THE increase in cardiac output during

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1 Effects of Cateeholamines and Atropine on Cardiovascular Response to Exercise in the Dog By ERNST W. 0. KECK, M.D., MICHAEL J. ALLWOOD, M.B., PH.D., ROBERT J. MARSHALL, M.D., M.R.C.P., AND JOHN T. SHEPHERD, M.D., M.CH., D.SC. THE increase in cardiac output during exercise in the dog is caused mainly by tachycardia, the stroke volume increasing only slightly from the resting value. 1 " In the present study, the response to exercise was analyzed further by observing the modifications induced by infusions of cateeholamines and by atropinization. The results show that under these conditions the increased cardiac output during exercise may be achieved by wide variations in the relative contributions of stroke volume and heart rate. Methods Twelve mongrel dogs, weighing from to 0 Kg., were taught to stand quietly and to run at graded speeds on a treadmill. The techniques were similar to those described previously but, in all observations being reported here, the cardiac catheters were introduced under local anesthesia, and a densitometer with a fast dynamic response was used. Infusions of epinephrine bitartrate (Supra - renin),t norepinephrine bitartrate (levarterenol; Levophed), and isoproterenol hydrochloride (Isuprel-Winthrop) in doses of to 0 ;ttg. of the salt per minute were made into the right atrium by means of a motor-driven syringe. The cardiac output was measured by the indicator-dilution methodt during the third minute of infusion. From the Mayo Clinic and the Mayo Foundation, Bochester, Minnesota. Supported in part by a grant from the Minnesota Heart Association, and in part by Eesearch Grant H- from the U.S. Public Health Service. Received for publication December 0, 10. *The densitometer was similar to model XC-0A manufactured by the Waters Corporation, Eochester, Minnesota, but it had a slightly larger internal diameter to permit higher sampling rates. tsynthetie J-epinephrine (Suprarenin) was generously supplied by Winthrop Laboratories, Xew York, New York. }The cardio-green dye used in this method was kindly supplied by Hynson, Westcott and Dunning, Baltimore, Maryland. When an infusion was given during exercise, both procedures were started almost simultaneously. After each infusion, sufficient time was permitted for the heart rate and blood pressure to return to previous levels. Atropine sulfate was given by injection into the right atrium, usually in divided doses, until no further increase in heart rate occurred. Results Table 1 summarizes the results from experiments in which the cateeholamines were infused. It includes only data obtained at rest and at one grade of exercise. Responses to other doses of the drugs and other grades of exercise were qualitatively similar. Table summarizes the results of five experiments, also at rest and at one grade of exercise, before and after atropinization. Figure 1 shows dilution curves obtained in one of the dogs during rest and exercise before and after atropinization. The effects of exercise alone were similar to those previously reported. For the 15 experiments summarized in the tables, the mean increases from rest to exercise were 1 per cent for cardiac output, per cent for heart rate, and per cent for stroke volume. Epinephrine Infusions of epinephrine at the rate of jug. per minute in three resting dogs increased the aortic blood pressure by per cent, the cardiac output by per cent, the heart rate by per cent, and the stroke volume by per cent (mean values). Infusions during exercise were associated with a cardiac output similar to that during identical exercise before any infusion was given. The heart rate was consistently less and the stroke volume consistently greater than values during control exercises. Results of four other experiments were discarded because the infusion was associated with ventricular extra- 5 Circulation Research, Volume IX. May 11

2 CATECHOLAMINES, ATROPINE, AND EXERCISE 5 (Dog- kg.) iorta- - REST - STANDING REST -STANDING (Following.0 mg. Alropine) (mg/l.j 1 W AQBTA ror! fftf A l i.l B mg Cert ran int > SupfiOf io-g Con/a 1 ' no EXERCISE - km.p.h. (mg.su h1 > a EXERCISE- km.p.h. (Following.0 mg. Atrotpine) V v,v AORTA A AQRT, - Z - w Figure 1 Indicator-dilution curves from dog, experiment 1, standing at rent (left panels) and running at km.p.h. (right panels) both before (above) and after (beloiv) intravenous injection of atropine. Electrically damped aortic pressure pulses, from winch the heart rate ivas counted, also are shown. Table 1 Cardiac Response 11 to Infusions of Catecholamines During Rest and Exercise Dog 1 5 Experiment 1 5 Weight, Kg Condition Best, standing Eunning, 1 km.p.h. Running, km.p.li. Running, km.p.h. Before infus;ion H During infusiont volume, ml. (Experiments 1 to : epinephrine bitartrate, pg. per minute. Experiments to : norepinephrine bitartrate, p%. per minute. Experiments to : isoproterenol hydrochloride, /ig. npr per minntp. minute. Circulation Reiearch, Volume IX, May 11 '

