Cardiodynamic changes during prolonged carbon monoxide exposure in the rat

Cardiodynamic changes during prolonged carbon monoxide exposure in the rat

TOXICOLOGY AND APPLIED PHARMACOLOGY (1979) s&213-218 Cardiodynamic Changes during Prolonged Carbon Monoxide Exposure in the Rat’ DAVID Departmen...

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TOXICOLOGY

AND

APPLIED

PHARMACOLOGY

(1979)

s&213-218

Cardiodynamic Changes during Prolonged Carbon Monoxide Exposure in the Rat’ DAVID Department

G. PENNEY, PETER C. SODT, AND ANTHONY

CUTILLETTA

of Physiology, Wayne State University, School of Medicine, Detroit, Michigan Northwestern University, School of Medicine, Chicago, Illinois 6061 I ; and The Johns Hopkins Hospital, Baltimore, Maryland 21205 Received February

48201;

1, 1979; accepted April 3, 1979

Cardiodynamic

Changes during Prolonged Carbon Monoxide Exposure in the Rat. P. C., AND CUTILLETTA, A. F. (1979). Toxicol. Appl. Pharmacol. 50, 213-218. Adult male rats were exposed to 500 ppm CO (38-42x COHb) for periods of time from l-42 days. Hematocrit rose gradually from 49.8 to 69.7%. Cardiomegaly developed as reported earlier. Using an open chest anesthetized preparation, stroke index, mean stroke power, and mean cardiac output were seen to increase sharply upon initial CO exposure and to remain elevated for the duration of exposure. Concurrently, both total systemic resistance and total pulmonary resistance fell sharply and remained depressed. Left ventricle (LV) and right ventricle (RV) systolic pressures and mean aortic pressure rose modestly, but nonsignificantly over the first 14 days of exposure, declining somewhat thereafter. The maximum rate of change of LV pressure (dP/dt) tended to rise above control values during the first 2 weeks of exposure. There was no consistent change in heart rate. Enhanced cardiac output via increased stroke volume is seen as a compensatory mechanism to provide adequate tissue oxygen delivery during CO intoxication. The greater continuous heart work involved may be the major factor responsible for development of CO-induced cardiomegaly. PENNEY,

D.

G.,

SODT,

Continuous inhalation of high sublethal levels of carbon monoxide in the rat produces rapid increases in hemoglobin (Hb) concentration, heart weight (HW), and alterations in myocardial lactate dehydrogenase (LDH) isozyme pattern (Penney et al., 1974b). In the adult male rat, a CO concentration in air of 500 ppm CO produces approximately a 40% increase in HW over several weeks, with four-fifths of the increase occurring within 14 days (Penney et al., 1974a,b). Both the hematological and cardiac morphological changes observed during such exposure are reversible, vanishing approximately 30 days postexposure (Penney and 1 Supported in part by U.S. Public Health Service Research Grant HL-16367 (NHLBI-NIH). 213

Bishop, 1978; Styka and Penney, 1978). However, exposure to higher concentrations of CO appears to leave some residuum of the changes in myocardial mass and LDH isozyme composition after the stress is relieved (Styka and Penney, 1978). The mechanism(s) responsible for the extraordinary heart growth when animals are placed in CO is unclear, although several possibilities exist; (1) a direct effect of CO on the heart muscle; (2) pressure overload resulting from the greatly elevated hematocrit; (3) volume overload resulting from increased cardiac output; (4) some combination of (l-3). Chiodi et al. (1941), us&g acute CO exposure in man and dog, saw no more than slight increases in cardiac output 0041-008X/79/1 10213-06$02.00/0 Copyright 0 1979 by Academic Press. Inc. All rights of reproduction in any form reserved. Printed in Great Britain

