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. 2002 Nov 4;545(Pt 1):305–312. doi: 10.1113/jphysiol.2002.018176

Role of cardiac–renal neural reflex in regulating sodium excretion during water immersion in conscious dogs

Kenju Miki *, Yoshiaki Hayashida *, Keizo Shiraki *
PMCID: PMC2290670  PMID: 12433970

Abstract

The present study was undertaken to determine the role of cardiopulmonary mechanoreceptors in inducing the sustained reduction of renal sympathetic nerve activity (RSNA) and concomitant changes in sodium excretion occurring during water immersion (WI) in intact dogs. Seven cardiac-denervated dogs were chronically instrumented for measuring RSNA, systemic arterial (Pa), central venous (Pcv) and left atrial pressures (Pla). WI initially decreased RSNA in cardiac denervated dogs by 10.0 ± 5.5 %; thereafter the RSNA fell to a nadir of 18.5 ± 5.6 % (P < 0.05) at 40–80 min of WI and then returned toward the pre-immersion level. Renal sodium excretion increased significantly by 211 ± 69 % (P < 0.05) only during the first 20–40 min of WI. WI increased Pa, Pcv and Pla in a step manner from 94 ± 3 to 108 ± 3 mmHg (P < 0.05), from 1.4 ± 0.5 to 12.3 ± 1.0 mmHg (P < 0.05) and from 4.9 ± 0.6 to 15.4 ± 1.2 mmHg (P < 0.05), respectively. These responses in RSNA and sodium excretion to WI in the cardiac-denervated dogs were significantly (P < 0.05) attenuated compared with those in a previous group of intact dogs. These data suggest that the attenuated responses of neural and excretory response to WI observed in cardiac-denervated dogs can be attributed to an interruption of afferent input originating from the cardiopulmonary mechanoreceptors to the central nervous system.

Head-out water immersion (WI) is associated with a translocation of blood into the thorax that leads to a diuresis and natriuresis in humans (Epstein, 1992; Schou et al. 2002) and animals (Krasney, 1996). The mechanisms underlying the diuresis and natriuresis are not completely understood. Mechanoreceptors located in the heart are believed to play a central role in sensing increased central blood volume, and initiating a neurohormonal adaptation (cardiac–renal hormonal axis), which increases water and sodium excretion (Krasney, 1996; Andersen et al. 2000). The cardiac–renal hormonal axis includes the reflex suppression of antidiuretic hormone (ADH; Gauer-Henry reflex), decreased aldosterone secretion, and increased atrial natriuretic factor (ANF) release secondary to stretch of the heart. However, the cardiac–renal hormonal axis does not adequately explain the WI-induced diuresis and natriuresis (Greenleaf et al. 1999). For example, Hajduczok et al. (1987) have reported that plasma ADH and aldosterone fail to change significantly during WI in conscious hydrated dogs although a diuresis and natriuresis occur. We have shown in humans that an attenuation of the diuresis and natriuresis was observed during WI at night while ADH, aldosterone and ANF responses to WI were the same whether performed during the day or night (Shiraki et al. 1986; Miki et al. 1988). Therefore, the cardiac–renal hormonal axis may not be of major importance in mediating the diuresis and natriuresis during WI.

The role of renal sympathetic nerve activity (RSNA) in regulating sodium and water excretion has been studied extensively (DiBona, 1982; DiBona & Kopp, 1997; Lohmeier, 2001). DiBona and his colleagues (DiBona, 1982; DiBona & Kopp, 1997) have shown clearly that RSNA directly regulates sodium excretion. We have reported previously that WI results in a step decrease in RSNA of 43 % throughout a 2 h period of WI in intact dogs (Miki et al. 1989a). Furthermore, renal denervation completely abolished the diuretic and natriuretic response to WI, whereas the haemodynamic responses to WI in renal-denervated dogs were similar to those in intact dogs. It is therefore likely that RSNA plays a major role in determining the natriuresis during WI. This conclusion supports the hypothesis that a reflex reduction of RSNA originating from cardiopulmonary mechanoreceptors (cardiac–renal neural reflex) may be responsible, in part, for the diuresis and natriuresis occurring during WI (Hajduczok et al. 1987). However, the potential role of the cardiac–renal neural reflex in regulating sodium excretion during WI has not yet been fully evaluated.

