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(Hypertension. 1995;25:866-871.)
© 1995 American Heart Association, Inc.
Articles |
Effect of Renal Perfusion Pressure on Renal Interstitial Hydrostatic Pressure and Sodium Excretion
Role of Vasopressin V1 and V2 Receptors
From the Second Department of Internal Medicine, Gunma University School of Medicine, Maebashi, Japan.
Correspondence to Tetsuya Nakamura, MD, The Second Department of Internal Medicine, Gunma University School of Medicine, Maebashi, 371, Japan.
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Abstract |
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Abstract Renal interstitial hydrostatic pressure (RIHP) has recently been cited as an important mediator of pressure natriuresis. Our objective was to determine the roles of vasopressin V1 and V2 receptors in mediating the effects of renal perfusion pressure (RPP) on RIHP and sodium excretion (UNaV). The effects of RPP on renal hemodynamics, RIHP, and UNaV were assessed in control Wistar rats (n=10) and in rats pretreated with intravenous infusion of the specific nonpeptide vasopressin V1 antagonist OPC-21268 (100 µg · kg-1 · min-1; n=8) and the V2 antagonist OPC-31260 (40 µg · kg-1 · min-1; n=10). Increasing RPP from 95 to 118 mm Hg in control rats increased RIHP (6.4±1.0 to 9.9±1.3 mm Hg), UNaV (0.29±0.03 to 0.52±0.05 µEq · min-1 · g-1), urine flow rate (UFR) (5.2±0.3 to 7.6±0.6 µL · min-1 · g-1), and the fractional excretion of sodium (FENa). In rats pretreated with V1 antagonist, similar results were obtained for urine osmolality and the responses of RIHP, UNaV, UFR, and FENa to RPP. V2 antagonist reduced urine osmolality (392±47 compared with 979±88 mOsm · kg-1 in control rats) and enhanced the responses of UNaV (0.43±0.08 to 1.32±0.32 µEq · min-1), UFR (17.8±3.2 to 29.2±3.8 µL · min-1 · g-1), and FENa to RPP, but the RIHP response resembled that observed in the control and V1 antagonist groups. Renal blood flow and glomerular filtration rate did not differ among the three groups.
Our findings indicate that neither V1 nor V2 receptor blockade influences the transmission of RPP into the renal interstitium, although V2 receptor blockade enhances pressure natriuresis. The pressure natriuresis is mediated primarily by increased RIHP, and the enhanced natriuretic response to the V2 antagonist is independent of RIHP.
Key Words: vasopressin • renal blood flow • pressure natriuresis • glomerular filtration rate
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Introduction |
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The kidney alters the urine volume and the excretion of sodium in response to acute changes in renal perfusion pressure (RPP) in the absence of detectable changes in total renal blood flow, glomerular filtration rate, or cortical peritubular capillary hydrostatic pressure.1 Although the effect of RPP is well recognized, and although RPP plays an integral role in the regulation of extracellular fluid volume and arterial pressure, its mechanism has not been fully explained. Changes in medullary blood flow in the setting of well-autoregulated cortical and total renal blood flow are thought to be important in the phenomenon of pressure natriuresis.1 Earley and Friedler2 3 4 and Selkurt et al5 suggested that the increases in medullary blood flow produced by an elevated RPP might wash out the corticomedullary solute gradient and, in so doing, inhibit sodium reabsorption from the loop of Henle. However, the finding that pressure natriuresis can occur during water diuresis,6 when the inner medullary gradient of tonicity would have been dissipated, argues strongly against the significance of medullary washout in the pressure-natriuresis response. Another explanation is that the elevation in RPP raises medullary blood flow and is transmitted into the renal medullary interstitium.1 7 The consequent rise in renal interstitial hydrostatic pressure (RIHP) inhibits net sodium reabsorption in both the superficial and the deep nephrons and causes natriuresis.8 9 10 11 Preventing increases in RIHP by prior renal decapsulation markedly attenuates pressure natriuresis.12
