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Division of Cardiovascular Medicine, University of California, Davis, CA 95616, USA
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Abstract |
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(Received 12 December 2003;
accepted after revision 6 May 2004; first published online 6 May 2004)
Corresponding author Dr C. T. Kappagoda Division of Cardiovascular Medicine, Bioletti Way, TB 172, University of California, Davis, CA 95616, USA. Email: ctkappagoda{at}ucdavis.edu
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Introduction |
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In a preliminary study performed in the rabbit, it was found that the increase in urine flow during pulmonary lymphatic obstruction was associated with an increase in nitrate excretion (Gunawardena et al. 2000). This finding suggested a potential role for nitric oxide synthase (NOS) in this response. It is known that all the isoforms of NOS are present in the kidney (Bachmann et al. 1995; Wu et al. 1999). Nitric oxide (NO) is thought to have direct effects upon various regions of the nephron regulating the excretion of sodium (Ortiz & Garvin, 2002). NO also has effects on the renal vasculature, particularly in the medulla (Cowley et al. 2003) and the glomerulus (Wilcox et al. 1992).
The investigation described in this paper was undertaken to clarify the potential role of NO in this response. The following specific hypotheses were tested: (a) the response is abolished by N-nitro-L-arginine methyl ester hydrochloride (L-NAME; Rees et al. 1990), a non-selective inhibitor of NOS; and (b) the response is abolished by 7-nitroindazole (7-NI; Moore et al. 1993), a relatively selective inhibitor for neuronal NOS (n-NOS).
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Methods |
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Anaesthesia was induced with ketamine hydrochloride (Ketaset; Fort Dodge Laboratories, Inc., Fort Dodge, IO, USA; dose 50 mg kg–1I.M.) and xylazine (AnaSed; Lloyd Laboratories, IO, USA; dose 5 mg kg–1, I.M.) and maintained with injections of sodium pentobarbitone (Veterinary Laboratories, Lenexa, KA, USA; 6.5 mg kg–1) injected I.V. every 45 min. The depth of anaesthesia was assessed periodically by testing the corneal reflex, pinching the paw and monitoring heart rate and blood pressure. A tracheotomy was performed low in the neck, and an uncuffed endo-tracheal tube inserted (i.d. 3 mm, length 3–4 cm; National Catheter, Clay Adams, Parsippany, NY, USA). The animals were ventilated (Harvard ventilator, Model 607, Harvard Instruments, Millis, MA, USA) at a rate of 20 breaths min–1 and a tidal volume of 10–12 ml kg–1. The inspired air was supplemented with O2 and the arterial PO2 was maintained above 100 mmHg. The arterial PCO2 and pH were maintained in the physiological range by adjusting the tidal volume and by infusing sodium bicarbonate (8.4%, w/v, I.V.). A polyethylene catheter was introduced into the tracheal cannula and was used for the measurement of airway pressure. The temperature of the animals was measured with a thermistor placed in the rectum and was maintained at 37 ± 1°C using heating lamps and pads.
Polyethylene catheters were introduced into the left femoral vein and artery. The venous catheter was used for giving maintenance doses of the anaesthetic as well as saline infusions, and the arterial catheter was used for measuring aortic blood pressure. Catheters were also introduced into the right femoral vein and artery. The venous catheter was advanced as far as the right atrium and used for measurement of right atrial pressure. The catheter in the right femoral artery was used for periodic withdrawal of blood samples for measurement of blood gases. The catheters used for pressure measurements were connected to strain gauge manometers (Model P23 DB, Statham Instruments Ltd, Hato Rey, Puerto Rico), the outputs of which were amplified and recorded on light-sensitive paper (Model TA 11 Gould Instruments, USA). In the experiments in which urine flow was measured, the animals were infused with 0.9% NaCl at 1.2 ml min–1 (Ravi et al. 1997).
In the three animals that were used for recording action potentials from rapidly adapting receptors (RAR), a mid-line thoracotamy was performed.
