Effects of physical training on several glycolytic enzymes in rat heart.

In response to a program of daily swimming for 16 weeks, the activities of pyruvate kinase and lactate dehydrogenase increased significantly in the hearts of young male rats. The isozyme composition in M of cardial lactate dehydrogenase increased from 28.5 to 32.7% in the trained animals. Phosphofructokinase activity and glycogen content were unchanged. The hearts of the exercising animals were 28% heavier than those of sedentary paired weight controls.

Cardiomegaly and haemodynamics in rats with a transplantable growth hormone-secreting tumour.

To investigate cardiovascular changes in experimental acromegaly, a growth hormone-secreting tumour (MtT-W-15) was implanted in adult female rats. Somatic and tumour growth occurred steadily during the 8 week study period, as did an increase in serum growth hormone titre. Weight of left ventricle and right ventricle increased directly with tumour growth, both on an absolute basis and when compared with normal rats of equal body weight. Atrial weight also increased substantially. Haematocrit declined sharply at first, and more slowly later with increasing tumour weight. Haemodynamic measurements were made on these animals at two stages of tumour growth using an anaesthetised open-chest preparation. Cardiac index (per g body wt), stroke index, stroke work, left ventricle +dP/dtmax, and dF/dtmax of aortic flow were greatly elevated in rats with the largest tumours (longer duration), and to a lesser extent in those with smaller tumours (shorter duration). Systemic peripheral resistance and heart rate were depressed. Ventricular weight increased non-linearly with increases in cardiac index. Cardiac output, stroke volume, stroke work and dF/dtmax normalised per g left ventricle weight were also elevated. Splenomegaly accompanied tumour growth; however, splenectomy of tumour-bearing animals failed to prevent development of anaemia and cardiomegaly. While a direct effect of elevated growth hormone provides the best explanation for development of cardiomegaly in this model, volume work overloading due to anaemia and water retention may be a contributory cause.

Cardiac compliance and dimensions in carbon monoxide-induced cardiomegaly.

Adult male rats inhaled 500 ppm CO continuously for 38 to 47 days to produce significant cardiomegaly. In a first experiment in which heart wall stiffness was examined, haematocrit rose 45.1% and the ratio of the sum of right ventricle (RV) and left ventricle (LV) to body weight (mg X g-1) increased from 2.69 to 3.34. Compliance (ml X mmHg-1) of CO LV's and RV's studied from 0 to 25 mmHg intraluminal pressure, was generally greater than that of LV's and RV's from controls at the same pressure. These differences were greater for RV's. There was no difference between control RV's and LV's at the same distending pressure. The differences between treated and control groups disappeared when compliance was normalised per g heart weight. In a second experiment in which heart dimensions were examined, haematocrit ratio increased 48.6% and 2V (RV + LV) to body weight ratio (mg X g-1) increased from 2.77 to 3.45. Atrial weight was also greater. LV apex to base length increased 6.4% and LV outside diameter increased 7.3. No significant differences in LV, RV or interventricular septum (S) thickness resulted from CO exposure, as measured at three sites in each, in four cross-sections of the heart between the apex and base. In general, LV wall was slightly thicker than S, while RV was about 35% that of LV. The findings suggest that chronic carboxyhaemoglobinaemia produces largely eccentric cardiomegaly, and that there is no intrinsic change in wall stiffness.

Hemodynamic response to carbon monoxide.

Historically, and at present, carbon monoxide is a major gaseous poison responsible for widespread morbidity and mortality. From threshold to maximal nonlethal levels, a variety of cardiovascular changes occur, both immediately and in the long term, whose homeostatic function it is to renormalize tissue oxygen delivery. However, notwithstanding numerous studies over the past century, the literature remains equivocal regarding the hemodynamic responses in animals and humans, although CO hypoxia is clearly different in several respects from hypoxic hypoxia. Factors complicating interpretation of experimental findings include species, CO dose level and rate, route of CO delivery, duration, level of exertion, state of consciousness, and anesthetic agent used. For example, tachycardia is commonly observed, although bradycardia also can result from myocardial and/or central nervous system (CNS) hypoxemia at high carboxyhemoglobin (COHb) saturations, as can electrocardiographic abnormalities. Augmented cardiac output usually observed with moderate COHb may be compromised in more severe poisoning for the same reasons, such that regional or global ischemia result. The hypotension usually seen in most animal studies is thought to be a primary cause of CNS damage resulting from acute CO poisoning, yet the exact mechanism(s) remains unproven in both animals and humans, as does the way in which CO produces hypotension. This review briefly summarizes the literature relevant to the short- and long-term hemodynamic responses reported in animals and humans. It concludes by presenting an overview using data from a single species in which the most complete work has been done to date.

