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Am J Physiol Renal Physiol 274: F516-F524, 1998;
0363-6127/98 $5.00
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Vol. 274, Issue 3, F516-F524, March 1998

Neuronal nitric oxide synthase modulates rat renal microvascular function

Atsuhiro Ichihara, Edward W. Inscho, John D. Imig, and L. Gabriel Navar

Department of Physiology, Tulane University School of Medicine, New Orleans, Louisiana 70112-2699

    ABSTRACT
Top
Abstract
Introduction
Methods
Results
Discussion
References

This study was performed to determine the influence of neuronal nitric oxide synthase (nNOS) on renal arteriolar tone under conditions of normal, interrupted, and increased volume delivery to the macula densa segment and on the microvascular responses to angiotensin II (ANG II). Experiments were performed in vitro on afferent (21.2 ± 0.2 µm) and efferent (18.5 ± 0.2 µm) arterioles of kidneys harvested from male Sprague-Dawley rats, using the blood-perfused juxtamedullary nephron technique. Superfusion with the specific nNOS inhibitor, S-methyl-L-thiocitrulline (L-SMTC), decreased afferent and efferent arteriolar diameters, and these decreases in arteriolar diameters were prevented by interruption of distal volume delivery by papillectomy. When 10 mM acetazolamide was added to the blood perfusate to increase volume delivery to the macula densa segment, afferent arteriolar vasoconstrictor responses to L-SMTC were enhanced, but this effect was again completely prevented after papillectomy. In contrast, the arteriolar diameter responses to the nonselective NOS inhibitor, Nomega -nitro-L-arginine (L-NNA) were only attenuated by papillectomy. L-SMTC (10 µM) enhanced the efferent arteriolar vasoconstrictor response to ANG II but did not alter the afferent arteriolar vasoconstrictor responsiveness to ANG II. In contrast, L-NNA (100 µM) enhanced both afferent and efferent arteriolar vasoconstrictor responses to ANG II. These results indicate that the modulating influence of nNOS on afferent arteriolar tone of juxtamedullary nephrons is dependent on distal tubular fluid flow. Furthermore, nNOS exerts a differential modulatory action on the juxtamedullary microvasculature by enhancing efferent, but not afferent, arteriolar responsiveness to ANG II.

renal microcirculation; autoregulation; Nomega -nitro-L-arginine; S-methyl-L-thiocitrulline; angiotensin II

    INTRODUCTION
Top
Abstract
Introduction
Methods
Results
Discussion
References

NITRIC OXIDE (NO) is recognized as a major paracrine regulator of renal microvascular function (20), and its production is regulated by at least two constituitive isoforms of NO synthase (NOS) (17). Endothelial NO synthase (eNOS) is primarily localized to the endothelium and is the principle source of vascular NO (17). Nonselective inhibition of NOS in the kidney has been shown to decrease renal blood flow and vasoconstrict both afferent and efferent arterioles (8, 11, 20, 21). The effects on glomerular dynamics and glomerular filtration rate have been more variable, with some studies showing decreases in glomerular filtration rate and the ultrafiltration coefficient (8, 20). Collectively, these studies have shown that NO plays an important role in regulating renal microvascular function. Intrarenal NO has been presumed to originate primarily from eNOS, which has been localized to the renal microvascular endothelium (3, 28); however, immunohistochemical studies have also revealed the presence of neuronal NO synthase (nNOS) in the kidney, with the principle expression being localized to the cells of the macula densa (3, 19, 28, 31) and the endothelia of the efferent arterioles (3). The macula densa cells serve as the sensing site of the tubuloglomerular feedback mechanism by monitoring flow-related changes in tubular fluid composition to the distal nephron and, in turn, releasing vasoactive paracrine signals that alter afferent arteriolar resistance, glomerular capillary pressure, and glomerular filtration rate (20).

The finding of nNOS localized to the macula densa cells suggested that nNOS may contribute to the macula densa-dependent tubuloglomerular feedback signals regulating glomerular dynamics (14, 19, 26, 27, 29-31). In a microperfusion study, infusion of the nonselective NOS inhibitor, Nomega -methyl-L-arginine, into the peritubular capillaries (31) or the lumen of the late proximal tubule (26, 29, 30) induced significant decreases in proximal stop-flow pressure, consistent with increases in preglomerular resistance. However, proximal stop-flow pressure was not influenced by the nonselective NOS inhibitor, Nomega -nitro-L-arginine (L-NNA), at low tubular perfusion rates and decreased only when the tubule was perfused at a high flow (26, 31). In microperfused rabbit afferent arterioles, distal tubular infusion of Nomega -methyl-L-arginine enhanced the afferent arteriolar vasoconstriction induced by high concentrations of NaCl in the distal tubular perfusate (14). These findings suggest that intrarenal NO, derived from distal tubular NOS, contributes to flow-dependent regulation of preglomerular vascular tone and tubuloglomerular feedback responses by partially counteracting the vasoconstrictor signals generated during elevated distal flows.

