Rieder, 1926) and bradyeardia (Jarisch & Zotterman, 1948) having been. (Received 25 September 1961)

Transcription

1 298 J. Phy8iol. (1962), 160, pp With 4 text-ftgurem Printed in Great Britain THE BAINBRIDGE REFLEX BY J. J. JONES From the Department of Physiology, King's College, London, W.C.2, and the Department of Physiology, University of Shiraz, Iran* (Received 25 September 1961) In 1915 Bainbridge demonstrated that intravenous infusions of blood or saline produced tachycardia in the anaesthetized dog. His observations were not confirmed by various workers in Wigger's laboratory (Wiggers, 1949 a); indeed, intravenous infusions have been reported to produce bradycardia (Wiggers & Katz, 1921; McCrea & Wiggers, 1933; Aviado, Li, Kalow, Schmidt, Turnbull, Peskin, Hess & Weiss, 1951). An explanation for these conflicting results has been put forward by Coleridge & Linden (1955), who found that the change in heart rate is related to the initial heart rate before the infusion. The purpose of the present investigations is to confirm Coleridge & Linden's findings for the dog, and to extend their observations to the cat, to determine whether its initial heart rate can account for the variability in its response to infusions, both tachycardia (Sassa & Miyazaki, 1920; Rieder, 1926) and bradyeardia (Jarisch & Zotterman, 1948) having been described. METHODS Dog. Infusions of autologous blood, Krebs's bicarbonate solution (Krebs & Henseleit, 1932) or NaCl solution 0-9 g/100 ml. were given in 230 experiments on 47 dogs (6-20 kg) anaesthetized with morphine sulphate (3 mg/kg subcutaneously) followed after 1 hr by chloroform, ether or a mixture of ethanol, chloroform and ether (Bainbridge, 1915) or by sodium phenobarbitone (70 mg/kg) or by chloralose (100 mg/kg) injected intravenously. The infusions were made into the femoral vein with a 50 ml. syringe at a rate of 5 ml./sec and the total volume injected was 8-50 ml./kg. The syringe and solutions were maintained in a water-bath at the dog's thoracic temperature until required. The mean arterial pressure was recorded on a smoked kymograph with a damped mercury manometer attached to the femoral artery. The right atrial pressure was measured with a water manometer by means of a glass cannula passed down the right external jugular vein to the atrium. In 8 of these dogs the sternum was removed and the thorax left open, artificial respiration being maintained by intermittent positive pressure from a pump. In these dogs the left atrial pressure was measured with a water manometer connected to a glass cannula tied into the left auricular appendage and the pulmonary arterial pressure was measured with a water manometer attached to a polyethylene cannula, which was passed through the conus of the right ventricle into the pulmonary artery and secured with a purse-string suture. A continuous record on * Present address: Charing Cross Hospital Medical School, London, W.C. 2.