The purpose of the present study was to establish the importance of the cardiac–renal neural reflex in the natriuresis occurring during WI. To achieve this aim, both RSNA and the renal response to WI were measured in conscious cardiac-denervated (CD) dogs. The time courses of the changes in RSNA, haemodynamics and the renal responses to WI obtained in the present study in CD dogs were compared with those of intact and renal-denervated dogs in our previous report (Miki et al. 1989a).

Methods

This study was conducted in accordance with the Guiding Principles for the Care and Use of Animals in the Field of Physiological Sciences approved by the Council of the Physiological Society of Japan (1988) with the prior approval of the Animal Care Committee of Nara Women's University and University of Occupational and Environmental Health.

Animal preparation

Seven female mongrel dogs with a mean weight of 9.7 ± 0.7 kg (s.e.m.) were used in this study. All animals were fed a standard kennel ration (CD-5, Clea Japan, Tokyo) with a daily sodium intake of ≈35 mmol. Dogs were selected that were temperamentally amenable to WI. They were trained to be immersed to the mid-cervical level whilst standing for 1 h periods daily over 1–2 weeks prior to the investigation. Once the training was completed, the dogs showed no agitation throughout the experimental period.

Three weeks before the experiment anaesthesia was induced by intravenous injection of pentobarbital sodium (25-30 mg kg−1). A left thoracotomy was performed at the level of the fourth intercostal space using sterile procedures. In CD dogs, the heart of each animal was denervated using the intrapericardial technique of Randall et al. (1980). We also added the modification of Fater et al. (1982) to this procedure, which extends the denervation to include the remaining pulmonary veins and the inferior vena cava at their junction with the pericardium. A Foley catheter (Fr-12), with the central channel sealed with silicone rubber was inserted into the left atrial appendage and positioned such that the inflatable latex balloon lay slightly above the mitral valve. Left atrial pressure (Pla) was controlled by adjusting the volume of the cuff to produce varying degrees of mitral stenosis. A catheter for the measurement of Pla was also inserted through the appendage. Its tip was placed proximal to the balloon cuff. The pericardium was loosely approximated, and the chest was closed. The catheters were routed through the chest wall, exteriorized to the interscapular space and protected by a fitted jacket. The catheters were flushed twice a week and kept filled with heparin sodium solution (1000 i.u. ml−1, Sigma). Two weeks after the thoracotomy, the dogs were again anaesthetized with pentobarbital sodium. Two further catheters were inserted with their tips positioned in the abdominal aorta and the inferior vena cava via the right femoral artery and vein, respectively, for measurement of systemic arterial pressure at the kidney (Pa) level and central venous pressure (Pcv). The catheters were exteriorized to the interscapular space and protected by the fitted jacket. Penicillin (50 000 U i.m., Viccillin, Meiji seiyaku, Tokyo) or sodium cefazolin (500 mg i.m., Cefamezin, Fujisawa, Tokyo) was given daily for 5 days after each operation. The catheters were flushed twice a week and kept filled with heparin sodium solution.

Post-operative care

Animals were examined four times a day for 3 days following the surgery, and twice a day thereafter. The examination score sheet was divided into three categories: category A included posture, activity, breathing, coat and eyes; category B included body temperature, body weight, food intake, drinking, urine volume, faecal volume and hydration status; category C (at request) included chest sound, conventional nociceptive mechanical threshold test, blood test, heart rate. An electrically heated blanket and special food were provided after the surgery. For the control of post-operative pain, a non-steroidal anti-inflammatory drug (diclofenac sodium - Voltaren; 0.5-3 mg kg−1 12-hourly for short term, indomethacin - Inteban; 0.2-1 mg kg−1 for long term) was given. The hydration status of the animals was controlled by the infusion of Ringer solution intravenously on the first post-operative day. The stitches were removed a week after the surgery.

