Elevated blood glucose is associated with poor outcome in the carbon-monoxide-poisoned rat

Levine-prepared, unanesthetized rats exposed to 2400 and 2700 ppm carbon monoxide (CO) for 90 min were used to examine the effect of acute CO poisoning on plasma glucose and insulin concentrations, and neurologic dysfunction. Body temperature and mean arterial blood pressure fell progressively during CO exposure. Glucose rose during initial CO exposure, then declined: glucose increased again after 2 h of room air recovery. Neurologic deficit, behaviorally-assessed after 4 h of recovery, was strongly correlated (r = 0.71, P less than 0.001) with glucose increase during the first 2 h of recovery. Recovery hyperglycemia was, in turn, correlated (r = 0.69, P less than 0.001) with the fall in glucose during the second half of CO exposure. Neurologic deficit was also correlated, but less strongly so, with hypoglycemia during CO exposure. Failure to rapidly regain body temperature during recovery was correlated with the post-CO rise in glucose concentration and with increased neurologic deficit. Plasma insulin activity was depressed immediately following CO exposure, and increased during recovery. CO-induced hypothermia was greater at 2700 than at 2400 ppm CO, as were post-CO recovery hyperglycemia, neurologic deficit and mortality, while body temperature recovery was less complete. The results provide evidence of an association between neurologic deficit and general morbidity following acute CO poisoning and the magnitude of post-CO hyperglycemia.     

Cardiovascular, metabolic and neurologic effects of acute carbon monoxide poisoning in the rat

Acute severe carbon monoxide poisoning was investigated in a modified Levine preparation. The rats inhaled 2700 p.p.m. CO for 90 min (COHb = 80%). Body temperature, heart rate and carotid systemic and 'stump' blood pressure declined sharply during CO exposure. By 2 and 4 h post-CO, body temperature and blood pressure had not renormalized, while heart rate was elevated. Blood glucose was unchanged at termination of CO exposure, but increased from 115 mg/dl to 191 mg/dl by 2 h post-CO. Hematocrit increased significantly during CO exposure, but no change in plasma volume was observed. Many rats showed one-sided muscle weakness and unidirectional rotation. By 4 h post-CO, behaviorally-assessed neurologic deficit was strongly correlated with an increase in left cerebral hemisphere water content, demonstrating a direct relationship between brain edema and dysfunction resulting from CO poisoning.     

Magnetic resonance imaging of the rat brain following acute carbon monoxide poisoning.

Magnetic resonance (MR) may be used for repeatedly and non-invasively imaging the brain. Until now, no studies have used this approach to study the effects of carbon monoxide (CO) poisoning in a defined animal model. Conscious, Levine-prepared female rats (unilateral carotid artery and jugular vein occlusion) were exposed to 2400 ppm CO for 90 min, with or without the infusion of 50% glucose solution; CO-stimulated increases in blood glucose and lactate occurred in both groups, while blood pressure and body temperature fell. One to four hours following termination of CO exposure, increased cortical pixel intensity, cortical surface area and brain midline shift were observed on the operated side of the brain in some rats of both groups (i.e. responders = R), providing evidence of edema. At sacrifice, 5 h following termination of CO exposure, gross water content was increased on the left side in the corresponding cortical slices in R rats, providing another measure of edema. Significant positive correlations were found between left to right pixel intensity difference and water content difference, and between the extent of midline shift and water content difference. The elevations of blood glucose and lactate concentrations, and the magnitudes of CO-induced hypothermia and hypotension were similar to those in past studies, but appeared to exert no effect on the severity of cortical edema in terms of differences in pixel intensity, surface area, midline shift or gross tissue water content. Thus, the observed differences between the R rats is not explained by the available data.(ABSTRACT TRUNCATED AT 250 WORDS)     

Blood lactate and catecholamine levels in the carbon monoxide-exposed rat: the response to elevated glucose.