2 THE BAINBRIDGE REFLEX 299 the kymograph was obtained by attaching the tops of the water manometers to float recorders. The cannulas and manometers contained saturated sodium bicarbonate solution to prevent coagulation. A Hiirthle's manometer was attached to the same arterial cannula as the damped mercury manometer and was used to record the heart rate on a second, more rapid, kymograph. A magnetic signal on the main kymograph showed the time at which the smaller kymograph was running and later the heart rate from the Hiirthle's manometer record was added to the pressure records on the main kymograph. The heart rate was recorded for at least one respiratory cycle and it was found that spontaneous variations of 5 or 6 % commonly occurred: consequently changes of heart rate produced by infusions could not be considered significant if they were less than 10 %. A quantitative estimate of the change in heart rate produced by intravenous infusions was given by the mean change of heart rate/cm H20 rise in right atrial pressure. The initial heart rate was varied by the use of the different anaesthetics (Table 1). TABLE 1. The initial heart rate in 47 dogs with different anaesthetics (recorded as soon as the preparation was set up) Heart rate (beats/min) No. of, Anaesthetic dogs Mean Range Morphine, chloroform and ether Morphine and sodium phenobarbitone Morphine and chloralose Cat. 453 infusions of autologous blood or Krebs's bicarbonate solution were given to 85 cats anaesthetized with chloralose (65 mg/kg injected intravenously) after induction with ether. The infusions were made into the femoral vein with a 10 ml. syringe at a rate of 1 ml./ see and the total volume injected was 5-30 ml./kg. The syringe and solutions were maintained in a water-bath at the cat's thoracic temperature until required. The pressures were recorded as described above for the dog, the thorax being opened and artificial respiration being maintained with a Starling 'Ideal' pump in 44 animals. The manometers and cannulas were filled with saline, coagulation being prevented by an intravenous injection of heparin ('Pularin', Evans) 1000 i.u./kg. The heart rate was recorded by an Ediswan electrocardiograph for at least one respiratory cycle and it was found that the cat's heart rate was constant, so that a change of 5 beats/min could be regarded as significant. A quantitative estimate of the effect of intravenous infusions on the heart rate was given by the mean change of heart rate/cm H20 rise in right atrial pressure. Simultaneous points for heart rate and pressure were obtained by reading the pressures on the manometers and writing them on the electrocardiogram at the instant that it was being recorded. Later these pressures and the corresponding heart rate were added to.the main kymograph record. The initial heart rate was reduced by an intravenous injection of ergotoxine ethane-sulphonate (British Drug Houses; 0 5 mg/kg) in 10 cats and it was increased by further injections of the anaesthetic, chloralose, in 65 cats. RESULTS An intravenous infusion produced an alteration of the heart rate of the dog and the cat which was related to the initial heart rate immediately before the infusion. Figures 1 and 2 and Tables 2 and 3 show that there is a significant negative correlation between the initial heart rate and the proportion of experiments in which tachycardia occurred, and that the degree of acceleration varies inversely with the initial rate. Figure 1 shows

3 300 J. J. JONES \X; ~ % ~40 E 30- % ~~~~x20- IntilherIrt(ets/min) Inita4) s 20 vlo 10g. 1U Fg 2 C C Initial heart rate (beats/min) Initial heart rate (beats/min) Fig. 1 Fig. 2 Fig. 1. Relationship between initial (pre-infusion) heart rate and the percentage of experiments in which tachycardia was produced by an infusion of blood or saline in 230 experiments on 47 dogs. The regression equation: Percentage with tachycardia = (initial rate). Fig. 2. Relationship between initial (pre-infusion) heart rate and the percentage of experiments in which tachycardia was produced by an intravenous infusion of blood or saline in 453 experiments on 85 cats. The regression equation: Percentage with tachycardia = (initial rate). TABLE 2. The change of heart rate produced by intravenous infusions in 47 dogs with different initial heart rates No. of experiments showing % of Ratio of mean change A Initial experiments of heart rate:right heart rate Tachy- No Brady- showing atrial pressure (beats/min) cardia change cardia tachycardia (beats/min. cm H20) < > The coefficient of correlation (r) of the initial heart rate with the percentage of experiments in which tachycardia occurred: t = r(n-2)i.(1-r2)-j = 14-0, D.F. = 6, P <

4 THE BAINBRIDGE REFLEX 301 TABLE 3. The change of heart rate produced by intravenous infusions in 85 cats with different initial heart rates No. of experiments showing % of Ratio of mean change Initial, experiments of heart rate:right heart rate Tachy- No Brady- showing atrial pressure (beats/min) cardia change cardia tachyeardia (beats/min. cm H20) < > The coefficient of correlation (r) of the initial heart rate with the percentage of experiments in which tachycardia occurred: t = r(n-2)i.(1-r2)-* = 12-1, D.F. = 3, P < that there is a discontinuity at 130/min in the dogs' histogram, tachycardia being the usual response at initial heart rates below 130/min, whereas bradyeardia is the more common effect when the initial heart rates are greater than 130/min. An intravenous infusion usually increased the pulmonary arterial pressure, left atrial pressure and mean arterial blood pressure (Table 4 and Figs. 3 and 4), but it was not possible to relate the change in heart rate to any particular change in these pressures or to the character or volume of the fluid injected, except that, in the cat, tachyeardia was more common when the rise in pulmonary arterial pressure was less than 5 cm of water (Table 5). It was noted that tachyeardia in the cat produced by intravenous infusions was always small when compared with that in the dog, the maximum changes being + 22 and % respectively. DISCUSSION Coleridge & Linden's (1955) results have been confirmed for the anaesthetized dog and have also been found to apply to the chloralosed cat: the change in heart rate produced by intravenous infusions is determined by the initial heart rate before the infusion. Bainbridge himself observed that when the dog's initial heart rate was greater than 170/min tachyeardia no longer occurred during subsequent intravenous infusions; and, in fact, all work in which attention has been paid to the initial heart rate is in accordance with his findings. Thus Warthen (1935), Bouckaert & Pannier (1942), Yeomans, Porter & Swank (1943), Piva & Zingoni (1956) and Koepchen & Thurau (1957) have all pointed out that the tachyeardia produced by intravenous infusions or transfusions could only occur when the initial heart rate was sufficiently slow. The experimental data of Meek & Eyster (1922) and DeGraff & Sands (1925) show that intravenous in- 20 Physiol. 160