Test for cardiac denervation

The initial test for completeness of the CD was performed during the surgery by stimulating electrically both the ansae subclaviae and thoracic vagi as described by Randall et al. (1980). A second series of tests was performed a few days before the experiment when the dogs were awake. The effectiveness of the denervation was assessed by the heart rate and arterial pressure responses to vena caval injections of phenylephrine (200 μg) or nitroprusside sodium (300 μg) and left atrial injection of veratrine (50 μg). Pa increased by 40 ± 9 mmHg and decreased by 32 ± 6 mmHg in response to the administration of phenylephrine and nitroprusside, respectively, in CD dogs. The heart rate failed to decrease upon the administration of phenylephrine and it failed to change after the administration of nitroprusside sodium. The injection of veratrine produced a small decrease in systemic arterial pressure and no change in heart rate. A third post-operative test for checking the elimination of certain afferent pathways was performed through the inflation of the left atrial balloon as described by Fater et al. (1982): a 60 min control period was followed by a 60 min balloon inflation, with a subsequent 60 min recovery period. During the 60 min balloon inflation period, Pla increased by 8.6 ± 2.3 mmHg, whereas HR showed no changes in CD dogs. Urine flow and urinary sodium excretion also remained constant during balloon inflation. By comparison in sham-operated dogs (n = 8, 9–13 kg body wt), HR increased by 49 ± 9 beats min−1 and urine flow and sodium excretion increased significantly by 441 ± 142 and 359 ± 160 % relative to the control level, respectively, with an increase in Pla of 7.6 ± 2.0 mmHg during balloon inflation. At the end of the entire experimental procedure, the animals were killed with an anaesthetic overdose, and the heart and kidneys were removed and stored frozen (-70 °C) for later measurement of tissue noradrenaline concentration (Nagutu, 1973).

Renal nerve recording

RSNA in conscious CD dogs was measured continuously using the same procedure and instruments as previously described (Miki et al. 1989a,b). Briefly, at least two days before the experiment, the dog was anaesthetized, and the left kidney was exposed retroperitoneally through a left flank incision. After the left renal plexus was identified, one of the postganglionic nerves was isolated carefully for a distance of 10–15 mm. A bipolar stainless steel wire electrode (AS633, Cooner Wire Co., CA, USA) was hooked onto the renal nerve and the wires of the electrode and the isolated nerve were embedded in two-component silicone rubber (932, Wacker-Chemie, Munich, Germany). The renal nerve activity was amplified using a differential amplifier with a band-pass filter of 30 Hz and 1 kHz, displayed on an oscilloscope (VC-11, Nihon Kohden, Tokyo, Japan) and made audible with an audio amplifier. The amplified neural activity was led to a rectifying voltage integrator with resetting time of 1 s (EI-601G, Nihon Kohden, Japan). Output signals were displayed on the eight-channel recorder utilizing an 8 dots mm−1 high-resolution thermal head (8M14, NEC San-Ei, Tokyo, Japan). The area of integrated nerve discharges was calculated simultaneously by processing the analog-to-digital conversion at 1 ms intervals, and the mean values converted over 30 s were calculated continuously by a computer. After the end of each experiment, the background noise was determined when nerve activity was eliminated either by increasing arterial pressure with adrenaline (5 μg kg−1i.v.) or by intravenous administration of hexamethonium (2 mg kg−1i.v.). The background noise was subtracted from the data of integrated RSNA obtained during the experiment. To quantify the RSNA response, percentage changes of the response were calculated by taking the mean of these values during the control period as 100 % RSNA.

Measurements

Pa, Pcv and Pla were measured with Statham strain gauge transducers (P23 ID). The zero pressure reference level for the pressure was taken to be the level of the tricuspid valve (two-thirds of vertical distance between the spinal column and sternum). HR was recorded with a cardiotachometer triggered by the Pa waveform. The Pa, Pcv, Pla, HR and integrated RSNA were continuously monitored and sampled for analog-to-digital conversion at 1 ms intervals. The mean values of the data converted over 30 s were calculated simultaneously, displayed on a computer and stored on a hard disk.