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with COHb saturation ranging up to 30%, while at COHb concentrations near 50%, cardiac output increased as much as half. They observed no consistent changes in blood pressure with increasing CO intoxication. More recently, Ayres et al. (1970), studying hemodynamic responses to acute increases in COHb in man during diagnostic cardiac catheterization, observed 10% increases in cardiac output at COHb saturations of 6-12%. Augmented cardiac output, as such, would presumably act to reestablish adequate tissue oxygen delivery by increasing organ perfusion. Adams et al. (1973) in another study, reported that left ventricle (L-V) systolic pressure in conscious dogs acutely exposed to CO was unchanged at graded COHb saturations up to 20%, while heart rate (HR) increased approximately in proportion to COHb saturation. They also observed proportional increases in coronary flow as CO intoxication progressed. As far as we are aware, no data are available on cardiodynamic effects of long-term exposure to CO. Therefore, the goal of the present study was to investigate possible changes in right and left heart function resulting from exposure to CO in time-course fashion over a period of 6 weeks. METHODS Animal treatment. Male Charles River-derived rats (COBS) 100-120 days of age (at sacrifice), born and reared in the animal facility at the University of Illinois at Chicago Circle, were used. They were randomly divided into two groups, controls and those animals which would inhale 500 ppm CO (CP grade) in air continuously under conditions previously described (Penney et al., 1974a) for a period of time ranging from 1 to 42 days. This conccriration of CO in inspired air binds approximately lo% of the circulating Hb as COHb within 2 hr of initial exposure (Montgomery and, Rubin, 1971). The rats were kept in metal cages enclosed in transparent plastic bags through which a metered flow of the air + CO mixture passed at a rate of 20-30 liters/min. The rats were removed from the CO every second day for approximately 10 min between 10 AM and 2 PM for routine maintenance. Both the treated and control groups were given standard laboratory rat chow diets (Ralston Purina Co., St. Louis, MO.) and

water ad libitum. The rats were maintained on a 12 hr12 hr light (8 AM-8 Pr+dark cycle at 20°C. Relative humidity was not controlled. Evaluation of heart function. With the exception of a few minor modifications this evaluation was carried out by the method of Dowel1 et al. (1975). Rats of the following numbers and body weights were used: controls, 6, 4385 18 g; 1 day exposed, 3, 428+ 14 g; 2 day exposed, 3, 389+ 18 g; 6 day exposed, 4,351 f 19 g; 14 day exposed, 4,421+ 7 g; and 42 day exposed, 5, 428f8 g. With regard to the six control rats, evaluation of heart function was carried out on 1 or 2 of these each time CO-exposed rats were evaluated. They were anesthetized with sodium pentobarbital (50 mg/kg, ip) and placed on a heating pad to maintain core body temperature at 3638°C. Positive pressure ventilation was initiated via a tracheostomy using a Harvard respirator (Model 680) at a rate of 40/min and a tidal volume of 2-3 ml. Controls were ventilated with room air, while treated rats were ventilated with 500 ppm CO in air. ECG leads were attached across the chest. A catheter was inserted above the bifurcation of the abdominal aorta and attached to a Statham Model P23Db pressure transducer for arterial pressure measurements. Midline thoractotomy was performed and a square wave electromagnetic flow probe (Carolina Medical Electronics, Model 400) placed on the ascending aorta. Flow calibrations were made in vitro with a short section of rat aorta and all flow measurements were corrected for hematocrit. LV and RV pressures were measured by puncturing the respective ventricle with a 3.8~cm 22-gauge needle attached directly to a Statham Model P37 miniature pressure transducer. This system has a resonant frequency of 140 Hz and flat amplitude (within 3 db) to 70 Hz. The first derivative of LV pressure (dP/dt) was measured by using a resistance
CARDIODYNAMIC

eluded. Total systemic peripheral resistance (TSPR) and total pulmonary resistance (TPR) were obtained by dividing mean left ventricujar and right ventricular outflow pressures by mean cardiac output. Hematocrit (Hct) was measured by the standard microhematocrit method. Carboxyhemoglobin (COHb) saturation was determined by the method of Commins and Lawther (1965). Statistical analysis. All values given are means+ SE of the mean (with the exception of TSPR and TPR). Student’s t test was used for deternination of statistical significance. Differences which resulted in

215

CHANGES AND CO

probability values (p) smaller than 0.05 were considered significant.

RESULTS Measured COHb saturation in all CO exposed rats was 38-42%. Cardiac enlargement in the treated rats proceeded over the same time course as previously reported (data not shown, Penney et al., 1974a).

.60 -

0 E

.55 .50 .45

TIME

(days)

FIG. 1. Cardiodynamic effects of inhalation of 500 ppm carbon monoxide on left ventricle and systemic circulation (HR = heart rate, LVP = left ventricular pressure, R = total systemic peripheral resistance, Hct = hematocrit). Vertical bars are SE. + indicates significant difference from controls (0 days group) (p < 0.05).

