Leed&, Leeds LS2 9JT (Received 23 May 1977)

Transcription

1 J. Phyaiol. (1977), 272, pp With 7 text-figuree Printed in Great Britain ATRIAL RECEPTORS IN THE DOG AND RABBIT BY C. T. KAPPAGODA, R. J. LINDEN AND D. A. S. G. MARY From the Department of Cardiovascular Studies, Univereity of Leed&, Leeds LS2 9JT (Received 23 May 1977) SUMMARY 1. Action potentials were recorded from slips of the cervical vagi in anaesthetized dogs and rabbits. Single functional units with atrial patterns of discharge (Paintal Type A, B and intermediate) were obtained and then attempts were made to alter (i.e. convert) their patterns of discharge. Finally the points of origin of these action potentials were located. 2. Thirty unselected units were investigated in thirty dogs. Twentyseven of these were located in the endocardium of the vein-atrial system and the ratio of the type A, type B and intermediate type receptors was 1: 16: 10; three units were located elsewhere in the chest. Conversion of the pattern of discharge was achieved in twenty of the twenty-seven units; conversion was achieved in the single type A unit. 3. In a second series of experiments in dogs, eight Paintal Type A units were selectively studied in fifteen animals. Four of these were located in the endocardium and all were converted. The remaining four were located outside the endocardium and conversion could not be achieved in two of these. Thus in the entire investigation, the 'type A' units which could not be converted were all located at sites other than the atrial endocardium. 4. In the corresponding unselected study in the rabbit, eleven units were studied in eleven animals. Nine of these units were located in the atrial endocardium and the ratio of the type A, type B and intermediate type receptors was 2:1:6. Conversion was achieved in both type A units, the sole type B unit and two of the intermediate units. One of the two units found outside the atrial endocardium was a 'type A' unit and could not be converted. 5. The present investigation has shown that the atrial receptors with a Paintal Type A pattern of discharge are relatively rare in both dogs and rabbits. Conversion of the pattern of discharge is a relatively common phenomenon. Evidence for the proposition that there is one basic type of atrial receptor whose pattern of discharge is determined by its precise location in the vein-atrial system is discussed.

2 800 C. T. KAPPAGODA, R. J. LINDEN AND D. A. S.G. MARY INTRODUCTION It was suggested that receptors in the atrial endocardium (atrial receptors) which discharge into myelinated nerves in the vagi could show three typical patterns of discharge: type A which discharge in time only with the 'a' wave of the atrial pressure pulse, type B, in time with the 'v' wave and intermediate, in time with both waves (Paintal, 1963, 1973). It has also been suggested that receptors which discharge with type A and type B patterns of discharge represent physiologically distinct receptors which embrace different physiological functions (Paintal, 1973) and that the intermediate type is an uncommon variant of the other two types. Recently, evidence was presented in the cat suggesting that there is only one basic type of atrial receptor whose pattern of discharge is determined by its precise location in the vein-atrial system (Kappagoda, Inder & Mary, 1976) and that only two patterns of discharge (type B and intermediate) emanate from receptors in the atrial endocardium. The pure 'type A' (inconvertible) discharge was shown to emanate from receptors anatomically outside the atrial endocardium. From this evidence in the cat a hypothesis was suggested that the precise position of any receptor in the atrial endocardium could explain its pattern(s) ofdischarge (Kappagoda et al. 1976). The present investigation was undertaken to extend to the dog and rabbit, these observations regarding the patterns of discharge from receptors in the atrial endocardium and to question the above hypothesis in the light of the results. Some of the results of this investigation have been presented to the Physiological Society as a communication (Kappagoda, Linden & Mary, 1977). In this paper receptors recognized solely by their patterns of discharge in slips of the vagi, will be designated Paintal Type A, Type B or Intermediate; those located subsequently to the endocardium will be designated type A, type B or intermediate and those at other sites as 'type A', 'type B' or 'intermediate'. METHODS Experimene in the dog. Dogs weighing 17 kg (mean; range 12-24) were anaesthetized with an intravenous injection of sodium pentobarbitone (dose 30 mg/kg, Nembutal, Abbot Laboratories Ltd, Queensborough, Kent). Artificial respiration was then begun with 40% oxygen, using a modified Starling 'Ideal' pump. Succinyl choline (dose 0-5mg/kg; repeated every min, 'Suxamethonium Chloride', B.D.H. Chemicals Ltd, Poole) was used to immobilize the animal preparation. A steady state of anaesthesia was maintained by further i.v. injections of pentobarbitone (approximately 3 mg/kg every 20 min). The chest was opened by splitting the sternum in the mid line and retracting the out edges. The pericardial sac was left intact. A thread was passed behind the