Pulmonary lymphatic obstruction
The lymph drainage from the rabbit lung occurs mainly via the right lymphatic duct (Courtice & Simmonds, 1954). The right lymphatic ducts open into the venous system in the region where the right internal jugular vein joins the right external jugular vein (Walker, 1965). A vascularly isolated pouch (length approximately 3 cm) was created in this region as previously described (Ravi et al. 1988; Hargreaves et al. 1991). A saline reservoir was connected to the pouch by means of a polyethylene catheter inserted through the axillary vein. The lymph flow was obstructed in a reversible manner by raising the fluid level of the reservoir to a height of 35 cm.
Collection of urine
A polyethylene catheter (i.d. 3 mm) was introduced into the bladder through a mid-line suprapubic incision. The urine was drained into a collection chamber and was measured at 10 min intervals. The bladder was flushed with normal saline through this catheter periodically between experimental runs in order to ensure the absence of residual urine and to remove any clots or crystalline debris from the catheter itself. In some experiments, both ureters were cannulated and the urine from each kidney was collected separately.
Measurement of renal blood flow
Total renal blood flow was measured using a dual-channel flowmeter (Model T206, Transonic, Ithaca, NY, USA). A perivascular probe (cuff measurement 0.5 mm) was placed around the renal artery without damaging the renal nerves. The total renal blood flow was expressed in millilitres per minute with a random error of ±3 ml min–1.
Effect of L-NAME injections
After the experimental preparation was completed, the animals were left undisturbed for 60–90 min to obtain a steady urine output, heart rate and blood pressure. Next L-NAME was administered I.V. in a bolus (dose 30 mg kg–1 in 3 ml of normal saline over 2 min) in order to inhibit NOS activity. The efficacy of the block was indicated by a rise in arterial blood pressure which was maintained for 3–4 h. Following attainment of a second steady state, the effect of lymphatic obstruction on urine flow was examined as described in the protocol below.
In some experiments, N
-nitro-D-arginine methyl ester hydrochloride (D-NAME; dose 30 mg kg–1 in 3 ml of normal saline over 2 min) was used instead of L-NAME as a control.
Effect of 7-NI injections
In other experiments, 7-NI was given as an I.P. bolus (dose 30 mg kg–1 in 5 ml of normal saline and 1.2 ml of ethanol). When a second steady state of urine flow was reached, the effect of lymphatic obstruction on urine flow was examined as described in the protocol below.
Intramedullary infusions
Intramedullary infusions of drugs were made through a flanged 20 gauge needle inserted into the left kidney to a depth of 8 mm. In preliminary studies it was established that at this depth, the tip of the cannula was located in the inner medulla. The solution containing the compounds was infused using a precision pump (Model A-99, Razel Scientific Instruments, Stanford, CT, USA) at a rate of 0.12 ml (10 min)–1. The dose of 7-NINA was 615 µg kg–1 h–1. In preliminary studies not reported here, infusion of saline at this rate did not alter urine flow in anaesthetized rabbits. This technique is an adaptation of a method previously described (Lu et al. 1992; Mattson, 1999). For the intramedullary infusions, 7-NINA was used instead of 7-NI because it was more soluble.
Recording of action potentials originating from rapidly adapting receptors
The right cervical vagus nerve was carefully dissected away from the carotid artery, and a small pool, filled with mineral oil, was created around it using the surrounding tissues. The vagus nerve was placed on a dissecting platform and desheathed under a dissecting microscope (D. F. Vasconcellos, Model M900, Thousand Oaks, CA, USA). Thin filaments of the vagus nerve were dissected away from the main trunk. A pair of bipolar platinum electrodes was used to record single unit activity of pulmonary RARs from these nerve filaments. The details of the procedures for identifying and recording action potentials from RARs have been described previously (Gunawardena et al. 1999). Action potentials arising from RARs were identified by their burst of activity and rapid adaptation (over 70% adaptation in 1 s) to a sustained inflation of the lungs with three tidal volumes of air.
