(Received 5 November 1963) rabbit were 65 and 80 mm Hg, respectively. The mean arterial blood

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1 J. Phy8iol. (1964), 174, pp With 5 text-figure8 Printed in Great Britain AORTIC BARORCPTOR THRSHOLD AND SNSITIVITY IN RABBITS AT DIFFRNT AGS BY C. M. BLOOR* From the Nuffield Institute for Medical Research, University of Oxford (Received 5 November 1963) Bauer (1939) deduced from measurements of heart rate that the baroreceptor reflexes were not elicited during asphyxia in new-born rabbits. He and Barcroft (1946) concluded that the threshold pressures for the aortic depressor and carotid sinus baroreceptor reflexes in the new-born rabbit were 65 and 8 mm Hg, respectively. The mean arterial blood pressure in the new-born rabbit is considerably less than these values and does not rise greatly during asphyxia. Downing (196) used changes in systemic arterial pressure as a measure of cardiovascular response. He demonstrated that the baroreceptor reflexes were functional in new-born rabbits and that the threshold for aortic afferent nerve discharges was less than 65 mm Hg. He also suggested that the threshold was higher in older rabbits than in the new-born. However, comparison of his pressureresponse curve from vascularly isolated carotid sinus preparations in newborn rabbits with the 'Blutdruck-Charakteristik' curves obtained by Koch (1931), who used similar preparations from adult rabbits, suggested that at least some baroreceptor fibres in the adult animal are active at the same low pressures as in the new-born. The aims of the present experiments were to test the validity of this hypothesis and to determine whether aortic baroreceptors change their sensitivity with increasing age. MTHODS Observations were made on eight adult (> 4 months), ten young (4-1 weeks) and fiftyfour new-born (-17 days) rabbits. New-born rabbits were anaesthetized with either pentobarbitone (1-15 mg/kg intraperitoneally) or urethane (1-2 g/kg intraperitoneally). Older rabbits received pentobarbitone (3 mg/kg I.v.). Supplementary anaesthesia was given when needed. The animal was placed on a table at 36-39o C and the trachea was cannulated. Arterial blood pressure was recorded by a capacitance manometer from a polyethylene catheter (external diameter -51 mm and internal -38 mm at the tip) in the cardiac end of the right common carotid artery. When critically damped, the catheter and manometer assembly used for observations on the new-born rabbits had a frequency response of 12 C/s. * Present address: Department of Pathology, Yale University School of Medicine, New Haven, Connecticut, U.S.A. 11 Physiol. 174

2 164 C. M. BLOOR The mean arterial pressure was calculated as the diastolic pressure plus one-third of the pulse pressure. In new-born rabbits the blood pressure was altered by abdominal compression only. In other rabbits larger variations in pressure were needed, and these were produced by large inflations ofthe lungs by syringe followed by rapid release, by haemorrhage, or by I.v. injections of 1 jug acetylcholine or 1 jtg noradrenaline, as well as by manual compression of the abdomen. Single-fibre records were made from slips dissected off the left depressor nerve and were recorded with a conventional resistance-capacity coupled amplifier. The records were analysed to determine the threshold blood pressure necessary for baroreceptor activity and the sensitivity of baroreceptors to arterial pressure changes in each age group. The threshold blood pressure for an individual fibre was determined by plotting discharge activity (expressed as impulses/heartbeat) against mean arterial blood pressure. The intercept of the regression line with the pressure axis was designated the threshold pressure. Histograms of discharge frequency during the cardiac cycle were plotted according to the method described by Whitteridge (1948) in order to determine the peak frequency at different pressures. The peak frequency was used to compare the activity of individual units at different times. With units showing more than one peak in each pressure pulse, the mean value of the peak frequencies has been used. Baroreceptor sensitivity was determined by plotting peak frequencies against mean arterial blood pressures and calculating the slope of the regression line. RSULTS The mean blood pressure of three rabbits less than 6 hr old was 3 mm Hg (Fig. 1). During the next 17 days the blood pressure rose by about 2 mm Hg a day. The mean blood pressure of young rabbits (4-1 weeks) { M 8 C * Young Adult Days from birth Fig. 1. Observations of mean arterial blood pressure from fifty-four new-born, ten young and eight adult rabbits. The vertical lines represent the standard error of the mean.