5 302 J. J. JONES fusions invariably produced bradycardia when the initial heart rate was 150/min or more, tachycardia occurring only at slower initial heart rates. The fundamental effect of intravenous infusions on the circulation is to augment the venous return, so that the ensuing changes in heart rate may be regarded as part of a servo mechanism which produces an increase in cardiac output in response to a rise in atrial pressure (Schaefer, 1960). When the initial heart rate is slow, filling is completed early in diastole and consequently, an increase in heart rate does not reduce the stroke Fig. 3. Dog 14 kg, morphine and chloralose. Effect of an intravenous infusion of 200 ml. of Krebs's bicarbonate solution between the arrows. Tracings and numbers from above downwards: R, the right atrial pressure; L, the left atrial pressure; P, the pulmonary arterial pressure (cm H20); A, the mean arterial pressure (mm Hg); H, the heart rate (beatslmin); time marker, 10 sec intervals (retouched).

6 THE BAINBRIDGE REFLEX 303 volume; on the other hand, when the heart is already accelerated, diastolic filling may become inadequate, so that further tachyeardia reduces the cardiac output (Wiggers, 1949 b). If such a servo mechanism exists it may explain why an increased venous return, through intravenous infusion, tends to produce tachycardia in a heart with a slow initial rate but bradycardia when the heart rate is already high. Unfortunately such a servo mechanism has never been unequivocally shown to exist (Schaefer, 1960). It has been found that intravenous infusions usually bring about tachycardia in the dog at initial heart rates of less than 130/min, whereas brady- Fig. 4. Cat 1.8 kg, chloralose. Effect of an intravenous infusion of 40 ml. of Krebs's bicarbonate solution between the arrows. Convention as for Fig. 3. Time marker, 1 min (retouched). 20-2

7 304 J. J. JONES TABLE 4. The mean pressure changes produced by 35 intravenous infusions in 8 dogs and by 145 intravenous infusions in 44 cats Increase of pressure (cm H20) Animal Right atrial Pulmonary arterial Left atrial Systemic arterial Dog Cat TABLE 5. The changes in heart rate produced by 145 intravenous infusions in 44 cats with different changes in pulmonary arterial pressure and with different initial heart rates Increase of pulmonary No. of experiments showing % of Initial arterial, experiments heart rate pressure Tachy- No Brady- showing (beats/min) (cm H20) cardia change cardia tachyeardia < 150 < <150 > < > > 200 < > 200 > AR < All > The % of experiments showing tachycardia is significantly greater when the increase in pulmonary arterial pressure is < 5 cm H20; P < The ratio of mean change of heart rate: right atrial pressure is + 3 beats/min. cm H20 when the increase in pulmonary arterial pressure is < 5 cm H20 and is -1 when the increase in pulmonary arterial pressure is > 5 cm H20. cardia is the more common effect at higher initial rates. That is to say, there is a tendency for the heart rate during intravenous infusions to approach 130/min, which, according to Landowne & Katz (1944), is the optimum rate for securing the maximum cardiac output in the dog's controlled circulation preparation. This optimum rate may vary according to the effective filling pressure, amongst other factors, which can account for differences between individual experiments and for the overlap of the initial rates at which tachycardia and bradycardia occurred. SUIMMARY 1. Coleridge & Linden's (1955) findings have been confirmed in the anaesthetized dog and have also been found to apply to the chloralosed cat: the change in heart rate produced by intravenous infusions of blood or saline is related to the initial heart rate before the infusion. 2. In both the cat and the dog there is a significant negative correlation between the initial heart rate and the proportion of experiments in which tachycardia occurred.