Is there a connection between carbon monoxide exposure and hypertension?

Exposure to carbon monoxide in our society is a frequent occurrence, from auto exhaust, industrial effluents, and cigarette smoke, and takes place over a wide range of concentrations. It has been suggested that chronic CO inhalation may alter blood pressure, even possibly provoking hypertension by acting alone or in combination with other environmental stressors. Some studies examining the response to CO exposure have reported decreases in blood pressure, whereas others have found increases or no change. Blood pressure in long-term cigarette smokers is generally decreased relative to nonsmokers, albeit a slight decrease. The strength of this finding is somewhat clouded by the effect of the lower body weight in smokers. The increases in blood pressure observed acutely with smoking are mainly due to nicotine. Chronically, the hypertensive action of nicotine is largely offset by the hypotensive action of CO. Several studies support the notion that environmental CO exposure or smoking accelerates or exacerbates hypertension in some people. It has been asserted that chronic CO exposure increases the development of atherosclerotic disease; however, convincing evidence from animal experiments is lacking. Nevertheless, CO may elevate plasma cholesterol and does appear to enhance atherosclerosis when serum cholesterol is greatly elevated by diet. Using the borderline hypertensive rat, an animal model reputed to have increased sensitivity to environmental stimuli, we found no evidence to suggest a provocatory role for CO in the development of hypertension; instead, CO exposure produced hypotension. On the whole, the human and animal literature, as well as our studies, fail to support the hypothesis that long-term CO exposure is capable of provoking an increase in blood pressure, even in borderline hypertensive or sensitive individuals.

Heart and lung alterations in neonatal rats exposed to CO or high altitude.

We wished to determine whether cardiac changes produced by CO are related to the development of pulmonary hypertension and whether they are specific for CO or also occur with high-altitude exposure. Newborn male Sprague-Dawley rats were exposed to 500 ppm CO for 32 days (CO) at Detroit, MI or to 11,500-ft simulated altitude at Fort Collins, CO (barometric pressure 495 Torr; 11K); ambient air controls were maintained at Detroit (657 ft, 200 m; AIR) and at Fort Collins (5,000 ft, 1,524 m; 5K). Rats were maintained at Fort Collins after 34 days of age. Hematocrit was elevated to a greater extent in the CO than in the 11K group 2 days postexposure; however, no differences existed 40, 76, or 112 days postexposure. Right ventricle (RV) and left ventricle plus septum (LV + S) mass in CO rats were increased 38.0 and 37.4%, respectively, relative to the AIR group 2 days after CO exposure; RV and LV + S in the 11K group were increased 55.7 and 9.3%, respectively, relative to the 5K group. Cardiac hypertrophy declined in the CO and 11K groups postexposure but remained significant for the RV, reaching 20.7% above the AIR group (CO) and 29.7% above the 5K group (11K) at 145 days of age. By use of an in vitro preparation, pulmonary vascular resistance (PVR) and pulmonary arterial pressure were significantly increased immediately after altitude but not after CO exposure and remained elevated in adulthood after altitude exposure. PVR was correlated with hematocrit in altitude- but not in CO-exposed rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Chronic CO inhalation and carotid body catecholamines: testing of hypotheses.