Urine samples were collected at 20 min intervals via a Foley catheter placed in the bladder. Arterial blood samples (1.8 ml) were collected every 20 min. Plasma and urine were analysed for sodium and potassium concentrations (IL943, flame photometer, Instrumentation Laboratory, Milan, Italy) and osmolality (F-2000, freezing point osmometer, Hermann Roebling, Berlin, Germany).

Tissue samples of heart or kidney were homogenized and centrifuged at 2500 g at 4 °C for 20 min. Tissue catecholamines were extracted over alumina. The noradrenaline concentration was measured by high-performance liquid chromatography (635 Hitachi, Tokyo, Japan) coupled with trihydroxyindole fluorometry (Nagutu, 1973).

Experimental protocol

The same experimental protocol was employed in the present study as was used in our previous study (Miki et al. 1989a). Experiments were performed on the conscious animals at least 2 days after implantation of the electrodes for the measurement of RSNA. The dog was positioned in a sling frame assembly in the normal quadruped position at 08.40 h on the day of the experiment. Mild hydration was achieved initially by infusion of a volume equivalent to 2 % of the dog's body weight over a 20 min period with 0.45 % NaCl solution. The urinary tract was infiltrated aseptically with lidocaine hydrochloride (Xylocaine Jelly, Fujisawa Co, Tokyo, Japan). After the connection of the instruments for the measurement of pressure, approximately 1 h was allowed for the stabilization of renal and circulatory function. The experiment consisted of a 60 min control period in air, 120 min of WI, and a 60 min recovery period in air. The dog was immersed to the midcervical level and water temperature was kept constant at 37 °C to ensure a thermoneutral condition (Hajduczok et al. 1987). The timed control (TC) experiments consisted of having the dog stand for a 240 min period in air. An interval of at least 2 days was allowed for recovery between WI and TC experiments and the experiments were performed in random order. It was found that most dogs liked the warm water and relaxed during the immersion period to the extent that the investigators usually had to prevent them from going to sleep during the study. During the recovery phase, the dogs were dried by hand with towels. The dogs were held by a sling frame assembly (Hajduczok et al. 1987), which was loosely applied and allowed them to move freely.

We incorporated into Figs 2, 3 and 4 mean values that had been obtained from intact dogs and had been presented in our earlier study (Miki et al. 1989a). This was done in order to reduce the number of dogs subjected to these complex surgical protocols. Cardiac denervation is the best way to assess the role of cardiopulmonary receptors in conscious animals and this surgical technique has only been established in dogs (Randall et al. 1980; Fater et al. 1982).

Figure 2. Changes in integrated renal sympathetic nerve activity (RSNA) in cardiac-denervated dogs with data in the intact dog obtained from a previous study.

Figure 2

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Changes shown are expressed as a percentage relative to the control level. Heavy lines represent mean values and hatched areas above the mean points represent + s.e.m. Mean values in the intact dogs obtained in our previous study are shown (dotted line, Miki et al. 1989a). WI, water immersion; TC, time control; CD, cardiac-denervated dogs; Int, intact dogs.

Figure 3. Time course of urine flow (V̇), urinary excretion of osmotic substance (UosmV̇), sodium (UNaV̇), free water clearance (CH2O) of time control in air (TC) and water immersion (WI) in cardiac-denervated (CD) dogs.

Figure 3

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Dotted lines represent mean value in intact (Int) dogs (Miki et al. 1989a). * P < 0.05, CD vs. time control; + P < 0.05, CD vs. experimental control level in air; † P < 0.05, CD vs. Int.

Figure 4. Changes in systemic arterial pressure measured at the kidney level (Pa), and central venous pressure (Pcv), left atrial pressure (Pla), and heart rate (HR) during 60 min control in air, 120 min of water immersion (WI) and 60 min of recovery period.