In several previous studies, 7-nitro indazole has been used to cause specific nNOS inhibition (4, 22, 27). Chronic administration of 7-nitro indazole led to elevated arterial pressure and enhanced tubuloglomerular feedback responsiveness in rats (22). In a microperfusion study, intratubular and intraperitoneal administration of 7-nitro indazole enhanced the increased tubular flow-mediated reduction of glomerular capillary pressure (27). Together with the studies utilizing tubular perfusion of nonspecific NOS inhibitors (14, 26, 29-31), the data suggest that nNOS localized in macula densa cells contributes to flow-dependent regulation of glomerular capillary pressure and filtration rate. The available data, however, do not provide direct evidence that nNOS selectively regulates preglomerular vascular tone through the macula densa pathway. In vivo studies using anesthetized rats demonstrated that 7-nitro indazole did not influence furosemide-induced changes in renal hemodynamics, although 7-nitro indazole inhibited furosemide-stimulated renin secretion (4). The inconsistent findings related to studies using 7-nitro indazole to achieve nNOS inhibition may be due, in part, to its low selectivity for nNOS, in that 7-nitro indazole is only about fivefold more selective for nNOS than Nomega -methyl-L-arginine (2, 18). The recent availability of S-methyl-L-thiocitrulline (L-SMTC), which is water soluble and 17-fold more selective for nNOS compared with eNOS (9), has provided a more selective means to evaluate the relative contribution of NO derived from nNOS in the control of renal microvascular dynamics.

The present study was performed to test the hypothesis that nNOS selectively regulates afferent arteriolar tone and that the magnitude of this influence is modulated by changes in distal tubular fluid flow. Using the in vitro blood-perfused juxtamedullary nephron technique combined with videomicroscopy (6, 7, 11-13, 21, 25), which allowed us to observe changes in diameters of afferent and efferent arterioles, we have investigated the responsiveness of afferent and efferent arterioles to nNOS inhibition under conditions of normal, interrupted, and increased volume delivery to the macula densa segment. Furthermore, the effects of nNOS inhibition on afferent and efferent arteriolar responsiveness to angiotensin II (ANG II), which enhances the vascular sensitivity of tubuloglomerular feedback responses (20), have been examined.

    METHODS
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Abstract
Introduction
Methods
Results
Discussion
References

Assessment of Afferent and Efferent Arteriolar Reactivity

The studies described here were performed in accordance with the guidelines and practices established by the Tulane University Animal Care and Use Committee. Afferent and efferent arteriolar responsiveness was assessed in vitro using the blood-perfused juxtamedullary nephron technique, combined with videomicroscopy, as previously described (7). Each experiment used two male Sprague-Dawley rats (Charles River, Wilmington, MA), weighing 350-400 g, with one rat serving as the blood donor and the second rat serving as the kidney donor. Rats had free access to water and standard rat chow (Ralston-Purina, St. Louis, MO) containing sodium content of 0.17 meq/g prior to the experiments. Rats were anesthetized with pentobarbital sodium (50 mg/kg ip), and a cannula was inserted into the left carotid artery of the blood donor. Donor blood was collected into a heparinized (500 units) syringe via the carotid arterial cannula and centrifuged to separate the plasma and cellular fractions. The buffy coat was removed and discarded. Plasma oncotic pressure was adjusted to 18 mmHg by the addition of bovine serum albumin (Sigma Chemical, St Louis, MO). The calcium ion concentration, measured using a Ca2+/pH analyzer (model M634; Ciba-Corning, Pensacola, FL), was adjusted to 1.0-1.2 mM by adding calcium chloride (1 M). After sequential passage of the plasma through 5- and 0.22-µm filters (Gelman Sciences, Ann Arbor, MI), erythrocytes were added to achieve a hematocrit of 33%. This reconstituted blood was passed through a 5-µm nylon mesh and thereafter stirred continuously in a closed reservoir that was pressurized with a 95% O2-5% CO2 gas mixture.

The right kidney of the kidney donor was perfused through a cannula inserted into the superior mesenteric artery and advanced into the right renal artery. The perfusate was a Tyrode solution (pH 7.4) containing 5.1% bovine serum albumin and a mixture of L-amino acids, as previously described (6). The kidney was excised and sectioned longitudinally, retaining the papilla intact with the perfused dorsal two-thirds of the organ. The papilla was reflected to expose the pelvic mucosa and tissue covering the inner cortical surface. Overlying tissue was removed to expose the tubules, glomeruli, and related vasculature of the juxtamedullary nephrons. The arterial supply of the exposed microvasculature was isolated by ligating the larger branches of the renal artery with fine suture (nylon black monofilament, 10-0; Vanguard Surgical, Houston, TX).

After the dissection was completed, the Tyrode perfusate was replaced with the reconstituted blood. Perfusion pressure was monitored by a pressure cannula centered in the tip of the perfusion cannula. Renal perfusion pressure was regulated by adjusting the rate of gas inflow into the blood reservoir and maintained at 100 mmHg throughout the study. The inner cortical surface of the kidney was continuously superfused with a warmed (37°C) Tyrode solution containing 1% bovine serum albumin.