3 BARORCPTOR THRSHOLD AND SNSITIVITY 165 was similar to that of the older new-born animals. Adult levels (mean 16 mm Hg) were not reached until 4 months of age. One hundred and forty-four single-fibre preparations (thirty-six in newborn, fifty-four in young and fifty-four in adult rabbits) have been isolated from the left depressor nerve. Multifibre preparations from every newborn rabbit showed numerous discharges coincident with the systolic pressure wave, even in rabbits only a few hours old, with a mean arterial pressure of 3 mm Hg. Histograms of the baroreceptor impulses from the thirty-six single-fibre preparations in new-born rabbits showed contours identical with those of the pressure pulses. There was a linear relation between peak discharge frequency (impulses/sec) and mean arterial pressure for any one fibre (Fig. 2). Raising the arterial pressure in the new-born rabbit did not cause recruitment of additional units and none 8 - u IV, Mean B.P. (mm Hg) Fig. 2. Peak discharge frequencies of four single fibres (,, O,O) from newborn rabbits plotted against mean arterial blood pressures. Blood pressure alterations were evoked by manual compression of the abdomen. of the fibres fired continuously during diastole, as sometimes observed in older rabbits. But mean arterial pressure was only raised in new-born rabbits to a maximum of 71 mm Hg by abdominal compression. Table 1 shows the mean arterial threshold pressures determined for 111 single depressor fibres in rabbits of different ages. Although the mean threshold pressure was significantly greater in rabbits of days than in those of -1 days from birth (P <.1), the mean threshold pressure in rabbits of -17 days ( mm Hg) was no greater than in rabbits of 4-1 weeks. The mean threshold pressure was significantly greater in 11-2

4 166 C. M. BLOOR adult rabbits compared with all rabbits under 1 weeks (P <.1) In each age group the range of threshold pressures varied widely. Figure 3 illustrates the discharges which persisted in a single-fibre preparation from the depressor nerve of an adult rabbit when the mean arterial pressure was less than 5 mm Hg, a marked fall from the rabbit's normal pressure of 14 mm Hg. TABL 1. Threshold (mean arterial pressure at which discharge ceases) of baroreceptor fibres in rabbits of different ages Mean Range of Mean threshold threshold arterial Mean heart No. of pressure +s.. pressures pressure + S.. rate +S.. Age fibres (mm Hg) (mm Hg) (mm Hg) (beats/min) New-born -1 days days Young 4-1 weeks X Adult > 4 months I o -1 sec. X, Oj_L 5 _ 1 sec. Fig. 3. Records of a single-fibre preparation from the left depressor nerve of a 1-83 kg adult rabbit at different blood pressures (see text). In each record, the upper trace shows the carotid arterial pulse, the middle trace the single-fibre impulses and the lower trace time in -1I sec. The single-fibre impulses precede the pressure pulse because of the delay in transmission of the arterial pulse to the carotid artery. Figure 4 shows the relation between peak discharge frequency and mean arterial pressure in rabbits of different ages. Since analysis showed no significant difference between the regression constants for rabbits of -1 and days, these have been combined. The arterial pressure was varied from 26 to 71 mm Hg in the new-born rabbits, from 24 to 112 mm Hg in the young and mm Hg in the adult rabbits. In twenty-one fibres from young and adult rabbits two or more methods of altering the arterial pressure gave similar linear relations between peak discharge frequencies and pressures. The slopes of the regression lines for peak frequency on mean arterial pressure (Fig. 4) were not significantly different