The role of arginine vasopressin (AVP) in maintaining renal medullary hypertonicity is crucial.13 Two subtypes of peripheral AVP receptors have recently been identified. AVP exerts an antidiuretic effect in the kidney through V2 vasopressin receptors by means of an adenosine 3',5'-monophosphate (cAMP)–dependent mechanism.14 AVP elicits vasoconstriction of vascular smooth muscle through the V1 receptors by means of a cAMP-independent mechanism coupled with phosphoinositide turnover.15 Although numerous AVP antagonists have been developed,16 17 they are peptide analogues with poor bioavailability when administered orally. Nonpeptide vasopressin V1 and V2 receptor antagonists were recently developed.18 19 We examined the roles of vasopressin V1 and V2 receptors and medullary tonicity in mediating the effects of RPP on RIHP and sodium excretion. The effects of the nonpeptide V1 receptor–selective antagonist 1-(1-[4-(3-acetylaminopropoxy)benzoyl]-4-piperidyl)-3,4-dihydro-2(1H)-quinolinone (OPC-21268) on pressure natriuresis were compared with the effects of the V2 receptor–selective antagonist 5-dimethylamino-1-(4-[2-methylbenzoylamino]benzoyl)-2,3,4,5-tetrahydro-1H-benzazepine (OPC-31260).18 19
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Methods |
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Male Wistar rats (Imai Rats), weighing between 275 and 300 g, were anesthetized with pentobarbital (40 mg/kg IP). An incision was made in the right flank, and the right kidney was removed. An antibiotic, carumonam 30 mg/kg, was injected intramuscularly. The rats were individually caged, given rat chow (Oriental Yeast Co) and water ad libitum, and maintained on a 12-hour light/dark cycle for 2 weeks until the acute experiments were performed.
Surgical Preparation
Overnight, before the acute experimental studies, all the rats
were fasted but had free access to water. Renal hemodynamic and
functional studies in rats have been conducted mostly using either
-chloralose/urethane or barbiturate anesthetic for
anesthesia.8 9 20 In the present study, the rats were
anesthetized intraperitoneally with 80 mg/kg urethane and 8 mg/kg
-chloralose at a volume of 0.77 mL/kg on the day after fasting and
were placed on a thermostatically controlled warming table to maintain
body temperature at 37°C. A tracheotomy was performed and a
3-cm–long PE-200 tube was inserted into the trachea to maintain an
open airway. Catheters (PE-50) were inserted into the left jugular vein
for maintenance infusion and into the left carotid artery for blood
sampling and arterial pressure monitoring. For continuous measurement
of RPP, the right femoral artery was cannulated using PE-10 tubing, and
the catheter was advanced into the aorta as far as the renal artery.
The carotid and femoral arterial catheters were connected to a pressure
transducer (model SPB-108, Biokit, NEC San-ei), and the arterial
pressures were recorded on a polygraph (model 363 and 8M14, Omnicorder,
NEC San-ei).
An anterior midline incision was made and the bladder was cannulated using a flare-tipped PE-50 tube (3 cm long) for urine collection. An electronic servocontrolled Silastic balloon occluder was positioned above the left renal artery in the aorta and connected to a saline-filled syringe. The occluder was used to maintain RPP at constant levels by inflation or deflation of the balloon.21 An electromagnetic flow probe (model MFV-3100, Nihon Koden) was placed around the left renal artery. A small-tipped portable cauterizer was used to make a 2- to 3-mm hole in the left kidney, and a PE-50 renal interstitial catheter containing a PE-10 tubing tip was implanted and sealed with cryoacrylic glue. The catheter was connected to a pressure transducer (model SPB-108, Biokit, NEC San-ei) for constant monitoring of RIHP. We checked renal interstitial catheters for patency and responsiveness by determining the RIHP response to partial renal vein occlusion.