The purpose of this study was twofold: one concerns carotid blood flow and tissue PO2 and the other the effect of chronic hypoxic hypoxia on enhanced catecholamine content. The rationale was that chronic CO inhalation would not mimic the effect of hypoxia on the carotid body if its tissue blood flow is sufficiently high to counteract the effect of CO on O2 delivery and, hence, on tissue PO2. The differential effects of CO on the carotid body and erythropoietin-producing tissue would also indicate that the effect of hypoxic hypoxia on the carotid body is the result of a direct action of a local low O2 stimulus rather than secondary to a systemic effect initiated by other O2-sensing tissues. To test these alternatives we studied the effects of chronic CO inhalation on carotid body catecholamine content and hematocrit in the rats, which were exposed to an inspired PCO of 0.4-0.5 Torr at an inspired PO2 of approximately 150 Torr for 22 days. The hematocrit of CO-exposed rats was 75 +/- 1.1% compared with 48 +/- 0.7% in controls. Dopamine and norepinephrine content of the carotid bodies (per pair) was 5.88 +/- 0.91 and 3.02 +/- 0.19 ng, respectively, in the CO-exposed rats compared with 6.20 +/- 1.0 and 3.29 +/- 0.6 ng, respectively, in the controls. Protein content of the carotid bodies (per pair) was 18.4 +/- 1.6 and 20.5 +/- 0.9 micrograms, respectively. Thus, despite a vigorous erythropoietic response, the CO-exposed rats failed to show any significant stimulation of carotid body in terms of the content of either catecholamine or protein. The results suggest that carotid body tissue PO2 is not compromised by moderate carboxyhemoglobinemia because of its high tissue blood flow and that the chronic effect of hypoxic hypoxia on carotid body is direct.

Chronic CO exposure stimulates erythropoiesis but not glomus cell growth.

The effect of chronic CO exposure, which stimulates erythropoietin production and erythropoiesis, was studied on carotid body cells in the rat. The hypothesis to be tested was that chronic CO inhalation would stimulate cellular hypertrophy and hyperplasia of carotid body if it caused local tissue hypoxia as in chronic hypoxia. The failure of an appropriate response would indicate a lack of a specific local effect on carotid body tissue PO2 presumably because of its unusually high tissue blood flow. Six young male rats were exposed to 0.4-0.5 Torr (0.05-0.07%) inspired PCO in air for 22 days. Control rats (n = 6) were maintained under similar conditions except for CO exposure. After the exposure period the rats were anesthetized, blood was collected for hematocrit, and the carotid bodies were surgically exposed and fixed for electron microscopy and morphometry of type I and type II cells and capillary endothelium. Hematocrit was significantly greater in the CO-exposed group (75 vs. 48%), whereas no significant difference was found in the carotid body parenchyma between the control and CO-exposed groups. We conclude that the lack of an effect of chronic CO exposure on the carotid bodies in contrast to the strong erythropoietic response indicates a relatively high tissue blood flow rate in the carotid body and that CO did not exert a direct cellular effect. The results also suggest that the hypertrophic response of carotid body glomus cells to chronic hypoxic hypoxia is the result of a local direct effect of low PO2 rather than secondary to systemic effects.

Exposure of neonatal rats to carbon monoxide alters cardiac adaptation to aortic constriction.

We tested the hypothesis that a 32-day exposure of newborn rats to 500 ppm carbon monoxide (CO) would alter the adaptive response of the heart to aortic constriction in adulthood. At 110 days of age aortic constriction or sham operations were performed, and hearts were studied 28 days later. Aortic constriction increased left ventricular (LV) mass by 40% over the control value of 611 +/- 27 mg; this adaptive response was not altered by CO exposure. Aortic constriction and CO exposure increased right ventricular (RV) mass by 10 and 11%, respectively, over the control value of 185 +/- 10 mg. The effects of both experimental procedures on RV mass were additive (23%). Peak LV pressure development (dP/dtmax) in vitro increased 29% after aortic constriction in the nonexposed rats. CO exposure blunted the increase in peak LV systolic pressure due to aortic constriction. Maximum positive and negative dP/dtmax decreased by 19% after aortic constriction and were unaffected by CO exposure. The percentage of alpha-myosin heavy chain (MHC) in the ventricles was 94 +/- 2% in the control group and was decreased to 81 +/- 3% by aortic constriction. In contrast, the percentage of alpha-MHC was 87 +/- 2% for CO-exposed rats and was not significantly altered after aortic constriction. In vitro coronary flow was increased 18% in hearts of adult rats exposed to CO as neonates. Exposure of neonatal rats to CO induced chronic adaptations in the myocardium, some of which became evident in adulthood only when hearts were challenged by aortic constriction.

Effects of verapamil and carbon monoxide on blood pressure and heart mass in the spontaneously hypertensive rat.