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HR did not change in a consistent manner during CO exposure, averaging between 335 and 396 beats/min (Fig. 1). LVEDP remained constant at 3.3-4.0 mm Hg during 6 weeks of treatment, while peak LV systolic pressure increased nonsignificantly from 117 to 141 mm Hg after 2 weeks. Peak LV systolic pressure returned to the control level after 6 weeks. Mean aortic pressure, likewise peaked after 2 weeks of CO exposure and returned to control values after 6 weeks. Stroke index (stroke volume per kg body weight) increased sharply after 1 day of CO exposure and after 2 days reached a level 54% above the control value. Stroke index declined somewhat toward control levels after 6 weeks. Mean cardiac output increased sharply within 1 day of CO exposure and peaked 73% above the control value after 6 days. It declined somewhat at 14 and 42 days of exposure, but remained above the control level. Mean stroke power (integral of left ventricular pressure and mean aortic flow) increased in a similar manner after initial CO exposure and remained elevated throughout

~---&--+-“----~--------~---------t-a 0 10

the period of exposure. The first derivative of aortic flow increased an average of 38% during CO exposure (data not shown). Maximum dP/dt was elevated above the control value at the 2nd, 6th, and 14th days of CO exposure, although to a significant degree, only on the 14th day. TSPR declined significantly from 0.59 PRU in control rats to 0.42, 0.46, and 0.40 PRUs at 1, 2, and 6 days, respectively, after initial CO exposure. TSPR increased somewhat at 14 and 42 days of exposure, but remained below the control value. Hct increased gradually from 49.8% in controls to 69.7% after 42 days exposure to co. RV end-diastolic pressure averaged 1.3 to 2.6 mm Hg throughout the period of CO exposure (Fig. 2). Peak RV systolic pressure, however, increased modestly, although insignificantly, from 28 to 36 mm Hg on the 14th day of exposure. Maximum dP/dt increased above the control value at Days 2, 6, and 14 of CO exposure, although only the latter departure from the control level was significant. TPR declined markedly from

20

30

40

TIME (days) FIG. 2. Cardiodynamic effects of inhalation of 500 ppm carbon monoxide on right ventricle and pulmonary circulation (RVP = right ventricular pressure, R = total pulmonary resistance). Vertical bars are SE. + indicates significant difference from controls (0 days group) (E,< 0.05).

CARDIODYNAMIC

control values on the lst, 6th, 14th, and 42nd days of exposure. Overall, the changes in RV performance measured during CO exposure were similar to those of the LV. DISCUSSION The results of the present study suggest that increased cardiac output, and not elevated blood pressure, is the major cardiodynamic effect of prolonged CO inhalation. This conclusion is in agreement with earlier observations of acute CO intoxication in both man and dog over a wide range of COHb saturation (Adams et al., 1973; Ayres et al., 1970; Stewart et a/., 1973). Thus, CO has primarily a volume, rather than pressure overloading action on the heart. Those studies, as well as this one, suggest that cardiac output increases approximately as COHb saturation increases. Presumably, augmented organ perfusion serves as a compensatory mechanism to reestablish tissue oxygen delivery. The results also show that elevation of cardiac output occurs via an increase in stroke volume, not an increase in HR. Since LVEDP was unchanged, no significant movement, right or left on the ventricular function curve presumably occurred. Therefore, enhanced stroke volume was probably accomplished by a combination of increased inotropicity and augmented ventricular luminal volume. The latter change is the essence of “eccentric hypertrophy,” which results from work overloading predominantly of the volume type (Ford et al., 1976). We saw no significant change in HR with CO inhalation. Killick (1940) claims HR is unaffected until the COHb saturation reaches 25-30%, above which pulse rate increases approximately in proportion to COHb saturation. In a more recent study in the dog (Adams et al., 1973), a 20% increase in HR was reported when COHb saturation reached 20%. In fact, HR was seen to increase approximately in proportion to COHb saturation. However, in another study with humans