Figure 4

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Heavy lines represent mean value. Stippled area above or below mean values represents ± s.e.m. Dotted lines represent mean value in intact (Int) dogs (Miki et al. 1989a). Significant (P < 0.05) differences between WI and TC in air in Pa (1-150 min), Pcv (1-120 min), Pla (1-120 min) and HR (128-180 min) occurred.

Statistics

Statistical analysis was performed by analysis of variance (ANOVA) for repeated measures. When the F values were significant (P < 0.05), individual comparisons were made using Fisher's least significant difference test (Sachs, 1982). Values are reported as means ± s.e.m.

Results

Heart tissue noradrenaline concentration of atrium and ventricle in the intact dogs (n = 8) was 1128.0 ± 204.0 and 679.7 ± 135.3 ng g−1 (Miki et al. 1993), respectively, whereas that in CD dogs was 28.1 ± 10.0 and 0.5 ± 0.1 ng g−1, respectively.

Typical responses of Pa, Pcv, Pla, RSNA, integrated RSNA and HR during control, 20 min after onset of WI and recovery (20 min after end of WI) in CD dogs are shown in Fig. 1. The magnitude of each burst of RSNA tended to decrease during WI such that integrated RSNA decreased. At the end of WI, integrated RSNA increased because both magnitude and bursting rate increased.

Figure 1. Typical recordings of control, water immersion and recovery.

Figure 1

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Traces show systemic arterial pressure measured at renal level (Pa), central venous (Pcv) and left atrial (Pla) pressures, renal sympathetic nerve activity (RSNA), integrated RSNA, and heart rate (HR) during resting in air (control), water immersion (WI) at 20 min, and during recovery period at 140 min (20 min after end of WI) in a conscious cardiac-denervated (CD) dog. Records are presented with two different recording speeds; see scale bars beneath traces).

The percentage changes in integrated RSNA relative to the control level are shown in Fig. 2. RSNA decreased immediately after the onset of WI by 10.0 ± 5.5 %; thereafter the RSNA fell gradually to a nadir of 18.5 ± 5.6 % at 40–80 min of WI and then recovered slowly to a level of 9.5 ± 8.1 % at 100–108 min of WI. A significant (P < 0.05) decrease in %ΔRSNA due to WI compared with TC experiments occurred between 35 and 90 min. The average reduction of RSNA throughout 120 min of WI was 15.8 ± 6.9 %, which was significantly (P < 0.05) less than the 43 % reduction of RSNA observed in the intact dogs (Miki et al. 1989a). Immediately after the end of the WI, RSNA increased significantly by 50.4 ± 15.5 % relative to the control level (130-150 min). In the TC experiment, RSNA remained constant.

The renal excretory responses to WI in CD dogs are shown in Fig. 3. Urine flow increased significantly (P < 0.05) from a control value of 0.22 ± 0.04 to 0.67 ± 0.18 ml min−1 at 20–40 min of WI, and then decreased gradually during WI. At the end of WI, urine flow remained at a high level relative to the TC experiment. Osmolar excretion increased significantly from a control value of 165 ± 15 to 269 ± 23 mosmol min−1 (by 68 ± 15 % relative to the control level) at 0–20 min of WI and then decreased gradually towards the end of WI. Sodium excretion also increased in a transient fashion to 40.7 ± 10.3 μmol min−1 (by 211 ± 69 % relative to the control level) at 20–40 min of WI from a control value of 16.7 ± 5.7 μmol min−1. Free water clearance did not change during WI. After the end of WI, free water clearance increased significantly (P < 0.05) to −0.05 ± 0.11 ml min−1 at 140–160 min (20- 40 min after end of the WI) from a control level of −0.36 ± 0.05 ml min−1.

