(Hypertension. 1999;33:462-466.)
© 1999 American Heart Association, Inc.
Scientific Contributions |
Neuronal Nitric Oxide Synthase-Dependent Afferent Arteriolar Function in Angiotensin II-Induced Hypertension
From the Department of Physiology, Tulane University School of Medicine, New Orleans, La.
Correspondence to L. Gabriel Navar, PhD, Department of Physiology, Tulane University School of Medicine, 1430 Tulane Ave, New Orleans, LA 70112-2699. E-mail navar{at}mailhost.tcs.tulane.edu
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Abstract |
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Abstract—This study was designed to determine the influence of neuronal nitric oxide synthase (nNOS) in tubular flow-dependent regulation of afferent arteriolar diameter in hypertensive Sprague-Dawley rats that received 60 ng/min angiotensin II (Ang II) subcutaneously for 13 days. Systolic blood pressure of control and Ang II–infused rats averaged 122±2 (n=23) and 194±2 mm Hg (n=24). Afferent arteriolar responses to the nNOS inhibitor S-methyl-L-thiocitrulline (L-SMTC; 0.1 to 10 µmol/L) and the nonselective NOS inhibitor N
-nitro-L-arginine (L-NNA; 1
to 100 µmol/L) were assessed in vitro using the blood-perfused
juxtamedullary nephron preparation. At a perfusion pressure of 160
mm Hg, afferent arteriolar diameters from control and Ang II–infused
rats averaged 18.7±1.1 µm (n=8) and 18.1±1.1 µm (n=9),
respectively, and decreased by 19.9±1.5% and 11.8±1.1%,
respectively, in response to 10 µmol/L L-SMTC. The
L-SMTC–induced afferent arteriolar constriction was significantly
greater in control than in Ang II–infused rats. In contrast, 100
µmol/L L-NNA constricted afferent arterioles similarly in both
control (n=8) and Ang II–infused (n=7) rats. After transection of the
loops of Henle to interrupt flow to the macula densa, the
vasoconstrictor responses to L-SMTC but not to L-NNA were reversed.
Increasing distal volume delivery by addition of 10 mmol/L
acetazolamide to the blood perfusate significantly
enhanced the afferent arteriolar constrictor responses to 10
µmol/L L-SMTC (34.5±4.8%, n=7) in normotensive rats. In contrast,
in Ang II–infused rats, acetazolamide treatment did not
enhance the responses to L-SMTC (n=8). These results indicate that
chronic Ang II infusion reduces the ability of nNOS-derived nitric
oxide to counteract the afferent arteriolar response to increased
distal tubular flow.
Key Words: rats • arterioles • macula densa • acetazolamide • papillectomy
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Introduction |
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Chronic infusion of subpressor doses of angiotensin II (Ang II) produces a hypertension that mimics 2-kidney, 1 clip (2K1C) Goldblatt hypertension.1 In this model of hypertension, renal Ang II levels are elevated, and afferent arteriolar responsiveness to Ang II is enhanced.2 However, renal blood flow and glomerular filtration rate are either not reduced or only slightly diminished,3 4 5 6 partially because nitric oxide (NO) production is maintained at the level of whole kidney6 7 and in afferent arterioles8 in this model of hypertension and counteracts the enhanced afferent arteriolar reactivity to Ang II.
NO is constitutively generated from endothelial NO synthase and neuronal NO synthase (nNOS). Recent studies have indicated that nNOS, which has been localized to macula densa cells, also contributes to the regulation of preglomerular and postglomerular microcirculation.9 10 In particular, when the activity of the tubuloglomerular feedback (TGF) mechanism is increased, the macula densa nNOS-derived NO influence increases to partially counteract the TGF-mediated preglomerular vasoconstriction.10 11 Recent immunohistochemical studies have demonstrated that NADPH diaphorase staining, which reflects nNOS activity, decreased in macula densa cells in the nonclipped kidneys of 2K1C Goldblatt hypertensive rats.12 In addition, macula densa NADPH diaphorase staining and renal nNOS mRNA levels have been shown to be increased in angiotensinogen gene knockout mice13 and angiotensin type 1A receptor gene knockout mice14 compared with wild-type mice. These findings suggest that chronic elevations in Ang II levels and/or perfusion pressure can downregulate macula densa nNOS activity.