5 BARORCPTOR THRSHOLD AND SNSITIVITY 167 at different ages (P >.5). Thus, peak discharge frequency would increase by 8-11 impulses/sec for every 1 mm Hg rise in mean arterial pressure. So far as these observations go it would therefore appear that the sensitivity of the aortic baroreceptors has not altered significantly with age I-. U v. 1l 8 F * / 6h *., 4 - pd 2 F I I I I I I, a o Mean B.P. (mm Hg) Fig. 4. Observations of single nerve fibre activity from the left depressor nerve. Peak discharge frequencies of thirty-six fibres from new-born rabbits (@), fiftyfour fibres from young rabbits () and fifty-four fibres from adult rabbits (O) have been plotted against mean arterial blood pressures. The lines represent the regression of peak frequency on blood pressure. Figure 5 shows the relation between peak discharge frequency and the percentage change of mean arterial pressure from the resting levels of individual rabbits in each age group. The range of relative pressure changes was the same in each group, from -6 to +4 %. The regressions for peak frequency on percentage change of arterial pressure (Fig. 5) were not significantly different at different ages (P > 1). Thus, a 1% change of mean arterial pressure from the resting level would alter peak discharge frequency by 7-9 impulses/sec.

6 168 C. M. BLOOR o 1 U~~~~~~~~~~8 o ~~~ o % ~ - *. o~~~ * a~~~ G. 2 ~~~~~~~~~~~~~~~~~~ -4 O (b ~~~~~~~~~~~~~~~~~~ Change of mean arterial B.P. from resting level (%) Fig. 5. Peak discharge frequencies plotted against relative presure changes expressed as the percentage change of mean arterial pressure from the resting levels of individual rabbits in the new-born (), young () and adult (CO) groups. Regression of peak frequency on percentage change of arterial pressure for each group is represented by the line. DISCUSSION The threshold pressure for aortic depressor single-nerve fibre discharges has been calculated from measurements of discharge frequency related to mean arterial pressure because it was not possible, in new-born rabbits with high heart rates and very small carotid arteries, to be sure that the phasic arterial pressure record was always faithful. The thresholds so calculated, and shown in Table 1, are therefore somewhat less than the true threshold pressure within the aortic arch when discharge ceased. This can be seen from the upper part of Fig. 3, where the mean arterial pressure at which discharge just ceased was 44 mm Hg while the peak systolic pressure was mm Hg. Although the relation between ambient pressure and the discharge frequency of baroreceptor nerve fibres is linear over quite a wide range of pressures at any age, it becomes non-linear as the pressure is reduced and discharge frequency drops below 1 impulses/sec (e.g. Price & Widdicombe, 1962). This is certainly so when the aortic pressure is reduced too far, possibly as a result of unphysiological collapse of the

7 BARORCPTOR THRSHOLD AND SNSITIVITY 169 vessel wall. The threshold value calculated in the present paper is, therefore, an abstraction used as an index of the behaviour of baroreceptor fibres at discharge frequencies in excess of 1 c/s. At first sight the results shown in Table 1 might lead to the conclusion that the mean arterial threshold pressure at which depressor-nerve single fibres cease to discharge may rise with increasing age. However, the range over which the arterial pressure could be varied in the new-born was different from that in the young rabbit or the adult. It was particularly difficult to maintain low arterial pressures in the adult, a fact which militated against discovering the threshold of thirteen fibres. Consequently, not too much weight can be put on the fact that the threshold was somewhat greater in the adult rabbit. It is probably more important that the range of thresholds was wide at any age. Whereas a sufficient range of pressure variations was induced by compression of the abdomen in new-born rabbits, it proved necessary to use other methods as well in young and adult rabbits. However, it is improbable that these methods will in themselves have altered the threshold or sensitivity of the baroreceptors. Price & Widdicombe (1962) observed that haemorrhage did not alter the static pressure threshold or the sensitivity of carotid sinus baroreceptors in dogs. Although noradrenaline when applied locally to the carotid sinus in cats alters its sensitivity (Landgren, Neil & Zotterman, 1952) the dose used (1-25,tg) was far greater than that injected intravenously to raise the arterial pressure in the present experiments (1 ltg). Diamond (1955) found that acetylcholine injected into the fluid perfusing the carotid sinus of the cat increased the frequency of baroreceptor discharge, but again the concentration used was much greater than in the present experiments. The facts that there was the same linear relation between discharge frequency and pressure whichever method was used in young and adult rabbits, and when more than one method was used while recording from a single fibre, also support the conclusion that the results were not distorted. Bronk & Stella (1932) showed that there was a linear relation between the peak discharge frequency of carotid sinus baroreceptor nerve fibres and mean arterial pressure in adult rabbits. The present results confirm this conclusion in rabbits of other ages. The range of fibre discharge frequencies over which the sensitivity of the aortic baroreceptors was measured in rabbits of different ages was wide (Fig. 4), and agrees well with the range observed by Bronk & Stella (1932) in adult rabbits (5-13 impulses/sec). Within this range the sensitivity of the baroreceptor did not vary significantly with age, when expressed in terms of mean arterial pressure (Fig. 4). The nature of the direct stimulus to the baroreceptor

