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(Circulation Research. 2001;88:347.)
© 2001 American Heart Association, Inc.

Integrative Physiology

Nitric Oxide Dependency of Arterial Pressure–Induced Changes in Renal Interstitial Hydrostatic Pressure in Dogs

Dewan S. A. Majid, Karim E. Said, Sophia A. Omoro, L. Gabriel Navar

From the Department of Physiology, Tulane University School of Medicine, New Orleans, La.

Correspondence to Dewan S.A. Majid, PhD, Department of Physiology SL39, Tulane University School of Medicine, 1430 Tulane Ave, New Orleans, LA 70112.

	Abstract

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Abstract—A direct relationship between renal arterial pressure (RAP) and renal interstitial hydrostatic pressure (RIHP) has been shown under conditions of efficient renal blood flow autoregulation. Experiments were performed in six anesthetized dogs to evaluate whether these RIHP responses to changes in RAP were modified during nitric oxide (NO) inhibition with nitro-L-arginine (NLA) or after administration of NO donor agents. A microtip catheter transducer was placed underneath the renal capsule to measure RIHP. Stepwise reductions in RAP (140 to 80 mm Hg) during control conditions resulted in decreases in RIHP from its basal value of 4.7±1.1 mm Hg with a slope of 0.04±0.026 mm Hg · mm Hg^-1 along with decreases in urinary nitrate/nitrite excretion rate (U_NOxV). Renal cortical and medullary blood flows, measured by laser-Doppler flowmetry, exhibited high autoregulatory efficiency over this RAP range. The changes in RIHP during alterations in RAP were positively correlated (r=0.743; P<0.001) with the changes in U_NOxV but not with cortical or medullary blood flow. NLA infusion decreased RIHP to 1.9±0.5 mm Hg and also reduced U_NOxV from 1.8±0.2 to 0.9±0.01 nmol · min^-1 · g^-1. Infusion of NO donors restored RIHP (4.3±0.9 mm Hg) and U_NOxV (1.5±0.2 nmol · min^-1 · g^-1). During NLA infusion, the RIHP responses to reductions in RAP were markedly attenuated and were not restored even during constant-rate infusion of NO donors. The results suggest that changes in RIHP in response to alterations in RAP are associated with changes in intrarenal NO, suggesting a direct effect of NO to regulate RIHP.

Key Words: renal regional blood flow • laser-Doppler flowmetry • nitrate/nitrite excretion

	Introduction

Top Abstract Introduction Materials and Methods Results Discussion References

 
Previous studies in dogs and rats have shown that changes in renal arterial pressure (RAP), within the autoregulatory range, are associated with changes in renal interstitial hydrostatic pressure (RIHP), and it has been suggested that these changes in RIHP contribute to the control of tubular reabsorptive function via alterations in the renal interstitial environment.^{1 2 3 4 5} The mechanism responsible for RAP-induced changes in RIHP has remained difficult to explain, because renal blood flow (RBF) and peritubular capillary pressure are efficiently autoregulated during alterations in RAP over a wide range.^{6 7 8} Findings in volume-expanded rats that the renal medullary blood flow (MBF) is more sensitive to changes in RAP than the cortical blood flow (CBF)⁹ have led to the suggestion that impaired autoregulatory efficiency of MBF may be linked to the changes in RIHP.^{1 10} However, direct associations between changes in RIHP and changes in regional blood flows in the kidney during alterations in RAP have not been established. In addition, studies in dogs as well as in euvolumic rats have failed to demonstrate reduced autoregulatory efficiency of MBF.^{6 9 11 12}

Inhibition of nitric oxide (NO) synthesis in rats was shown to decrease RIHP and attenuate RIHP responses to changes in renal perfusion pressure.³ Moreover, selective inhibition of NO in the rat renal medulla¹³ and the administration of the NO precursor L-arginine to Dahl salt-sensitive rats¹⁴ have been shown to influence RIHP. Intrarenal administration of agents that elicit NO release, such as acetylcholine and bradykinin, have also been shown to increase RIHP,^{2 15} whereas renal vasodilator agents such as secretin that do not involve cGMP as a second messenger¹⁶ have failed to elicit changes in RIHP.^{2 15} These findings suggest that changes in RIHP may be more closely associated with alterations in intrarenal NO activity during changes in RAP rather than with specific changes in regional hemodynamics.¹¹

