David G. Penney & Kangmei Chen
Abstract Levine-prepared, female, Sprague-Dawley rats were used to investigate the possible protective effects of the NMDA receptor blocker-anesthetic ketamine and the Ca++ channel-blocker verapamil (0.4 mg/kg, "low dose" and 1.0 mg/kg, "high dose"), in rats during acute 2,400 ppm carbon monoxide (CO) poisoning. Blood glucose and lactate concentrations, heart rate, mean arterial blood pressure (BP), body temperature (BT), neurologic function, and cerebral cortical water content were measured. In most cases glucose increased after 45 min, then fell to initial values after 90 min. Lactate concentration increased sharply during CO exposure in the saline, and in the low and high dose verapamil groups, while the lactate increase in rats given ketamine at 40 mg/kg was significantly lower than with saline. Lactate was also significantly lower in these rats after 90 min than in the high dose verapamil group. Lactate was normal in all four groups after 2 and 4 hrs of air recovery. Ketamine significantly lowered heart rate prior to CO exposure, and heart rate remained significantly below values for the saline, and the low and high dose verapamil groups throughout CO exposure. BP decreased in all groups during CO exposure. BP recovery which took place in all four groups, was significantly more rapid in the ketamine group. Recovery from CO-induced hypothermia was similar in the ketamine and saline groups, whereas rewarming tended to occur more slowly and less completely in the two verapamil-treated groups. There were no significant differences in neurologic function among the four groups, as assessed after four hrs of recovery. However, cerebral edema was significantly reduced by treatment with 40 mg/kg ketamine as compared with saline. Verapamil at neither the low nor the high doses was of significant benefit in this regard. No rat in the 40 mg/kg ketamine group died during CO exposure, whereas all deaths in the other groups took place during CO exposure. The use of higher and lower doses of ketamine, suggest 40-80 mg/kg as most effective in suppressing lactate produc-tion; 40 mg/kg ketamine may be optimal with regard to survival. The results suggest that ketamine is beneficial when administered before and during acute severe CO poisoning, in reducing blood lactate and cerebral edema, and in improving BP recovery and survival. Verapamil, in contrast, appears to provide no benefits in these respects.
Key words: Blood Pressure, Carbon Monoxide, Cerebral Edema, Dose-Response, Glucose, Heart Rate, Hypothermia, Ketamine, Lactate, Neurologic Index, Verapamil
Alicia A. Salkowski & David G. Penney
Abstract 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.
Key words: Body temperature; Brain; Glucose; Heart rate; Lactate; Lethality
David G. Penney, Alvaro A. Giraldo & Eve M. Van Egmond
Abstract Adult male rats were exposed to 500 ppm CO continuously for 30 days, while litter-mate controls remained in room air (AIR). Heart weight-to-body weight ratio and hematocrit were increased significantly. Right ventricle (RV) free wall thickness was increased significantly as was right to left heart diameter and average heart diameter. Cross-sectional areas of the left ventricle (LV) free wall, interventricular septum (S) and RV midway between the apex and base were increased significantly. Morphometric analysis of the CO-exposed and AIR hearts revealed no significant differences in the number of small (27-114 um) or larger (>114 um) blood vessels in any region; however, there was a trend towards an increased number of the smaller vessels, both arterioles and venules, in the CO-exposed rats. The larger arteries in the S and RV were significantly larger in the CO-exposed rats. There was a significant overall effect of CO on larger artery diameter across all heart regions, consistent with the appearance of heart radiographs taken. There were no differences in the diameter of the small vessels in any region of the heart between the CO-exposed and AIR rats. The vessel cross-sectional area of the larger vessels tended to be increased in all regions of the heart. The cross-sectional area of the large arteries in the LV was increased significantly. Arterial wall thickness was decreased significantly in RV and there was a significant overall effect of CO in decreasing wall thickness and the ratio of wall thickness-to-vessel luminal diameter in these vessels. No vascular pathology was observed. The results of this study suggest changes in coronary vessel architecture during chronic CO-induced cardiac hypertrophy and are consistent with earlier hemodynamic and morphometric studies of CO-exposed hearts.