The tissue was transilluminated on the fixed stage of a Leitz Laborlux-12 microscope (Midland, Canada), equipped with a water-immersion objective (×40, Zeiss). Video images of the microvessels were transferred by a Newvicon camera (model NC-67M; Dage-MTI, Michigan City, IN) through an image enhancer (MFJ-1452; MFJ Enterprises, Starkville, MS) to a video monitor (Conrac Display Systems, Covina, CA). The video signal was recorded on videotape for later analysis (Super VHS Videocassette Recorder; Panasonic, Secaucus, NJ). Afferent and efferent arteriolar inside diameters were measured at 12-s intervals, using a calibrated digital image-shearing monitor (Instrumentation for Physiology and Medicine, San Diego, CA). Measurement sites along the microvasculature were selected to achieve the maximum clarity of the vascular walls at a location as close to the glomerulus as possible. Afferent arteriolar diameters were measured at sites 90-150 µm upstream from the glomerulus, and efferent arteriolar diameters were measured at sites within 100 µm of the glomerulus, prior to the first branch. A 10-min equilibration period was allowed before the initiation of each experimental protocol. The average diameter during the final 1 min of each 3-min treatment period was utilized for statistical analysis of steady-state responses.

Experimental Protocols

Effect of nNOS inhibition on afferent and efferent arteriolar diameters. The effects of nNOS blockade on afferent and efferent arteriolar diameters were determined in control kidneys. Afferent and efferent arteriolar diameters were measured before and during exposure to increasing concentrations (0.1, 1, 10, and 100 µM) of the selective nNOS inhibitor, L-SMTC (Alexis, San Diego, CA). A second series of experiments were performed to assess the influence of distal tubular flow on the afferent and efferent arteriolar responses to L-SMTC. The juxtamedullary nephrons visualized in this preparation give rise to long loops of Henle that extend into the papilla before looping back to the distal tubule and past the macula densa (7). Acute papillectomy interrupts the flow of distal tubular fluid past the macula densa (24) and minimizes tubuloglomerular feedback-dependent influences on microvascular function (25). Experiments were performed as described above, except that, after the initial 5-min control period, acute papillectomy was performed by cleanly severing the papilla near the corticomedullary junction by a single cut, thus preventing unnecessary damage to the adjacent tissue. After a 5-min stabilization period, the afferent and efferent arteriolar responses to increasing concentrations of L-SMTC (0.1-100 µM) were determined. To further evaluate the effects of acute papillectomy on renal vascular responsiveness, we determined the afferent arteriolar responses to ANG II (0.1-10 nM) before and after papillectomy in enalaprilat-treated rats. In a third series of experiments, kidneys were treated with the carbonic anhydrase inhibitor, acetazolamide (10 mM), to determine whether the microvascular responses to L-SMTC were influenced by increases in distal tubular flow. After control measurements were made to determine baseline vessel diameter, acetazolamide was added to the blood perfusate to inhibit proximal tubular reabsorption and increase distal volume and sodium delivery (16, 23). To confirm that the effect of acetazolamide on renal arteriolar responsiveness resulted from acetazolamide-mediated increases in distal tubular flow, renal arteriolar responsiveness to L-SMTC was also assessed in papillectomized kidneys perfused with the acetazolamide-containing blood.

Effect of NOS inhibition on afferent and efferent arteriolar diameters. For comparison, the afferent and efferent arteriolar diameters were measured in control kidneys during exposure to increasing concentrations (1, 10, 100, and 1,000 µM) of the nonspecific NOS inhibitor, L-NNA (Sigma Chemical). The same assessment was also performed in papillectomized kidneys harvested from a separate group of rats.

Effects of selective nNOS and nonselective NOS inhibition on acetylcholine-induced vasodilation. Studies were performed to assess the selectivity of L-SMTC for nNOS over eNOS. The vasodilator responses of the afferent and efferent arterioles to acetylcholine (ACh, 10 µM) were determined under control conditions and again in the presence of 10 µM L-SMTC or 100 µM L-NNA.

Effects of selective nNOS and nonselective NOS inhibition on microvascular responsiveness to ANG II. In this series of experiments, rats were pretreated with the angiotensin-converting enzyme inhibitor, enalaprilat (2 mg ia), 30 min prior to the experiment to decrease endogenous ANG II levels and thus reduce the influence of ANG II on microvascular tone. In a separate group, the dose-response relationships of L-SMTC and L-NNA were also determined in kidneys harvested from enalaprilat-treated rats.

To examine whether nNOS activity modulates ANG II-induced vasoconstriction of afferent and efferent arterioles, we compared the effects of selective nNOS and nonselective NOS inhibition on microvascular responsiveness to ANG II. The changes in afferent and efferent arteriolar diameter in response to 0.1, 1, and 10 nM ANG II were determined before and during exposure to 10 µM L-SMTC or 100 µM L-NNA.