The present investigation was designed to examine the link between intrarenal NO activity and RIHP during changes in RAP in anesthetized dogs. To assess RIHP, a microtip catheter transducer was placed under the renal capsule.¹⁷ This procedure was preferred because it did not require insertion into the cortical tissue and thus minimized disruption of the renal microcirculation.⁴ RIHP and other renal responses were evaluated before and during inhibition of NO synthase by nitro-L-arginine (NLA) and also during renal arterial infusion of NO donors. The objective was to evaluate RIHP responses to changes in RAP during control conditions, after blockade of endogenous NO formation, and after infusion of NO donors, which would restore a relatively constant level of intrarenal NO activity but would not lead to changes in intrarenal NO in response to changes in arterial pressure.¹⁸

	Materials and Methods

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Experiments were conducted in 6 mongrel dogs (18 to 21 kg · body weight), which were given supplemental amounts of sodium chloride (1.5 g · kg^-1 · body weight · day^-1 for 3 days) added to the normal laboratory diet, so that they achieved a sodium-replete state. On the day of the experiment, dogs were anesthetized with pentobarbital sodium intravenously at 30 mg/kg body weight, and supplemental doses were given during the experiments as needed. The surgical preparation of the animals and basic experimental techniques are identical to those previously described.^{6 11 12 18 19 20} Laser-Doppler flowmetry was used to measure renal CBFs and MBFs, as described previously.^{6 11 12}

Measurement of RIHP
A microtip catheter transducer (Millar Instruments, Inc) was placed under the renal capsule to measure RIHP.¹⁷ This device consists of a microtransducer mounted on the tip of an insulated wire catheter,⁴ which can be connected to the recording equipment (model D, Grass Instruments). A small incision was created in the renal capsule for introduction of the catheter transducer, and the opening was then sealed by applying agar. The microtransducer was calibrated electronically (0 to 20 mm Hg pressure range) with a standard calibration device before and after the experimental protocol. Reference 0 pressure was taken by placing the microtransducer at the opening of the renal capsule. This transducer catheter was found highly responsive to constriction of the renal vein and occlusion of the ureter and to intrarenal infusion of the vasodilators acetylcholine and bradykinin. We observed in separate anesthetized dogs²¹ that acetylcholine increased RIHP from 2.7±0.6 to 6.9±1.5 mm Hg (P<0.01; n=7) and bradykinin increased RIHP from 2.0±0.4 to 7.9±1.9 mm Hg (P<0.05; n=4) without significant changes in RAP.

After completion of surgery, a 2.5% solution of inulin in normal saline was administered into the jugular vein. An initial dose of 1.6 mL/kg body weight was followed by a continuous infusion of 0.03 mL · min^-1 · kg^-1 for at least 45 minutes before the implementation of the experimental protocol. Basal level of arterial pressure in these dogs was raised to 140 mm Hg by partial occlusion of both common carotid arteries to allow evaluation of the arterial pressure-RIHP relationship over a wider range of RAP. Urine samples were collected for 2 consecutive 10-minute periods at the spontaneous RAP of 140 mm Hg. At the midpoint of each urine collection period, an arterial blood sample (2 mL) was taken to measure plasma inulin, sodium, and potassium concentrations. After control measurements, step reductions in RAP (110 and 80 mm Hg) were produced by adjusting a renal arterial clamp. At each level of RAP, a period of at least 5 minutes was allowed for stabilization before a 10-minute urine collection was made. After the last sample was collected at reduced RAP, the clamp was released to return to control RAP. To inhibit NO synthesis, a continuous intra-arterial infusion of NLA (Aldrich Chemical Co) was initiated at a rate of 50 µg · kg^-1 · min^-1.^{18 19} After 30 minutes of NLA infusion, the protocol was repeated. After re-establishment of the control RAP, a continuous infusion of an NO donor was added to the NLA infusion.¹⁸ NO donors used were S-nitroso-n-acetylpenicillamine (2 µg · kg^-1 · min^-1; n=3, Sigma) and diethylamine/NO complex (0.3 µg · kg^-1 · min^-1; n=3, Sigma). As both of these NO donors showed similar responses, the values were pooled together and presented as one group. Ten minutes after the initiation of combined NO donor and NLA infusion, the same protocol was repeated.

Inulin, sodium, and potassium and osmolar concentrations in urine and plasma were measured as previously reported.^{6 11 12 18 19 20} Urine concentrations of nitrate and nitrite (NO_x) were measured using the Greiss reaction technique after enzymatic reductions of nitrate to nitrite in the samples as previously reported.^{11 12 19} Values are reported as mean±SEM. Statistical comparisons of differences in the responses were conducted with ANOVA for repeated measures followed by the Newman-Keuls test. Correlation of the responses were made by the Spearman test. Differences in the mean values were deemed significant at a value of P0.05.