3 ATRIAL RECEPTORS 801 descending thoracic aorta and a snare formed through short lengths of polyethylene tubing; occlusion of the aorta was achieved by tightening the snare. The pressure in the aorta and the right atrium were measured through nylon cannulae (Portex Surgical Quality No. 4, Portland Plastics Ltd) inserted through the right femoral artery and vein respectively. The pressures in the cardiovascular system, along with the tracheal pressure, end-tidal Poo, and the e.c.g. were recorded on an ultra-violet recorder. The oesophageal temperature and the acid-base status of the animals were measured and maintained within normal limits. The techniques used for the above procedures have been described in detail previously (Kappagoda, Linden & Snow, 1972). The cervical vagus was dissected out and a stretch of at least 5 cm in length was immersed in warm liquid paraffin. Action potentials in slips of the upper end of this length of the vagus nerve were displayed and recorded in the manner previously described (Coleridge, Hemingway, Holmes & Linden, 1957). Single functional units having an atrial pattern of discharge, i.e. Paintal Type A, B or Intermediate (Paintal, 1963, 1973), were isolated during dissection of the vagus. Once such units were obtained, attempts were made to alter the pattern of discharge from one type to another by methods which have been described in detail previously (Kappagoda et al. 1976). These methods comprised (1) sustained inflation of the lungs and sustained expiration, (2) occlusion of the thoracic aorta, (3) infusion of dextran and hemorrhage (5-16% of estimated blood volume) so as to alter the level of pressure in the atria, and (4) i.v. injections of adrenaline (0.5 mg/kg). Successful alteration of the pattern of discharge from one type to another will be referred to as conversion. Evidence for conversion was accepted only when the alteration of the pattern of discharge from one type to another was consistent throughout at least one respiratory cycle or an equivalent period of time. A second record was always taken after reversal of the procedure. Conduction velocities of the fibres transmitting the atrial volleys of impulses were measured using conventional techniques. The vagal trunk was stimulated at a point > 5*0 cm caudal to the recording electrode using a pair of silver electrodes and a stimulator (Grass Instrument Co., Massachusetts, U.S.A.). The stimulation was triggered by the QRS complex of the e.c.g. to deliver pulses of jus duration and strength V. The particular evoked spike potential was identified by altering the delay in the stimulus so as to demonstrate collision with a naturally occuring spike within the volley relating to one cardiac cycle. The distance between the recording and stimulating electrode was measured post-mortem. The time taken for the impulse to traverse this length of nerve was measured on a time calibrated oscilloscope using a fast sweep (RM 565: Tektronix Inc., Portland, Oregon, U.S.A.). The temperature of the pool of paraffin was maintained at 37 ±1 C during the measurement of the conduction velocity. Critria for definition of single functional units. When units with atrial patterns of discharge were converted care was taken to establish that the additional spikes were from the same functional unit. In the first series of experiments (on dogs) such a conclusion was based on the height and shape of the spikes and the subsequent destruction of the unit during localization as described by Kappagoda et al. (1976). Further evidence was obtained by defining the action potentials evoked by stimulation of the cervical vagus. From the profile of the evoked potential in the slip of the vagus, it was possible to determine whether there was more than one unit in it which was activated by the procedures of conversion. Such a conclusion was based on the shape and amplitude of the evoked spike and the demonstration of collison with the naturally evoked spikes. Finally, every receptor was accurately located as described by Kappagoda et al. (1976).