Experimental Protocol
After surgery, all the rats were administered a bolus injection
of 360 mg/kg polyfructosan (Inutest, Laevosan-Gesellschaft), followed
by a maintenance dose of isotonic saline containing 14.3 mg/mL
polyfructosan and 1% bovine serum albumin infused into the jugular
vein at a rate of 7 mL/h. The 7 mL/h infusion rate of isotonic saline
produces a volume expansion in these rats. Eight rats were administered
5 mg/kg OPC-21268 (V1 antagonist group), 10 were
administered 2 mg/kg OPC-31260 (V2 antagonist group), and
10 were administered the vehicle, saline (control group). The drugs or
vehicle were given through a jugular venous catheter as a bolus
injection in a volume of 0.5 mL. In the V1 and
V2 antagonist groups, the appropriate antagonist was added
to the maintenance saline solution and infused at the rate of 100 or 40
µg · kg-1 · min-1,
respectively. Preliminary findings confirmed that the intravenous
injection of 5 mg/kg OPC-21268 followed by the continuous infusion of
100 µg · kg-1 · min-1 OPC-21268
completely eliminated the pressor response induced by the bolus
injection of 30 mU/kg AVP. We have reported that the intravenous
injection of 2 mg/kg OPC-31260 followed by the continuous infusion of
40 µg · kg-1 · min-1 OPC-31260
reduced urine osmolality markedly.22
After a 1-hour period of equilibration, we reduced RPP to 95 mm Hg in half of the rats in each group by inflating the occluder above the renal artery, using a servocontroller. After a 15-minute equilibration period, urine samples were collected during a 20-minute period. We then increased RPP to 118 mm Hg by deflating the occluder; after a 15-minute equilibration period, urine samples were again collected during the next 20-minute period.
Preliminarily, we confirmed that a 1-hour period of equilibration was long enough for steady-state sodium excretion to be achieved. However, the order of applying RPP may influence the renal humoral or hemodynamic factors. Therefore, in the remaining rats in each group, the order of the setting of RPP was reversed; RPP was set at 118 mm Hg for the first urine collection and at 95 mm Hg for the second. A 0.8-mL arterial blood sample was obtained from the carotid artery at the midpoint of each urine collection period.
Rats were killed by administration of an intravenous injection of potassium chloride. The left kidney was weighed and the position of the interstitial catheter was verified. Sodium and potassium concentrations were measured using flame photometry (HITACHI 736-60E, Hitachi Medical). Serum and urine osmolality were measured using freezing-point depression osmometry (Osmostat OM-6020, Kyoto Dai-Ichi Chemical). Anthrone methods were used to measure polyfructosan in serum and urine. OPC-21268 and OPC-31260 were generously donated by Otsuka Pharmaceutical.
Statistical Analyses
Values are expressed as mean±SEM. Carotid arterial pressure and
RIHP measurements recorded at 5-minute intervals were averaged, and one
value per period was reported. Glomerular filtration rate, renal blood
flow, urine flow rate, urinary excretion of sodium and potassium,
osmolar clearance, and free water clearance were factored by kidney
weight in grams. Multiple data were analyzed by ANOVA, followed by
multiple comparisons made with Scheffé's F test. Statistical
significance was considered to be P<.05.
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Results |
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Fig 1 shows how the changes in RPP affected the urine osmolality and the urinary excretion of sodium and potassium. Urine osmolality at both low and high RPP was significantly lower in the V2 antagonist group (506±71 mOsm · kg-1 at low RPP and 392±47 mOsm · kg-1 at high RPP) than in the control (988±99 mOsm · kg-1 at low RPP and 979±88 mOsm · kg-1 at high RPP) and V1 antagonist groups (943±94 mOsm · kg-1 at low RPP and 1015±117 mOsm · kg-1 at high RPP). Increasing RPP from 95 mm Hg to 118 mm Hg significantly increased urinary excretion of sodium and potassium in all three groups (RPP was actually changed between 95±1 and 118±2 mm Hg in the control group, between 95±1 and 118±1 mm Hg in the V1 antagonist group, and between 95±2 and 118±1 mm Hg in the V2 antagonist group). Urinary sodium excretion at high RPP was significantly greater in the V2 antagonist group (1.32±0.32 µEq · min-1 · g-1) than in the control (0.52±0.05 µEq · min-1 · g-1) and the V1 antagonist groups (0.47±0.09 µEq · min-1 · g-1).
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Fig 2 shows the response of the RIHP, the urine flow rate, and the fractional excretion of sodium to the changes in RPP. Increasing RPP from 95 to 118 mm Hg significantly increased RIHP, urine flow rate, and fractional excretion of sodium in all three groups. The RIHP response in the V2 antagonist group (6.2±0.9 to 8.7±1.7 mm Hg) was comparable to that observed in the control (6.4±1.0 to 9.9±1.3 mm Hg) and V1 antagonist groups (6.8±1.2 to 9.9±1.8 mm Hg). Urine flow rate at both low and high RPP was significantly greater in the V2 antagonist group (17.8±3.2 µL · min-1 · g-1 at low RPP and 29.2±3.8 µL · min-1 · g-1 at high RPP) than in the control (5.2±0.3 µL · min-1 · g-1 at low RPP and 7.6±0.6 µL · min-1 · g-1 at high RPP) and V1 antagonist groups (5.1±0.5 µL · min-1 · g-1 at low RPP and 7.6±0.8 µL · min-1 · g-1 at high RPP). Fractional excretion of sodium at high RPP was significantly higher in the V2 antagonist group (0.82±0.16%) than in the control (0.41±0.08%) and V1 antagonist groups (0.33±0.07%).
