide-Induced Cytochrome A,A3 Oxidation-Reduction Responses in Rat Brain in Vivo Cyanide-induced cytochrome a,a3 oxidation-reduction responses in rat brain in vivo. C A Piantadosi, … , A L Sylvia, F F Jöbsis J Clin Invest. 1983;72(4):1224-1233. https://doi.org/10.1172/JCI111078. Research Article The sensitivity of the brain to cyanide-induced histotoxic hypoxia and the protective effects of known cyanide antagonists, have been assessed in vivo by reflectance spectrophotometry. Cyanide-related changes in cytochrome a,a3 (cytochrome c oxidase) oxidation-reduction (redox) state, tissue hemoglobin saturation, and local blood volume were continuously monitored in cerebral cortex of rats. Noncumulative, dose-dependent inhibition of the in situ mitochondrial respiratory chain was evaluated directly by measuring increases in reduction levels of the terminal oxidase. These transient cytochrome a,a3 reductions were accompanied by increases in regional cerebral hemoglobin saturation and blood volume. Cytochrome redox responses were not altered either in magnitude or kinetics by hyperoxia; however, the cyanide-cytochrome dose-response curve was greatly shifted to the right by pretreatment with sodium nitrite, and the recovery rate of cytochrome a,a3 from cyanide-induced reduction was enhanced fourfold by pretreatment with sodium thiosulfate. Find the latest version: https://jci.me/111078/pdf Cyanide-induced Cytochrome a,a3, Oxidation- Reduction Responses in Rat Brain In Vivo C. A. PIANTADOSI, A. L. SYLVIA, and F. F. JOBSIS, Departments of Medicine and Physiology, Duke University Medical Center, Durham, North Carolina 27710 A B S T R A C T The sensitivity of the brain to cyanide- chrome oxidase in vitro with cyanide concentrations induced histotoxic hypoxia and the protective effects as low as 3 X 10' M (9), 50% decreases in cytochrome of known cyanide antagonists, have been assessed in oxidase activity in rat brain homogenates after lethal vivo by reflectance spectrophotometry. Cyanide-re- intraperitoneal injections of sodium cyanide (10), and lated changes in cytochrome a,a3 (cytochrome c oxi- an inverse correlation between tissue cyanide levels dase) oxidation-reduction (redox) state, tissue hemo- and cytochrome oxidase activity in rabbits (11). globin saturation, and local blood volume were con- Prophylactic and therapeutic protection against tinuously monitored in cerebral cortex of rats. Non- death by cyanide poisoning has been reported for so- cumulative, dose-dependent inhibition of the in situ dium nitrite, sodium thiosulfate, and oxygen (12-16), mitochondrial respiratory chain was evaluated directly with enhancement of the protective effects of nitrite by measuring increases in reduction levels of the ter- and thiosulfate by high oxygen partial pressures (16, minal oxidase. These transient cytochrome a,a3 reduc- 17). Nitrites oxidize ferrous hemoglobin to methe- tions were accompanied by increases in regional ce- moglobin, which then competes with cytochrome c rebral hemoglobin saturation and blood volume. Cy- oxidase and other hemoproteins for cyanide, forming tochrome redox responses were not altered either in nontoxic cyanmethemoglobin (12). Thiosulfate distrib- magnitude or kinetics by hyperoxia; however, the cy- utes throughout total body water, binds to serum al- anide-cytochrome dose-response curve was greatly bumin, and functions as a sulfur donor for the enzyme shifted to the right by pretreatment with sodium ni- rhodanese (thiosulfate sulfurtransferase), which cata- trite, and the recovery rate of cytochrome a,a3 from lyzes the transfer of a sulfur atom to cyanide, con- cyanide-induced reduction was enhanced fourfold by verting it to nontoxic thiocyanate (18-20). Rhodanese pretreatment with sodium thiosulfate. concentration is highest in hepatic mitochondria, how- ever, because a large fraction of exogenously admin- INTRODUCTION istered thiosulfate remains serum albumin bound and enhances serum rhodanese activity, serum has been Among the many known cellular effects of cyanide proposed as a major in vivo site of cyanide detoxifi- (1-6), inhibition of the mitochondrial respiratory chain cation (20). The means by which oxygen might poten- has long been considered its predominant toxic effect tiate cyanide antagonist activity is unknown, although (7). This in vitro action of cyanide, first observed by a number of mechanisms, including activation of cy- Keilin and Hartree (8) during absorption studies of anide-insensitive respiration, oxygen displacement of cytochrome spectra in yeast and heart muscle prepa- cyanide from cytochrome oxidase by mass action, en- rations, defined cytochrome a3 as the component of hanced detoxification of cyanide by oxygen, and non- cytochrome a,a3 (cytochrome c oxidase) that reacted specific metabolic inhibitory effects of high P02 have with