4 802 C. T. KAPPAGODA, R. J. LINDEN AND D. A. S. a. MARY Experiments in the rabbit. Eleven rabbits weighing 3-8 kg (mean; range ) were anaesthetized with pentobarbitone. The dose of pentobarbitone was calculated on the basis of 30 mgirg. A quarter of this dose was given i.p. Later (15 min) the rest of the dose was given i.v. through an ear vein in 10% aliquots. The basic techniques as described above in the dog, were also used in the rabbit. RESULTS Experiments in the dog General condition of animak8. When recording began in forty-five dogs, the heart rate was 167 beats/min (mean; range ), the mean pressure in the femoral artery was 135 mmhg (mean; range ). The ph, Pco, and PO, of arterial blood were 7 39 (mean; range ), 39-2 mm- Hg (mean; range 32-44) and 175 mmhg (mean; range ). In these dogs a total of two hundred and three units were obtained and of those thirty-eight were fully investigated and eventually located. Conduction velocities of one hundred and ten afferent vagal fibres carrying units with atrial patterns of discharge were measured. (i) Types of receptors First series. In this series, the units investigated were unselected, i.e. the first single unit encountered which had an atrial pattern of discharge was investigated. On the evidence of this pattern of discharge each such unit was classified into Paintal Type A, B or Intermediate Type according to the following definitions (Paintal, 1953a, 1963): Type A, receptors discharging during atrial contraction alone with occasional action potentials during filling; Type B, receptors discharging during filling alone and the Intermediate Type receptors discharging during both filling and contraction (Fig. 1). Attempts were then made to convert the pattern of discharge and finally the point df origin of the nerve ending was located. Thirty units with atrial patterns of discharge were obtained from thirty dogs. Twenty-seven units were located in the atrial endocardium and three were found at other sites. The units in the atrial endocardium comprised one type A, sixteen type B and ten intermediate units (i.e. the ratio of atrial units was 1: 16: 10). Of the units found outside the endocardium, one possessed a 'type A' pattern and two a 'type B' pattern of discharge (Table 1). Of the twenty-seven atrial units, twenty were successfully converted (see below). Since only two Paintal Type A units were encountered in the first series, one convertible and located in the atrial endocardium and the other inconvertible and found in the left main bronchus, a further series of experiments were performed selectively to examine units with Paintal type A patterns of discharge.

5 ATRIAL RECEPTORS 803 Second series. In this series the dissection of the vagus was continued until a unit with a Paintal Type A pattern of discharge was encountered, which was then investigated and finally located. In fifteen dogs one hundred and seventy-three units with atrial patterns of discharge were obtained. A B C type A type B intermediate Act. pot. 4ja a A one zco , E.c.g. IN_ I+ 1 sec Fig. 1. Types of atrial receptors in the dog. From above downwards record of action potentials, right atrial pressure and electrocardiogram (e.c.g.). The vertical lines are drawn to show the temporal relationship between bursts of action potentials and waves of the atrial pressure pulse. The continuous line indicates the end of the 'a' wave and the interrupted line in. dicates the peak of the 'v' wave of the atrial pressure pulse. A, a record of a type A unit in which a high frequency burst of action potentials coincided with the 'a' wave. B, a record of a type B unit in which the burst of action potentials coincided with the 'v' wave. C, a record of an intermediate unit which possessed both type A and type B activity. These three units were located to the atrial endocardium. TABLE 1. Positions of receptors with atrial patterns of discharge located at sites other than the atrial endocardium Location Convertible Unconvertible Dog 'type A' Bronchi 2 Lungs 1 Posterior mediastinum 1 Parietal pericardium 1 'type B' Bronchi 1 1 Rabbit 'type A' Trachea 1 'type B' Superior mediastinum 1

6 804 C. T. KAPPAGODA, R. J. LINDEN AND D. A. S. G. MARY Of these, eight units with Paintal Type A discharge were studied and eventually located. Four of them were located in the atrial endocardium and their pattern of discharge was altered. The remaining four units were located outside the atrial endocardium (i.e. 'type A'). The pattern of discharge was not altered in two of these units. In addition to the eight units of Paintal Type A described, there was a further unit of Paintal Type A which could not be converted. Following determination of the conduction velocity and attempts at conversion, this unit was lost and was therefore not located. A B C Control Haem.+adr. Control Act. pot. W W '15 F I4 W M. I..1 0 E.c.g. r " J 1 SWC Fig. 2. Conversion of the pattern of discharge in a left atrial type B unit (dog no. 108/75; weight 22 kg). Abbreviations and positions of vertical lines are the same as in Fig. 1. A, initial control record. B, after bleeding 180 ml. and the ainistration of 8 jug adrenaline i.v. C, final control record. In the control periods the unit behaved as a type B receptor and during the haemorrhage it behaved as a type A receptor. (ii) Conversion of the pattern of discharge from atrial receptors A total of thirty-one receptors from the first two series were subjected to procedures of conversion and were eventually located in the endocardium of the vein-atrial system. In twenty-four of these receptors, the pattern of discharge was converted from one type to another. Examples of these conversions are shown in Figs The details of these conversions are given below. Type.A" units. All five atrial units with type A patterns of discharge (four left atrial and one right atrial) were converted by the procedures used. The left atrial units were converted into intermediate types by the