We hypothesized that nNOS activity may be selectively reduced in Ang II–infused hypertensive rats, leading to reduced influences on afferent arteriolar tone. To test this hypothesis, we used the in vitro blood-perfused juxtamedullary nephron preparation15 16 ; we determined the effects of nNOS inhibition on afferent arteriolar diameters under normal conditions and during increased distal nephron volume and sodium delivery, which was achieved by inhibition of proximal tubular reabsorption after addition of acetazolamide to the blood perfusate.10
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Methods |
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Preparation of Animals
Male Sprague-Dawley rats (Charles River Laboratories, Wilmington, Mass) were housed in wire cages and maintained in a temperature-controlled room that was regulated on a 12/12-hour light/dark cycle. Rats had free access to water and standard rat chow (Ralston-Purina). All experimental protocols were approved by the Tulane University Animal Care and Use Committee. Rats (175 to 200 g body weight) were anesthetized with sodium pentobarbital (50 mg/kg IP). An osmotic minipump (model 2002, Alza Corp) was implanted subcutaneously at the dorsum of the neck. Ang II–infused rats received Ang II (Novabiochem) at a rate of 60 ng/min for 13 days. Control rats were sham-operated. Systolic arterial pressure was measured every 3 days in conscious rats by tail-cuff plethysmography (model 52-0338, Harvard Apparatus).
Assessment of Afferent Arteriolar Responsiveness
Afferent arteriolar responsiveness was assessed on day 13 after
minipump implantation using the in vitro blood-perfused juxtamedullary
nephron preparation combined with videomicroscopy, as previously
described.2 8 10 15 16 17 Briefly, each experiment used 2
rats from the same treatment group, with 1 rat serving as the blood
donor and the second rat as the kidney donor. Rats were
anesthetized with sodium pentobarbital (50 mg/kg IP). Donor
blood was collected into a heparinized (500 U) syringe and
centrifuged to separate the plasma and cellular fractions.
Plasma oncotic pressure was adjusted to 18 mm Hg by the addition
of bovine serum albumin (Sigma Chemical Co). After processing
of the plasma through filters, erythrocytes were added to achieve a
hematocrit level of 33%. The reconstituted blood was stirred
continuously in a closed reservoir that was pressurized with a 95%
O2-5% CO2 gas mixture.
The right renal artery of the kidney donor was cannulated and perfused with Tyrode's solution (pH 7.4) containing 5.1% bovine serum albumin and a mixture of L-amino acids (Sigma).16 The kidney was excised and prepared as previously described2 8 10 15 16 17 so that the vasculature of the juxtamedullary nephrons could be visualized directly. The arterial supply of the exposed microvasculature was isolated by ligating the large branches of renal artery with fine suture (nylon black monofilament, 10-0; Vanguard Surgical System).
After the dissection was completed, the Tyrode's perfusate was replaced with the reconstituted blood. Renal perfusion pressure (RPP) was monitored by a pressure cannula centered in the perfusion cannula and regulated by adjusting the rate of gas inflow into the blood reservoir. RPP was set at 100 mm Hg for the initial 5 minutes and then raised and maintained at 160 mm Hg during the experimental protocols. The perfusion chamber was warmed, and the inner cortical surface was continuously superfused with warmed (37°C) Tyrode's solution containing 1% bovine serum albumin.
The tissue was transilluminated on the fixed stage of a Leitz Laborlux-12 microscope. Video images of the microvessels were obtained with a Newvicon camera (model NC-67 M, Dage-MTI) and recorded on videotape for later analysis (videocassette recorder HR-VP618U, JVC). Afferent arteriolar inside diameters were measured at 12-second intervals using a calibrated digital image-shearing monitor (Instrumentation for Physiology and Medicine) that yielded diameter measurements reproducible within 0.5 µm. Afferent arteriolar diameters were measured at sites within 100 µm upstream from the glomerulus. A minimum 10-minute equilibration period was allowed before the initiation of each experimental procedure. The average diameter during the final 2 minutes of each 5-minute treatment period was used for statistical analysis of steady-state responses.