Previous studies have shown that elevated blood glucose is detrimental to the outcome in acute carbon monoxide (CO) poisoning. The present goals were to characterize the blood lactate and catecholamine changes and to determine whether elevated blood glucose results in increases in the levels of these substances. Two groups of adult Sprague-Dawley, Levine-prepared, female rats (n = 22 each) were exposed to 2400 ppm CO for 90 min: one group received nothing (CO alone), while the other group was infused with a 50% glucose solution (4 ml/kg) (CO + glucose). The usual hypothermia, hypotension, bradycardia and hemoconcentration associated with acute severe CO poisoning were observed. Survival rates were 68% and 54% in the CO alone and CO + glucose groups, respectively. Arterial blood pressure tended to decline more in rats that died; the difference was significant in the CO + glucose group. In the CO alone group, plasma glucose concentration was significantly lower after CO exposure in rats that died than in survivors (35 +/- 15 vs. 99 +/- 16 mg/dl). In the CO + glucose group, glucose concentration was significantly higher after 45 min in rats that died (d) than in survivors (s) (447 +/- 29 vs. 324 +/- 31 mg/dl). Elevated blood glucose in the CO + glucose group failed to significantly increase blood lactate; however, lactate tended to be higher in rats that died in both groups [CO alone group: 175 +/- 17 (d) vs. 138 +/- 9 (s); CO + glucose group: 154 +/- 10 (d) vs. 143 +/- 8 (s)]. Plasma epinephrine and norepinephrine increased significantly 6-10-fold and 2-6-fold in each of the two groups, respectively; however, catecholamine levels were not related to either the administration of glucose or survival. With regard to CO poisoning in this animal model, the results do not support the hypotheses that elevated blood glucose exacerbates the increase in blood lactate, that increased catecholamine increases glucose, or that greater CO-induced hypoglycemia results from increased lactate production. The results do show that death is related to abnormally high or low blood glucose, but that it is not due to higher blood lactate or catecholamine levels.     

Effects of ethanol in acute carbon monoxide poisoning

The combined effects of ethyl alcohol (ETOH) intoxication and carbon monoxide (CO) poisoning were studied in the Levine-prepared rat. Infusion or injection of ETOH before and during 90 min of CO exposure to blood levels 2-4 times those considered legally drunk in humans, increased survival at 2400 ppm, and extended the tolerance time at 2400 ppm and 3000 ppm. CO exposure produced the usual hypothermia, hypotension and hemoconcentration; these responses were not altered by concurrent ETOH treatment. Blood ETOH concentration was increased in the presence of CO, and this was related to CO concentration. Although ETOH did not alter the average degree of hypoglycemia seen during the later stages of CO exposure, rats with the highest ETOH concentration tended to have the lowest blood glucose. ETOH increased the magnitude of the hyperglycemic rebound during recovery from exposure to both CO concentrations. Moreover, the magnitude of the recovery hyperglycemic rebound was directly related to the magnitude of the previous hypoglycemia, at both CO concentrations, with or without ETOH. Rats dying during exposure to both CO concentrations were severely hypoglycemic, whereas survivors maintained more or less normal blood glucose concentrations. The results suggest that the presence of ETOH during CO poisoning increases blood ETOH to higher than expected levels and provides a significant degree of survival protection.     

Effect of intermittent carbon monoxide inhalation on erythropoiesis and organ weights in rats

Sprague-Dawley rats were exposed to 450 ppm carbon monoxide (CO) for 6 h per day, 5 days per week for 33 days. The effect of CO on reticulocyte count, hematocrit, hemoglobin concentration, body weight and selected organ weights was measured. Exposure to CO caused a three-fold increase in the youngest reticulocyte population, concomitant with an increase in the total reticulocyte count. Despite continued CO exposure, reticulocyte number and distribution returned to normal by day 9, suggesting that reticulocyte response of the organism to CO had changed. Both hematocrit and hemoglobin concentrations began to increase 16 days after CO exposure and remained at the increased level for the duration of the exposure period. There were no changes in kidney, liver and adrenal weights throughout the course of study. However, spleen weight was increased after 5 days of CO exposure. Left and right ventricular organ weight ratios increased equally at the same time during the study. These results indicate that the increase in the young reticulocyte population and the subsequent increase in total reticulocyte count are the earliest erythropoietic responses to intermittent CO exposure and that CO-induced polycythemia is associated with cardiac hypertrophy in rats.     