7 ATRIAL RECEPTORS A B C Control Haemorrhage Control Act. pot. I -SnJ4 Ị 'L4.._..41 J. IIa4I ~~~~~~~~II i I I I I I I I I ~ ~ ~~~~~~~~I 5Fr Ii I ~~~~~~~~~~~~I II I I. o ni-.ci 0 A.JyJYy E.c.g. i+ I I sec Fig. 3. Conversion of the pattern of discharge in an intermediate type receptor (dog no. 105; weight 12 kg). Abbreviations and position of vertical lines are the same as in Fig. 1. A, initial control record. B, after bleeding 140 ml. C, final control record. In the control periods the unit behaved as an intermediate type receptor and during the haemorrhage it behaved as a type A receptor. A Control B After infusion C Control -_j Act. Pot. IJ ISTI1 I.A. pressure (cm H20) 15 - E.c.g. 1 sec Fig. 4. 'Conversion' of the pattern of discharge in a left atrial type A unit (dog no. 30; weight 19 kg). The abbreviations and the position of the vertical lines are as in Fig. 1. A, initial control record. B, records obtained after infusion of dextran (130 ml. I.v.). C, final control record. During the initial control period this receptor possessed a type A pattern of discharge. Following infusion of dextran, the pattern of discharge was that of an intermediate type unit. During the final control period this receptor regained its initial pattern of discharge, i.e. type A.

8 806 C. T. KAPPAGODA, R. J. LINDEN AND D.A. S. G. MARY infusions of dextran (5-14 % of estimated blood volume). Occlusion of the aorta and the release of the occlusion of the pulmonary artery achieved the same effect in two of these units. The right atrial unit was converted into a type B pattern of discharge by an infusion of dextran and into an intermediate pattern by occlusion of the pulmonary artery. Alterations in the respiratory pressures (both sustained inspiration and expiration) were without effect on the pattern of discharge of type A units. Act. pot. A Control B After infusion R.A. pressure (cm H20) 0 1 5i E.c.g. JKJK&A 1 sec Fig. 5. A, 'type A' unit which could not be converted (dog no. 111; weight 21 kg). The abbreviations and the position of the vertical lines are as in Fig. 1. A, initial control record. B, records taken after an infusion of dextran (240 ml.). The pattern of discharge of this receptor could not be converted. The receptor was eventually located in the left main bronchus. Type B unite. Eleven units with a type B pattern of discharge which were eventually located in the endocardium of the left atrium were converted to type A and/or intermediate type by haemorrhage (10-13 % of estimated blood volume) or the administration of adrenaline. In four of these units one of the above manoeuvres was successful in effecting the conversion while in the remaining seven a combination of both manoeuvres was successful. Two of the receptors were also converted by occlusion of the pulmonary artery (one only) and by sustained inflation of the lungs respectively. Intermediate units. Eight left atrial units with an intermediate pattern

9 ATRIAL RECEPTORS 807 of discharge were converted. Five units were converted into type B by infusion of dextran (10-1 % of estimated blood volume) and two by occlusion of the aorta. Five units were converted to type A by haemorrhage (8-16 % of estimated blood volume) and/or the administration of adrenaline and by sustained inflation of the lungs. In four of these, conversion into type A was achieved by occlusion of the pulmonary artery. Five of the eight units with an intermediate pattern of discharge were converted into both type A and type B patterns of discharge. Conversion of units outside the atrial endocardium. Of the seven units located outside the atrial endocardium, five had a 'type A' pattern of discharge and two had a 'type B' pattern of discharge (Table 1). Two of the 'type A' units could not be converted (Fig. 5). Of the remaining three, two were converted to 'intermediate type' by infusion and one by occlusion of the pulmonary artery. One of the 'type B' units was converted into an 'intermediate type' by sustained inflation of the lungs. (iii) Location of receptors A total of thirty-eight units were located. Of these, seven units were located at sites other than the atrial endocardium as shown in Table 1. The remaining thirty units were located in the endocardium of the veinatrial system and their location is shown in Fig. 6. Receptors with type A (five) :or intermediate (ten) patterns of discharge were found only at veinatrial junctions. Receptors with type B (sixteeen) pattern of discharge were located at the vein atrial junctions and at sites remote from veinatrial flexures such as the distal regions of the pulmonary veins or lateral atrial walls. It is of interest to note that the five type B units which could not be converted were in fact located in the lateral wall of the atria and the distal region of the pulmonary veins (Fig. 6). (iv) Conduction velocities in fibres with atrial patterns of discharge In thirteen dogs conduction velocities were measured in one hundred and ten afferent fibres carrying an atrial pattern of discharge and in fortyone fibres whose patterns of discharge resembled those from pulmonary stretch receptors (Table 2). The differences between conduction velocities in fibres originating in Paintal Type B receptors and that of either Type A or intermediate Type did not reach statistical significance (P > 0.05). Rabbit experiments General condition of animals At the time when recording was started, the heart rate was 269 beats/ min (mean; range ) and the mean pressure in the femoral artery was 85 mm Hg (mean; range ).