Afferent Arteriolar Response to nNOS Inhibition
To assess the degree of nNOS influence on afferent arterioles of
control normotensive rats and Ang II–infused hypertensive rats,
afferent arteriolar diameters were measured under control conditions
and during exposure to increasing concentrations (0.1, 1, and 10
µmol/L) of the nNOS inhibitor
S-methyl-L-thiocitrulline
(L-SMTC; Alexis Co). Using another series of control
normotensive rats and Ang II–infused hypertensive rats, we also
examined the nNOS activity in afferent arterioles during increased
distal nephron volume and sodium delivery, which was achieved by
inhibition of proximal tubular reabsorption after
acetazolamide treatment. After control measurements were
made to determine baseline diameter, 10 mmol/L
acetazolamide (Sigma) was added to the blood
perfusate. Our previous study confirmed that this dose of
acetazolamide significantly decreases afferent arteriolar
diameters through a tubular flow-dependent
mechanism.10 After a 5-minute stabilization period,
afferent arteriolar responsiveness to the same concentrations of L-SMTC
was determined.
Because juxtamedullary nephrons have long loops of Henle reaching into the papilla,15 acute papillectomy interrupts the flow from proximal tubules to distal nephron segments.18 To confirm that the effects of L-SMTC and acetazolamide depend on intact distal tubular flow, at the end of protocols the papilla was transected near the corticomedullary junction, and afferent arteriolar diameters were measured.
Afferent Arteriolar Response to NOS Inhibition
To determine the total NOS influence in afferent arterioles of
control normotensive rats and Ang II–infused hypertensive rats,
afferent arteriolar diameters were assessed under control conditions
and during exposure to increasing concentrations (1, 10, and 100
µmol/L) of the nonselective NOS inhibitor
N-nitro-L-arginine
(L-NNA; Aldrich Chemical Co). To examine whether the effect of
L-NNA depends on intact distal tubular flow, acute papillectomy was
also performed at the end of these protocols.
Statistical Analysis
One-way ANOVA for repeated measures combined with Newman-Keuls
post hoc test was used for within-group analyses. Between-group
analyses were performed with a 2-way ANOVA for repeated
measures combined with Newman-Keuls post hoc test. A value of
P<0.05 was considered significant. Data are
presented as mean±SEM.
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Results |
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On day 13, conscious systolic arterial pressures averaged 194±2 mm Hg in chronically Ang II–infused rats (n=24). This value was significantly greater than that determined in control rats (122±2 mm Hg, n=23). In control and Ang II–infused rats, afferent arteriolar diameters at an RPP of 100 mm Hg averaged 21.8±0.7 (n=23) and 21.6±0.9 (n=24), respectively, and decreased by 14.6±0.9% and 13.1±1.0% in response to elevating RPP to 160 mm Hg.
Afferent Arteriolar Response to nNOS Inhibition
Figure 1
describes afferent
arteriolar responsiveness to nNOS inhibition with L-SMTC at an RPP of
160 mm Hg. In control rats, basal afferent arteriolar diameter
averaged 18.7±1.1 µm (n=8) and significantly decreased by
8.4±1.2%, 12.9±1.8%, and 19.9±1.5% in response to 0.1, 1, and
10 µmol/L L-SMTC, respectively. In Ang II–infused hypertensive
rats, basal afferent arteriolar diameter averaged 18.1±1.1 µm
(n=9), and the same concentrations of L-SMTC significantly decreased
afferent arteriolar diameters by 3.4±0.9%, 6.0±0.9%, and
11.8±1.1%, respectively. The decrease in diameter observed in
hypertensive rats was significantly lower than that observed in control
rats. In control and Ang II–infused rats, papillectomy reversed
afferent arteriolar constrictor responses to 10 µmol/L L-SMTC,
and afferent arteriolar diameters after papillectomy averaged 19.8±1.3
and 19.0±1.0 µm, respectively. The inhibition of
L-SMTC–induced afferent arteriolar constriction by papillectomy is
consistent with our previous finding that L-SMTC at a level of
up to 10 µmol/L does not affect afferent arteriolar diameters in
papillectomized kidneys.10
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, n=8) and Ang II–infused hypertensive rats (
,
n=9). Papillectomy (PX) was performed at the end of the experiment.
Data are expressed in micrometers (A) and percent changes
(B). Experiments were performed at an RPP of 160 mm Hg.
*P<0.05 vs control diameter; 
P<0.05
vs control rats.
Afferent Arteriolar Response to nNOS Inhibition During Increased
Distal Nephron Volume Delivery
As shown in Figure 2, afferent
arteriolar responsiveness to L-SMTC was also assessed at an RPP of
160 mm Hg when 10 mmol/L acetazolamide was added
to the blood perfusate to increase distal nephron volume
delivery. Acetazolamide treatment decreased afferent
arteriolar diameters of control and Ang II–infused rats similarly by
14.0±0.9% and 11.3±2.1%, respectively, at an RPP of 160
mm Hg.
