THE ATRIAL RECEPTORS RESPONSIBLE FOR THE DECREASE IN PLASMA VASOPRESSIN CAUSED BY DISTENSION OF THE LEFT ATRIUM IN THE DOG

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1 Quarterly Journal of Experimental Physiology (1984) 69, Printed in Great Britain THE ATRIAL RECEPTORS RESPONSIBLE FOR THE DECREASE IN PLASMA VASOPRESSIN CAUSED BY DISTENSION OF THE LEFT ATRIUM IN THE DOG The Department of Cardiovascular Studies, University of Leeds, Leeds, LS2 9JT (RECEIVED FOR PUBLICATION 10 MAY 1983) SUMMARY In dogs anaesthetized with chloralose, the effects of cooling the cervical vagi on the reflex decrease in plasma concentration of vasopressin, caused by distension of a large balloon in the lumen of the left atrium, were examined. Distension of the balloon in ten dogs with the vagi at 37 C resulted in a decrease in plasma concentration of vasopressin and, as before, an increase in urine flow. The responses were not significantly affected by cooling to C but were abolished at 9 IC. At 'C the increase in activity in myelinated vagal afferent fibres is largely unchanged and at 9 'C is abolished (Kappagoda, Linden & Sivananthan, 1979; Sivananthan, Kappagoda & Linden, 1981). It is concluded that the decrease in plasma concentration of vasopressin during distension of the left atrium is mediated by the Paintal-type atrial receptors with myelinated vagal afferent fibres. INTRODUCTION Recently, Bennett, Linden & Mary (1982, 1983) showed conclusively that distension of a balloon in the lumen of the left atrium resulted consistently in a significant decrease in the plasma concentration of vasopressin. Discrete stimulation of the atrial receptors by distension of small balloons in the pulmonary vein-left atrial junctions and left atrial appendage, resulted in a decrease in the plasma concentration of vasopressin which was independent of secondary haemodynamic changes. Sivananthan, Kappagoda & Linden (1981) demonstrated that distension of a balloon in the left atrium stimulates atrial receptors attached to myelinated and non-myelinated vagal afferent fibres, and using the technique of graded cooling of the cervical vagi, showed that these receptors were responsible for the reflex increase in urine flow. The present investigation was undertaken to determine which vagal afferent fibres, myelinated or non-myelinated, were involved in the reflex response of a decrease in plasma vasopressin. A preliminary report of part of this investigation has already been presented to the Physiological Society (Bennett et al. 1982). METHODS Dogs weighing kg were anaesthetized with z-chloralose and artificially ventilated. Anaesthesia was maintained using a continuous infusion of chloralose in saline solution (10 mg.cm-3, 100 mmol.l- NaCl). Experimental methods prevously described in detail (Ledsome & Linden, 1968; Kappagoda, Linden & Snow, 1972) are briefly oulined below. The chest was opened on the left side and a rubber balloon attached to a polythene catheter was inserted into the lumen of the left atrium through the atrial appendage. Injection of warm saline into the balloon was used partially to obstruct the mitral orifice so as to increase left atrial pressure and distend the left atrium. Pressures in the descending aorta and left atrium were recorded from polythene cannulae inserted

2 74 into the right femoral artery and through the tip of the left atrial appendage respectively, along with tracheal pressure, expired Pco, and e.c.g.; the oesophageal temperature and the ph, Pco, and PO of arterial blood were monitored and maintained within normal limits, as previously described (Kappagoda, Linden & Snow, 1970). Each ureter was catheterized through a midline suprapubic incision and the urine was collected and the volume measured every 10 min. Both cervical vagal nerves were dissected clear of the carotid arteries and a cooling thermode (2 5 cm wide) applied to each nerve (see Linden, Mary & Weatherill, 1981, for details). The plasma concentration of vasopressin in arterial blood samples taken before, during and after distension of the balloon (Fig. 1) was measured by radioimmunoassay (see Bennett et al. 1983, for details). Plasma concentration of vasopressin is expressed in pg.cm-3 (I pg is equivalent to4,u.). 