Statistical Analysis

Analyses of changes in microvascular diameters with NOS inhibitors and ANG II were performed using a paired t-test. Differences in control diameters among kidneys treated with papillectomy, enalaprilat, and acetazolamide were compared by an unpaired t-test. We also utilized two-way analysis of variance with repeated measures on one factor and Fisher's protected least square difference test to determine differences in microvascular diameter responsiveness to NOS inhibitors among kidney treatments and to determine differences in ANG II responsiveness before and during addition of L-SMTC or L-NNA. P < 0.05 was considered as statistically significant. Data are presented as means ± SE.

    RESULTS
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Abstract
Introduction
Methods
Results
Discussion
References

Effects of Papillectomy and Acetazolamide on Afferent and Efferent Arteriolar Diameters

Control afferent arteriolar diameter averaged 21.2 ± 0.2 µm (n = 61) and efferent arteriolar diameter averaged 18.5 ± 0.2 µm (n = 51) in the present study. In paired studies, papillectomy significantly increased afferent arteriolar diameters by 5.5 ± 0.8% (n = 16), consistent with our previous findings (25). It was also noted that acetazolamide significantly decreased afferent arteriolar diameters of papilla intact kidneys from 22.0 ± 0.8 to 20.3 ± 0.7 µm, a decrease of 7.4 ± 0.4% (n = 8). Neither treatment significantly affected efferent arteriolar diameters. In addition, papillectomy did not influence afferent arteriolar responsiveness to ANG II (n = 4). Control afferent arteriolar diameter averaged 21.5 ± 1.8 µm and decreased by 4.7 ± 0.5, 12.2 ± 0.8, and 26.6 ± 2.9% in response to ANG II concentrations of 0.1, 1, and 10 nM, respectively. Similar to the studies described above, papillectomy increased afferent diameters by 5.0 ± 0.1%, and ANG II decreased the diameter by 5.9 ± 1.0, 13.4 ± 1.1, and 28.2 ± 3.4%, respectively, at each concentration treated. On the basis of group comparisons, however, there were no significant differences in basal diameters among the four distinct groups treated with L-SMTC (control kidneys and kidneys treated with acetazolamide, papillectomy, and acetazolamide + papillectomy), as shown in Figs. 1 and 2.

Effect of nNOS Inhibition on Afferent and Efferent Arteriolar Diameters

Figure 1 depicts that L-SMTC dose-dependently decreased afferent arteriolar diameters by 11.3 ± 0.6 and 16.2 ± 0.2% at 10 and 100 µM concentrations, respectively. Papillectomy prevented the L-SMTC-induced decreases in afferent arteriolar diameter up to doses of 10 µM and attenuated the vasoconstrictor response to 100 µM L-SMTC. In contrast, acetazolamide treatment enhanced the dose-response relationship of afferent arterioles to L-SMTC. Afferent arteriolar diameters decreased by 23.8 ± 1.6 and 30.2 ± 2.1% at 10 and 100 µM L-SMTC concentrations, respectively. These responses were significantly greater than those observed in control kidneys. The afferent arteriolar responses to L-SMTC were also markedly attenuated by papillectomy in kidneys treated with acetazolamide. Average afferent arteriolar diameter was unchanged with L-SMTC at concentrations up to 10 µM. Only 100 µM L-SMTC significantly decreased afferent arteriolar diameters by 10.0 ± 1.0%. The afferent arteriolar responses to L-SMTC in papillectomized kidneys treated with acetazolamide were similar to those observed in kidneys with papillectomy alone.


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  		Fig. 1.   Effect of S-methyl-L-thiocitrulline (L-SMTC) on afferent arteriolar diameter (in µm) (A) and as percent change (Delta ) from control diameter (B). Arteriolar responses to L-SMTC were performed using different groups of kidneys, i.e., control kidneys (open circle , n = 7), papillectomized kidneys (triangle , n = 5), acetazolamide-treated kidneys (bullet , n = 8), and papillectomized kidneys treated with acetazolamide (black-triangle, n = 5). There was no significant difference in basal diameter between these 4 unpaired groups. However, in individual groups, papillectomy significantly increased afferent diameter, from 20.0 ± 1.2 to 21.2 ± 1.1 µm, an increase of 6.3 ± 2.5%, and acetazolamide significantly decreased the afferent diameter, from 22.0 ± 0.8 to 20.3 ± 0.7 µm, a decrease of 7.4 ± 0.4%. * P < 0.05 vs. basal diameter. dagger  P < 0.05 vs. response of control kidneys.