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In the presence of acetazolamide, afferent arteriolar
diameters of control rats averaged 15.2±0.7
µm (n=7) and significantly decreased by
8.7±0.5%, 16.8±2.6%, and 34.5±4.8% in response to 0.1, 1, and
10 µmol/L L-SMTC, respectively. The decrease in diameter was
significantly greater than that observed in the absence of
acetazolamide (Figure 1
). In contrast, in Ang
II–infused hypertensive rats, afferent arteriolar diameters of
acetazolamide-treated kidneys averaged 18.5±1.8 µm
(n=8). Superfusion with 0.1, 1, and 10 µmol/L L-SMTC
significantly decreased afferent arteriolar diameters by 3.1±0.6%,
5.4±0.8%, and 9.7±0.8%, respectively. The L-SMTC–induced decrease
in diameter in Ang II–infused rats was similar to that observed in the
absence of acetazolamide (Figure 1) and was
significantly lower than that determined in
acetazolamide-treated kidneys of control rats. Thus,
acetazolamide treatment significantly enhanced afferent
arteriolar responsiveness to L-SMTC in control rats but did not
influence the L-SMTC response in afferent arterioles of Ang
II–infused hypertensive rats. In acetazolamide-treated
kidneys of control rats and Ang II–infused rats, papillectomy reversed
the afferent arteriolar vasoconstriction caused by 10 µmol/L
L-SMTC and increased afferent arteriolar diameters to 17.3±0.7 and
20.8±1.6 µm, respectively. These values were similar to
afferent arteriolar diameters before addition of
acetazolamide. Thus, consistent with our previous
findings,10 papillectomy significantly prevented the
effect of acetazolamide on afferent arterioles.
Afferent Arteriolar Response to NOS Inhibition
Figure 3 demonstrates afferent
arteriolar responsiveness to NOS inhibition with L-NNA at an RPP of
160 mm Hg. In control rats, basal afferent arteriolar diameter
averaged 19.4±1.4 µm (n=8) and significantly decreased by
6.9±0.6%, 11.1±0.9%, and 16.6±1.3% in response to 1, 10, and
100 µmol/L L-NNA, respectively. In Ang II–infused hypertensive
rats, basal afferent arteriolar diameter averaged 18.1±1.5 µm
(n=7). Superfusion with 1, 10, and 100 µmol/L L-NNA
significantly decreased afferent arteriolar diameters by 6.0±1.6%,
12.5±1.6%, and 17.5±1.3%, respectively, and the decrease was
similar to that observed in control rats. Papillectomy did not
significantly influence the afferent arteriolar constrictor response to
100 µmol/L L-NNA in either control rats or Ang II–infused
rats.
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Discussion |
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Renal constitutive NOS activity has been reported to be maintained or elevated in various models of hypertension including young and adult spontaneously hypertensive rats (SHR),19 20 21 stroke-prone SHR,22 early hypertensive 1-kidney, 1 clip rats,23 and chronically Ang II–infused hypertensive rats.6 7 8 Nevertheless, a recent study demonstrated that nNOS activity and protein levels decrease in the macula densa cells of the nonclipped kidney of 2K1C rats.12 In normotensive rats, nNOS plays an important role in the counteracting modulation of TGF-mediated afferent arteriolar constriction,9 10 and thus it would be possible that a decreased nNOS activity partially accounts for the enhanced TGF activity observed in Ang II–dependent hypertension.24 The present experiments were performed to determine the contribution of nNOS activity to the tubular flow-dependent regulation of afferent arteriolar tone.
The present study evaluated the contributions of total NOS and nNOS activity to afferent arteriolar tone. Afferent arteriolar responses to L-NNA at an RPP of 160 mm Hg were similar in normotensive control and Ang II–infused hypertensive rats. We previously reported that L-NNA responses at an RPP of 100 mm Hg were greater in Ang II–infused hypertensive rats than in normotensive control rats,8 suggesting an overall increase in NOS contribution to afferent arteriolar tone. In contrast, the decrease in afferent arteriolar diameter in response to L-SMTC was significantly less in Ang II–infused hypertensive rats compared with that in normotensive control rats. These results suggest that nNOS activity is inappropriately reduced in Ang II–infused hypertensive rats, while total NOS activity is similar or increased in Ang II–infused hypertensive rats compared with that in normotensive rats.