8 17 C. M. BLOOR sensory ending on raising the transmural pressure is not known. Nevertheless, physical considerations may go far to explain the at first surprising observation that the apparent sensitivity ofthe receptors (as defined above) is unchanged with increasing age. At birth the aorta is small and the transmural pressure is low. In the adult the aorta is larger and the transmural pressure is greater. Nevertheless, it is possible that the circumferential tension in the vessel wall is not greatly different at the two ages, and, consequently, that the distortion of the receptor produced by a given transmural pressure change could be similar. From the physiological point of view the conclusion that peak discharge frequency changes with a given percentage rise or fall in mean arterial pressure by almost the same amount at different ages whether the resting arterial pressure is 3-6 mm Hg or about 1 mm Hg, is interesting. This may further suggest the similarity of circumferential tensions in the aortic wall at different ages. However, this conclusion does not imply that the total afferent discharge alters to the same proportion in the new-born as in the adult; the extent to which this may be modified by recruitment of additional sensory units is not known. Nor does it follow that the central and efferent consequences will be similar at different ages. But it does imply that control of the cardiovascular system in the new-born rabbit could be better than was once supposed. SUMMARY 1. The threshold and sensitivity of baroreceptor fibres were measured in rabbits of different ages. 2. In each age group the range of threshold pressures varied widely suggesting that similar mixed-fibre populations were present. 3. The relation between peak discharge frequency and mean arterial pressure was linear for each age group. The change in peak frequency accompanying a given rise or fall of mean arterial pressure was of similar magnitude at all ages. 4. Peak discharge frequency also altered with the proportionate change from resting blood pressure levels by the same amount at different ages although the resting arterial pressures varied from 3 mm Hg to more than 1 mm Hg. 5. The apparent unchanging sensitivity of baroreceptors with increasing age and the possible similarity of stimuli to baroreceptor endings at different ages have been discussed. The author wishes to express his gratitude to Dr G. S. Dawes for his encouragement and interest in this work, to Dr D. G. Wyatt for designing the amplifier and to Mr H. Holt for his technical assistance. This work was done during the tenure of a Life Insurance Medica Research Fellowship.

9 BARORCPTOR THRSHOLD AND SNSITIVITY 171 RFRNCS BARCROFT, J. (1946). Researches on Pre-natal Life. Oxford: Blackwell. BAUR, D. J. (1939). Vagal reflexes appearing in asphyxia in rabbits at different ages. J. Physiol. 95, BRONK, D. W. & STLLA, G. (1932). Afferent impulses in the carotid sinus nerve. I. The relation of the discharge from single end organs to arterial blood pressure. J. cell. comp. Phy8iol. 1, DIAMOND, J. (1955). Observations on the excitation by acetylcholine and by pressure of sensory receptors in the cat's carotid sinus. J. Physiol. 13, DOWNING, S.. (196). Baroreceptor reflexes in new-born rabbits. J. Phy8iol. 15, KoCm,. (1931). Die reflektori8che Selb8tsteurung de8 Krei8laufe8. Dresden, Leipzig: Steinkopff. LANDGRN, S., NIL,. & ZOTTRMAN, Y. (1952). The response of the carotid baroreceptors to the local administration of drugs. Acta physiol. scand. 25, PRIC, H. L. & WIDDICOMB, J. G. (1962). Actions of cyclopropane on carotid sinus baroreceptors and carotid body chemoreceptors. J. Pharmacol. 135, WHITrRIDG, D. (1948). Afferent nerve fibres from the heart and lungs in the cervical vagus. J. Physiol. 17,