CHANGES

AND

CO

217

(Stewart et al., 1973) there was no change in HR as COHb saturation increased briefly up to 15 %. The lack of concerted change in HR in the present study is not viewed as having resulted from the masking effect of pentobarbital anesthesia, since other studies reporting changes have used similar anesthetic procedures (Adams et al., 1973). It is clear that elevated Hct and blood volume, normal consequences of prolonged high-level CO inhalation (Penney and Bishop, 1978; Wilks et al., 1959), are not essential for the increase in cardiac output, as the increase takes place well before there are significant changes in Hct and blood volume. Although proof is lacking, it is conceivable that increased cardiac sympathetic tone and higher levels of circulating epinephrine may be responsible. The enhanced inotropic state of the heart muscle and the depressed TSRR we observed are consistent with this notion. The average 47”,/0 increase in cardiac output sustained during CO exposure dictated a sizeable, sustained increase in cardiac work, as demonstrated by the elevated mean stroke power. By comparison, CO exposure as we used it here, is crudely comparable cardiodynamically to mild endurance exercise continued 24 hr a day for 6 weeks. Presumably, increased cardiac work is the major factor responsible for induction of cardiomegaly in CO-exposed rats. A major inductive role for polycythemia was ruled out by our earlier time-course study of CO effects where onset of cardiomegaly preceded polycythemia (Penney et al., 1974b). Although LV and RV systolic and mean aortic pressures tended to increase, the changes were not statistically significant. Undoubtedly blood pressure would have risen considerably, elevating heart work to an even greater extent, had not TSPR and TPR declined sharply. While a number of previous studies of acute CO exposure (Adams et al., 1973; Chiodi et al., 1941; Stewart et al., 1973) report no change in LV or arterial systolic pressure during CO inhalation, there appear to be no other studies of the same

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SODT,

duration with which to compare our present results. ACKNOWLEDGMENTS We wish to thank Dr. R. T. Dowel1 and P. E. Styka for help in the preparation of this manuscript.

REFERENCES ADAMS, J. M., ERICKSON, H. H., AND STONE, H. L. (1973). Myocardial metabolism during exposure to carbon monoxide in the conscious dog. J. Appl. Physiol.

34, 238-242.

AND

CUTILLETTA

FORD, L. E. (1976). Heart size. Circ.

Res.

39, 297-

303.

KILLICK, E. M. (1940). Carbon monoxide anoxemia. Physiol. Rev. 20, 313-344. MONTGOMERY, M. R., AND RUBIN, R. J. (1971). The effect of carbon monoxide inhalation on in vivo metabolism iu the rat. J. Pharm. Exp. Thu. 179, 465473.

PENNEY, D. G., BENJAMIN, M., AND DUNHAM, E. (1974a). Effect of carbon monoxide on cardiac weight as compared with altitude effects. J. Appl. PhysioI.

37, 80-84.

D. G., DUNHAM, E., ‘AND BENJAMIN, M. (1974b). Chroniccarbon monoxide exposure: Time course of hemoglobin, heart weight and lactate dehydrogenase isozyme changes. Toxicol. Appt.

PENNEY,

Pharmacol.

Z&493-497.

M., GIANNELLI, S., JR., AND MUELLER, H. (1970). Effects of low concentrations of carbon monoxide. IV. Myocardial and systemic responses to carboxyhemoglobin. Ann. N. Y. Acad. Sci. 174,

PENNEY,

268-293.

STEWART, R. D., PETERSON, J. E., FISHER, T. N., HOSKO, M. J., BARETTA, E. D., DODD, H. C., AND HERRMANN, A. A. (1973). Experimental human exposure to high concentrations of carbon monoxide.

AYRES,

S.

CHIODI, H., DILL, D. B., CONSOLAZIO, F., AND HORVATH, S. M. (1941). Respiratory and circulatory responses to acute CO poisoning. Amer. J. Physiol.

134, 683-693.

B. T., AND LAWTHER, P. J. (1965). A sensitive method for the determination of carboxyhemoglobin in a finger prick sample of blood. &it.

COMMINS,

J. Ind.

Med.

22, 139-143.

R. T., CUTILLETTA, A. F., AND SODT, P. C. (1975). Functional evaluation of the rat heart in situ. J. Appl. Physiol. 39, 104331047.

DOWELL,

D. G., AND BISHOP, P. A. (1978). Hematologic changes in the rat during and after exposure to carbon monoxide. J. Environ. Pathol. Toxicol. 2,407-415.

Arch.

Environ.

Health

26, 1-7.

P. E., AND PENNEY, D. G. (1978). Regression of carbon monoxide-induced cardiomegaly. Amer. J. Physiol. 235, H516H522. WILKS, S. S., TOMASHEFSKI,J. F., AND CLARK, R. T., JR. (1959). Physiological effects of chronic exposure to carbon monoxide. J. Appl. Physiol. 14, STYKA,

305-3

10.