We previously demonstrated that L-SMTC did not influence afferent arteriolar diameter of papillectomized kidneys in which distal tubular flow past the macula densa was interrupted,10 suggesting that renal nNOS activity depends on intact distal tubular flow. The present results are consistent with the previous report in that papillectomy prevented the L-SMTC–induced afferent arteriolar constriction. However, the afferent arteriolar constrictor responses to L-NNA were not influenced by papillectomy. This result indicates that L-NNA–induced afferent arteriolar constriction does not depend on distal tubular flow past the macula densa segment and thus may be distinguished from the L-SMTC actions on afferent arterioles.
In normotensive control rats, nNOS influence on afferent arteriolar diameter was enhanced after procedures that increase distal nephron volume and sodium delivery, such as during inhibition of proximal tubular reabsorption rate with acetazolamide. Because papillectomy prevented the acetazolamide effect, the possibility that nonspecific effects of acetazolamide other than tubular flow-dependent effects might influence afferent arteriolar diameters was eliminated. The acetazolamide-induced enhancement of the afferent arteriolar response to L-SMTC in normotensive rats at an RPP of 160 mm Hg is similar to our previous results in experiments performed at an RPP of 100 mm Hg.10 In contrast, acetazolamide-induced increases in distal nephron delivery did not influence the nNOS contribution to afferent arteriolar diameter in Ang II–infused hypertensive rats. These results indicate that the ability of nNOS to counteract the afferent arteriolar constriction in response to increased volume and sodium chloride delivery past the macula densa is impaired in Ang II–infused hypertensive rats. This may be a physiological mechanism to allow maximum TGF sensitivity under sodium-depleted conditions, which would be the major stimulus activating the renin-angiotensin system.
Previous studies have shown that renal nNOS activity is regulated by changes in the renin-angiotensin system and blood pressure. Macula densa NADPH diaphorase staining, an indicator of nNOS activity, decreased in the nonclipped kidney of 2K1C Goldblatt hypertensive rats.12 Likewise, macula densa NADPH diaphorase staining and renal nNOS mRNA levels were elevated in angiotensinogen gene13 and angiotensin type 1A receptor gene knockout mice14 compared with levels in wild-type mice. In addition, the intensity of nNOS immunostaining in the glomeruli has been reported to decrease in hypertensive rats treated with deoxycorticosterone acetate salt that have low plasma levels of renin and Ang II.25 Therefore, Ang II and/or RPP play important roles in the regulation of the macula densa nNOS activity. The diminished nNOS activity after increased distal nephron delivery observed in Ang II–infused hypertensive rats may be the result of a decreased nNOS mRNA, protein, and/or enzyme activity. However, a recent study has shown that the number of nNOS immunostaining-positive glomeruli is increased in hypertensive rats infused with Ang II (40 ng/min, 14 days).25 One possible explanation for these contradictory findings could be that the enzyme activity, but not the protein level, of the macula densa nNOS may be specifically decreased in Ang II–infused hypertensive rats. Alternatively, afferent arterioles of Ang II–infused hypertensive rats may have a decreased sensitivity to NO derived from the macula densa nNOS compared with normotensive control rats.
The diminished contribution of nNOS in counteracting TGF-mediated afferent arteriolar constriction in Ang II–infused hypertensive rats could also be due to alterations in the signaling components of the macula densa cells. The macula densa senses distal sodium chloride or solute concentration and responds by releasing vasoconstrictor TGF mediators to the afferent arteriole. This feedback mechanism is thought to depend on cytosolic Ca2+,26 and intracellular Ca2+ is also required for activation of constitutive NOS enzymes.27 In Ang II–infused hypertensive rats, increased renal Ang II levels1 2 may elevate cytosolic Ca2+ concentration. Thus, the macula densa cells of Ang II–infused hypertensive rats could be less sensitive to further changes in intracellular Ca2+ caused by increased volume and sodium chloride delivery.
The delivery of the NO substrate L-arginine to macula densa cells may also influence the amount of NO generated by nNOS. In salt-restricted rats, decreased NO generation at the macula densa may result from decreased distal tubular L-arginine delivery and cellular uptake.28 This report suggests that tubular supply of a NO substrate is one of the decisive factors in the ability of the macula densa nNOS to generate NO. Therefore, distal tubular L-arginine delivery and cellular uptake may decrease in Ang II–infused hypertensive rats, although this issue was not assessed in the present study.