10 808 C. T. KAPPAGODA, R. J. LINDEN AND D. A. S. G. MARY Eleven units were obtained from eleven rabbits. (i) Types of receptor: All the eleven units investigated were 'unselected' as has been described in the first series in dogs. Nine units were located in the atrial endocardium and two were found at other sites. The nine atrial receptors comprised two units with a type A discharge, one unit with a type B discharge and six units with an intermediate type of discharge (i.e. the ratio of atrial units was 2:1:6). Examples of each type are shown LLPV RLPV Fig. 6. A schematic diagram drawn from transverse sections made at three levels in the heart of a dog to demonstrate locations of thirty-one atrial receptors in the endocardium of the vein-atrial system. The levels of the sections were as follows: A, the entrances of the upper pulmonary veins (L and RITPV) into the left atrium (LA); B, entrances of the middle pulmonary veins (L and RMPV) into the left atrium; C, the entrances of the lower pulmonary veins (L and RLPV) into the left atrium. *, type A units all of which were converted; 0O type J3 units which could not be converted; 0, type B units which could be converted; A, intermediate units. All the type A units were located at the entrances of the veins into the atria whereas all type B receptors which could not be converted were located in the pulmonary veins distal to their entrances into the left atrium or on the lateral walls of the atria. Ao, aorta; PA, pulmonary artery; IVC, inferior vena cava.

11 ATRIAL RECEPTORS 809 Type of discharge Cardiac atrial Type A Type B Intermediate Pulmonary stretch TABLE 2. Conduction velocities of afferent vagal fibres Number of fibres Conduction velocity (rn/sec) (mean ± S.E. of mean) 23*6 + 3* * Act. pot. A type A I-A4 4>4FL 15 (cm H20) A A A v-- R.A. pressure II-- I B type B i I I I C intermediate III LL I 1ij 'II i Ex.g. N l 1 sec Fig. 7. Types of atrial receptors in the rabbit. Abbreviations and positions of vertical lines are the same as in Fig. 1. A, a record of a type A unit in which a high frequency burst of action potentials coincided with the 'a' wave. B, a record of a type B unit in which the burst of action potentials coincided with the 'v' wave. C, a record of an intermediate unit which possessed both type A and type B activity. in Fig. 7. The two units found outside the atrial endocardium consisted of one with a 'type A' pattern of discharge and one with a 'type B' pattern (Table 1). (ii) Conversion of the pattern of discharge. As in the dog, atrial receptors with a type A discharge were altered to an intermediate type by infusion of dextran (5 % of estimated blood volume) and by occlusion of the aorta in the case of receptors situated in the left atrium. The atrial unit with the type B discharge was altered to an intermediate type by bleeding (13 % of estimated blood volume). One intermediate unit was converted to a type A by bleeding and another to type B by infusion. l