A muscle relaxant was used when action potentials were recorded to minimize movements which could interfere with the experiment. Gallamine triethiodide (1.5 mg kg–1, Sigma) was administered I.V. to the animals as a muscle relaxant every half an hour while they were being artificially ventilated. Conduction velocity of the nerve fibres was measured at the end of each experiment by stimulating the nerve electrically (strength, 1.5–4 V; duration, 0.07–2 ms) 1.5–2.5 cm caudal to the recording electrode (Grass Instruments Co., Model SMD 9 J). The location of the RAR was ascertained at the end of each experiment by gently probing the bronchial tree externally at the hilum of the lung. Initially, a cotton-tipped applicator was used to localize the RAR. Following this, a glass rod with a blunt tip of approximately 1 mm in diameter was used to determine the precise location of the receptor.
Experimental protocols
Effects of pulmonary lymphatic obstruction on urine flow. After completion of surgery, the animals (n= 44) were permitted to attain a steady state with respect to urine flow (approximately 90 min) before commencing an experimental run. Urine was collected over successive 10 min periods as follows: three collections before (initial control), three collections during and four collections after release of pulmonary lymphatic obstruction. the final two collections during lymphatic obstruction and the first collection following it were considered to be the experimental sample. The last three samples formed the final control.
This protocol was repeated under the following experimental conditions: (i) control state; (ii) after sectioning the vagi at the level of the diaphragm; (iii) after injection of L-NAME I.V.; (iv) after injection of D-NAME I.V.; (v) after injection of 7-NI I.P.; and (vi) after renal intramedullary infusion of the sodium salt of 7-NI (7-NINA).
Effects of pulmonary lymphatic obstruction on renal blood flow. Lymphatic drainage from the lung was obstructed in the same sequence as described above. Total renal blood flow was measured concurrently in five animals.
Effects of pulmonary lymphatic obstruction on RAR activity. In three animals, the effect of pulmonary lymphatic obstruction on the activity of RARs was recorded after injection of L-NAME. Action potentials were recorded for an initial control period of 10 min, a period of lymphatic obstruction lasting 20 min and a final control period of 10 min. The activities were expressed as the average action potentials per minute for the two control periods and the last 10 min of lymphatic obstruction.
At the conclusion of all experiments, animals were killed by giving an i.v. injection of saturated potassium chloride.
Analytical methods
Urine volume was measured to an accuracy of 0.1 ml, and flow was expressed as millilitres per ten minutes. Sodium and potassium concentrations in urine were measured using an ion-selective electrode system (Model NOVA 13, NOVA Biomedical, Walthan MA, USA). Sodium and potassium excretions were calculated from the urine volume and their respective concentrations. Nitrate and nitrite concentrations in urine were measured using high-performance ion chromatography and conductivity detection (Dionex Dx 500 equipped with auto-sampler and conductivity detector; Iskandarani & Pietrzyk, 1982). Excretions were calculated using their concentrations and urine volumes.
Statistical analysis of data
Group data were expressed as means ±S.E.M. or as stated otherwise in parentheses. When there were three groups of data (e.g. initial control, lymphatic obstruction and final control), the differences among means were compared using an ANOVA for repeated measures. Where there were two groups, the differences between means were established by Student's paired t test. Individual responses to lymphatic obstruction were quantified by determining the differences between the experimental values (during lymphatic obstruction) and the average of the values during the initial and final control periods. A P value less than 0.05 was accepted as indicative of significance.
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Results |
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In the 44 animals, at the start of the control periods, the heart rate, mean arterial blood pressure, mean right atrial pressure and peak airway pressure were 213.6 ± 2.4 beats min–1, 96.6 ± 2.4 mmHg, –0.2 ± 0.2 mmHg and 8.6 ± 0.2 mmHg, respectively. The mean arterial PO2, PCO2 and pH in these rabbits were 385 mmHg (range 167–502), 37.9 mmHg (range 27.9–54.3) and 7.39 (range 7.31–7.46), respectively.
Effects of pulmonary lymphatic obstruction on urine flow in intact animals
In the animals, the effect of pulmonary lymphatic obstruction on urine flow was examined in the control state in 17 experiments. As previously reported (Ravi et al. 1997), an increase in urine flow was observed in each instance. The urine flows (ml (10 min)–1) before, during and after pulmonary lymphatic obstruction were 8.9 ± 0.5, 12.1 ± 0.6 and 8.9 ± 0.6, respectively (Table 1). The increase in urine flow during pulmonary lymphatic obstruction was significant (P < 0.001, repeated measures of ANOVA).