The neuroprotective effect of hyperoxygenate hydrogen-rich saline on CO-induced brain injury in rats

This study was designed to investigate the neuroprotective effect of hyperoxygenate hydrogen-rich saline (HOHS) against brain injury induced by carbon monoxide (CO) poisoning in rats. A rat model of CO poisoning was established by administering CO via intraperitoneal injection to male Sprague-Dawley rats. Forty-eight adult male rats were randomly divided into the following groups: normal control group (NG), CO poisoning group (CO), HOS treatment group (hyperoxygenated solution, HOS) and HOHS treatment group (HOHS). After CO poisoning, the carboxyhemoglobin (COHb) contents in the blood of rats in all the CO poisoning groups were increased significantly. However, HOS and HOHS significantly decreased COHb contents, furthermore, the HOHS group had lower COHb contents than the HOS group. Arterial oxygen partial pressure (PaO₂) and arterial oxygen saturation (SaO₂) results showed that HOS and HOHS could improve the oxygenation of the rats with CO poisoning. Compared with the CO group, the HOS group and the HOHS group had persistently neuroprotective effect on CO-induced brain injury, as assessed by modified neurological severity score (mNSS), furthermore, the HOHS group had better neurological functional recovery than the HOS group. The neuronal apoptosis induced by CO was also evaluated. Except the NG group, all the CO-poisoning groups had varying degrees of neuronal apoptosis. There was lesser degree of neuronal apoptosis in both the HOS group and the HOHS group than that in the CO group. Moreover, the HOHS group had more minor degree of neuronal apoptosis than the HOS group. Compared with the CO group, the free radicals production in the HOS group and the HOHS group were significantly inhibited. In addition, there were significantly difference in the free radicals production between the HOS group and the HOHS group. We could conclude that HOHS exerted a stronger neuroprotective effect against CO-induced brain injury than HOS, and the neuroprotective mechanism of HOHS may be related with inhibition of both neuronal apoptosis and free radicals.     

The time-dependent protective effect of hyperbaric oxygen on neuronal cell apoptosis in carbon monoxide poisoning

Introduction:?The progressive clinical course with delayed neurological damage in carbon monoxide (CO) poisoning may be due to neuron apoptosis. The usefulness of hyperbaric oxygen (HBO) in different time periods after CO exposure in neuronal cell apoptosis reduction has not been evaluated thus far. The aim was to evaluate HBO efficacy in reducing neuronal apoptosis in different time periods after CO exposure.

Methods:?Wistar rats were exposed to 3000?ppm CO in air for 60?min and 100% oxygen at a pressure of three bar for 30?min 0–12?h after CO exposure. The apoptosis was evaluated by immunohistochemical analysis with antibodies against activated caspase-3 and the percentage of caspase-3 positive hippocampal ganglionic cells was reported.

Results:?It was shown that CO poisoning results in ganglionic cell apoptosis. The percentage of apoptotic cells in rats exposed to CO was the highest (32%), whereas the percentage of apoptotic cells in rats exposed to HBO 0 and 1?h after CO was similar with a lower percentage than rats exposed to CO. The percentage of apoptotic cells in rats exposed to HBO 3 and 5?h after CO was similar with a lower percentage than rats exposed to HBO 0 and 1?h after CO. The percentage of apoptotic cells in rats exposed to HBO 7–12?h after CO was similar with a higher percentage than rats exposed to HBO 5?h after CO.

Conclusion:?HBO has a time-dependent protective effect on CO-induced neuron apoptosis with the highest efficiency at 3 and 5?h after CO poisoning.     

Effects of resveratrol on carbon monoxide-induced cardiotoxicity in rats

Carbon monoxide (CO) poisoning leads to tissue hypoxia resulting in cardiovascular disturbances. Resveratrol (RES) is considered a natural cardioprotective agent especially in the setting of ischemia/reperfusion injury. In the present study, the cardioprotective potential of RES against CO-induced cardiotoxicity was evaluated. 45 male Wistar rats, animals were randomly assigned to 5 experimental groups. The first group served as negative control and was not exposed to CO. All remaining rats were exposed to CO 3000 ppm for 60 min. The second group received normal saline following CO exposure, while groups 3, 4 and 5 were injected intraperitoneally with different doses of RES (1, 5 and 10 mg/kg, respectively). Histopathological examination showed that RES administration reduced myocardial lesions compared to control groups. Myocardial Akt expression was significantly increased in rats treated with the highest dose of RES (p < 0.05) compared to CO-exposed non-treated animals. Caspase-3 activity in rat cardiomyocytes of RES-treated animals was significantly decreased in a dose-dependent manner. ECG findings did not differ significantly among CO-exposed groups. In conclusion, the present study offers evidence of a protective effect of RES administration on CO-induced cardiotoxicity via Akt up-regulation and attenuation of caspase-3 activity in rat hearts.     