12 810 C. T. KAPPAGODA, R. J. LINDEN AND D. A. S. G. MARY DISCUSSION There has been a considerable debate about the existence and numbers of the various types of receptors and about the integrity of the pattern of discharge in a given receptor. Much of the variation in the results of investigations has been explained by evoking species differences (Paintal, 1973; Rao, Fahim & Gupta, 1975). However, recently it has been claimed that most of the controversy about atrial receptors in the cat is probably the result of the various means of preparing the animal and in the selection of units for investigation (see Kappagoda et al. 1976, for review of literature). Also in an attempt to resolve some of these reported variations in findings in the cat, Kappagoda et al. (1976) studied a group of randomly selected units possessing atrial patterns of discharge. The important feature of the methods in this investigation was that in studying these units the vagus was dissected systematically until the first unit possessing an atrial pattern of discharge was encountered and that pattern then defined the type of receptor. The receptor was located post mortem, thus examining only one unit in each animal and establishing its true origin. Using this method it was possible to have a 'correct' estimate of the occurrence of the three types of receptors; the proportion of type A, type B and intermediate type was found to be 1: 7-5:4. Also in that investigation Kappagoda et al. (1976) observed that conversion of the discharge of a receptor from one pattern to another was a relatively common phenomenon. It was found that procedures which tended to increase atrial volume (e.g. infusion, aortic occlusion in the case of the left atrium and pulmonary artery occlusion in the case of the right atrium) resulted in conversion of type A units into intermediate and type B forms; a decrease in volume (haemorrhage and/or the infusion of adrenaline) resulted in the conversion of type B receptors into intermediate and type A forms. These observations, taken in conjunction with the precise location of the receptor endings into the atrial endocardium and the nature of the movement of the atrial wall during contraction, resulted in the formulation of an hypothesis to explain the natural stimulus of various types of receptor endings. This hypothesis suggests that the discharge from an atrial receptor is dependent on tension in the adjacent wall. An increase in wall tension could occur with atrial filling or with local distortion during atrial contraction. Thus receptors located in a position which is unaffected by the movements of atrial contraction would exhibit a type B pattern of discharge while receptors located in a position which is solely affected by the movements of the atrial wall during contraction would exhibit a type A discharge. It is known that during atrial contraction, the posterior wall of

13 ATRIAL RECEPTORS 811 the left atrium remains relatively fixed while the lateral walls contract towards it. Thus the borders of the posterior wall, i.e. consisting mainly of the entrances of the pulmonary veins, would be the region subjected to the greatest degree of distortion during atrial contraction. Thus receptors positioned in this region would tend to show a preponderance of activity during atrial contraction (type A or intermediate). The units located in the lateral walls and in the more distal regions of the veins would tend to be activated by wall tension due to filing and hence exhibit activity during filling (type B). In the cat the data relating to location of these receptors within the endocardium clearly supported this-- proposition (Kappagoda et al. 1976). The phenomenon of conversion of the pattern of discharge could be easily explained by movement of the receptors from one curvature to another, at the junctional regions of the relatively fixed posterior wall of the atrium, during changes in the volume of the atrium (e.g. an increase during infusion and a decrease during haemorrhage). Thus, to summarize the previous work (Kappagoda et al. 1976), the precise pattern of discharge in an atrial receptor is governed by its position within the atrium. Acceptance of this hypothesis also implies that fundamentally there is only one type of atrial receptor (receptors in the atrial endocardium), some of which discharge during filling alone (type B) and others which discharge during contraction as well (intermediate). Receptors with a pattern only of 'type A' are not found in the endocardium. Gupta (1977) has reported a study on cats which yielded results which were significantly different from those observed by Kappagoda et al. (1976) in that a much bigger proportion of type A units were observed. However, a close scrutiny of the data indicated that there may be several explanations for the difference. Gupta (1977) does not state the precise definition of a type A receptor and it is possible that his population included many that could be classified as intermediate types. Some evidence to support this proposal is lent by the fact that the type A and intermediate type units when taken together form approximately the same proportion in both series, i.e. 40% as reported by Kappagoda et al. (1976) and 41 % as reported by Gupta (1977). It is also not clear from the report whether the units examined were, in fact, the first 'atrial units' encountered in a given animal. The possibility of 'selection' of fibres has to be considered seriously for two reasons. First, Gupta (1977) has not specifically indicated that only one unit was examined in each cat. Second, no receptors having atrial patterns of discharge which originated from extra cardiac sites were encountered in this study. The existence of such units have been described in several previous investigations (e.g. Coleridge, Coleridge & Kidd, 1964; Kappagoda et al. 1976) and has also been confirmed in the present study. The present investigation was undertaken to determine whether the