3 5 KECK, ALLWOOD, MARSHALL, SHEPHERD Table Cardiac Response" to Atropinizution During Rest and Exercise Dog H 1 Experiment Weight, Kg. 0 Total dose. mg 'Same abbreviations as in table 1. Condition Running, 1 km.p.li. Running, kin.p.li. Running, km.p.li. Running, km.p.li. Running, 1 km.p.li. Before injection Duri CO ng injection H.R. S.V systoles, ventricular tachycardia, or severe sinus arrhythmia. Norepinephrine Infusions of norepinephrine at a rate of /xg. per minute in three resting dogs increased the mean aortic blood pressure by 5 per cent; the cardiac output was reduced by 11 per cent, the heart rate was reduced by per cent, and the stroke volume was increased by 5 per cent (mean values). Infusions of norepinephrine during exercise were associated with a cardiac output slightly less than that during control periods of exercise; the heart rate was considerably less and the stroke volume was greater than corresponding values during control exercises. Thus, the increased stroke volume induced by both epinephrine and norepinephrine at rest was maintained at a comparable level during exercise. Figure (a) illustrates the results in dog 5 when norepinephrine was infused at a rate of /xg. per minute. Isoproterenol Infusions of isoproterenol at a rate of /xg. per minute in four resting dogs reduced the mean aortic blood pressure by 15 per cent; the cardiac output increased by per cent, the heart rate increased by per cent, and the stroke volume was reduced by per cent (mean values). During exercise, the cardiac output was to (mean ) per cent greater than during identical exercise when no infusion was given; the corresponding heart rate was to (mean 1) per cent greater; the stroke volume was almost unchanged, varying by to + (mean 0) per cent. The mean blood pressure was to 0 mm. Hg less than that under control conditions of exercise. Atropine Figure (b) shows the comprehensive results in experiment ; as noted previously, representative results from all five experiments involving atropine are summarized in table. Before atropinization, the cardiac output, heart rate, and stroke volume during exercise were increased by 5, 0, and per cent over the resting values. Measurements made after atropinization both at rest and during exercise showed corresponding increases of 1,, and 0 per cent. Discussion As already mentioned, the response of the heart rate and stroke volume during moderate exercise prior to the administration of the drugs was similar to that previously reported. When epinephrine was infused during exercise, the cardiac output was similar to that during comparable exercise without the drug, but the heart rate was less; therefore, the stroke volume was greater. Thus, the increase in stroke volume induced by the infusion of epinephrine at rest was maintained at a comparable level during exercise (table 1). Similarly, the smaller increase induced by the infusion of norepinephrine at rest was main- Circitlation Research, Volume IX, May 11

4 CATECHOLAMINES, ATROPINE, AND EXERCISE 5 DOG (1 kg.) (Dog. kg.) MEAN l AORTIC PRESSURE,<0 (mm. Hg) HEART RATE (beats/min.) 0 HEART RATE (bears /min.) 1 STROKE VOLUME (ml.) 0 STROKE VOLUME (ml.) CARDIAC OUTPUT (L./ min.) CARDIAC OUTPUT (L.min.) 5 SPEED (km.p.h.) b Figure 1 1 SPEED (km.p.h.) (a) Cardiovascular response to exercise in dog before (closed circles) and during (open circles) infusion of norepinephrine bitartrate at /xg. per minute, (b) Cardiovascular response to exercise in dog, experiment, before (closed circles) and after (open circles) intravenous injection of atropine. tained at a comparable level during exercise (table 1 andfig. a). The bradycardia caused by infusion of norepinephrine is a reflex vagal effect mediated by the pressure receptors. In an added experiment, norepinephrine was infused at a rate of 0 jig. per minute in an atropinized dog. Despite an increase in mean aortic pressure from 1 to 0 mm. Hg, the heart rate increased from 0 to 0 beats per minute, the stroke volume increased from 15 to 1 ml., and the cardiac output doubled. Infusion of epiuephrine at the rate of yug. per minute increased the mean blood pressure from 1 to mm. Hg; the heart rate increased from 1 to beats per minute, and the stroke volume increased from 1 to 5 ml.; the cardiac output was doubled. Thus, the increase in stroke volume in nonatropinized dogs during infusion of epinephrine and norepinephrine is unlikely to be caused solely by a relative or absolute increase in the filling period, but is probably also a consequence of the direct effect of these substances on the heart. Rushmer and associates previously pointed Circulation Research, Volume IX, May 11 out certain similarities between the effects of infusion of isoproterenol at rest and those of exercise in dogs. Both circumstances are characterized by tachycardia, increased cardiac output, reduced ventricular diameter, increased arterial pulse pressure, and decreased peripheral resistance. Little change occurs in stroke volume. However, isoproterenol decreases the mean blood pressure, whereas exercise increases it. With mild and moderate exercise, the cardiac output during atropinization was similar to, or slightly less than, that obtained during previous exercise of comparable degree. However, the relative contribution of changes in the heart rate and stroke volume to the increased output during exercise differed. Thus, after injection of atropine, the heart rate at rest was as much, or almost as much, as that during subsequent exercise; hence, the increase in output with exercise was wholly or predominantly caused by an increase in stroke volume. Although recent evidence has shown that exercise is accompanied in both man and