04 Experimental protocol After a steady state, with respect to heart rate, arterial blood pressure and urine flow, had been reached for at least 60 min, the balloon was distended for a period of 30 min. Observations were continued for 40 min after release of the distension. The test period of distension for the urine response was the final 20 min of the distension and the first 10 min after release of the distension. The 30 min period immediately preceding the distension and the 30 min following the test period constituted the two control periods; the difference between the urine flow during the test period and the average of the values during the two control periods was taken as the response to the distension. This method of calculation of the response is the same as that used previously (e.g. Henry, Gauer & Reeves, 1956; Ledsome & Linden, 1968). Haemodynamic changes brought about by distension of the balloon were calculated in a similar manner. Statistical analysis of the results was carried out using Student's t for paired data. The results are expressed as mean + S.E.M. The balloon was distended initially with the cervical vagi at 37 IC, with the vagi cooled to 9 C (group I) or IC (groupii) and finally with the vagi rewarmed to 37 IC. Only those experiments in which the whole protocol was completed (i.e. three distensions) were included in the calculations. In each experiment, plasma samples were collected at the times indicated by the arrows in Fig. 1. Three samples were obtained during each of the two control periods and during the period of distension respectively. The difference between the concentration during the period of distension and the average of the values during the control periods was taken as the response to the distension. The results are expressed as absolute differences and as percentage changes relative to the average value obtained during the control periods. The statistical significance of the change in plasma vasopressin at each temperature was assessed using Student's t test for paired data. The effect of cooling on the response was assessed using Student's t test for paired data by averaging the two responses at 37 IC and comparing this value with the response with the vagi cooled. In addition, each response with the vagi cooled was expressed as a percentage of the average response at 37 'C in each animal. RESULTS When recording commenced in ten dogs, the heart rate was 1I18 beats.min-1 (mean; range ), the mean arterial pressure was 19-4 kpa (mean; range l6) and the left atrial pressure was0o80 kpa (mean; range ). The ph, Pco, and Po2 of the arterial blood were 7-38 (mean; range A42), 5-19 kpa (mean; range ) and 26-2 kpa (mean; range ) respectively. The haematocrit of the arterial blood was 40O6% (mean; range 32-48). After a steady state had been attained with respect to urine flow, heart rate, mean arterial pressure and anaesthetic state, h after completion of the surgical procedures, the balloon in the lumen of the left atrium was distended by injecting 13-8 cm3 (mean; range 9-18) of saline. The balloon was distended thirty times in ten dogs, i.e. twenty distensions with the cervical vagi at 37 'C, five with the vagi cooled to 9 IC, four distensions at 16 'C and one at 18 'C. For statistical analysis the distensions at 16 and 18 'C were treated as one group. The results of one experiment are illustrated in Fig. 1. Each distension of the balloon test

3 H.R. (beats. min-'), ATRIAL RECEPTORS AND VASOPRESSIN RESPONSE 37 C 9 c 37 c 2-5 *.. * *. L.A.P. (kpa),... * * * * * * * * * * * * * * * * -.. M.A.P. (kpa) 13I * 6 *.,. o s <.X 0 AVP (pg. cm 3) U( m (cm'3. min-') 2 F: OL IT, r r 7 LJ,t Time in 10 min intervals 75 C T C C T C C T C Fig. 1. An example of one experiment. The ordinate depicts, from above downwards, the mean left atrial pressure (L.A.P.), heart rate (H.R.), mean arterial pressure (M.A.P.), plasma concentration of vasopressin (AVP) and urine flow (U). A large balloon was distended in the lumen of the left atrium with the cervical vagi at 37 C, with the vagi cooled to 9 C and again with the vagi at 37 'C. Each 30 min period of distension is included within each pair of vertical dashed lines. The arrows indicate the times at which arterial blood samples were withdrawn for estimation of plasma concentration of vasopressin. Plasma samples were pooled to give a total of nine samples: six control samples (C) and three test samples (T). was accompanied by an increase in left atrial pressure and a decrease in mean arterial pressure. The magnitude of the increase in urine flow was calculated as described in the Methods. Before cooling the vagi, the increase in urine flow (i.e. initial control response) was 503%0 and the decrease in plasma concentration of vasopressin was 3-2 pg.cm-3 (77% of the control values). When the vagi were cooled to 9 C both the increase in urine flow and the decrease in plasma concentration of vasopressin in response to distension of the balloon were abolished. After rewarming the vagi the increase in urine flow (i.e. final control response) was 263% and the decrease in plasma vasopressin was 2 5 pg.cm-3 (81 % of the average control values). The large variation in the size of the urine response obtained during the course of an experiment in any one dog, indicated in Fig. 1, illustrates the essential requirement for control responses obtained both before and after cooling the cervical vagi. The results of all experiments are presented as two groups to distinguish between activity