	Results

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Responses to Reductions in RAP on RIHP, RBF, and Excretory Function
Figures 1 and 2 illustrate the responses to reductions in RAP on RIHP, urinary excretion rate of nitrate/nitrite (U_NOxV), and renal regional blood flows. The Table summarizes the other results obtained. As previously reported, step reductions in RAP during control conditions caused decreases in urine flow, sodium excretion, fractional excretion of sodium, and U_NOxV.^{11 12 18 19} The average RIHP at the spontaneous RAP during control conditions was 4.7±1.1 mm Hg, and step reductions in RAP within the autoregulatory range resulted in significant decreases in RIHP (slope, 0.041±0.016 mm Hg · mm Hg^-1 ) (Figure 1A). There were also decreases in U_NOxV (slope, 0.014±0.003 nmol · min^-1 · g^-1 · mm Hg^-1) from the basal value of 1.8±0.2 nmol · min^-1 · g^-1 during reductions in RAP (Figure 1B). The percentage changes in U_NOxV in response to reductions in RAP during control conditions were positively correlated with the percentage changes in RIHP (r=0.743; P<0.001). However, these RAP-dependent changes in RIHP occurred without significant changes in renal CBFs or MBFs (Figure 2), which remained efficiently autoregulated during reductions in RAP in association with autoregulation of total RBF and glomerular filtration rate (Table).

View larger version (16K): [in this window] [in a new window]   Figure 1. Responses to reductions in RAP on RIHP (A) and UNOxV (B) during control period and during NLA and NO donor agent–infusion periods.

View larger version (14K): [in this window] [in a new window]   Figure 2. Responses to reductions in RAP on renal MBF (A) and CBF (B) during control period and during NLA and NO donor agent–infusion periods.

View this table: [in this window] [in a new window]   Table 1. Renal Responses to Reductions in RAP Before and During NO Synthesis Inhibition and NO Donor Administration (n=6)

RIHP and Renal Responses to Reductions in RAP During Infusions of NLA and NO Donor Agents
Figure 1A illustrates the RAP-induced changes in RIHP during NO synthase inhibition as well as during infusion of NO donors. In response to NLA administration, RIHP decreased significantly (1.9±0.5 mm Hg; P<0.05). As previously reported, CBF and MBF decreased concomitantly with total RBF during NO synthase inhibition.^{9 12} During NLA treatment, RIHP was not altered significantly in response to reductions in RAP (Figure 1A). After addition of NO donor infusion, RIHP increased toward control levels (4.3±0.9 mm Hg; P<0.05 versus NLA period). Although control values of RIHP were restored after NO donor infusion to the NLA-treated dogs, RIHP did not respond to reductions in RAP as had been observed during control conditions, and RIHP exhibited autoregulation in association with CBF and MBF autoregulation (Figure 1A). The slopes of the RAP-versus-RIHP relations were significantly reduced from 0.041±0.016 to 0.0002±0.003 mm Hg · mm Hg^-1(P<0.001) during the NLA period and to -0.007±0.007 (P<0.05) during the NLA+NO donor period. The slopes of these relationships during NLA and NLA+NO donor infusions were not significantly different from 0.

The relationship between RAP and U_NOxV was likewise markedly attenuated during NO synthase inhibition as well as during infusion of NO donor agents (Figure 2B). As reported previously,^{11 12 19} NO synthase inhibition by NLA administration resulted in significant decreases in U_NOxV to 0.9±0.1 nmol · min^-1 · g^-1. NO donor agent infusion after NLA administration restored the U_NOxV level to 1.5±0.1 nmol · min^-1 · g^-1. The mean slope of the RAP-versus-U_NOxV relation was significantly reduced from 0.014±0.003 to 0.002±0.001 nmol · min^-1 · g^-1 · mm Hg^-1 (P<0.05) during the NLA period and to 0.001±0.004 nmol · min^-1 · g^-1 · mm Hg^-1 (P<0.05) during NLA+NO donor infusion. The slopes of the relationship between RAP and U_NOxV during the NLA or NO donor infusion period were not significantly different from 0. In addition, autoregulatory efficiency for total or regional blood flows remained intact during all of these periods (Figure 2 and the Table). The glomerular filtration rate did not change significantly during NLA or NO donor infusion and remained autoregulated during changes in RAP (Table). As reported previously,^{11 12 18 19} there were decreases in urine flow, sodium excretion, and fractional excretion of sodium during NO inhibition that were restored to close to control values during NO donor infusion (Table). Importantly, the NO donors did not restore the slopes of the relationship between RAP and sodium excretion or U_NOxV.