Nitric oxide-independent cGMP efflux in the striatum of rats exposed to carbon monoxide as determined by microdialysis

Extracellular cGMP in the striatum of rats exposed to 3000 ppm carbon monoxide (CO) or 8% O2 was decreased during the early period of exposure. Thereafter, extracellular cGMP in rats exposed to CO, but not 8% O2, was transiently increased. A nitric oxide (NO) synthase inhibitor, NG-nitro-L-arginine, strongly reduced the steady-state level of extracellular cGMP in the striatum, indicating a primary role of NO in cGMP production. However, it failed to suppress the CO-induced increase in extracellular cGMP in the striatum. These findings suggest that CO may stimulate cGMP production in rat striatum independently of NO and hypoxia.     

Modification of the striatal dopaminergic neuron system by carbon monoxide exposure in free-moving rats,as determined by in vivo brain microdialysis

Acute carbon monoxide (CO) intoxication in humans results in motor deficits, which resemble those in Parkinson's disease, suggesting possible disturbance of the central dopaminergic (DAergic) neuronal system by CO exposure. In the present study, therefore, we explored the effects of CO exposure on the DAergic neuronal system in the striatum of freely moving rats by means of in vivo brain microdialysis. Exposure of rats to CO (up to 0.3%) for 40 min caused an increase in extracellular dopamine (DA) levels and a decrease in extracellular levels of its major metabolites, 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), in the striatum depending on the CO concentration. Reoxygenation following termination of the CO exposure resulted in a decline of DA to the control level and an overshoot in the recovery of DOPAC and HVA to levels higher than the control. A monoamine oxidase type A (MAO-A) inhibitor, clorgyline, significantly potentiated the CO-induced increase in DA and completely abolished the subsequent overshoot in the recovery of DOPAC and HVA. Tetrodotoxin, a Na(+) channel blocker, completely abolished both the CO-induced increase in DA and the overshoot of DOPAC and HVA. A DA uptake inhibitor, nomifensine, strongly potentiated the CO-induced increase in DA without affecting the subsequent overshoot of DOPAC and HVA. Clorgyline further potentiated the effect of nomifensine on the CO-induced increase in DA, although a slight overshoot of DOPAC and HVA appeared. These findings suggest that (1) CO exposure may stimulate Na(+)-dependent DA release in addition to suppressing DA metabolism, resulting in a marked increase in extracellular DA in rat striatum, and (2) CO withdrawal and subsequent reoxygenation may enhance the oxidative metabolism, preferentially mediated by MAO-A, of the increased extracellular DA. In the light of the neurotoxicity of DA per se and reactive substances, such as quinones and activated oxygen species, generated via DA oxidation, the significant modification of the striatal DAergic neuronal system by CO exposure might participate in the neurological outcome following acute CO intoxication.     

Population-Based Case-Control Study of Risk Factors for Unintentional Mortality from Carbon Monoxide Poisoning in Taiwan

We carried out a population-based case-control study to identify people in Taiwan who are at increased risk of unintentional mortality from carbon monoxide (CO) poisoning (ICD-9 CM: 986 or E868). The study included all 439 deaths from unintentional CO poisoning registered in Taiwan's National Mortality Registry during 1997–2003, whereas 878 control subjects were randomly selected, with a control/case ratio of 2, from all deceased individuals from other causes during the same period. The annual mortality rate of CO poisoning significantly increased in Taiwan over the 7-yr period from 1.6 to 3.5 per 10⁶ person-years. Thirty-six percent (n = 160) of the deaths occurred at home, and 21% (n = 93) were registered as in-hospital mortalities. A multivariate logistic regression analysis indicated that married people had a significantly reduced mortality odds ratio (MOR) of 0.50 (95% CI = 0.30–0.82) compared to single individuals. Additionally, residents of northern Taiwan (which is relatively urban) had a notably higher MOR of CO poisoning (MOR = 3.44, 95% CI = 1.40–8.44) than people residing in eastern Taiwan (which is relatively rural). Moreover, the MOR peaked in cold periods. A daily maximum temperature of < 18.4°C was associated with a 2.15-fold increase in the MOR compared to a daily maximum temperature of ≥ 27.1°C. This study demonstrates an alarming increase in the unintentional death rate from CO poisoning in Taiwan between 1997 and 2003. Certain demographic and geographic characteristics were significant predictors for CO poisoning, suggesting a need for preventive strategies targeting these high-risk populations. Precautions should also be taken during periods of low temperatures.     