4 76 Table 1. Changes (mean+s.e.m.) in left atrial pressure (L.A.P.), mean arterial pressure (M.A.P.), heart rate (H.R.) and urineflow (UV) produced by distension ofa balloon in the lumen of the left atrium in group I (vagi at 37 and 9 C) and group II (vagi at 37 and C) Change in L.A.P. Change in M.A.P. Change in H.R. Change in UV Group I (kpa) (kpa) (beats.min-1) (%) Vagiat37 C(n= 10) +1 21± P <00005 <00005 <001 <005 Vagi at 9 C (n = 5) P < < >0-05 >0-05 Group II Vagi at 37 C (n = 10) P < < < < Vagi at C (n =5) ± P < <0.025 <0-005 <0 05 Statistical significance of the changes (P) was assessed using Student's t test for paired data. Table 2. Effect ofcooling the vagi on the baseline levels (mean + S.E.M.) of left atrial pressure (L.A.P.), mean arterialpressure (M.A.P.), heart rate (H.R.), plasma concentration ofvasopressin (A VP) and urine flow (UV) L.A.P. M.A.P. H.R. AVP Up Group I (kpa) (kpa) (beats.min-1) (pg.cm-3) (cm3.min-') Vagi at 37 C Vagi at 9 C P >0 10 >0 15 >0 35 <0 025 >0 20 Group II Vagi at 37 C Vagiat C P >0 40 >0 20 >0 45 >0 15 >0 20 Statistical significance of the differences (P) between the vagi at 37 C and cooled to either 9 C or C was assessed using Student's t test for paired data. in myelinated fibres and each of two groups of non-myelinated fibres. In group I, the responses are compared with the vagi at 37 C and 9 OC and in group II, a comparison is made at 37 OC and C; the responses in the two groups of non-myelinated fibres were abolished at different temperatures (Kappagoda, Linden & Sivananthan, 1979; Sivananthan et al. 1981; see Discussion). Group L The balloon was distended three times in each of five dogs. Distension of the balloon with the vagi at 37 C caused an increase in left atrial pressure, a decrease in mean arterial pressure and an increase in heart rate (Table 1). The urine flow increased by % (P<0005) from a control value of cm3.min-'. The plasma concentration of vasopressin decreased (P < 0025) from a control value of I11 pg.cm-3 (range ) to pg.cm-3 during the distension (Fig. 2). These responses were similar to those obtained previously (Bennett et al. 1983).

5 ATRIAL RECEPTORS AND VASOPRESSIN RESPONSE 77 8 Group I Group II 6 E C 9 C 37 C C Fig. 2. Plasma concentration of vasopressin (AVP) during control (stippled columns) and test periods (open columns) in group 1 (37 and 90C) and group 11 (37 and C). The values represented are means +S.E.M. Distension of the balloon with the vagi cooled to 9 C caused an increase in left atrial pressure and a decrease in mean arterial pressure (Table 1). The increase in left atrial pressure was not significantly different from the increase with the vagi at 37 0C (P > 0 25, paired t test). The increases in urine flow and heart rate were abolished (Table 1). Cooling the vagi to 9 C had no significant effect on the control values of left atrial pressure, mean arterial pressure, heart rate or urine flow (Table 2). Distension of the balloon with the vagi cooled to 9 OC caused no significant change in plasma concentration of vasopressin. The concentration during the control periods was pg.cm-3 and during the distension was pg.cm-3 (Fig. 2). This response was significantly different (P < 0-05) from the response with the vagi at 37 OC. The decrease in plasma vasopressin with the vagi at 9 C was always either smaller than at 37 C or was completely abolished. Cooling the vagi to 9 IC caused a small but significant decrease in the control concentration of vasopressin (P < 0-025, paired t test; Table 2), however, the range of control values ( pg.cm-3) was within the range from which a decrease was consistently observed with the vagi at 37 IC. Group II. Distension of the balloon with the vagi at 37 IC caused significant increases in left atrial pressure, heart rate and urine flow and a decrease in mean arterial pressure (Table 1). The plasma concentration of vasopressin decreased (P < ) from a control value of 3A pg.cm-3 to 1[ pg.cm-3 (Fig. 2). Distension of the balloon with the vagi cooled to 'C caused increases in left atrial pressure, heart rate and urine flow and a decrease in mean arterial pressure (Table 1). The increase in left atrial pressure was not significantly different from the increase observed with the vagi at 37 'C (P > 0 25, paired t test) and cooling had no significant effect on the control values of left atrial pressure, mean arterial pressure, heart rate, urine flow and plasma concentration of vasopressin (Table 2). When the cervical vagi were cooled to 'C, distension of the balloon caused a significant decrease (P < 001) in plasma concentration of vasopressin ( pg.cm-3 to 1* pg.cm-3; Fig. 2). The response at C was not significantly different