In control kidneys, L-SMTC decreased efferent arteriolar diameters by 14.5 ± 0.4 and 16.4 ± 0.3% at 10 and 100 µM concentrations, respectively (Fig. 2). Papillectomy completely inhibited the L-SMTC-induced decreases in efferent arteriolar diameter up to a concentration of 10 µM and attenuated the vasoconstrictor responses to 100 µM L-SMTC. Acetazolamide treatment did not influence the L-SMTC dose-response relationship in efferent arterioles, except for a slight enhancement at 100 µM L-SMTC. L-SMTC reduced efferent arteriolar diameters by similar degrees in both control and acetazolamide-treated kidneys. The efferent arteriolar responses to L-SMTC were also markedly attenuated by papillectomy in kidneys treated with acetazolamide. Efferent arteriolar diameter was unaltered with L-SMTC at concentrations up to 10 µM. Only 100 µM L-SMTC significantly decreased efferent arteriolar diameters by 7.3 ± 0.3%. The efferent arteriolar responses to L-SMTC in papillectomized kidneys treated with acetazolamide were similar to those observed in the kidneys with papillectomy alone.


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  		Fig. 2.   Effect of L-SMTC on efferent arteriolar diameter (in µm) (A) and as percent change (Delta ) from control diameter (B). Arteriolar responses to L-SMTC were performed using different groups of kidneys, i.e., control kidneys (open circle , n = 5), papillectomized kidneys (triangle , n = 5), acetazolamide-treated kidneys (bullet , n = 5), and papillectomized kidneys treated with acetazolamide (black-triangle, n = 5). There was no significant difference in basal diameters between these 4 unpaired groups. Any individual treatments did not significantly influence efferent diameter of the respective group. * P < 0.05 vs. basal diameter. dagger  P < 0.05 vs. response of control kidneys.

Effect of NOS Inhibition on Afferent and Efferent Arteriolar Diameters

As depicted in Fig. 3 and consistent with previous findings (11, 21), L-NNA decreased afferent arteriolar diameters in a dose-dependent manner. Maximum vasoconstriction occurred at a L-NNA concentration of 100 µM, which decreased afferent arteriolar diameters by 16.7 ± 0.4%. Papillectomy slightly attenuated the L-NNA dose-response relationship in afferent arterioles, but most of the L-NNA-mediated vasoconstriction was retained. L-NNA (100 µM) decreased afferent arteriolar diameters by 11.3 ± 0.4% in papillectomized kidneys.


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  		Fig. 3.   Effect of Nomega -nitro-L-arginine (L-NNA) on afferent arteriolar diameter expressed in µm (A) and as percent change (Delta ) from control diameter (B). Arteriolar responses to L-NNA are shown for control kidneys (open circle , n = 5) and papillectomized kidneys (triangle , n = 6). * P < 0.05 vs. basal diameter. dagger  P < 0.05 vs. response of control kidneys.

As shown in Fig. 4, L-NNA elicited dose-dependent decreases in efferent arteriolar diameter and caused maximum vasoconstriction of 16.6 ± 0.6% at a concentration of 100 µM. The L-NNA dose-response relationship in efferent arterioles was also attenuated significantly by papillectomy. The decrease in efferent arteriolar diameter with 100 µM L-NNA averaged 8.8 ± 0.6% in papillectomized kidneys. In contrast to the results obtained with L-SMTC, both afferent and efferent arteriolar responsiveness to L-NNA were well preserved; however, the magnitude of the L-NNA-induced vasoconstriction was significantly attenuated following papillectomy.


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  		Fig. 4.   Effect of L-NNA on efferent arteriolar diameter (in µm) (A) and as percent change (Delta ) from control diameter (B). Arteriolar responses to L-NNA are shown for control kidneys (open circle , n = 4) and papillectomized kidneys (triangle , n = 5). * P < 0.05 vs. basal diameter. dagger  P < 0.05 vs. response of control kidneys.

Effects of Selective nNOS and Nonselective NOS Inhibition on ACh-Induced Vasodilation

Figure 5 illustrates the effect of L-SMTC and L-NNA on the ACh-induced afferent and efferent arteriolar vasodilatory responses. ACh (10 µM) increased both afferent and efferent arteriolar diameters by 20.3 ± 1.6 and 11.6 ± 2.5%, respectively. L-SMTC (10 µM) did not alter the magnitude of the ACh-induced vasodilation of afferent or efferent arterioles. In contrast, 100 µM L-NNA completely prevented the ACh-induced vasodilation of these arterioles, consistent with previous findings (21).


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  		Fig. 5.   Effects of L-SMTC and L-NNA on afferent (solid bars, n = 6) and efferent (open bars, n = 6) arteriolar vasodilation in response to 10 µM acetylcholine (ACh) in normal kidneys. Afferent and efferent arteriolar responses are expressed as percent changes (Delta ) from control diameter. * P < 0.05 vs. 10 µM ACh alone.

