Hypertension is not exacerbated by chronic carbon monoxide exposure, with or without added salt, in the borderline hypertensive rat.
Explore the source record for details and available documents.
Aging↗
Biomedical subjects
D G Penney
Publications and source records attributed to D G Penney.
Modifying role of plasma glucose in acute carbon monoxide poisoning.
Explore the source record for details and available documents.
Animals↗
Acute severe carbon monoxide exposure in the rat: effects of hyperglycemia and hypoglycemia on mortality, recovery, and neurologic deficit.
Human and animal studies suggest a poorer outcome in the presence of abnormal blood glucose concentration during cerebral hypoxia-ischemia. It is unknown whether this is also the case in acute severe carbon monoxide poisoning. Using Levine-prepared rats, three groups were established and exposed to CO to answer this question: (1) hyperglycemics resulting from the administration of a 50% glucose solution, (2) hypoglycemics resulting from the administration of normal saline, and (3) untreated controls. The rats inhaled 2400 ppm CO for 90 min in the absence of anesthesia. Blood glucose was raised to a mean value of 402 mg/dL just prior to CO exposure in group 1. This resulted in an increased mortality rate (i.e., 54%), and during 4 h of room air recovery an impaired ability to regain body temperature, an increased plasma lactate dehydrogenase activity, and an increased neurologic deficit as compared with group 3. Hypoglycemia, which developed during CO exposure in group 2 (mean minimum glucose after 90 min, 44 mg/dL), resulted in an increased mortality rate (i.e., 46%), and during 4 h of room air recovery an impaired ability to regain body temperature and an increased neurologic deficit as compared with group 3. Blood glucose concentration in the rats in groups 2 and 3 that died during or shortly after CO exposure was significantly depressed relative to the survivors of those groups. Plasma insulin activity was elevated during CO exposure in group 1 as compared with group 3, but fell during recovery; insulin remained low throughout CO exposure and recovery in group 2. The results demonstrate the deleterious effects of both a very high and a very low blood glucose concentration during acute CO exposure.
Animals↗
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.
Adaptation, Physiological↗
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.
Animals↗
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.
Animals↗
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.
Acute Disease↗
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.
Alcoholic Intoxication↗
Value of notching and slurring of the resting QRS complex in the detection of ischemic heart disease.
The resting 12-lead ECG has long been known to be an insensitive marker of underlying ischemic heart disease (IHD). The purpose of this study was to determine if QRS complex notching and slurring is of significant value as a diagnostic discriminator in the detection of IHD. The data from 205 consecutive patients coming to cardiac catheterization for evaluation of probable IHD were initially analyzed. Eighty-three patients were excluded based upon ventricular hypertrophy, bundle-branch block, lack of data, and pacemaker rhythm. The balance, 122 patients (mean age 61.7 years), were evaluated for angiographic evidence of IHD, ECG findings of QRS notching or slurring, and abnormal Q waves. The data revealed a high prevalence of QRS notching or slurring; 62.2% in those patients with IHD, double the prevalence of significant Q waves (33.3%). The two markers had an approximately equal prevalence (QRS notching or slurring 61.7% vs. Q waves 53.2%) in patients with angiographic evidence of infarction; however, in patients with less than infarct criteria for IHD, the prevalence of QRS notching or slurring was 62.8%, while only 11.6% showed abnormal Q waves. Analysis indicated that QRS notching or slurring has a sensitivity of 62.2% and a specificity of 93.8% for the detection of IHD. The study demonstrates that QRS notching or slurring is a moderately sensitive and a very specific marker of ischemic heart disease in selected patients when using the resting ECG, and is of greatest value in those patients with lesser degrees of ischemic myocardial injury where the prevalence of Q waves is low.
Coronary Disease↗
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.
Animals↗
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.
Animals↗
Atrial natriuretic peptide: a hormone with implications for clinical practice.
The heart functions as an endocrine organ, releasing atrial natriuretic peptide (ANP), a hormone, in response to sodium and fluid overload. Specifically, ANP is released by cardiac myocytes in response to atrial distension. As a hormone, ANP has far-reaching multiorgan effects. The body systems affected include the cardiovascular, renal, neural, gastrointestinal, and endocrine systems. However, the main effects of this hormone are on the renin-angiotensin-aldosterone system. ANP acts to oppose this system by causing vasorelaxation, blocking the secretion and sodium-retaining effects of aldosterone, and inhibiting renal renin secretion. ANP has many potential implications for clinical practice in both short-term and long-term care of patients with fluid and electrolyte balance. Clinicians may use methods to enhance or block endogenous ANP secretion based on assessment of clinical disorder, cause, status of homeostatic mechanisms, and implications for treatment. In addition, ANP may soon be administered pharmacologically, as well as monitored hematologically, in patients with fluid volume overload. In this article we describe the physiologic effects of ANP and address specific implications for clinical practice.