The impaired ability of nNOS to counteract the afferent arteriolar response to increased distal tubular flow in Ang II–infused hypertensive rats could also be secondary to altered cyclooxygenase-2 (COX-2) levels at the macula densa. We recently demonstrated that during increased distal nephron volume and sodium delivery, increased levels of nNOS-derived NO stimulate COX-2, which is constitutively present in the macula densa segment of rat kidney29 and generates vasodilatory COX-2 products.17 Therefore, an impaired COX-2–mediated afferent arteriolar vasodilatory mechanism may be involved in the diminished responsiveness to L-SMTC observed in Ang II–infused hypertensive rats. In support of this concept, studies have shown that COX-2 mRNA levels are decreased in the nonclipped kidneys of 2K1C hypertensive rats30 and that conversion of prostaglandin H2 to prostaglandin I2 is impaired in aortic rings harvested from Ang II–infused hypertensive rats.31
In conclusion, afferent arteriolar constrictor responses to L-SMTC were decreased in Ang II–infused hypertensive rats compared with those in normotensive control rats, and the hypertensive rats exhibited an impaired ability to increase nNOS activity in response to acetazolamide treatment. This was specific to nNOS-mediated actions because afferent arteriolar constrictor responses to L-NNA were similar in normotensive control and Ang II–infused hypertensive rats, suggesting that total NOS activity is maintained in kidneys of this model of hypertension. These results indicate that chronic elevations in renal Ang II levels and/or blood pressure selectively reduce the ability of the macula densa nNOS activity to counteract TGF-mediated afferent arteriolar constriction.
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Acknowledgments |
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This study was supported by a J. Walter Libby Fellowship Grant from the American Heart Association, Louisiana Affiliate (Dr Ichihara) and grant HL-26371 from the National Institutes of Health. The authors thank Anthony K. Cook and Paul C. Deichmann for technical assistance.
Received September 16, 1998; first decision October 12, 1998; accepted October 22, 1998.
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 A. Ichihara, M. Hayashi, Y. Koura, Y. Tada, T. Sugaya, N. Hirota, and T. Saruta Blunted Tubuloglomerular Feedback by Absence of Angiotensin Type 1A Receptor Involves Neuronal NOS Hypertension, December 1, 2002; 40(6): 934 - 939. [Abstract] [Full Text] [PDF]
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 M. FRANCO, E. TAPIA, J. SANTAMARIA, I. ZAFRA, R. GARCIA-TORRES, K. L. GORDON, H. PONS, B. RODRIGUEZ-ITURBE, R. J. JOHNSON, and J. HERRERA-ACOSTA Renal Cortical Vasoconstriction Contributes to Development of Salt-Sensitive Hypertension after Angiotensin II Exposure J. Am. Soc. Nephrol., November 1, 2001; 12(11): 2263 - 2271. [Abstract] [Full Text] [PDF]
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L. Cervenka, H. J. Kramer, J. Maly, and J. Heller Role of nNOS in Regulation of Renal Function in Angiotensin II-Induced Hypertension Hypertension, August 1, 2001; 38(2): 280 - 285. [Abstract] [Full Text] [PDF]
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A. Ichihara, M. Hayashi, N. Hirota, and T. Saruta Superoxide Inhibits Neuronal Nitric Oxide Synthase Influences on Afferent Arterioles in Spontaneously Hypertensive Rats Hypertension, February 1, 2001; 37(2): 630 - 634. [Abstract] [Full Text] [PDF]
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R. Komers, J. N. Lindsley, T. T. Oyama, K. M. Allison, and S. Anderson Role of neuronal nitric oxide synthase (NOS1) in the pathogenesis of renal hemodynamic changes in diabetes Am J Physiol Renal Physiol, September 1, 2000; 279(3): F573 - F583. [Abstract] [Full Text] [PDF]
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S. Y. Chin, K. N. Pandey, S.-J. Shi, H. Kobori, C. Moreno, and L. G. Navar Increased activity and expression of Ca2+-dependent NOS in renal cortex of ANG II-infused hypertensive rats Am J Physiol Renal Physiol, November 1, 1999; 277(5): F797 - F804. [Abstract] [Full Text] [PDF]
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A. Ichihara, J. D. Imig, and L. G. Navar Cyclooxygenase-2 Modulates Afferent Arteriolar Responses to Increases in Pressure Hypertension, October 1, 1999; 34(4): 843 - 847. [Abstract] [Full Text] [PDF]
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