Effects of Selective nNOS and Nonselective NOS Inhibition on Microvascular Responsiveness to ANG II

The studies evaluating ANG II responsiveness were performed on tissue harvested from enalaprilat-treated rats to lower the endogenous ANG II levels. Enalaprilat treatment slightly but significantly attenuated the L-SMTC dose-response relationships in both afferent and efferent arterioles. In kidneys harvested from enalaprilat-treated rats, 0.1, 1, 10, and 100 µM L-SMTC decreased afferent arteriolar diameters (21.3 ± 0.8 µm, n = 6) by 2.4 ± 0.4, 5.1 ± 0.6, 8.9 ± 1.3, and 11.6 ± 1.1%, respectively, and efferent arteriolar diameters (19.2 ± 0.6 µm, n = 6) by 2.1 ± 0.7, 5.6 ± 1.2, 8.8 ± 0.9, and 12.4 ± 1.3%, respectively. These responses are significantly smaller than those observed in nontreated control kidneys. The L-NNA dose-response relationships in afferent and efferent arterioles were also attenuated by enalaprilat treatment, consistent with previous findings (21). In response to 1, 10, 100, and 1,000 µM L-NNA, afferent arteriolar diameters (20.3 ± 0.6 µm, n = 5) decreased by 3.6 ± 0.4, 8.0 ± 0.6, 11.8 ± 0.9, and 11.3 ± 0.8%, respectively, and efferent arteriolar diameters (18.4 ± 1.1 µm, n = 4) declined by 3.8 ± 1.1, 7.6 ± 1.4, 12.0 ± 1.3, and 12.0 ± 1.2%, respectively. The magnitudes of these changes are significantly smaller than those obtained from untreated control kidneys.

Figure 6 illustrates the effects of nNOS and NOS inhibition on the responsiveness of afferent arterioles to ANG II. Afferent arteriolar diameter averaged 22.3 ± 0.6 µm under control conditions and decreased by 5.1 ± 0.4, 15.6 ± 1.1, and 32.3 ± 1.7% in response to 0.1, 1, and 10 nM ANG II, respectively. L-SMTC (10 µM) significantly reduced basal afferent arteriolar diameters by 9.3 ± 0.4% to 20.2 ± 0.5 µm but did not significantly increase ANG II responsiveness. In the presence of L-SMTC, 0.1, 1, and 10 nM ANG II decreased afferent arteriolar diameters by 6.5 ± 0.6, 17.8 ± 1.4, and 34.8 ± 1.6%, respectively. Unlike L-SMTC, however, 100 µM L-NNA reduced basal afferent arteriolar diameter by 12.6 ± 0.6% to 19.5 ± 0.5 µm and significantly enhanced afferent arteriolar responsiveness to ANG II. During superfusion with L-NNA, afferent arteriolar diameter decreased by 10.1 ± 0.8, 24.5 ± 1.0, and 46.3 ± 2.0% in response to the same ANG II concentrations, respectively.


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  		Fig. 6.   Effect of angiotensin II (ANG II) on afferent arteriolar diameter before (open circle ) and during (bullet ) addition of 10 µM L-SMTC and 100 µM L-NNA (black-triangle). Data are presented in µm (A) and as percent change (Delta ) from control diameter (B) in kidneys harvested from enalaprilat-treated rats (n = 9). * P < 0.05 vs. basal diameter. dagger  P < 0.05 vs. control response. § P < 0.05 for L-NNA vs. L-SMTC.

Efferent arteriolar responsiveness to ANG II was also assessed before and during addition of L-SMTC and L-NNA, as shown in Fig. 7. Control efferent arteriolar diameter averaged 18.3 ± 0.6 µm. Efferent arteriolar diameters decreased by 4.3 ± 0.2, 14.2 ± 0.8, and 32.3 ± 1.1% in response to 0.1, 1, and 10 nM ANG II, respectively. L-SMTC (10 µM) reduced basal efferent arteriolar diameter by 8.7 ± 0.3% to 16.7 ± 0.6 µm and significantly enhanced the ANG II responsiveness. In the presence of L-SMTC, 0.1, 1, and 10 nM ANG II decreased efferent arteriolar diameters by 8.5 ± 0.5, 23.3 ± 1.1, and 45.9 ± 1.2%, respectively. The magnitude of the ANG II-mediated vasoconstriction in the presence of L-SMTC is significantly greater than that observed under control conditions. Efferent diameter decreased by 12.1 ± 0.5% to 16.1 ± 0.6 µm with 100 µM L-NNA. Efferent arteriolar diameter decreased by 9.7 ± 0.2, 24.5 ± 0.8, and 48.4 ± 1.8% in response to the same ANG II concentrations during addition of L-NNA. The magnitude of the vasoconstriction was greater than that observed under control conditions but similar to that observed during addition of L-SMTC.


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  		Fig. 7.   Effect of ANG II on efferent arteriolar diameter before (open circle ) and during (bullet ) addition of 10 µM L-SMTC and 100 µM L-NNA (black-triangle). Data are presented in µm (A) and as percent change (Delta ) from control diameter (B) in kidneys harvested from enalaprilat-treated rats (n = 7). * P < 0.05 vs. basal diameter. dagger  P < 0.05 vs. control response. § P < 0.05 for L-NNA vs. L-SMTC.