	Discussion

Top Abstract Introduction Materials and Methods Results Discussion References

 
As the present study was designed to observe simultaneously the regional blood flow and the RIHP responses to changes in RAP, it allowed us to characterize the relationships between RIHP and renal CBFs and MBFs in response to reductions in RAP. Our findings clearly show that RIHP responses to changes in RAP are not associated with changes in blood flow to either the medullary or cortical regions. The finding that RAP-induced changes in RIHP are not dependent on changes in total or regional RBFs suggests an alternative mechanism that is independent of changes in intrarenal hemodynamic events. The present results showing that the changes in RIHP during alterations in RAP are positively correlated with the changes in U_NOxV indicate that RAP-induced changes in intrarenal NO may be involved in mediating the changes in RIHP.^{7 11 19} It was shown earlier that the changes in intrarenal NO activity in response to changes in RAP were positively correlated with the changes in U_NOxV.^{11 12}

The commonly used techniques to measure RIHP reported previously include polyethylene matrix capsules^{2 15} or microtransducers⁴ implanted either acutely or chronically in the renal parenchyma and insertion of a catheter into the subcapsular interstitial space.¹⁷ The subcapsular space is considered a part of the renal interstitium and is in close functional connection with the deeper interstitial space, as it has been shown that injection of labeled albumin into the subcapsular space rapidly appeared in the hilar lymph.¹⁷ The measurement of RIHP from the subcapsular space was preferred to the implantation procedures in the present study to avoid possible tissue injury and tearing of glomerular and peritubular capillaries. It was reported that pressure in the subcapsular space was in the range of 2 to 7 mm Hg, measured using a micropipette (tip diameter, 1 to 2 µm) connected with a polyethylene catheter filled with paraffin oil.¹⁷ The subcapsular pressure recorded in the present study using the microtip transducer connected with insulated wire catheter is within the range that has been reported previously.¹⁷

The present data demonstrate that RIHP decreases during NO synthase inhibition and increases back to control levels during NO donor infusion. Studies in rats³ have demonstrated that NO synthase inhibition results in decreases in RIHP and prevents arterial pressure–dependent changes in RIHP. Increases in NO production rate elicited by L-arginine infusion in rats also caused a rise in RIHP.¹⁴ We have also observed that intrarenal administration of the NO agonists acetylcholine and bradykinin in our dog preparations resulted in increases in RIHP, which were also associated with increases in U_NOxV.²¹ Additionally, it was observed that another renal vasodilator, secretin, which did not cause changes in U_NOxV, likewise failed to cause any significant changes in RIHP.²¹ Collectively, these findings support a causal relationship between RIHP and intrarenal NO activity. However, there are also reports showing increases in RIHP in response to acute systemic administration of NO inhibitors in rats.^{22 23 24 25} Although the reasons for these contrasting findings are not yet clear, they have uniformly been observed in response to systemic administration of NOS inhibitors. Thus, these contrasting findings may not be specific to intrarenal NO inhibition but could be mediated by other factors such as systemic hypertension and inhibition of renal nerves via changes in baroreceptor activity or release of a secondary factor.^{22 23 24 25}

In our experimental preparation in dogs, we have not observed any role played by MBF in mediating RIHP changes during alterations in RAP, as suggested by some investigators.^{1 9 10} MBF was seen efficiently autoregulated in dogs even during acutely volume-expanded states.⁶ Although we have not examined the relationship between NO and RIHP under conditions of acute volume expansion, in the present study the dogs were given a salt load for 3 days before the experiment, which could have caused a mild volume-expanded state. There are reports that volume loading increases both RIHP and NO production in various experimental animal models.^{1 6 10 13} Thus, it can be speculated that there would be an enhancement of the relationship between NO and RIHP during an increase in body fluid volume.