Hypothermia and Fever After Organophosphorus Poisoning in Humans—A Prospective Case Series

There have been many animal studies on the effects of organophosphorus pesticide (OP) poisoning on thermoregulation with inconsistent results. There have been no prospective human studies. Our aim was to document the changes in body temperature with OP poisoning. A prospective study was conducted in a rural hospital in Polonnaruwa, Sri Lanka. We collected data on sequential patients with OP poisoning and analyzed 12 patients selected from 53 presentations who had overt signs and symptoms of OP poisoning and who had not received atropine prior to arrival. All patients subsequently received specific management with atropine and/or pralidoxime and general supportive care. Tympanic temperature, ambient temperature, heart rate, and clinical examination and interventions were recorded prospectively throughout their hospitalization. Initial hypothermia as low as 32°C was observed in untreated patients. Tympanic temperature increased over time from an early hypothermia (<35°C in 6/12 patients) to later fever (7/12 patients >38°C at some later point). While some of the late high temperatures occurred in the setting of marked tachycardia, it was also apparent that in some cases fever was not accompanied by tachycardia, making excessive atropine or severe infection an unlikely explanation for all the fevers. In humans, OP poisoning causes an initial hypothermia, and this is followed by a period of normal to high body temperature. Atropine and respiratory complications may contribute to fever but do not account for all cases.     

Cellular and learned tolerances for pentobarbital hypothermia

The development of behavioral tolerance to pentobarbital-induced hypothermia, as separable from cellular and metabolic tolerance, was established. Pentobarbital (PB) was administered to 4 groups of rats, 2 groups of which received intermittent (INT) IP PB treatment. One of these groups, INT/EXP, experienced the hypothermic (measured as rectal body temperature) drug effect after PB injection. The other group, INT/NONEXP, was monitored for body temperature functions (room temperature) before receiving PB (vehicle administration) and then prevented from experiencing PB-induced hypothermia by maintenance of body temperature with a towel wrap restraint and a heating lamp. The INT/EXP group also received equivalent exposure to this towel wrap after vehicle administration. Two other groups received chronic PB treatment (IP and in ground chow), one with experience for hypothermia after injections (CHR/EXP) and one prevented from experiencing the hypothermia (CHR/NONEXP). These groups also received equivalent exposure to the body temperature (at room temperature) testing and towel wrap restraint, EXP rats after vehicle injections and NONEXP after drug injections. A postchronic test of all groups compared the extent of PB hypothermia to prechronic test effects to assess the degree of tolerance. The INT/EXP group demonstrated behavioral tolerance for PB-induced hypothermia, as contrasted with the INT/NONEXP group which demonstrated little or no tolerance. Prominent tolerance was noted in both chronic groups for PB hypothermia, without a significant difference between them. After the postchronic test, chronic treatment was discontinued for 9 days (withdrawal) followed by 9 days of extinction training (vehicle behavioral testing). The two intermittent groups demonstrated no change in the hypothermic drug response during the postwithdrawal and postextinction drug tests.(ABSTRACT TRUNCATED AT 250 WORDS)     

Cardiovascular, metabolic and neurologic effects of carbon monoxide and cyanide in the rat.

Levine-prepared, female Sprague-Dawley rats were used to investigate the effects of carbon monoxide (CO) and cyanide (CN) on heart rate, blood pressure, hematocrit, body temperature, blood glucose, lactate, and neurologic function. Rats were exposed to either 2400 ppm CO, 1500 ppm CO, 4 mg/kg NaCN, or both 1500 ppm CO and 4 mg/kg NaCN for 90 min, followed by 4 h of room air recovery. Following exposure to 2400 ppm CO, rats exhibited a significant bradycardia which normalized by 2 h of recovery. All groups exhibited an initial hypotension which was either maintained or exaggerated during exposure in all but the rats exposed to CN, and which returned to pre-exposure values by 90 min. All groups experienced a significant hypothermia during the exposure period, with those in the 1500 ppm CO or the CN returning to initial values over the recovery period. The only significant change in hematocrit was due to 2400 ppm CO (4.1% increase). During exposure, all groups experienced an initial surge in glucose concentration which was maintained in all but rats exposed to 2400 ppm CO. The greatest hyperglycemic response resulted from the combination of CO and CN, whereas 2400 ppm CO produced the smallest. CN alone produced no significant rise in lactate concentration. However, lactate concentration in all other groups was significantly elevated during the exposure period, returning to initial values by 4 h of recovery. Lactate concentrations and neurologic deficit in rats exposed to 1500 ppm CO, when added to those rats treated with CN, closely approximated the lactate and neurologic deficit of the combination treatment. Neurologic deficit was greatest in rats exposed to 2400 ppm CO. While in most cases the responses of the rats to CO and CN differed whether the substances were administered alone or in combination, a synergistic relationship is not suggested. An additive or less than additive relationship is more likely.     