Key words: artery; blood vessel; carbon monoxide; cardiomegaly; cardiac hypertrophy; coronary; left ventricle; rat, right ventricle; vein
David G. Penney, Alvaro A. Giraldo & Eve M. Van Egmond
Abstract The goal of this study was to determine whether chronic monoxide exposure in the developing heart produces long-lasting coronary vasculature alterations. One-day-old male rat pups were exposed to 500 ppm CO continuously for 30 days, while littermate controls remained in room air (AIR). At 61 and 110 days of age hearts were removed, perfusion fixed, x-rayed, and processed for analysis of coronary vessel architecture. Body weight (BW) and heart weight (HW) increased with age; the ratio of HW/BW decreased. There were no differences in HW and ventricular dimensions at either age due to prior CO exposure. Morphometric analysis of the fixed hearts from CO-exposed and AIR rats revealed no significant individual group differences in the number of small (27-114 um) or larger (>114 um) vessels in any heart region. The septum (S) in CO rats was an exception: There were more small veins at 61 days of age and more larger veins at 110 days of age. There was a significant increase in the number of small arteries at both ages in the CO rats across all heart regions, and in the smaller veins at 61days of age. The large vessels in the S at 61 days of age had a significantly greater diameter in CO compared to AIR rats. This was also true for the large arteries in the S and right ventricle (RV) of the 110-day-old rats. Taking all heart regions together, the large arteries in CO rats were larger than in AIR rats. Previous CO exposure significantly increased large artery and total cross-sectional area in the S and RV at 61 days of age, and in RV at 110 days of age. Total cross-sectional area of veins in the S was also increased. Taking all heart regions together, CO significantly increased small artery crosssectional area at 61 d of age, and small, large, and total artery cross-sectional area at 110 days of age. With one exception (small veins, 110 days of age), there was no effect of CO on vein cross-sectional area. These changes resulted in the percentage of total crosssectional area contributed by the larger vessels being increased. Pathological examination showed nothing abnormal. The results suggest profound and persistent changes in coronary vessel architecture following chronic neonatal CO exposure.
Alan Tucker & David G. Penney
Abstract Exposure of adult and neonatal rats to high altitude increases pulmonary vascular responsiveness during the exposure. A study was undertaken to determine if a short exposure of neonatal rats to either high-altitude or carbon monoxide (CO) hypoxia would cause persistent alterations in pulmonary vascular responsiveness postexposure. One-day-old male Sprague-Dawley rats were obtained as 16 litters of 10-12 pups each. At 2 days of age, 4 litters were exposed to CO (500 ppm) for 32 days, and 4 litters were exposed to ambient air (AIR) in Detroit (200 m). Another 4 litters were exposed to 3500 m altitude (ALT) in a chamber for 32 days, and 3 litters were exposed to ambient conditions in Fort Collins (CON, 1524 m). After the exposures, all rats were maintained at 1524 m. At 2, 40, 76, and 112 days postexposure, lungs were isolated and perfused with Earle's salt solution (+Ficoll, 4 g%). Pulmonary vascular responsiveness was assessed by dose responses to angiotensin II (AII, 0.025-0.40 ug) and acute hypoxia (3% ¡2 for 3 min). AII responses were higher in ALT vs CON rats at all ages, but no differences were noted between CO and AIR rats. Acute hypoxic responses were higher in ALT versus CON rats at 2 and 40 days postexposure, but no differences were noted between CO and AIR rats. Baseline pulmonary vascular resistance and pulmonary arterial pressure (in isolated lungs) were higher in ALT rats at all four ages compared to the other three groups. Both the ALT and CO rats displayed hypertrophy of the right ventricle (RV) and the left ventricle (LV) at the termination of treatment and elevated hematocrit. LV hypertrophy and polycythemia regressed with time, but RV hypertrophy remained significant in the ALT rats through 112 days postexposure. The results indicate that neonatal exposure to ALT, but not CO, causes a persistent increase in pulmonary vascular responsiveness and RV hypertrophy for at least 112 days after termination of the exposure.
David G. Penney & John M. Formolo
Summary 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-l 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. Iowered LV afterload), and the blockade of either alpha or beta-l reccptors. 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 suggcst the potentially powerful role ol' enhanced preload in driving myocardial hypertrophy.
Key words: Atenolol; Blood pressure; Carbon monoxide; Cardiac hypertrophy; Heart rate; Heart weight; Hypotension; Prazosin; Ventricle
Gary M. Katzman & David G. Penney
Summary 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.
Key words: Blood pressure; Carbon monoxide; Cyanide; Electrocardiogram; Glucose; Heart rate; Hypothermia; Lactate; PR interval; QT interval; T wave
Acute carbon monoxide poisoning in an animal model: The effects of altered glucose on morbidity and mortality
David G. Penney
Summary 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.
Key words: ATP; Brain; Carbon monoxide; Cerebral Cortex; Creatine Phosphate; Cyanide; Edema; Electrocardiogram; Glucose; Hypoglycemia; Lactate; Morbidity; Rat
David G. Penney, Alan Tucker & Gregory A. Bambach
Abstract 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 llK groups post-exposure 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 the CO-exposed rats. RV mass was correlated with PVR immediately after altitude but not CO exposure. CO and altitude resulted in increases in RV DNA content immediately after exposure as well as at 74, 110, and 145 days of age, changes interpreted as likely due to increases in cardiac myocyte numbers. Adult RV DNA concentration was unchanged suggesting unchanged average myocyte volume. The results demonstrate that early postnatal CO exposure is not associated with pulmonary hypertension; thus persistent changes in cardiac mass and myocyte number cannot be attributed to it; however, pulmonary hypertension may contribute to similar changes that occur after high-altitude exposure of neonates.
Key words: cardiac hypertrophy; deoxyribonucleic acid; hematocrit; heart mass; persistent cardiomegaly; pulmonary arterial pressure; pulmonary hypertension; pulmonary vascular resistance; right ventricle