The haemodynamic responses elicited by WI in CD dogs are illustrated in Fig. 4. Pa increased significantly after the start of WI from a control value of 94 ± 3 mmHg to 120 ± 5 mmHg at 1 min of WI and then decreased gradually to the steady state level of 108 ± 3 mmHg at 20–120 min of WI. Pcv increased in a step manner from 1.4 ± 0.5 to 12.3 ± 1.0 mmHg due to WI. There was also a step increase in Pla from 4.9 ± 0.6 to 15.4 ± 1.2 mmHg in WI. HR remained constant during WI, but it increased gradually after the termination of WI (by 15 ± 4 beats min−1 at 160–180 min).

Discussion

We have shown previously that WI results in a step reduction of RSNA by 43 % accompanied by a sustained increase in sodium excretion throughout 120 min of WI in conscious intact dogs (Miki et al. 1989a). In the present study, RSNA decreased transiently by only 16 % in CD dogs while both urinary sodium excretion and urine flow increased only transiently in an inverse relationship with RSNA. There were no quantitative differences in responses of Pa and Pcv relative to the pre-immersion level between intact and CD dogs (Fig. 4). Thus the attenuated responses of both RSNA and the natriuresis could be attributed to the elimination of afferent input originating from cardiopulmonary mechanoreceptors and not to any haemodynamic effects. These results suggest that reflex changes in RSNA originating from cardiopulmonary mechanoreceptors (cardiac–renal neural reflex) are important for eliciting the sustained decrease in RSNA and the sustained increase in sodium excretion observed during WI in conscious dogs.

Relative contribution of cardiopulmonary mechanoreceptors to the sustained reduction of RSNA during WI

The present study is the first to demonstrate the time course of the changes in RSNA during WI in conscious CD dogs. RSNA decreased due to WI in a temporary fashion in CD dogs while it decreased in sustained fashion in intact dogs (Fig. 2). Because Pla increases in a step manner throughout 2 h of WI (Fig. 4), the cardiopulmonary mechanoreceptors are loaded during the entire immersion period. Gilmore & Zucker (1974) have shown that type B atrial receptors fail to adapt during a step increase in Pla. It is well established that the cardiopulmonary mechanoreceptors exert a tonic inhibitory influence on RSNA (Linden et al. 1980). For example, the loading of cardiopulmonary mechanoreceptors by left atrial balloon inflation results in a sustained reduction of RSNA over a period of 1 h (Miki et al. 1993). These results indicate that the step increase in Pla detected at the cardiopulmonary mechanoreceptors is transferred to the efferent RSNA via the central nervous system without adaptation during 2 h of WI. Sustained reductions of RSNA failed to occur after elimination of the cardiac innervation despite the fact that there were no quantitative differences in responses of Pcv relative to the pre-immersion level between intact and CD dogs (Fig. 4). We conclude that the cardiopulmonary mechanoreceptors contribute to the sustained reduction of RSNA observed during WI in intact dogs.

Although cardiopulmonary mechanoreceptors play a dominant role in inducing the sustained decrease in RSNA during WI, the present data also indicate that cardiopulmonary mechanoreceptors are not solely responsible for the entire reduction of RSNA. The factors which induce the transient residual reduction of RSNA during WI in CD dog are unknown at present. One possible mechanism involves the sino-aortic baroreceptors, because Pa increased in a step manner in WI. Humoral factors, such as ANF and ADH, may possibly modify centrally the reflex reduction of RSNA (Miki et al. 1988; Bishop et al. 1991). Other afferent systems including somatic receptors may also be involved in the transient reduction of RSNA (Vallbo et al. 1979; Hajduczok et al. 1987; Huang & Johns, 1998). It is possible that the cardiopulmonary baroreflexes interact at the level of the CNS with reflex systems and humoral factors operating during WI in intact dogs (Bishop et al. 1991). Thus, while unknown factors cause the transient reduction of RSNA in CD dogs, the cardiopulmonary reflexes are clearly essential for causing sustained reductions of RSNA during WI in intact dogs.