Population-based case-control study of risk factors for unintentional mortality from carbon monoxide poisoning in Taiwan

We carried out a population-based case-control study to identify people in Taiwan who are at increased risk of unintentional mortality from carbon monoxide (CO) poisoning (ICD-9 CM: 986 or E868). The study included all 439 deaths from unintentional CO poisoning registered in Taiwan's National Mortality Registry during 1997-2003, whereas 878 control subjects were randomly selected, with a control/case ratio of 2, from all deceased individuals from other causes during the same period. The annual mortality rate of CO poisoning significantly increased in Taiwan over the 7-yr period from 1.6 to 3.5 per 10(6) person-years. Thirty-six percent (n = 160) of the deaths occurred at home, and 21% (n = 93) were registered as in-hospital mortalities. A multivariate logistic regression analysis indicated that married people had a significantly reduced mortality odds ratio (MOR) of 0.50 (95% CI = 0.30-0.82) compared to single individuals. Additionally, residents of northern Taiwan (which is relatively urban) had a notably higher MOR of CO poisoning (MOR = 3.44, 95% CI = 1.40-8.44) than people residing in eastern Taiwan (which is relatively rural). Moreover, the MOR peaked in cold periods. A daily maximum temperature of < 18.4 degrees C was associated with a 2.15-fold increase in the MOR compared to a daily maximum temperature of > or = 27.1 degrees C. This study demonstrates an alarming increase in the unintentional death rate from CO poisoning in Taiwan between 1997 and 2003. Certain demographic and geographic characteristics were significant predictors for CO poisoning, suggesting a need for preventive strategies targeting these high-risk populations. Precautions should also be taken during periods of low temperatures.     

Effects of granulocyte colony-stimulating factor on electrocardiogram changes after carbon monoxide poisoning in rats

Carbon monoxide (CO), which is produced by the incomplete combustion of hydrocarbons, has many toxic effects on different organs, especially the brain and heart. CO-induced cardiotoxicity leads to several deleterious effects, including electrocardiogram (ECG) abnormalities. The present study aimed to evaluate the protective effect of recombinant human granulocyte colony-stimulation factor (G-CSF) on ECG after CO poisoning in rats. Single and multiple doses of G-CSF (10, 50, and 100 μg/kg) were administered to groups, each containing 5 male Wistar rats (16 groups for ECG analysis and 16 groups for pathological analysis). Rats were already exposed to CO at either 1,500 or 3,000 ppm concentrations for 60 minutes. ECG findings (e.g., ST-segment and T-wave changes), cardiac arrhythmias (e.g., heart blocks and ventricular and supraventricular arrhythmias), and histological changes were determined after G-CSF administration. At 3,000 ppm, frequencies of ST elevation, depression, and T inversion in ECG were significantly reduced after G-CSF treatment. Also, some of the cardiac arrhythmias (e.g., atrioventricular block type 1 and 2) after CO poisoning were suppressed after G-CSF treatment. However, G-CSF did not show protective effects on cardiomyocyte pathological consequences in CO-poisoned rats. Therefore, G-CSF could protect against ECG changes after CO-induced cardiac ischemia, but did not affect pathological changes.     