6 78 (P > 0-10) from the response observed with the vagi at 37 IC (Fig. 2); cooling had no consistent effect on the response. With the vagi at 37 C in both groups, there was no significant correlation between the change in urine flow and either the percentage decrease or the absolute decrease in plasma vasopressin. DISCUSSION Electrophysiological studies in the dog and cat have demonstrated the presence, in the atrial endocardium, of receptors which discharge into myelinated fibres of the cervical vagus (e.g. Paintal, 1953; Kappagoda, Linden & Mary, 1977). On the left side of the heart, these receptors are situated mainly at the pulmonary vein-left atrial junctions (Coleridge, Hemingway, Holmes & Linden, 1957; Kappagoda et al. 1977). Receptors with nonmyelinated vagal afferent fibres (e.g. Thames, Donald & Shepherd, 1977; Kappagoda et al. 1979) and receptors with afferent fibres running in the rami communicantes (Malliani, Recordati & Schwartz, 1973; Holton, 1977) have been demonstrated, more widely distributed in the atrial walls. Although distension of a balloon in the lumen of the left atrium stimulates all three types of receptor (Sivananthan et al. 1981; Holton, 1977), the reflex increase in urine flow (e.g. Henry & Pearce, 1956; Ledsome & Linden, 1968; Kappagoda, Linden, Snow & Whitaker, 1974; Sivananthan et al. 1981) is mediated by receptors attached to myelinated vagal afferent fibres (Sivananthan et al. 1981). Recently, Bennett et al. (1983) showed conclusively that distension of a balloon in the lumen of the left atrium resulted consistently in a decrease in the plasma concentration of vasopressin. As no cause-and-effect relationship linking this decrease in vasopressin and the increase in urine flow has yet been unequivocally established, it was of interest to determine whether the same type of receptors were responsible for both the decrease in vasopressin and the increase in urine flow. Kappagoda et al. (1979), found that the response of an increase in activity in myelinated vagal afferent fibres, during distension ofsmall balloons in the pulmonary vein-left atrial junctions, was blocked over a range of temperature in the vagal nerves different from that at which the response in non-myelinated fibres was affected (see Figs. 5 and 11, Kappagoda et al. 1979). The response in myelinated fibres was reduced and abolished over a narrow range of temperature (18-9 IC) but the response in the majority of non-myelinated fibres was unaffected at 9 IC. Sivananthan et al. (1981) observed similar effects on the increase in activity in myelinated and non-myelinated vagal afferent fibres when the atrial receptors were stimulated by distension of a balloon in the lumen of the left atrium. In the present investigation, the effect of cooling the vagi on the increase in urine flow produced by atrial distension was similar to that observed by Sivananthan et al. (1981). The results are therefore consistent with the increase in urine flow being mediated by atrial receptors attached to myelinated vagal afferent fibres, since the response was blocked over a similar range of vagal temperature. The decrease in the plasma concentration of vasopressin, in response to distension of a balloon in the lumen of the left atrium, was blocked over a narrow range of temperature similar to that over which the increase in activity in myelinated vagal afferent fibres was blocked in the study by Sivananthan et al. (1981). The response was abolished at 9 C, suggesting that the atrial receptors attached to myelinated vagal afferent fibres were responsible for the decrease in vasopressin. With four of the five distensions of the balloon with the vagi cooled to 9 C, there was an increase- in the plasma concentration of

7 ATRIAL RECEPTORS AND VASOPRESSIN RESPONSE 79 vasopressin. The increase was probably due to the unopposed effect of decreased stimulation of the arterial baroreceptors (Share, 1965) caused by the decrease in mean arterial pressure accompanying obstruction of the mitral orifice. The possibility that the response is mediated by a population of non-myelinated vagal fibres whose increase in activity is abolished above 18 C (Kappagoda et al. 1979; Sivananthan et al. 1981) is ruled out because the decrease in vasopressin was not significantly affected at IC. In addition, because the response was completely abolished at 9 'C, it is unlikely that atrial receptors attached to sympathetic afferent fibres are involved. These