14 812 C. T. KAPPAGODA, R. J. LINDEN AND D.A.S.G. MARY results in the cat and the hypothesis derived from them could be supported in the dog. The ratios of the various types of receptors in the dog are essentially the same as in the cat. Even though Paintal Type A units defined at first observation are rare in both cats and dogs, there are even fewer Type A units in the dog. In the dog, conversion from one pattern of discharge to another is a relatively common phenomenon (twenty out of twenty-seven receptors in first series), a finding which is similar to that observed in the cat. In addition as in the cat, those Paintal Type A fibres which could not be converted were located outside the atrium. Once again it was observed that procedures likely to enlarge the size of the atrium (e.g. infusion) resulted in the appearance of trains of action potentials during atrial filling while those which tended to diminish the atrial volume (e.g. haemorrhage) resulted in either the disappearance of the action potentials during filling or the appearance ofthem during atrial contraction. Finally, the locations of the receptor endings in the endocardium also were similar to those observed in the cat. For instance, those receptors discharging solely during atrial filling were positioned in the lateral walls of the atrium and in the distal regions of the vein draining into the atria; those which discharged during atrial contraction (i.e. type A and intermediate) were positioned near the vein-atrial orifices in areas which are likely to be distorted during atrial contraction. Thus the essential features of the earlier study in the cat have been substantiated in the dog and the evidence from the dog supports the hypothesis erected from the results obtained in the cat. In the context of this hypothesis, it is interesting to consider two recent publications by Recordati and his colleagues (Recordati, Lombardi, Bishop & Malliani, 1975, 1976). In the cat, they observed (Recordati et al. 1975) that the discharge from type B receptors was dependent on the tension and the rate of change of tension in the atrial wall: the tension being calculated according to the Law of Laplace. Evidence was also presented to indicate that inotropic intervention on the atrial muscle exerted an influence through changes in wall tension which result from alterations in atrial volume and pressures. In a subsequent investigation Recordati et al. (1976) studied the effect of inotropic influence on the type A receptors. They concluded that the 'systolic discharge from type A atrial receptors is a function of active tension developed by atrial muscle during contraction'. This observation is entirely consistent with the hypothesis outlined above which suggests that the type A discharge is due to distortion during atrial contraction. If this is the case, then positive and negative inotropic intervention would influence the discharge regardless of changes in atrial volume, a finding which was confirmed by Recordati et at. (1975). The other significant observation was that changes in atrial volume indepen-

15 ATRIAL RECEPTORS 813 dent of inotropic intervention merely resulted in alterations in the discharge during filling, i.e. conversion. This finding led the authors to conclude that 'only type A receptors may display an Intermediate pattern of discharge'. In the previous investigation, a group of receptors which mimicked atrial receptors in their pattern of discharge but were located at sites other than the atrial endocardium were observed. Some of those which exhibited a 'type A' pattern were impossible to convert using the manoeuvres adopted in this study. It was suggested (Kappagoda et al. 1976) that these units could account for some of the claims (Paintal, 1973) that type A atrial receptors are not converted by changes in atrial pressure. The present investigation has confirmed that a similar group of units which mimic atrial receptors also exist in the dog - a finding first reported by Coleridge et al. (1964). Even the examination of conduction velocities of these units did not reveal any features which permitted the detection of their real identity, thus emphasizing the importance of locating the units examined. The conduction velocities of the fibres examined confirmed the earlier findings of Paintal (1953 b) (in a smaller number of fibres) regarding the essential similarity of the conduction velocities of the fibres having the various patterns of discharge. This judgement must be tempered with the thought that approximately 10% of the 110 fibres examined would not originate from the atrial receptors. Inveatigations in the rabbit In a recent study Rao et al. (1975) have indicated that whereas there was histological evidence of atrial receptors in the rabbit, there was no electrophysiological evidence in fibres in the vagi. Using techniques adopted in the cat and the dog, the present investigations have clearly demonstrated the existence of atrial receptors which discharge into the vagal fibres. The ratio of the three types of atrial receptors in the rabbit was 2: 1: 6. Both type A units and the type B unit were converted into the intermediate form while four of the intermediate type receptors remained unchanged. Thus it could be concluded that unlike the cat and dog, almost all the atrial receptors in the rabbit exhibit action potentials during atrial contraction. It is interesting to speculate that this phenomenon is a species difference. Our own unpublished observations and those of Miller & Kasahara (1967) suggest that there are no fundamental differences between species in respect of histological appearances either in terms of size or number. Assuming that the movement of the atrial wall in the rabbit is qualitatively the same as in the cat and dog, it seems that the only variation in the