Induction of heme oxygenase-1 with hemin attenuates hippocampal injury in rats after acute carbon monoxide poisoning

Carbon monoxide (CO) poisoning is a major cause of brain injury and mortality; delayed neurological syndrome (DNS) is encountered in survivors of acute CO exposure. The toxic effects of CO have been attributed to oxidative stress induced by hypoxia. Heme oxygenase-1 (HO-1) is the inducible heme oxygenase isoform, and its induction acts as an important cellular defense mechanism against oxidative stress, cellular injury and disease. In this study, we examined the functional roles of HO-1 induction in a rat model of CO-exposured hippocampal injury. We report that acute CO exposure produces severe hippocampal injury in rats. However, hemin pretreatment reduced both the CO-induced rise in hippocampal water content and levels of neuronal damage in the hippocampus; survival rates at 24 h were significantly improved. Upregulation of HO-1 by hemin pretreatment resulted in a significant decrease in hippocampal levels of malondialdehyde (MDA), a marker of oxidative stress; levels of pro-apoptotic caspase-3 were also reduced. In contrast, inhibition of HO activity by administration of tin protoporphyrin IX (SnPP, a specific inhibitor of HO) abolished the neuroprotective effects of HO-1 induction. These data suggested that the upregulation of endogenous HO-1 expression therefore plays a pivotal protective role in CO neurotoxicity. Though the precise mechanisms underlying hemin-mediated HO-1 induction and neuroprotection are not known, these may involve the anti-oxidant and anti-apoptotic effects of HO-1 enzyme activity.     

Carbon monoxide-induced cardiac hypertrophy is not reduced by alpha- or beta-blockade in the rat

The stimulus for carbon monoxide-induced cardiac hypertrophy was investigated. Two experiments were carried out in which adult male Sprague-Dawley rats were exposed continuously to 700 ppm CO for 30 days (CO) or inhaled room air (Air). In each experiment, 2/3s of the rats received either the beta-1-adrenergic blocker, atenolol, or the alpha-1 adrenergic blocking agent, prazosin, in the food daily, at low and high doses. Systolic blood pressure (SBP) was significantly lowered (20–25 mmHg) by CO alone. Atenolol alone lowered SBP, but only at the high dose. Low dose and particularly high dose atenolol, lowered SBP even more in the CO rats. Prazosin lowered SBP, particularly at the high dose and further lowered SBP in the CO rats. Heart rate was significantly lowered by atenolol and prazosin alone at both doses in the Air rats. Heart rate remained the same or was slightly elevated by CO exposure. Heart rate in the presence of CO was significantly depressed by prazosin, but not by atenolol. Carbon monoxide alone resulted in 30–43% and 18–25% weight increases in right ventricle free-wall (RV) and left ventricle + septum (LV+S), respectively, relative to untreated controls. Neither low nor high dose prazosin significantly decreased RV and LV+S weights in the CO rats. Low dose atenolol failed to alter RV and LV+S weights in the CO rats; however, high dose atenolol, significantly (P < 0.01) increased RV weight in the CO rats. Right ventricle weight was positively correlated with SBP lowering by CO and/or atenolol, or prazosin. Carbon monoxide exposure increased lung/body weight ratio; atenolol, but not prazosin, attenuated this effect. Hematocrit increased from 50% in the Air to 77% in the CO rats; it was unaltered by prazosin or atenolol treatment. Thus, CO-induced cardiac hypertrophy develops in spite of lowered SBP (i.e. lowered LV afterload), and the blockade of either alpha or beta-1 receptors. It is suggested that the increased ventricular preload caused by atenolol and prazosin is directly responsible for the cardiac hypertrophy, regardless of the ameliorating effects of decreased inotropicity and heart rate produced by the adrenergic blocking agents. The results suggest the potentially powerful role of enhanced preload in driving myocardial hypertrophy.     

Role of hypothermia in ethanol-induced conditioned taste aversion

Two experiments examined the effect of ambient temperature during ethanol exposure on development of conditioned taste aversion to saccharin. In both studies, male albino rats receiving saccharin-ethanol (1.5 g/kg, IP) pairings followed by 6-h exposure to a 32° C environment developed a weaker saccharin aversion than did rats experiencing ethanol at room temperature. Exposure to the warm environment reduced ethanol-induced hypothermia, but enhanced ethanol's motor-impairing effect. The influence of ambient temperature on ethanol-induced taste aversion may be due to changes in body temperature, neural sensitivity, or elimination rate. Although alternative accounts cannot be entirely dismissed, this outcome suggests that ethanol-induced hypothermia plays a role in determining strength of conditioned taste aversion and thus may be involved in the regulation of oral ethanol intake in rats. Offprint requests to: C.L. Cunningham