results support the conclusion that the decrease in plasma concentration of vasopressin is mediated by atrial receptors attached to myelinated vagal afferent fibres. The reduction in the magnitude of the decrease in plasma vasopressin, during cooling of the vagi, cannot be attributed to a change in the magnitude of the stimulus; the increase in left atrial pressure during distension of the balloon with the vagi at 37 C was not significantly different from the increase in experiments with the vagi at C or 9 C. Also, the attenuation of the reflex response was not attributable to either a change in the haemodynamic state of the animal or to a change in the control level of plasma vasopressin. Cooling the vagi to IC had no significant effect on the control plasma concentration of vasopressin, but cooling to 9 'C led to a small but significant decrease. However, the five control levels of plasma vasopressin seen with the vagi cooled to 9 'C were all within the range of baseline vasopressin concentration from which a decrease was consistently observed with the vagi at 37 'C. This finding, that the control concentration of vasopressin is reduced at 9 'C, is not consistent with the observations of Ledsome, Ngsee & Wilson (1983) that cooling the vagi to 9 IC led to an increase in plasma vasopressin. However, cooling to 9 C in that study (Ledsome et al. 1983) caused haemodynamic changes, which could have been secondarily responsible for the change in vasopressin, and were absent in the present study. Cooling the vagi to 9 C, in addition to abolishing the reflex increase in urine flow and decrease in plasma vasopressin, also abolished the increase in heart rate accompanying distension of the balloon. However, the decrease in plasma concentration of vasopressin is not dependent on the increase in heart rate accompanying the stimulus to atrial receptors (Bennett et al. 1982, 1983). Thoren (1979) suggested that the atrial receptors attached to non-myelinated fibres in the vagi might be responsible for the reflex decrease in plasma vasopressin. His argument was based on the observation that distension of a large balloon in the lumen of the left atrium, which stimulates receptors attached to both myelinated and non-myelinated vagal afferent fibres, causes a decrease in plasma vasopressin (de Torrente, Robertson, McDonald & Schrier, 1975), whereas distension of the small balloons in the pulmonary vein - atrial junctions (Kappagoda et al. 1974), stimulating predominantly receptors attached to myelinated fibres, did not cause a decrease in the antidiuretic activity of the plasma. The results of the present study do not support the above hypothesis that the atrial receptors attached to non-myelinated afferent vagal fibres are responsible for the decrease in plasma vasopressin. It is evident that the decrease in plasma vasopressin is reduced and abolished over a range of temperature similar to that over which the reflex diuresis is reduced during left atrial distension and therefore is probably mediated by the same group of atrial receptors. Thus, it is possible that a decrease in plasma vasopressin plays a role in the production of an increase in urine flow. However, a concomitant change is not evidence of a cause-and-effect relationship. In addition, the hypothesis is not supported by the fact that in these

8 80 experiments the magnitude of the reflex diuresis is not consistently related to the magnitude of the decrease in plasma vasopressin (e.g. Fig. 1). Therefore, whether vasopressin is involved in the reflex diuresis will depend on an investigation in animals anaesthetized and prepared in this way, which compares any change in urine flow to measured changes in plasma concentration of vasopressin. These results do not affect other results purporting to show that a diuretic substance is released on stimulation of atrial receptors (e.g. Linden & Kappagoda, 1982; Knapp, Linden & Pearson, 1981; Knapp, Linden, Pearson & Pither, 1983). The present position is that a substance is released, possibly diuretic, which affects water transport in the Malpighian tubule; the response of an increase in urine flow in the anaesthetized dog and the effect on the Malpighian tubules of the diuretic agent are abolished by cooling the vagi to 9 C (Knapp et al. 1983). As stated above, there is no evidence that changes in plasma vasopressin of the magnitude described in this investigation in response to stimulation of atrial receptors can cause changes in urine flow in our anaesthetized-dog preparation. Should a positive relationship be established, then the very interesting question would be: what is the proportional effect of the two substances, vasopressin and the possible diuretic substance, on