16 814 C. T. KAPPAGODA, R. J. LINDEN AND D.A.S.G. MARY three species would be in the size of the heart and thus in the size of the atria; the atria in the rabbit would be smaller than that of the cat which in turn would be smaller than that of the dog. Thus it could be argued that relatively more receptors would be in areas affected by distortion during atrial contraction, and hence the preponderance of receptors which discharge during contraction. Such an explanation would fit our hypothesis which was constructed to explain the patterns of discharge from atrial receptors in the cat and substantiated by the results in the dog (see above). Conclsion8 The findings of the present investigation taken in conjunction with the previous study permit the following conclusions. There is one basic type of atrial receptor which responds to a rise in wall tension which could result from a rise in atrial pressure during filling or from distortion during atrial contraction. Depending on its position in the atrial endocardium, a receptor would be affected by one or both of the above mechanisms. Thus if a classification of atrial receptors based on the pattern of discharge is to be maintained, Paintal's Type B should form one group and the Paintal Intermediate the second group; this second group would contain all receptors which, on first examination, discharged with an Intermediate or a Type A pattern. Any receptor with an inconvertible 'type A' discharge would not be regarded as atrial. It must also be recognized that the intermediate type of discharge from atrial receptors is not as rare a phenomenon as has been suggested (Paintal, 1963; Rao et al. 1975; Gupta, 1977). As was stated previously (Kappagoda et al. 1976) the above evidence allows the correct anatomical and physiological (in terms of patterns of response) descriptions of receptors found in the endocardium of the atria and discharging into myelinated fibres in the vzgi. It does not provide an argument for or against a proposition that receptors having these different patterns of discharge have different functions; and it is again suggested that the term 'atrial receptors' should be used to refer to those receptors situated in the endocardium and contained within the previous classification as Paintal Type B and Intermediate and which discharge into myelinated fibres in the vagi. The authors are indebted to Mr G. Wade and Mr D. Kaye for their technical assistance and are grateful to the Medical Research Council, British Heart Foundation and the Wellcome Trust for financial support.

17 ATRIAL RECEPTORS 815 REFERENCES COLERIDGE, J. C. G., HEMINGWAY, A., HOLMES, R. L. & LINDEN, R. J. (1957). The location of atrial receptors in the dog: a physiological and histological study. J. Physiol. 136, COLERIDGE, H. M., COLERIDGE, J. C. G. & KIDD, C. (1964). Cardiac receptors in the dog, with particular reference to two types of afferent ending in the ventricular wall. J. Phy8iol. 174, GUPTA, B. N. (1977). The location and distribution of type A and type B atrial endings in cats. Pfluger8 Arch. ge8. Phy8iol. 367, KAPPAGODA, C. T., LINDEN, R. J. & MARY, D. A. S. G. (1976). Atrial receptors in the cat. J. Phy8iol. 262, KAPPAGODA, C. T., LINDEN, R. J. & M.Ay, D. A. S. G. (1977). Patterns of discharge from atrial receptors in the dog. J. Physiol. 270, 65-66P. KAPPAGODA, C. T., LINDEN, R. J. & SNOW, H. M. (1972). The effect of stretching the superior vena caval-right atrial junction on right atrial receptors in the dog. J. Phy8iol. 227, MTTITLER, M. R. & KAsAHARA, M. (1964). Studies on the nerve endings in the heart. Am. J. Anat. 115, PAINrAL, A. S. (1953a). A study of right and left atrial receptors. J. Phyaiol. 120, PAINTAL, A. S. (1953b). The conduction velocities of respiratory and cardiovascular afferent fibres in the vagus nerves. J. Phy8iol. 121, PAiNTAL, A. S. (1963). Vagal afferent fibres. Ergebn. Phy8iol. 52, PAiNTAL, A. S. (1973). Vagal sensory receptors and their reflex effects. Phypiol. Rev. 53, RAO, P. S., FAHIM, M. & GUPTA, B. N. (1975). Relative distribution of types A and B atrial receptors in dogs, cats, monkeys and rabbits. Experientia 31, RECORDATI, G., LOMBARDI, F., BISHOP, V. S. & MA1i1iTAI, A. (1975). Response of type B atrial vagal receptors to changes in wall tension during atrial filling. Circulation Res. 36, RECORDATI, G., LOMBARDI, F., BISHOP, V. S. & MALLIANI, A. (1976). Mechanical stimuli exciting type A atrial vagal receptors in the cat. Circulation Res. 38,