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Table 1 summarizes body weight, left kidney weight, carotid arterial pressure, and the response of renal function to changes in RPP. Body weight, left kidney weight, carotid arterial pressure, renal blood flow, and glomerular filtration rate did not differ among the three groups. Renal blood flow and glomerular filtration rate were well autoregulated, and osmolar clearance increased significantly in all three groups. Free water clearance at high RPP was significantly higher in the V2 antagonist group than in the control and V1 antagonist groups.
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Table 2 summarizes the changes in RIHP, urine flow rate, urinary excretion of sodium and potassium, fractional excretion of sodium, osmolar clearance, and free water clearance in response to the changes in RPP. The changes in RIHP did not differ significantly among the three groups. The changes in RPP led to significantly greater changes in urine flow rate, urinary sodium excretion, fractional excretion of sodium, and free water clearance in the V2 antagonist groups than in the control and V1 antagonist groups.
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Discussion |
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The V2 antagonist reduced urine osmolality and enhanced the responses of urine flow rate, urinary sodium excretion, and fractional excretion of sodium to the changes in RPP. The RIHP response was similar in all three groups. Renal blood flow and glomerular filtration rate were well autoregulated and did not differ among the three groups. These results indicate that neither V1 nor V2 receptor blockade influences the transmission of RPP into the renal interstitium, although V2 receptor blockade enhances pressure natriuresis.
Although AVP is one of the most potent vasoconstrictors, the issue of whether endogenous AVP contributes to the maintenance of blood pressure and regional blood flow in vivo remains controversial. In studies of water-deprived and anesthetized rats,23 the administration of a peptidergic V1 receptor antagonist reduced the arterial pressure because water deprivation increased the release of AVP. No change in blood pressure was demonstrated with peptidergic V1 receptor antagonism during either water diuresis or antidiuresis in other experiments on conscious rats.24 25 However, these studies were conducted with a peptidergic structural analogue of AVP. We recently reported that the infusion of the V1 antagonist OPC-21268 did not alter the systemic arterial pressure or the total renal blood flow in anesthetized hydrated rats.22
Using videomicroscopy, Zimmerhackl et al26 demonstrated that the infusion of AVP reduced medullary blood flow without causing detectable changes in total renal blood flow. Medullary blood flow was not decreased when AVP was administered concomitantly with a peptidergic V1 antagonist. However, those authors observed that the infusion of V1 antagonist alone produced a change in medullary blood flow as little as that seen in control rats. Our findings are compatible with theirs. Using a new nonpeptide specific V1 antagonist, we demonstrated that V1 receptor blockade did not influence the transmission of RPP into the renal interstitium in anesthetized hydrated rats, because the RIHP response did not differ between the control and the V1 antagonist groups. These effects of the V1 antagonist contrast with those of vasodilators such as acetylcholine, which produce renal vasodilation, facilitate the transmission of RPP into the renal interstitium, and induce natriuresis.27
It is postulated that AVP has both antidiuretic and antinatriuretic effects on the kidney. AVP infused at a low rate28 exerts sodium-retaining effects on conscious rats in vivo and increases sodium reabsorption in vitro, as observed in the isolated perfused rat kidney29 30 and isolated nephron segments.31 However, the effect of a specific V2 receptor antagonist should be determined to clarify the role of AVP at physiologically relevant levels and unmask the endogenous activity of AVP in the kidney. Results of earlier experiments showed that the intravenous injection of a peptidergic V2 antagonist was associated with an increase in sodium excretion.32 More recently, we reported that the infusion of the V2 antagonist OPC-31260 induced a small but significant increase in urinary sodium excretion.22