8 THE BAINBRIDGE REFLEX It is suggested that intravenous infusions tend to change the heart rate to its optimal value for increasing the cardiac output and thereby restoring the venous pressure to its initial level. The advice and encouragement of Professor R. J. S. McDowall are gratefully acknowledged. The part of this work that is related to the cat was included in a Ph.D. thesis in London University, REFERENCES AvIADo, D. M., JR., Li, T. H., KALow, W., SCHMIDT, C. F., TURNBULL, G. L., PESKIN, G. W., HEss, M. E. & WEIss, A. J. (1951). Respiratory and circulatory reflexes from the perfused heart and pulmonary circulation of the dog. Amer. J. Physiol. 165, BAINBRIDGE, F. A. (1915). The influence of venous filling upon the rate of the heart. J. Phy8iol. 50, BOUCKAERT, J. J. & PANNIER, R. (1942). Au sujet des influences r6flexes de la pression veineuse sur la circulation et sur la respiration. Arch. int. Pharmacodyn. 67, COLERIDGE, J. C. G. & LINDEN, R. J. (1955). The effect of intravenous infusions upon the heart rate of the anaesthetized dog. J. Physiol. 128, DEGRAFF, A. C. & SANDS, J. (1925). Are reflexes from the large veins or auricle of importance in the regulation of the circulation? Amer. J. Physiol. 74, JARISCH, A. & ZOTTERMAN, Y. (1948). Depressor reflexes from the heart. Acta physiol. scand. 16, KOEPcHEN, H. P. & THURAU, K. (1957). tyber die Rolle des Vagus bei den durch venose Infusionen erzeugten Herzfrequenzsteigerungen (Bainbridge-reflex). Pflug. Arch. ges. Physiol. 264, KREBS, H. A. & HENSELEIT, K. (1932). Untersuchungen uber die Harnstoffbildung i Tierkorper. Hoppe-Seyl. Z. 210, LANDOWNE, M. & KATZ, L. N. (1944). Heart: work and failure. In Medical Physics, ed. GLASSER, O., vol. 1, p Chicago: Year book publishers. MCCREA, F. D. & WIGGERS, C. J. (1933). Rhythmic arterial expansion as factor in control of heart rate. Amer. J. Physiol. 103, MEEK, W. J. & EYSTER, J. A. E. (1922). The effect of plethora and variations in venous pressure on diastolic size and output of the heart. Amer. J. Physiol. 61, PrvA, G. & ZINGCONI, U. (1956). A proposito del riflesso di Bainbridge. Arch. Fisiol. 56, RIEDER, W. (1926). Herzschadigung infolge arteriovenosen Aneurysmas. Arch. klin. Chirurgie, 139, SASSA, K. & MIYAZAKI, H. (1920). The influence of venous pressure upon the heart-rate. J. Physiol. 54, SCHAEFER, H. (1960). Central control of cardiac function. Physiol. Rev. Supplement, 40, WARTHEN, H. J. (1935). Massive intravenous injections; experimental study. Arch. Surg., Chicago, 30, WIGGERS, C. J. (1949a). Physiology in Health and Disease. 5th ed., p London: Kimpton. WIGGERs, C. J. (1949b). Physiology in Health and Disease. 5th ed., p London: Kimpton. WIGGERS, C. J. & KATZ, L. N. (1921). The contour of the ventricular volume curve under different conditions. Amer. J. Physiol. 58, YEoMANs, A., PORTER, R. R. & SwANK, R. L. (1943). Observations on certain manifestations of circulatory congestion produced in dogs by rapid infusion. J. clin. Invest. 22,