When intrarenal NO levels were restored by NO donors but were prevented from changing because the constant-rate infusion of NO donor was superimposed on the endogenous NO inhibition, the relationship between RAP and RIHP remained markedly attenuated and was not restored to that seen in the control conditions (Figure 1). These results indicate that alterations in intrarenal NO activity rather than the simple presence of NO are requisite for RAP-induced changes in RIHP. RIHP is regulated by a variety of factors, which determine the net flow of fluid into and out of the renal interstitium.⁵ As a consequence of multiple transport mechanisms, the renal tubules generate transtubular solute concentration gradients, which are responsible for net fluid reabsorption. The bulk of the fluid transferred into the renal interstitial compartment is then reabsorbed by the peritubular capillaries into the vascular compartment to be removed from the kidney. The rate of fluid uptake is determined by the filtration coefficient of the peritubular capillaries and the net force for peritubular capillary uptake, which is dependent on the transcapillary hydrostatic and colloid osmotic gradients. The steady-state RIHP that results provides the force needed to balance net peritubular capillary uptake with net tubular reabsorption rate. The exact mechanisms of how RIHP may be influenced by the alterations in NO activity are not yet clearly understood. However, there are several studies indicating that NO influences microvascular endothelial permeability.^{26 27 28 29 30} Although the role of NO in the renal microvascular permeability has not yet been examined, studies conducted in other vascular beds suggest that peritubular capillary permeability may be influenced by alterations in intrarenal NO and thus could influence RIHP.^{26 27 29 30} Thus, one possible mechanism by which increased NO could increase RIHP is by decreasing the filtration coefficient.^{27 30} It was reported, however, that hydraulic conductivity in frog mesenteric capillaries was increased by luminal exposure of a NO donor agent, sodium nitroprusside, and decreased by superfusion with a NO inhibitor agent.^{31 32} These findings indicate that NO can elicit changes in RIHP by altering the filtration coefficient (K_f) of the peritubular capillary membrane, but the available data indicate that such changes are opposite to those required.

Because peritubular capillary pressure is greater than RIHP, the hydrostatic pressure gradient (P_c-P_i) is positive, favoring net fluid efflux. However, this positive hydrostatic pressure gradient is countered by the net colloid osmotic gradient (_c-_i), which is generally greater than the hydrostatic pressure gradient in the peritubular capillaries and is recognized as being the principal driving force for fluid reabsorption. However, the interstitial colloid osmotic pressure (_i) partially offsets that net reabsorptive force in the peritubular capillary and is due primarily to protein leakage from the peritubular capillaries into the renal interstitium. At steady state, the net protein leak-out is balanced by the net protein return via renal lymphatics. In addition, the effective colloid osmotic pressure is determined by the reflection coefficient (), which determines the actual effectiveness of the colloid osmotic gradient across the peritubular capillary wall. NO has been implicated in the control of capillary permeability for macromolecules,²⁹ which could influence and thus could lead to an alteration in RIHP in the renal interstitium. It has been reported that the osmotic reflection coefficient for albumin in the pulmonary vessels is decreased by administration of NO inhibitors at high intravascular pressure during lung ischemia.³³ To the extent that intrarenal NO is able to influence , the increases in intrarenal NO due to increases in RAP could reduce the effective colloid osmotic pressure. Thus, the efficiency of net peritubular capillary uptake would be diminished leading to an accumulation of volume in the renal interstitial compartment. The resultant effect would be a rise in RIHP sufficient to compensate for the reduced net colloid osmotic pressure gradients. Thus, the RAP-associated changes in RIHP could occur in the absence of any other hemodynamic changes and would be associated primarily with the concomitant changes in intrarenal NO activity. However, further studies are required to examine the exact mechanism that is involved in NO-mediated changes in RIHP.

Although the mechanisms of NO to influence microvascular endothelial permeability are not yet clearly defined, the available evidence indicates that NO-dependent changes in cGMP may be involved in this process.²⁹ It is conceivable that NO-induced permeability changes in renal peritubular capillaries may involve activation of cGMP. In the present study, we have observed that a change in RIHP occurs within a minute of inducing a change in RAP. In our earlier studies using NO electrodes in the renal interstitium,^{11 12} we have also observed that a change in renal interstitial NO concentration occurred within a minute of alterations in RAP. Thus, considering the kinetics observed in the RIHP responses to changes in RAP, it is reasonable to speculate that the alterations in RIHP are not due directly to the changes in RAP but require a secondary stimulus such as NO-induced permeability changes in renal peritubular capillaries. However, further experiments are needed to clarify the mechanisms involved in these RAP-induced changes in RIHP.

In conclusion, the results of the present investigation indicate that the mechanism mediating arterial pressure–induced changes in RIHP may be due to pressure-dependent alterations in intrarenal NO activity and do not require any associated changes in regional RBF.

	Acknowledgments

 
This study was supported by Grants HL-51306 and HL-18426 from the National Heart, Lung, and Blood Institute, NIH. We are grateful to Agnes C. Buffone and Debbie Olavarrieta for preparing the manuscript.

	Footnotes

 
Original received September 19, 2000; revision received January 10, 2001; accepted January 10, 2001.

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