Earley and Friedler2 3 4 and Selkurt et al5 suggested that alterations in medullary hemodynamics and tonicity may affect sodium transport in the loop of Henle. They proposed that the increased medullary blood flow in response to a rise in RPP leads to a washout of medullary interstitial hypertonicity. Consequently, water abstraction out of the descending limbs of Henle's loop, which is relatively impermeable to sodium, would be diminished. Thus, an increased volume of fluid with the same quantity of sodium but decreased sodium concentration would be delivered to the water-impermeable ascending limb. Assuming that sodium reabsorption in the ascending limb of Henle's loop continues until a minimal sodium concentration is reached, the total amount of sodium delivered to the distal tubules would be enhanced (medullary washout theory). However, the absence of a natriuretic response to water diuresis, in which medullary tonicity is clearly reduced, casts doubt on the validity of this hypothesis.7 In the present study, medullary hypertonicity was expected to be diminished in the V2 antagonist group, because the withdrawal of AVP has been shown to reduce medullary tonicity markedly.13 33 34 Under such conditions, if medullary washout plays a primary role in pressure natriuresis, a change in RPP should produce little or no change in diuresis and natriuresis. However, we demonstrated that pressure diuresis and natriuresis were preserved, and even enhanced, in rats pretreated with the V2 antagonist. This finding is compatible with those of previous reports, which demonstrated that pressure natriuresis occurs in animals with diabetes insipidus35 and in water diuresis,6 in which a medullary washout is already present.
Reineck and Parma,33 however, suggested that an additional factor, enhanced delivery from the proximal tubules, was required to demonstrate an effect of medullary tonicity on urinary sodium excretion. They found that the clonidine-induced inhibition of AVP release reduced urine osmolality and increased the urine flow rate but had no effect on sodium excretion. A 2% body weight volume expansion produced a significant drop in proximal sodium reabsorption but little change in sodium excretion. When the same degree of volume expansion was done in animals undergoing clonidine-induced water diuresis, a marked increase in absolute and fractional excretion of sodium resulted. Segmental analysis of superficial and deep nephron function suggested that this effect was limited to the juxtamedullary nephrons and was probably localized to the thin ascending limb of the loop of Henle. Thus, their study suggests that a reduction in medullary tonicity enhances sodium excretion, but only when proximal sodium reabsorption is reduced or when glomerular filtration rate is increased.7
It has been repeatedly demonstrated that the increase in RIHP, in response to either a rise in RPP8 10 or direct renal interstitial volume expansion,9 11 reduces proximal reabsorption of sodium. We observed that urinary sodium excretion increased markedly in the V2 antagonist group in response to a rise in RPP, although the RIHP response was similar among the three groups. In rats pretreated with V2 antagonist, the rise in RIHP in response to a rise in RPP may reduce proximal sodium reabsorption. Amplification of the increased delivery of sodium from the proximal tubules is possible with V2 receptor blockade or medullary hypotonicity and may produce an enhanced natriuretic response to the changes in RPP.
Blandford and Smyth32 reported that a peptidergic V2 antagonist increased sodium excretion in anesthetized rats only at higher doses, although free water clearance increased at all doses tested. Their observations suggest that the receptors involved in producing the natriuretic response might be separate from the receptors involved in regulating water reabsorption. Imbert et al36 reported the presence of AVP-sensitive adenylate cyclase not only in the collecting tubule, which should regulate water reabsorption, but in the medullary thick ascending limb of Henle's loop. AVP has been shown to stimulate sodium chloride transport by the medullary thick ascending limb of Henle's loop, possibly through the V2 receptor.37 Therefore, it is also possible that part of the increased sodium excretion observed with V2 receptor blockade is due to an inhibition of sodium reabsorption by the thick ascending limb of juxamedullary nephrons.
In conclusion, a V2 antagonist reduced urine osmolality and enhanced pressure diuresis and natriuresis in rats. Renal blood flow and the glomerular filtration rate were autoregulated and did not differ among the three groups. The RIHP responses were also similar among the groups, suggesting that V1 or V2 receptor blockade did not influence the transmission of RPP into the renal interstitium. Our results indicate that the pressure natriuresis is mediated primarily by increased RIHP and that the enhanced natriuretic response to V2 receptor blockade is independent of RIHP.
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Acknowledgments |
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The authors are grateful to Mari Kurosawa and Shizuko Saiki for their expert technical assistance.
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References |
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