Studies were carried out to examine the relationship between blood pressure lowering using the Ca2+ channel blocker verapamil, and regression of ventricular hypertrophy, in the spontaneously hypertensive rat (SHR). Untreated male SHR showed rapidly developing hypertension (systolic pressure 194 +/- 2 mm Hg, 109 days of age) and moderate ventricular hypertrophy. Verapamil (Calan-SR, G.D. Searle Co.) treatment for 30 days at maximum doses of 18.7 and 49.9 mg/kg per day supplied in the food, lowered blood pressure maximally 37 mm Hg. The drug had no effect on heart rate. Decrease in the mass of the left ventricle plus interventricular septum was positively correlated with the verapamil-induced decrease in blood pressure (r = 0.69, P less than 0.001). SHR exposed continuously to 500 ppm carbon monoxide (CO) for 30 days showed a similar decrease in blood pressure (33.0 mm Hg). Such SHR, however, displayed increases in mass of the left ventricle plus septum and right ventricle, and of hematocrit, nearly identical to same age Sprague-Dawley rats similarly exposed to CO. Neither verapamil nor CO treatment altered myocardial water content. The results suggest that a modest lowering of blood pressure with verapamil in the SHR produces a relatively rapid decrease in left ventricular mass. It also shows that even when afterload is reduced in the SHR, as with CO, substantial ventricular hypertrophy develops, probably because of augmented preload, and that it is comparable to that produced in non-hypertensive rats.

Acute carbon monoxide poisoning in an animal model: the effects of altered glucose on morbidity and mortality.

An animal model in which the common carotid artery and the jugular vein serving one side of the brain are occluded by indwelling catheters has been used during the past few years to investigate acute carbon monoxide (CO) poisoning. This article reviews the recent research examining the pattern of changes in blood glucose concentration which results from CO exposure, and the manner in which altered glucose concentration alters neurologic outcome and mortality. At present it appears that either greatly depressed glucose or greatly elevated glucose during and/or after CO exposure increases morbidity and mortality. Cyanide (CN) poisoning, in contrast to CO, produces a different pattern of changes in blood glucose and lactate, and unlike CO, fails to slow cardiac AV conduction and ventricular repolarization. Through the use of magnetic resonance imaging and spectroscopic techniques, cerebral cortical edema and the changes in brain phosphagens have been assessed following CO poisoning in the rat. The published results as well as data from recent pilot studies are discussed in the light of our current understanding of CO toxicology.

Acute carbon monoxide poisoning: animal models: a review.

Animals have been used for well over a century in an attempt to understand the toxicology, physiology, and pathology of acute carbon monoxide poisoning. Whether the toxic effects of this gas result from primary hypoxia, as in hypoxic hypoxia to which it is frequently compared, or from direct tissue effects since it enters cells and binds to certain vital components, remains a point of controversy. Acute severe poisoning in man and animals affects primarily the cardiovascular and nervous systems, and frequently produces neurologic dysfunction. Morphologically, tissue damage is usually confined to the white matter. The root cause is at best poorly understood and major investigative efforts have been made toward its elucidation. Many studies with rats, cats and primates indicate a major role for CO-induced hypotension, which serves to compromise blood flow and exacerbate acidosis. The likely cellular mechanisms in this process are only now becoming apparent. This review critically examines the recent as well as a few older CO-animal studies. In scope, they fall into several broad categories: general cardiopulmonary effects, metabolic and tissue effects, general resistance (i.e. tolerance), effects on the central nervous system including blood flow, neurochemistry, morphology and behavior, and finally, experimental therapeutic approaches.

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.

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.

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.

Electrocardiographic responses to carbon monoxide and cyanide in the conscious rat.