    DISCUSSION
Top
Abstract
Introduction
Methods
Results
Discussion
References

Although it is now well recognized that there are several sources of NO within the kidney (3, 19, 28, 31), the relative contributions of NO derived from nNOS vs. NO produced by eNOS in the control of the renal microcirculation has remained unclear. Because nNOS has been localized to the macula densa cells (3, 19, 28, 31), it has been suggested that NO produced by the macula densa participates as part of the tubuloglomerular feedback mechanism that regulates glomerular hemodynamics by controlling afferent arteriolar tone (14, 26, 30, 31). The present study was focused on delineating the role of nNOS in regulating vascular responsiveness of the afferent and efferent arterioles to tubuloglomerular feedback signals and to ANG II. This was made possible by the availability of a new NOS inhibitor with greater selectivity to nNOS than eNOS (9). Furthermore, the use of the in vitro juxtamedullary nephron preparation allowed direct evaluation of vascular responsiveness to NOS blockade under conditions of maintained tubular flow to the macula densa (control); after interruption of flow to the macula densa, as a consequence of transecting the loops of Henle of the juxtamedullary nephrons by papillectomy (25); and under conditions of enhanced distal volume and sodium delivery following treatment with acetazolamide, a carbonic anhydrase inhibitor, which inhibits net tubular fluid reabsorption and thus increases distal volume and sodium delivery (16, 23).

In agreement with previous findings (11, 21), nonspecific NOS inhibition with L-NNA led to vasoconstriction of both afferent and efferent arterioles. Maximal inhibition was achieved with a L-NNA concentration of 100 µM, which also blocked the vasodilator action of 10 µM ACh. L-NNA vasoconstricted afferent and efferent arterioles to a similar extent, and this response was attenuated but not prevented after interruption of distal volume delivery by papillectomy.

L-SMTC concentrations as high as 10 µM did not interfere with the vasodilator effect of ACh, suggesting that these concentrations of L-SMTC do not inhibit eNOS activity. Nevertheless, L-SMTC also caused dose-dependent vasoconstriction of afferent and efferent arterioles. Interestingly, papillectomy completely prevented the vasoconstrictor responses to L-SMTC up to 10 µM. These findings indicate that maintained flow to the macula densa is required for NO derived from nNOS, presumably from the macula densa, to exert a vasodilator effect on the glomerular arterioles. Furthermore, in the presence of increased distal volume and sodium delivery, the L-SMTC-mediated vasoconstriction of afferent arterioles but not of efferent arterioles was enhanced. That the effects of acetazolamide on afferent arteriolar responses are due primarily to alterations in tubuloglomerular feedback-dependent signals is supported by the findings that they were also prevented by papillectomy. Therefore, the increased distal tubular flow elicited by acetazolamide may stimulate nNOS activity at the macula densa to increase NO formation and thus exert a greater vasodilatory influence on afferent arterioles. Under these conditions of increased distal volume delivery, the increased NO influence partially counteracts tubuloglomerular feedback-mediated vasoconstriction. These results are consistent with recent studies demonstrating that infusion of NOS inhibitors into tubules causes afferent arteriolar vasoconstriction (14) and an increase in the magnitude of tubuloglomerular feedback responses to increases in tubular flow (26, 27, 29, 30).

Although efferent arteriolar diameter responses to L-SMTC were not enhanced by acetazolamide treatment, papillectomy also abrogated the efferent arteriolar responses to L-SMTC. These results indicate that macula densa-derived NO exerts vasodilator actions on efferent arterioles, as well as afferent arterioles, and support the concept that tubuloglomerular feedback-mediated signals also control efferent arteriolar tone. The failure to further enhance efferent arteriolar responses to L-SMTC at high tubular flows may indicate that efferent arterioles have already responded maximally to nNOS-derived NO. As noted in Fig. 5, vasodilator responses to ACh are less in efferent than in afferent arterioles.

ANG II has been shown to enhance the vascular sensitivity of the tubuloglomerular feedback response (20). A recent microperfusion study (5) demonstrated that peritubular capillary but not intraluminal infusions of ANG II-containing solutions enhanced tubuloglomerular feedback-mediated reductions in stop-flow pressure during administration of L-NNA to peritubular capillaries. It is therefore possible that nNOS-derived NO contributes to the tubuloglomerular feedback-dependent signaling mechanism through an interaction with ANG II. Although nNOS blockade did alter the baseline afferent arteriolar diameter, there was no indication of an increased afferent arteriolar responsiveness to ANG II following treatment with L-SMTC. These results indicate that macula densa-derived NO and ANG II exert independent modulatory influences on tubuloglomerular feedback responsiveness. In contrast, the present findings indicate that nNOS-derived NO reduces efferent arteriolar responsiveness to ANG II. One explanation for this observation is suggested by the novel histological finding that nNOS is also expressed in the endothelial cells lining efferent but not afferent arterioles (3). The nNOS-derived NO may buffer the efferent arteriolar vasoconstrictor influence of ANG II. Inhibition of nNOS with L-SMTC could selectively remove this modulatory influence on efferent arteriolar reactivity and thus selectively enhance efferent but not afferent arteriolar responsiveness to ANG II. In contrast, inhibition of both nNOS and eNOS with L-NNA should eliminate the NO buffering influence derived from endothelial cells of both afferent and efferent arterioles and thus enhance the responsiveness of both microvascular segments to ANG II. This prediction is supported by the results in the current study.

