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Experimental Physiology 90.3 pp 341-347
DOI: 10.1113/expphysiol.2004.028654
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Role of adrenergic receptors in the reflex diuresis in rabbits during pulmonary lymphatic obstruction

K. M. McCormick1, E. M. Bravo1 and C. T. Kappagoda1

1 Division of Cardiovascular Medicine, University of California, Davis, CA 95616, USA


   Abstract
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 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
The role of adrenergic receptors in the reflex diuresis in response to pulmonary lymphatic drainage was examined in anaesthetized, artificially ventilated New Zealand White rabbits. Pulmonary lymphatic drainage was obstructed by raising the pressure in a pouch created from the right external jugular vein. This pulmonary lymphatic obstruction results in a reflex increase in urine flow and sodium excretion. This reflex is abolished by renal denervation and by administration of L-NAME, a non-selective inhibitor of nitric oxide synthase. Also, infusion of the relatively selective neuronal nitric oxide synthase blocker, 7-nitroindazole sodium salt, into the renal medulla abolished the reflex diuresis. In this study the effects of adrenergic receptor antagonists on the reflex increase in urine were observed. Both ureters were cannulated in order to determine urine flow from both kidneys separately. Prazosin, an {alpha}1 adrenergic receptor antagonist, was infused into the renal medulla of the right kidney, while the left kidney acted as control. Administration of prazosin in this manner did not block the reflex diuresis in response to pulmonary lymphatic obstruction in either kidney. However, rauwolscine, an {alpha}2 adrenergic receptor antagonist, abolished the reflex increase in urine and sodium excretion in the ipsilateral kidney while preserving it in the contralateral kidney. These findings suggest that the increase in urine flow in rabbits caused by pulmonary lymphatic obstruction is dependent upon activation of {alpha}2 adrenergic receptors within the renal medulla.

(Received 19 July 2004; accepted after revision 5 January 2005; first published online 14 January 2005)
Corresponding author C. T. Kappagoda: Division of Cardiovascular Medicine, Bioletti Way, TB 172, University of California, Davis, CA 95616 USA. Email: ctkappagoda{at}ucdavis.edu


   Introduction
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 Abstract
 Introduction
Methods
 Results
 Discussion
 References
 
Obstruction of lymph drainage from the lung activates the rapidly adapting receptors in the lung (Ravi et al. 1988; Hargreaves et al. 1991). In anaesthetized rabbits, this procedure results in an increase in urine flow which is reflex in nature (Ravi et al. 1997). The afferent pathway of this reflex is located in the myelinated branches of the cervical vagi. It has been suggested that the efferent pathway of this reflex lies in the sympathetic nerves to the kidney, as renal denervation abolished the response. Previous studies have shown that infusion of the relatively selective neuronal nitric oxide synthase (n-NOS) inhibitor 7-nitroindazole sodium salt (7-NINA; Moore et al. 1993) into the renal medulla abolishes the reflex. Thus it was suggested that NO released through the action of n-NOS within the renal medulla is involved in mediating this reflex. However, the link between renal sympathetic nerve activity and activation of n-NOS has not been established.

Noradrenaline (norepinephrine) has been shown to elevate NO levels in the kidney by acting on {alpha}2 receptors within the renal medulla (Szentivanyi et al. 2000). It is known that {alpha}1 and {alpha}2 receptors are present in the kidney throughout the nephron (Muntz et al. 1985; Feng et al. 1991; Cohen et al. 1992). The aim of this investigation was to clarify the potential role of {alpha} adrenergic receptors in this response. The following hypotheses were tested: (a) the response is abolished by the infusion of the {alpha}1 blocker, prazosin; and (b) the response is abolished by infusion of the {alpha}2 antagonist rauwolscine. Both drugs were administered by an intramedullary infusion.


   Methods
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 Abstract
 Introduction
 Methods
Results
 Discussion
 References
 
Experiments were performed on New Zealand White rabbits weighing 2.36–3.60 kg. All protocols were approved by the Animal Use and Care Committee of the University of California, Davis, CA, USA. Anaesthesia was induced with ketamine HCl (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 pentobarbital (Veterinary Laboratories, Lenexa, KS, USA; 6.5 mg kg–1 injected I.V. every 45 min). The depth of anaesthesia was assessed periodically by testing the corneal reflex and pinching the paw. After administration of gallamine (see below), the animals were allowed to recover from the effect of the drug every 2 h to test for these reflexes. In addition, adequacy of anaesthesia was monitored by carefully observing the animals for any spontaneous fluctuations in mean arterial pressure and heart rate. 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 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%, wt/vol, I.V., Abbott Laboratories, North Chicago, IL, USA). 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, Valley Views, OH, USA). The animals were infused with 0.9% NaCl at 1.2 ml min–1 (Ravi et al. 1997). A muscle relaxant was used to minimize movements. 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.