Role of RSNA in the natriuresis

RSNA appears to play a primary role in mediating the natriuretic response to WI as evidenced by the present and previous observations in dogs. In the present study, sodium excretion increased in a transient fashion during WI in accordance with an inverse change in RSNA (Fig. 3) in the CD dogs. In contrast to the CD dogs, a step reduction of RSNA occurred accompanied by a sustained increase in sodium excretion in intact dogs (Miki et al. 1989a). Furthermore, we have shown previously that renal denervation abolishes the natriuretic response to both WI (Miki et al. 1989a) and left atrial distention (Miki et al. 1993). These results suggest that the magnitude of the increase in sodium excretion is correlated inversely with the magnitude of the decrease in RSNA. This view is in good agreement with studies by DiBona and colleagues (DiBona, 1982; DiBona & Jones, 1994, DiBona & Kopp, 1997) who clearly showed that renal sympathetic nerves directly regulate renal tubular sodium and water reabsorption. Therefore RSNA appears to regulate sodium excretion directly and quantitatively during WI in conscious dogs.

cardiac–renal neural reflex and sodium excretion

This discussion emphasizes the following two major points: (1) cardiac innervation plays a dominant role in eliciting the sustained decrease in RSNA during WI, (2) the sustained decrease in RSNA adequately accounts for the natriuresis during WI. These two issues lead to the conclusion that the cardiac–renal neural reflex plays a dominant role in regulating sodium excretion during WI. This conclusion is consistent with our previous study in which cardiopulmonary mechanoreceptors were loaded selectively (Miki et al. 1993). We raised Pla selectively by 8 mmHg by inflating a balloon implanted in the left atrium, which is the same magnitude of increase in Pla as observed in WI. The left atrial balloon inflation results in a sustained reduction of RSNA associated with a natriuresis. Cardiac denervation completely abolished both the decrease in RSNA and the natriuresis in response to left atrial balloon inflation. This experiment, in conjunction with the present study, further addresses the importance of the cardiac–renal neural reflex in controlling sodium excretion in the awake dog.

The present study and previous reports suggest that the cardiac–renal neural reflex seems to operate the primary negative feedback loop for regulating central blood volume (Miki et al. 1989a, b, 1993). The reflex decrease in RSNA originating from cardiopulmonary mechanoreceptors persisted for more than 2 h (Miki et al. 1989a,b, 1993). The present results emphasize that sustained suppression of RSNA over 1 h cannot occur without involvement of the cardiopulmonary mechanoreceptors. It has been shown that graded distention of the left atrium decreases RSNA linearly with an estimated gain of 12–13 % mmHg−1 (Miki et al. 1991). Therefore, the kidneys are capable of receiving information as to the level of loading of cardiopulmonary mechanoreceptors via the RSNA without adaptation over several hours. The sustained decreases in RSNA enable the kidney to excrete sodium and fluid in relation to the magnitude of loading of cardiopulmonary mechanoreceptors, which in turn results in decreases in central blood volume.

The attenuated responses of sodium and water excretions to WI observed in CD dogs are consistent with the observations in human heart-transplant recipients. It has been recognized that heart-transplant recipients exhibit expansion of extracellular fluid volume and blunted renal response to volume expansion (Geny et al. 1999). Braith et al. (1996a,b) demonstrated that the renin-angiotensin- aldosterone system was not responsive to a hypervolaemic stimulus and concluded that this was likely a consequence of chronic cardiac deafferentation. Unfortunately, neither plasma renin, angiotensin, nor aldosterone concentrations were measured in the present study, but it is likely that the attenuated response of RSNA to WI in CD dogs may lead a blunted plasma renin release such that the response of angiotensin-aldosterone system might be blunted in CD dogs. Therefore, the fluid retention occurring in heart-transplant recipients may be partly engendered by an impairment of the cardiac–renal neural reflex.

Acknowledgments

The authors thank Drs J. A. Krasney (Sate University of New York at Buffalo, NY, USA) and E. J. Johns (University College Cork, Ireland) for critical reading of the manuscript. This study was supported in part by a Grant-in-Aid for Scientific Research from Ministry of Education, Culture, Sports, Science and Technology of Japan.

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