oxygen, carbon monoxide, and cyanide. Subse- all been proposed (14, 17). quent studies reported complete inhibition of cyto- Spectrophotometric evidence from mitochondrial and purified enzyme preparations has indicated that Preliminary data were published in April 1982, Clin. Res. HCN binds with both the reduced and oxidized forms 30:487A. (Abstr.) of cytochrome a3 (21-24); however, the rate of inter- This work was supported by National Institutes of Health action with oxidized cytochrome a3 is two orders of grants AG-00517 to Dr. Sylvia and HL-07896 to Dr. J6bsis. Address reprint requests to Dr. Piantadosi. magnitude slower than the reaction rate for reduced Received for publication 25 October 1982 and in revised cytochrome a3 and cyanide, leading others to conclude form 13 April 1983. that the kinetically significant site of cyanide inter- 1224 J. Clin. Invest. C The American Society for Clinical Investigation, Inc. 0021-9738/83/10/1224/10 $1.00 Volume 72 October 1983 1224-1233 ruption of mitochondrial electron transport is at the reduced cytochrome a3 level (24). Further progress in this field awaited development of dual wavelength spectrophotometry by Chance (25), making it possible to monitor cellular electron transport systems in situ. Subsequent technological advances by Jobsis et al. (26) have allowed continuous, simultaneous, monitoring of cytochrome c oxidase re- dox state and changes in hemoglobin saturation and regional blood volume. Such technological application to living brain has shown that the redox state of cy- tochrome oxidase in vivo is labile to changes in tissue oxygenation (27, 28). This led us to speculate that the increased oxidation level of cytochrome a,a3 in the presence of high oxygen partial pressures could de- crease the rate of HCN binding to cytochrome a3 dur- FIGURE 1 Reflectance spectrophotometry arrangement. Sample and reference light beams from tunable monochro- ing cyanide detoxification. A further objective was to mators alternately passed down a 6.35 mm fiber bundle il- define in vivo reversal of cyanide-induced cytochrome luminating the skull and underlying cerebral cortex. Re- a,a3 inhibition by known cyanide antagonists and pos- flected light was collected in an internally clad glass rod sible mediation of their effects by oxygen. coupled to the skull with optical gel and shielded by an 0- ring. METHODS the differences in intensity of sample and reference wave- 30 Adult male Sprague-Dawley rats (250-350 g) were used lengths were recorded on a multi-channel strip chart re- in the experiments. The animals were anesthetized with so- corder (Beckman Instruments, Inc., Fullerton, CA, model dium pentobarbital (Nembutal; 50 mg/kg i.p.) and trache- R611). otomized. The inferior vena cava was cannulated via the Changes in tissue hemoglobin saturation were estimated femoral vein and both femoral arteries were cannulated for by subtracting the hemoglobin isosbestic wavelength at 569 arterial blood gas sampling and continuous monitoring of nm from the oxyhemoglobin absorption maximum at 577 arterial blood pressure. The animals were paralyzed with nm. To compensate for blood volume changes that would tubocurarine chloride (1.2 mg/kg i.v.) and upon cessation produce changes in absorption at the 569 nm reference wave- of spontaneous breathing were immediately placed on a pos- length, this reference signal was held constant by feedback itive pressure rodent respirator (Harvard Apparatus Co., on the photomultiplier gain. This feedback signal was Inc., S. Natick, MA, model 680) using a control gas mixture then used to follow relative changes in regional blood of 30% 02 and 70% N2. Tidal volume and/or respiratory volume (26). rate was adjusted to maintain normal Paco2 (35-40 mmHg) The optical absorption characteristics of cytochrome c and Pao2> 90 mmHg; if not achieved, the animal was not oxidase depend upon the redox state of the enzyme. The studied. Rectal temperature was maintained at 37±10C by difference spectrum (reduced-oxidized) shows an absorption an external heating pad. The animal's head was placed in maximum at "603-605 nm predominantly derived from a stereotaxic head-holder and a longitudinal scalp incision cytochrome a heme (31). Absorption changes at this 605-nm was made exposing the dorsal skull. The skull was 'cleared sample wavelength were compared with absorption changes to the periosteum, but maintained intact so as to leave in- at a reference wavelength of 620 nm. The 590-nm hemo- tracranial pressure relationships undisturbed. globin equibestic reference wavelength usually employed in Changes in optical absorption characteristics of brain cy- this laboratory (26) could not be used in these cyanide studies tochrome c oxidase (cytochrome a,a3) and hemoglobin sat- because a prominent reduced
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