5 KECK, ALLWOOD, MARSHALL, SHEPHERD dog 1 " by relatively small changes in stroke volume, great changes in stroke volume may occur under other circumstances. Thus, Warner and Toronto, who produced complete atrioventricular dissociation in dogs and stimulated the ventricles at various rates, found that, within wide limits, the cardiac output was independent of the heart rate both at rest and during mild exercise. The present observations provide further evidence of the ability of the heart in unusual circumstances to regulate its output largely or predominantly by changes in stroke volume. In the atropinized dog, owing to the tachycardia at rest, the stroke volume is small, but it increases during exercise to approach the premedication value. By contrast, both epinephrine and norepinephrine increase the stroke volume in the resting animal, and a similar increase in stroke volume is maintained when these agents are infused during exercise. Thus, we agree with Warner and Toronto, who concluded that the cardiac output may be regulated to provide the required flow mainly through changes in stroke volume, even though adjustment of the heart rate is the usual means of attaining this end. Summary The manner in which the administration of epinephrine, norepinephrine, isoproterenol, and atropine modifies the cardiovascular response to exercise has been studied in 1 dogs. In control observations, exercise increased the cardiac output by 1 per cent, the heart rate by per cent, and the stroke volume by per cent. When epinephrine was infused during identical exercise, the cardiac output was similar; however, the stroke volume was increased by per cent. During infusion of norepinephrine, the cardiac output was reduced by 11 per cent compared with that during control exercise, and the stroke volume was increased by 5 per cent. With isoproterenol, the cardiac output exceeded that during control exercise, but the stroke volume was unchanged. Prior to administration of atropine, the cardiac output at rest averaged. L. per minute. After injection of atropine, the cardiac output averaged. L. per minute, the heart rate increased from 11 to beats per minute, and the stroke volume decreased from 5 to 15 ml. Before atropinization, the cardiac output, heart rate, and stroke volume during exercise were increased by 5, 0, and per cent over the resting values; after atropinization, the corresponding increases were 1,, and 0 per cent. Thus, while cardiac output during exercise normally is regulated mainly by changes in the heart rate, the stroke volume may make a major contribution under other circumstances. Acknowledgment The authors wish to thank W. A. Meeker and Julius Zarins for their assistance. References 1. FRANKLIN, D. L., ELLIS, R. M., AND EOSHMBR, R. F.: Aortic blood flow in dogs during treadmill exercise. J. Appl. Physiol. 1: 0, 15.. EUSHMEE, R. F.: Constancy of stroke volume in ventricular responses to exertion. Am. J. Physiol. 1: 5, 15.. WANG, Y., MARSHALL, R. J., AND SHEPHERD, J. T.: Stroke volume in the dog during graded exercise. Circulation Research : 55, 10.. RUSHMER, R. F., SMITH, O., AND FRANKLIN, D.: Mechanisms of cardiac control in exercise. Circulation Research : 0, WANG, Y., MARSHALL, R. J., AND SHEPHERD, J. T.: Effect of changes in posture and of graded exercise on stroke volume in man. J. Clin. Invest. : 51, 10.. WARNER, H. R., AND TORONTO, A. F.: Regulation of cardiac output through stroke volume. Circulation Research : 5, 10. Circulation Research, Volume IX, May 11