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) (Fig. 1). A vascularly isolated pouch (length, approximately 3 cm) was created in this region (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.



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  		Figure 1.  Right lymphatic ducts
The figure shows the location of the main right lymphatic duct on the medial side of the superior vena cava (SVC) prior to entry into the vein. A second lymph duct is shown on the lateral side of the superior vena cava. The lymph ducts are visualized as black vessels after injection of India ink into the interstitial space of the top two lobes of the right lung. A balloon inserted into the left atrium was inflated to increase the left atrial pressure by 10 mmHg in order to facilitate lymph flow. The dissection was performed 2 h after injection of India ink. The caudal end of the superior vena cava is on the right hand bottom corner, and the cranial end is in the opposite corner.

 
Collection of urine

Both ureters were cannulated using a polyethylene catheter. The ureters were approached through a mid-line suprapubic incision. The urine was drained into separate collection chambers and measured at 10-min intervals.

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 (Lu et al. 1992; Mattson, 1999). 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 0.12 ml (10 min)–1. The dose of rauwolscine was 30 µg kg–1 min–1 (Zou & Cowley, 2000). In preliminary studies, infusion of saline at this rate did not alter urine flow in anaesthetized rabbits.

Prazosin, which has a maximum solubility of 0.5 mg ml–1 in water, was also administered via intramedullary infusion. At an infusion of 0.12 ml (10 min)–1, the dose of prazosin was 1.67 µg kg–1 min–1. Over 1 h, approximately 100 µg of the prazosin was infused into the renal medulla. In three additional animals, the {alpha}1 agonist methoxamine (1.67 µg kg–1 min–1) was infused into the renal medulla following intramedullary infusion of prazosin at the same dose. Mean arterial pressure and heart rate were recorded before and after infusion.

Intravenous infusions

In three animals, the same dose of rauwolscine (30 µg kg–1 min–1) administered by the intramedullary route was given intravenously. In another three animals, the same dose of prazosin (1.67 µg kg–1 min–1) used for intramedullary infusions was delivered intravenously. Mean arterial pressure and heart rate were recorded at 10-min intervals 30 min before and after infusion.

Experimental protocols

Effects of pulmonary lymphatic obstruction on urine flow.  After completion of surgery, the animals 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) after renal intramedullary infusion of prazosin; and (ii) after renal intramedullary infusion of rauwolscine.

At the conclusion of all experiments, animals were killed by an I.V. injection of saturated KCl.

Effects of I.V. infusions of prazosin and rauwolscine on heart rate and blood pressure.  As intramedullary infusions of these compounds did not elicit any significant changes in heart rate and mean arterial pressure, in a final series of experiments the drugs were administered I.V. at a dose similar to that used for intramedullary infusions to establish whether the drugs had any effect on these haemodynamic variables.

Analytical methods

Urine volume was measured to an accuracy of 0.1 ml, and flow was expressed as ml kg–1 (10 min)–1. Sodium and potassium concentrations in urine were measured using an ion-selective electrode system (Model NOVA 13, NOVA Biomedical, Waltham, MA, USA). Sodium and potassium excretions were calculated from the urine volume and their respective concentrations.

Statistical analysis

Group data were expressed as mean ±S.E.M. or as stated otherwise in parentheses. 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. The differences between means of these responses were established by a Student's paired t test. A P value less than 0.05 was accepted as indicative of significance.


   Results
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 Abstract
 Introduction
 Methods
 Results
Discussion
 References
 
The effect of adrenergic receptor antagonists on the diuresis to pulmonary lymphatic obstruction was examined in 12 New Zealand White rabbits. At the start of the control periods, the heart rate, mean arterial pressure, mean right atrial pressure and peak airway pressure were 206 ± 8 beats min–1, 91 ± 2 mmHg, 0.5 ± 0.9 mmHg and 9.0 ± 0.5 mmHg, respectively. The mean arterial PO2, PCO2 and pH in these rabbits were 354.5 mmHg (range 248–410), 39.5 mmHg (range 27.7–50.0) and 7.39 (range 7.33–7.45), respectively.

Effect of intramedullary infusions of prazosin and methoxamine on the urine response to pulmonary lymphatic obstruction

The responses were examined in five animals after intramedullary infusion of prazosin into one kidney. Pulmonary lymphatic obstruction caused an increase in urine flow in both kidneys. The mean increases from the control and the prazosin-infused kidney were 0.5 ± 0.1 ml kg–1 (10 min)–1 and 0.6 ± 0.1 ml kg–1 (10 min)–1, respectively. The increases in urine flow were similar on the two sides (P > 0.05, Student's t test). Sodium and potassium excretion increased in both the control kidney and in the kidney receiving prazosin (Table 1).