Animals↗
Carboxyhemoglobin in the rat: improvements in the spectrophotometric measurement and comparison to other studies.
An improved and simplified spectrophotometric method for the determination of carboxyhemoglobin (COHb) is described, which employs an equation to correct for the dissociation error during analysis. Two microliters, or less, of blood is diluted with an ammonium hydroxide solution directly in the measuring cuvette. A layer of light mineral oil overlying the diluent was found to increase measured COHb saturation of blood equilibrated with 100% CO. Sodium dithionite treatment of the oil further increased this value in one case. The measured COHb was shown to be affected directly by factors that alter hemoglobin concentration in the diluent (i.e. blood volume, hematocrit). Blood samples kept cold and under oil may be stored safely for as long as 10 days. Measurement of COHb by this method in rats exposed to 525, 900, 1800 and 2400 ppm CO produces higher values than those obtained with the 1965 spectrophotometric method of Commins and Lawther. Variations on the method of Commins and Lawther, as well as COHb values available in the literature for animals exposed to CO, are reviewed briefly.
Animals↗
Cardiomegaly in neonatal rats exposed to 500 ppm carbon monoxide.
Increased hemodynamic workload was induced in growing neonatal rats to study alterations in myocyte structure and number and to determine if carbon monoxide (CO) produced a volume-induced model of cardiomegaly. Newborn rats were exposed to 500 ppm CO for up to 32 days of age, at which time the remaining CO exposed rats and ambient air controls continued development in room air to 200 days of age. In the CO group, ventricular weight to body weight ratio was 26% greater than controls at 6 days of age, more than double at 15 days, and remained 47% greater at 28 days. Although absolute myocyte volumes were not different between the two groups at any time period, the CO group did have greater myocyte volume relative to body weight during the CO exposure period. Binucleated myocytes of both ventricles were longer than controls during the exposure period, but did not have increased width. By 200 days of age, myocytes from left ventricle plus septum of CO exposed rats were significantly shorter and CO exposed rats had more total myocytes than controls (36 x 10(6) versus 32 x 10(6) for controls, P less than 0.05). In this study, cardiomegaly induced by 500 ppm CO from birth to 32 days of age was primarily due to myocyte hypertrophy with myocytes having increased length to width ratios (i.e., alterations consistent with a volume-induced model). Following removal from CO exposure, there was regression of both cardiomegaly and myocyte hypertrophy. With increasing time after removal from CO, myocytes tended to become shorter and smaller compared to age matched controls. This trend was present at 105 days and statistically significant by 200 days of age, resulting in an increased number of myocytes in the myocardium long after removal of rats from CO exposure. We conclude that neonatal exposure to CO causes cardiomegaly by increase in cell length and cell volume, consistent with a volume overload model of cardiac hypertrophy.
Animals↗
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.
Acute Disease↗
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.
Administration, Inhalation↗
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.
Animals↗
Heart and lung hypertrophy, changes in blood volume, hematocrit and plasma renin activity in rats chronically exposed to increasing carbon monoxide concentrations.
Changes in blood volume, heart and lung mass and composition and plasma renin activity were examined in two strains of male albino rats inhaling incrementally-increasing concentrations of CO: 250 ppm for 17 days, 500 ppm for 13-14 days, 750 ppm for 10 days, and 1300 ppm for 10 days. Blood volume increased 86% and erythrocyte mass increased 212% at 1300 ppm, while plasma volume was unchanged or decreased slightly. 'Real' hematocrit (hematocrit corrected for plasma trapping) increased from 50% in controls to a peak of 75% at 1300 ppm CO. Wet weight of right ventricle (RV) and combined right and left atria (2A) increased linearly with CO concentration, paralleling changes in blood volume; while real hematocrit increased non-linearly. Left ventricle + interventricular septum (LV + S) wet weight increased less than RV, but more in Sprague-Dawley than in Wistar rats. Plots of RV, LV + S and 2A weight vs real hematocrit showed sharp upward inflections at real hematocrit 65%, suggesting a possible role of increased viscosity in CO cardiomegaly at the higher hematocrit. Assymetric septal hypertrophy was not present. Lung weight increased with CO concentration, but was not due to increased lung blood volume or edema. Hydroxyproline measurements on heart and lung failed to show increased collagen content. Plasma renin activity measured by radioimmunoassay was depressed at 500 ppm, but was normal at 750 and 1300 ppm CO. Neither heart, lung, liver nor plasma renin measurements suggest congestive heart failure, supporting previous studies in the rat with chronic carboxyhemoglobinemia, in spite of enormously increased blood volume, hematocrit and heart weight.
Animals↗