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In 11 of these animals, the concentrations of nitrates in urine were measured. There was an increase in the excretion of nitrates during pulmonary lymphatic obstruction in 9 of the 11 animals. Overall, the nitrate excretion increased from 1.8 ± 0.53 µmol (10 min)–1 during control conditions to 2.4 ± 0.93 µmol (10 min)–1 during lymphatic obstruction. Nitrate excretion returned to 1.8 ± 0.62 µmol (10 min)–1 after lymphatic obstruction. An analysis of variance on the raw data in all 11 experiments showed that the increase was not statistically significant.
There were also no significant changes in free water clearance during pulmonary lymphatic obstruction. The changes in plasma and urine osmolality values which were used to derive the free water clearances are shown in Table 1. The heart rate, mean arterial blood pressure, right atrial pressure and peak airway pressure were unchanged during pulmonary lymphatic obstruction (Table 1).
In three animals not included in the above analysis, the vagi were sectioned at the level of the diaphragm. Pulmonary lymphatic obstruction in these three animals caused an increase in urine flow (ml (10 min)–1) from 4.33 ± 0.7 to 8.07 ± 1.1. The urine flow returned to 5.64 ± 0.7 ml (10 min)–1 after pulmonary lymphatic obstruction. The values for sodium excretion were similar to those described above.
Effect of pulmonary lymphatic obstruction on total renal blood flow
In 5 of the 17 experiments described above, total renal blood flow during pulmonary lymphatic obstruction was measured. In these five animals, the urine flow increased from 7.0 ± 2.4 ml (10 min)–1 during the control period to 10.2 ± 2.8 ml (10 min)–1 during lymphatic obstruction. It returned to 8.0 ± 2.4 ml (10 min)–1 during the final control period. These changes were statistically significant (P < 0.05, repeated measures ANOVA). The corresponding values for total renal blood flow were 25.7 ± 6.9, 22.7 ± 5.4 and 22.3 ± 5.1 ml min–1, respectively. The changes in renal blood flow were not statistically significant.
Effect of I.V. L-NAME on the urine response to pulmonary lymphatic obstruction
The responses were examined in six animals after I.V. administration of L-NAME. In these six animals the mean arterial pressure before and after injection was 120 ± 4.0 and 130 ± 4.3 mmHg, respectively. The corresponding heart rates were 255 ± 16 and 212 ± 7.2 beats min–1, respectively. Pulmonary lymphatic obstruction failed to increase urine flow. There were no changes in sodium, potassium or nitrate excretion. These findings are summarized in Table 2.
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The responses were examined in 5 animals after i.v. administration of D-NAME. In these five animals the mean arterial pressure before and after injection was 114 ± 9.7 and 119 ± 2.7 mmHg, respectively. The corresponding heart rates were 210 ± 19.1 and 230 ± 17.9 beat min–1, respectively. In these 5 animals, pulmonary lymphatic obstruction increased urine flow from a control value of 5.3 ± 0.7–8.6 ± 0.7 ml 10 min–1. The final control value was 6.6 ± 1.1 ml 10 min–1. The increase in urine flow was significant (P < 0.05). The changes in electrolyte excretions were similar to those observed in the responses observed in the control state. These findings are summarized in Table 2.
Effect of L- NAME on the response of RAR to pulmonary lymphatic obstruction
In three other animals we examined the effect of L-NAME on the responses of RARs to pulmonary lymphatic obstruction. The mean arterial pressure, following injection of L-NAME, increased by 8.3 mmHg in these animals (Mean; range 7–11 mmHg). The initial control activities in the 3 units were 16.9, 1.7, and 124 impulses min–1. During lymphatic obstruction (final 10 min) the activity increased to 35.3, 20.8, and 256 impulses min–1, respectively. The final control values were 15.4, 3.2, and 212 impulse min–1. Thus, all three receptors increased their activity during lymphatic obstruction indicating that the absence of the urine response after administration of L-NAME was not due to inactivation of RARs.