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  		Table 1.  Effect of prazosin administered by intramedullary infusion
 
In three animals, methoxamine was infused into the renal medulla 2 h after the commencement of the intramedullary infusion of prazosin. The urine flow before methoxamine infusion was 1.9 ± 0.5 ml kg–1 (10 min)–1 and 1.9 ± 0.5 ml kg–1 (10 min)–1 after infusion. The absence of a change suggests that the dose of prazosin used for intramedullary infusions was adequate to cause blockade of {alpha}1 receptors. No changes in heart rate and mean arterial pressure were observed. The mean arterial pressure and the heart rate before methoxamine infusion were 79 ± 5 mmHg and 217 ± 12 beats min–1, respectively. The corresponding values after methoxamine infusion were 83 ± 5 mmHg and 236 ± 4 beats min–1.

Effect of intramedullary infusions of rauwolscine on the urine response to pulmonary lymphatic obstruction

The responses were examined in seven animals after intramedullary infusion of rauwolscine into one kidney. Pulmonary lymphatic obstruction failed to produce a detectable change in urine flow from the kidney receiving the intramedullary infusion of rauwolscine. There were also no changes in sodium and potassium excretion. Urine flow from the control kidney increased during pulmonary lymphatic obstruction in all animals (mean increase, 0.8 ± 0.1 ml kg–1 (10 min)–1). In control kidneys, the urine flow increased from 1.3 ± 0.3 ml kg–1 (10 min)–1 during the control period to 2.3 ± 0.3 ml kg–1 (10 min)–1 during lymphatic obstruction and returned to 1.7 ± 0.3 ml kg–1 (10 min)–1 during the final control period. The increases in urine flow on the control side were greater than those on the side receiving intramedullary infusions of rauwolscine (P < 0.001, Mann Whitney rank sum test) (Fig. 2 and Table 2).



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  		Figure 2.  Intramedullary infusion of rauwolscine into a single kidney abolishes the urine response to pulmonary lymphatic obstruction (PLO) on the ipsilateral side (n= 7)
During intramedullary infusion of rauwolscine into one kidney, the contralateral kidney showed a normal urine response to pulmonary lymphatic obstruction. See text for analysis. The response on the control side was greater than that on the side receiving the intramedullary infusion (P < 0.001, Mann Whitney rank sum test).

 

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  		Table 2.  Effect of rauwolscine administered by intramedullary infusion
 
Effect of I.V. infusions of rauwolscine and prazosin

Previous studies have shown that drugs administered by intramedullary infusion are retained in the medulla (Mattson, 1999). In order to obtain evidence that significant quantities of drugs administered by the intramedullary route did not escape into the systemic circulation in the present series, the same doses of the drugs were administered intravenously. The observed changes in heart rate and blood pressure were taken as evidence of significant levels of the drug in the general circulation. As shown above, no significant changes in blood pressure or heart rate were observed with prazosin and rauwolscine during intramedullary administration. However when the same dose of prazosin was given intravenously, blood pressure was reduced from 108 ± 5 mmHg to 94 ± 4 mmHg. When rauwolscine was given intravenously, blood pressure increased from 95 ± 9 mmHg to 122 ± 6 mmHg and heart rate increased from 205 ± 9 beats min–1 to 246 ± 9 beats min–1 (Fig. 3).



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  		Figure 3.  Effect of intramedullary and I.V. prazosin and rauwolscine on blood pressure
Intramedullary infusions of rauwolscine and prazosin had no effect on mean arterial pressure. When the drugs were infused I.V. at the same respective doses, rauwolscine increased mean arterial pressure while prazosin lowered it. The absence of haemodynamic changes during intramedullary infusions indicate that drugs infused in the fashion do not escape into the general circulation.

 

   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
Previous reports from this laboratory have described a reflex diuresis resulting from pulmonary lymphatic obstruction in New Zealand White rabbits. The afferent path of the reflex lies in the cervical vagi, and the efferent in the renal sympathetic nerves (Ravi et al. 1997). In this model, obstruction of lymph drainage from the lungs causes extra-vascular fluid to accumulate in the carina and extra-pulmonary airways (Ma et al. 2003). The rapidly adapting receptors located in this region are activated by this stimulus (Ravi et al. 1997). As obstruction of lymphatic drainage from the lung is not accompanied by concurrent changes in haemodynamic variables, it is a unique stimulus to the rapidly adapting receptors in vivo.

Previous investigations have suggested that the response was mediated by NO produced by n-NOS in the renal medulla (McCormick et al. 2004). The present study has shown that the reflex diuresis is abolished by intramedullary infusions of the {alpha}2 adrenergic receptor antagonist rauwolscine. While this observation links the response to {alpha}2 adrenergic receptor activity, it does not specify whether NO is released as a cotransmitter from sympathetic nerves or by activation of n-NOS through sympathetic receptors.