urine flow in response to discrete stimulation of atrial receptors? In conclusion, the present evidence shows that the reflex decrease in the plasma concentration of vasopressin resulting from distension of a large balloon in the lumen of the left atrium involves stimulation of atrial receptors attached to myelinated fibres in the vagi; non-myelinated vagal fibres and sympathetic afferent nerves are not involved in this response. The authors wish to express their gratitude to the Medical Research Council, British Heart Foundation and the Wellcome Trust for financial assistance and to Messrs D. Kaye and P. Berry for technical assistance. Our thanks go to Prof. D. B. Morgan for the use of the radioimmunoassay facilities and the technical assistance of Mrs M. Goodall in the Department of Chemical Pathology, Leeds University. REFERENCES BENNETT, K. L., LINDEN, R. J. & MARY, D. A. S. G. (1982). Left atrial receptors and the antidiuretic hormone. Journal of Physiology 330, 23-24P. BENNETT, K. L., LINDEN, R. J. & MARY, D. A. S. G. (1983). The effect of stimulation of atrial receptors on the plasma concentration of vasopressin. Quarterly Journal ofexperimental Physiology 68, 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. Journal of Physiology 136, DE TORRENTE, A., ROBERTSON, G. L., MCDONALD, K. M. & SCHRIER, R. W. (1975). Mechanism of diuretic response to increased left atrial pressure in the anaesthetized dog. Kidney International 8, HENRY, J. P., GAUER, 0. H. & REEVES, J. L. (1956). Evidence of the atrial location of receptors influencing urine flow. Circulation Research 4, HENRY, J. P. & PEARCE, J. W. (1956). The possible role of cardiac atrial stretch receptors in the induction of changes in urine flow. Journal of Physiology 131, HOLTON, A. (1977). Characteristics of cardiac receptors with fibres in the rami communicantes. Ph.D. Thesis, University of Leeds. KAPPAGODA, C. T., LINDEN, R. J. & MARY, D. A. S. G. (1977). Atrial receptors in the dog and rabbit. Journal of Physiology 272, KAPPAGODA, C. T., LINDEN, R. J. & SIVANANTHAN, N. (1979). The nature of the atrial receptors responsible for a reflex increase in heart rate in the dog. Journal of Physiology 291, KAPPAGODA, C. T., LINDEN, R. J. & SNOW, H. M. (1970). An approach to the problems of acid-base balance. Clinical Science 39,

9 ATRIAL RECEPTORS AND VASOPRESSIN RESPONSE 81 KAPPAGODA, C. T., LINDEN, R. J. & SNOW, H. M. (1972). The effect of distending the atrial appendages on urine flow in the dog. Journal of Physiology 227, KAPPAGODA, C. T., LINDEN, R. J., SNOW, H. M. & WHITAKER, E. M. (1974). Left atrial receptors and the antidiuretic hormone. Journal of Physiology 237, KNAPP, M. F., LINDEN, R. J. & PEARSON, M. J. (1981). Diuresis from stimulatioii of left atrial receptors: ADH and the Malpighian tubules of Rhodniusprolixus. Quarterly Journal ofexperimental Physiology 66, KNAPP, M. F., LINDEN, R. J., PEARSON, M. J. & PITHER, J. M. (1983). Abolition of atria! receptor diuresis and of release of humoral agent by cooling the vagal nerves. Quarterly Journal of Experimental Physiology 68, LEDSOME, J. R. & LINDEN, R. J. (1968). The role of the left atrial receptors in the diuretic response to left atrial distension. Journal of Physiology 198, LEDSOME, J. R., NGSEE, J. & WILSON, N. (1983). Plasma vasopressin concentration in the anaesthetized dog, before, during and after atrial distension. Journal of Physiology 338, LINDEN, R. J. & KAPPAGODA, C. T. (1982). Atrial Receptors. Monographs of the Physiological Society. pp Cambridge: Cambridge University Press. LINDEN, R. J., MARY, D. A. S. G. & WEATHERILL, D. (1981). The effect of cooling on transmission of impulses in vagal fibres attached to atrial receptors in the dog. Quarterly Journal of Physiology 66, MALLIANI, A., RECORDATI, G. & SCHWARTZ, P. J. (1973). Nervous activity of afferent cardiac sympathetic fibres with atrial and ventricular endings. Journal of Physiology 229, PAINTAL, A. S. (1953). A study of right and left atrial receptors. Journal of Physiology 120, SHARE, L. (1965). Effects of carotid occlusion and left atrial distension on plasma vasopressin titer. American Journal of Physiology 208, SIVANANTHAN, N., KAPPAGODA, C. T. & LINDEN, R. J. (1981). The nature of atrial receptors responsible for the increase in urine flow caused by distension of the left atrium in the dog. Quarterly Journal of Experimental Physiology 66, THAMES, M. D., DONALD, D. E. & SHEPHERD, J. T. (1977). Behaviour of cardiac receptors with non-myelinated vagal afferents during spontaneous respiration in cats. Circulation Research 41, THOREN, P. (1979). Role of cardiac vagal C-fibres in cardiovascular control. Reviews of Physiology, Biochemistry and Pharmacology 86, 1-94.