Effect of I.P. 7- NI on the urine response to pulmonary lymphatic obstruction
The responses were examined in five animals after I.P. administration of 7-NI. The mean arterial pressures before and after injection were 98.1 ± 1.4 and 95.6 ± 2.6 mmHg, respectively. The corresponding heart rates were 211.5 ± 11 and 221.2 ± 7.2 beats min–1, respectively. In these five animals, pulmonary lymphatic obstruction failed to increase urine flow. There were no changes in sodium, potassium or nitrate excretion. These findings are summarized in Table 3.
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The responses were examined in five animals after intramedullary infusion of 7-NINA into one kidney. The mean arterial pressures before and after injection were 95.7 ± 2.2 and 95.5 ± 2.7 mmHg, respectively. The corresponding heart rates were 225 ± 15.3 and 230.4 ± 12.7 beats min–1, respectively. In these five animals, pulmonary lymphatic obstruction failed to increase urine flow from the kidney receiving the intramedullary infusion of 7-NINA (mean change: –0.25 ± 0.27 ml (10 min)–1). There were no changes in sodium or potassium excretion. Urine flow from the control kidney increased during pulmonary lymphatic obstruction in all five animals (mean increase 1.45 ± 0.27 ml (10 min)–1). The response on the control side was significantly greater than that on the side receiving the intramedullary infusion (P= 0.008, Mann–Whitney rank sum test; Fig. 1). Sodium and potassium excretion also increased in the control kidney. These findings are summarized in Table 3.
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Discussion |
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Role of renal nerves
The reflex response was abolished by renal denervation. Hence the efferent limb of the reflex was considered to be in the renal nerves, which are adjacent to renal blood vessels (Ravi et al. 1997). Apart from their influence on renal blood flow (Pomeranz et al. 1968), the renal nerves also influence other functions of the nephron. These effects can occur either directly through the action of neurotransmitters or indirectly through the production of NO (Zou & Cowley, 2000; Plato & Garvin, 2001).
Zou & Cowley (2000) showed that subpressor doses of norepinephrine (I.V.) increased interstitial NO in the renal medulla while cortical and medullary blood flow remained unchanged. The increase in intramedullary NO was abolished by infusion of L-NAME and by the administration of rauwolscine directly into the renal medulla. Suppression of NO production during infusions of adrenaline was associated with a reduction in renal blood flow. The authors concluded that the increase in medullary NO production was mediated by activation of 
2-receptors. It was suggested also that NO and activation of 2-receptors were important in maintaining the constancy of medullary blood flow. Plato & Garvin (2001) emphasized the link between 2-receptors and functions of the ascending thick limb of the loop of Henle (THAL). They observed an inhibitory effect on chloride flux in the THAL which was also mediated by 2-receptors and NO. These two studies were undertaken in rats and provide strong evidence of a relationship between adrenoreceptor activity, NO and renal medullary function. In addition, studies using immunoflourescent imaging have demonstrated the presence of 1- and 2-receptors in most regions of the nephron (Snavely & Insel, 1982; Feng et al. 1991). Based on these considerations, it is suggested that renal sympathetic nerves have the capacity to release adrenergic transmitters and modulate renal function by exerting an effect either on medullary blood vessels or on portions of the nephron located in the medulla.
In contrast to these studies addressing the role of adrenoreceptors, other investigators (Wu et al. 1999; Wu & Johns, 2002) have examined the effect of low-frequency stimulation of sympathetic nerves to the kidney on both urine flow and proximal tubular function in Wistar rats. This mode of stimulation reduces urine flow without changing systemic blood pressure and blood flow to the kidney. It was also found that intratubular administration of L-NAME increased proximal tubular absorption. This effect was not evident in animals after renal denervation. The authors concluded that NO exerts a tonic attenuation of proximal tubular epithelial transport which is dependent upon the renal sympathetic nerves. Since these effects were also blocked by 7-NI, it was suggested that they were mediated by n-NOS (Wu et al. 1999; Wu & Johns, 2002). Thus, it could be argued that proximal tubular function is altered, at least in part by changes in sympathetic tone. NO could be released either as a cotransmitter from these nerves or in response to activation of adrenoreceptors.