It is also possible that the selective enhancement of efferent arteriolar responsiveness to ANG II during nNOS inhibition could be due to the different signal transduction pathways utilized by ANG II in afferent and efferent arterioles (6, 13). Recent studies have shown that NO inhibits Ca2+ release from sarcoplasmic reticulum in pulmonary artery smooth muscle cells (32). However, NO did not influence Ca2+ influx from extracellular fluid or repletion of intracellular Ca2+ stores in tracheal smooth muscle cells (15). Afferent arterioles utilize both the release of intracellular Ca2+ (13) and Ca2+ influx through L-type calcium channels (6), whereas efferent arterioles appear to rely almost exclusively on the mobilization of intracellular Ca2+ (13). Accordingly, NO may exert a tonic suppression of ANG II-mediated calcium mobilization and thereby modulate efferent arteriolar reactivity to ANG II to a greater extent than afferent arteriolar reactivity. Afferent arterioles, which rely on multiple signal transduction pathways to evoke ANG II-mediated vasoconstriction (6, 12, 13, 20) and which do not express nNOS (3), would be less likely to exhibit altered responsiveness to ANG II during nNOS inhibition.

Intrarenal NO activity should decrease during L-SMTC or L-NNA treatment, even if each inhibits different NOS isoforms. Nevertheless, L-SMTC predominantly enhanced efferent arteriolar responsiveness to ANG II, and L-NNA enhanced both afferent and efferent arteriolar responsiveness to ANG II (11). Because L-NNA and L-SMTC similarly influenced efferent arteriolar responsiveness to ANG II, the reduced efferent arteriolar responsiveness to ANG II was most likely due directly to the decreases in intrarenal NO levels caused by NOS inhibition. In afferent arterioles, however, L-NNA did and L-SMTC did not modulate ANG II responsiveness. Nevertheless, it was clear that L-SMTC treatment significantly vasoconstricted afferent arteriolar diameter, as under conditions of maintained or enhanced distal nephron volume delivery. These differential actions suggest that NOS blockade may influence other vasoactive paracrine systems that indirectly modulate afferent arteriolar responsiveness. A recent study demonstrated that L-NNA increased mean arterial pressure and decreased renal blood flow and these changes were attenuated by the 20-hydroxyeicosatetraenoic acid inhibitor, dibromo-dodecenyl-methylsulfimide (1). Because 20-hydroxyeicosatetraenoic acid is a potent vasoconstrictor and contributes to afferent arteriolar tone (12), the effect of L-NNA on afferent arteriolar responsiveness to ANG II might be mediated through 20-hydroxyeicosatetraenoic acid production or some other vasoactive agents released by adjoining cells in response to elevations in intracellular NO levels. Likewise, the response to L-SMTC may also be due to alterations in other macula densa vasoactive systems that are influenced by NO (10).

In conclusion, the present study revealed a novel and differential regulation of juxtamedullary afferent and efferent arterioles by nNOS. Inhibition of nNOS with L-SMTC elicited vasoconstrictor responses of afferent and efferent arteriolar diameters that were prevented following interruption of distal volume delivery by papillectomy. Acetazolamide-induced increases in distal volume delivery enhanced afferent but not efferent arteriolar responsiveness to L-SMTC. These findings indicate that distal tubular flow influences nNOS-derived NO production, which contributes to tubuloglomerular feedback-mediated control of afferent arteriolar tone by counteracting the tubuloglomerular feedback-mediated vasoconstrictor signals. The results suggest that nNOS also exerts an important influence on efferent arteriolar tone. In addition, L-SMTC enhanced efferent but not afferent arteriolar responsiveness to ANG II, suggesting a unique role for nNOS in regulating efferent arteriolar responsiveness to ANG II.

    ACKNOWLEDGEMENTS

We thank Anthony K. Cook for technical assistance.

    FOOTNOTES

This work was supported by J. Walter Libby Fellowship Grant from the American Heart Association, Lousiana Affiliate (A. Ichihara) and National Heart, Lung, and Blood Institute Grant HL-18426. E. W. Inscho is an Established Investigator of the American Heart Association.

Address for reprint requests: A. Ichihara, Dept. of Physiology, Tulane Univ. School of Medicine, 1430 Tulane Ave., New Orleans, LA 70112.

Received 8 September 1997; accepted in final form 21 November 1997.

    REFERENCES
Top
Abstract
Introduction
Methods
Results
Discussion
References

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H. Tanioka, K. Nakamura, S. Fujimura, M. Yoshida, M. Suzuki-Kusaba, H. Hisa, and S. Satoh
Facilitatory role of NO in neural norepinephrine release in the rat kidney
Am J Physiol Regulatory Integrative Comp Physiol, May 1, 2002; 282(5): R1436 - R1442.
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