Role of renal nerves

It is known that sympathetic nerve activity influences renal function in several ways. High frequency stimulation of renal nerves reduces renal blood flow (Pomeranz et al. 1968). However, by altering the stimulus parameters, it is possible to stimulate the renal nerves in a manner which does not change renal blood flow or systemic arterial pressure (Wu et al. 1999; Wu & Johns, 2002). Under these conditions, there is a decrease in urine flow and sodium excretion with no change in glomerular filtration rate. This effect is frequency dependent (Thomson & Vallon, 1995).

Location of renal nerves and adrenergic receptors in the renal medulla

Histological studies have confirmed the presence of sympathetic nerves in close proximity to the components of the nephron located in the medulla (McKenna & Angelakos, 1968; Dolezel et al. 1976; Dorup et al. 1992). Immunofluorescent imaging has demonstrated the presence of ß1 and ß2 adrenergic receptors in the kidney (Boivin et al. 2001). ß1 adrenoceptors are present in the renin-producing juxtaglomerular granular cells, proximal tubules, ascending loop of Henle, macular densa cells, distal tubules and collecting ducts. The ß2 receptors are predominantly located in the membranous portions of the proximal tubules.

The presence of {alpha}1 and {alpha}2 adrenergic receptors within different portions of the kidney has also been confirmed. {alpha}1A and {alpha}1B receptor subtypes have been demonstrated in the cortical proximal tubules and the blood vessels using the same immunofluorescent imaging techniques (Stephenson & Summers, 1986; Feng et al. 1991). The density of {alpha}1 adrenoceptors is highest in the cortex and decreases from cortex to papilla. The {alpha}1A and {alpha}1B subtypes are approximately equally distributed in the cortex and outer strip of the outer medulla while the {alpha}1B subtype predominates in the inner strip of the outer medulla. {alpha}2 receptors have also been demonstrated in all regions of the nephron (Snavely & Insel, 1982). Autoradiography has revealed {alpha}2 receptor binding of tritiated rauwolscine to be higher in the tubules of the renal cortex than in both the glomeruli and the tubules of the renal medulla (Muntz et al. 1985). The renal vasculature was shown to have far less radiolabelling of {alpha}2 receptors than the tubules. In the present study we focused on {alpha}1 and {alpha}2 adrenergic receptors.

Intramedullary infusions

The cortical regions of the nephron are readily accessible to micropuncture techniques. However, medullary portions are not readily accessible in vivo with these techniques. Intramedullary infusions are an alternative means of delivering pharmacological interventions to parts of the nephron located in the renal medulla. Ninety-two percent of drugs administered in this way are retained in the medulla and 98% stays localized in the infused kidney (Mattson, 1999). This concept is demonstrated by the absence of haemodynamic changes in response to intramedullary infusions of prazosin and rauwolscine. When the same doses of these drugs were infused I.V. immediate changes in mean arterial pressure were observed. This can be taken as evidence that drugs administered in this manner do not escape into the general circulation. It can be concluded that drugs which are introduced through intramedullary infusion could potentially act on the loop of Henle, the ascending loop of Henle, the collecting duct, medullary blood vessels and possibly the macula densa, and provide a means of investigating reflex responses involving the renal medulla. These studies do not specify the extent of the spread within the renal medulla.

Potential mechanisms

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. Intramedullary infusions of the {alpha}2 adrenergic receptor antagonist rauwolscine abolished the reflex diuresis resulting from pulmonary lymphatic obstruction. In contrast, intramedullary infusions of the {alpha}1 adrenergic receptor antagonist prazosin had no effect on the response. These findings indicate that the reflex diuresis is mediated by {alpha}2 receptors located in the medulla.

Zou & Cowley (2000) showed that subpressor doses of adrenaline (epinephrine; 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 {alpha}2 receptors. It was suggested also that NO and activation of {alpha}2 receptors were important in maintaining the constancy of medullary blood flow. Plato & Garvin (2001) emphasized the link between {alpha}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 {alpha}2 receptors and NO.

These two studies were undertaken in rats and provide strong evidence of a relationship between {alpha}2 adrenoreceptor activity, NO and renal medullary function. However, they do not define the location of the action of NO in the medulla. {alpha}2 receptors are present in the collecting ducts located in the medulla (Clarke & Garg, 1993) and play a role in regulating water absorption at that location (Krothapalli & Suki, 1984). As more {alpha}2 receptors are located in the medullary tubules than in the arterioles, it is suggested that the diuresis in response to pulmonary lymphatic obstruction is more likely to be due to changes in tubular function. However, due to the close proximity of medullary structures, we cannot distinguish between primary alterations in tubular function and secondary ones mediated by changes in blood flow.


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   Acknowledgements
 
This work was supported by a National Institutes of Health grant (no. HL 52165).




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