These two approaches to examining the role of NO on renal function appear to yield findings which are contradictory. However, it is important to appreciate that NO-mediated changes in renal function could occur through a variety of mechanisms. These effects are not only dependent on the site of action of NO but also upon whether sympathetic activity increases or decreases from a particular baseline value. Our study was not designed to address the effect of bidirectional changes in sympathetic activity on renal function. Thus, the conclusions we could draw are limited to indicating that the efferent pathway of the reflex increase in urine flow observed following pulmonary lymphatic obstruction was in the sympathetic nerves to the kidney.
Role of NO in the response to pulmonary lymphatic obstruction
Generally, in vivo studies of NO activity within the kidney have been limited to observing changes in urinary nitrate excretion or the effects of inhibiting NOS activity. In the absence of an extraneous source of NO (e.g. an infusion of sodium nitroprusside), the amount of nitrate ions in urine has been demonstrated to be an index of NO production within the kidney (Godfrey & Majid, 1998). NOS inhibitors such as L-NAME have been used extensively to identify changes in renal function mediated by NO (Radermacher et al. 1992). In the present study, there was an increase in the excretion of nitrates during pulmonary lymphatic obstruction from the lungs in 9 of the 11 animals. However, after I.V. administration of L-NAME, the reflex increases in urine flow and nitrate excretion were not evident. In contrast, the administration of D-NAME did not abolish the effect of lymphatic obstruction on urine flow. These findings form the basis for suggesting that NO was involved in this reflex.
Site of action
It is evident that NO could act upon several different regions of the nephron (Ortiz & Garvin, 2002) and the renal blood vessels (Mattson, 2003). One of the problems in evaluating reflex effects on parts of the nephron located in the medulla is the inability to access these regions in vivo. Cortical regions of the nephron can be studied using micropuncture techniques, while medullary portions of the nephron are not as readily accessible. Intramedullary infusions provide an alternative means of investigating renal medullary function in vivo. A large proportion of drugs administered by intramedullary infusion are retained mainly in the medulla (see below). Thus, drugs which are introduced in this manner could potentially act on the loop of Henle, the ascending loop of Henle, the collecting duct, medullary blood vessels and possibly the macula densa. The studies we have reported in this paper do not address the precise locus of action.
NOS isoforms
It is recognized that L-NAME is a nonselective inhibitor of NOS. Thus it could be argued that the failure to demonstrate the increase in urine flow after administration of L-NAME I.V. was due to a secondary, centrally mediated effect upon renal nerve activity. However, 7-NI, which is a relatively selective blocker of n-NOS, has no significant effects on renal nerve activity and mean arterial pressure in both conscious and anaesthetized rabbits (Murakami et al. 1998). This study showed that the stimulus–response curve linking arterial pressure to renal sympathetic activity was unaffected by 7-NI. However, the corresponding curve linking pressure to heart rate was altered. The reduction in heart rate at high systemic pressures was enhanced by 7-NI. Thus 7-NI does not have a consistent effect on all components of the baroreflex. Hence, it could also be argued that the ability of I.P. 7-NI to block the reflex increase in urine flow following pulmonary lymphatic obstruction is also due to a specific central effect on those renal sympathetic nerves involved in the reflex initiated by this stimulus.
However, the present study has shown that the effect of pulmonary lymphatic obstruction on urine flow was blocked by both I.P. 7-NI and intramedullary 7-NINA. Ninety two per cent of drugs administered in this way are retained in the medulla and 98% stays localized in the infused kidney (Mattson, 1999). In the present study, administration of 7-NINA by an intramedullary infusion to one kidney abolished the response on the ipsilateral side while the response was preserved on the contralateral side. These observations suggest that the inhibition of n-NOS occurs through a peripheral mechanism within the renal medulla.
n-NOS isoforms have been demonstrated in microdissected portions of the renal vasculature and in the renal tubules. Both n-NOS and endothelial NOS (e-NOS) mRNA have been identified in all vascular segments of the kidney, but inducible NOS (i-NOS) mRNA has been detected only in the arcuate arteries (Wu et al. 1999). The inner medullary collecting ducts and the THAL contain n-NOS (Zou & Cowley, 2000) and provide a possible site of action for NO in the reflex increase in urine flow to pulmonary lymphatic obstruction.
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