Carbon monoxide (CO) and cyanide (CN), commonly found in exhaust fumes and smoke, act as hypoxic agents in eliciting morbid and lethal effects. This study explored the effects of these two toxicants on the ECG in a controlled and well-characterized animal model. Levine-prepared awake female rats were treated with 1500 and 2400 ppm CO for 90 min, CN at 4 mg/kg, or 1500 ppm CO plus 4 mg/kg CN. As in past studies, CO initially induced hyperglycemia and many-fold increases in blood lactate concentration, and rebound increases in blood glucose during recovery. CN produced hyperglycemia, however, there was no glucose rebound, nor was there a significant increase in lactate. CN plus 1500 ppm CO produced glucose changes similar to that of CO alone. CO exposure also induced hypothermia and hypotension, while CN produced little change in these parameters. CO increased heart rate, while CN tended to decrease heart rate. PR interval was increased significantly 4.5-17.0 ms by exposure to CO, with or without combination with CN, while CN alone produced minimal change in the PR interval. QT interval was increased up to 20 ms by exposure to CO, with or without combination with CN. CN alone produced no change in the QT interval. T wave duration was increased up to 22.5 ms by exposure to 1500 ppm CO, with or without combination with CN. CN alone produced minimal changes in T wave duration. There were no changes in duration of the (Q)RS complex or of the R wave. QT interval lengthening was positively correlated with the decrease in systolic blood pressure (0-30 min, r = 0.657, P < 0.05; 0-60 min, r = 0.704, P < 0.05). Hypothermia was correlated with increase in lactate concentration (r = 0.73, P < 0.05) and with decrease in blood pressure (r = 0.69, P < 0.05). No correlation between body temperature and QT interval was observed. The results indicate that CO at the concentrations used in the Levine-prepared rat has major effects on the ECG in slowing AV conduction and ventricular repolarization. In contrast, CN at 4 mg/dl has little or no effect on either conduction or repolarization in this animal model. These findings are discussed in light of past animal and human studies.

Metabolic, cardiovascular, and neurologic aspects of acute cyanide poisoning in the rat.

Acute cyanide (CN) toxicity was investigated in the Sprague-Dawley rat. Conscious, loosely restrained rats received sodium CN solution at varying dose rates through a jugular cannula (low CN, 0.077-0.155 mg/kg/min; high CN, 0.157-0.204 mg/kg/min). Blood glucose concentration was significantly increased 45 min after initial CN treatment in both the low and the high CN groups compared to the saline controls. Blood lactate concentration was significantly increased only in the high CN group after 45 min. Lactate increased directly with CN dose rate in surviving high CN rats. In rats that succumbed during CN infusion, lactate concentration reached nearly 150 mg/dl. Body temperature decreased modestly at low CN dose rates, but increased markedly at high CN dose rates. Heart rate was relatively constant in the low CN group, but decreased rapidly in the high CN group with increasing CN dose rate. In rats surviving CN treatment, no significant alterations in either cerebral cortical water content or neurologic status were detected. This contrasts with another potent poison, carbon monoxide, which produces marked neurologic deficit and cerebral edema in this animal model. The mean lethal CN dose was 4.6 mg/kg (range 4.25-4.90 mg/kg). Expressed on the basis of CN infusion rate, the lethal zone was from 0.16 to 0.21 mg/kg/min, a surprisingly narrow range. Assuming that extrapolations are possible to other species, the data provide strong evidence that greatly elevated blood lactate may be a useful marker for CN poisoning very near or within the lethal zone.

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.

Hypothermia following acute carbon-monoxide poisoning increases mortality.

The effect of body temperature during recovery from acute severe carbon monoxide (CO) poisoning on morbidity and mortality was investigated using an unanesthetized animal model. Levine prepared female rats were exposed to 2700 ppm CO for 90 min, displaying the usual hypothermia, hypotension and bradycardia. Body temperature in survivors was either maintained at the terminal CO exposure value for 4 h ('cooled'), rapidly raised to the pre-CO exposure value for 4 h ('heated') or allowed to return to normal naturally ('unheated'). Following this period of recovery, the 'heated' rats sustained the lowest mortality rate (22%), the 'unheated' rats a greater mortality rate (44%), and the 'cooled' rats the highest mortality rate (50%). Inclusive of the surviving rats, there were no significant differences in neurologic deficit between the three groups, after 4, 24 or 48 h of recovery. Aside from a significant delay in recovery of blood pressure in the 'heated' rats relative to the other two treatment groups post-CO, there were no differences in blood pressure, heart rate or plasma glucose. The results suggest that rapid return to euthermia improves survival following acute severe CO poisoning, contrasting with an earlier study showing the detrimental effect of euthermia during CO poisoning.

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.