(Hypertension. 1996;27:613-618.)
© 1996 American Heart Association, Inc.
Articles |
Role of Renal Nerves in Mediating the Hypertensive Effects of Nitric Oxide Synthesis Inhibition
From the Department of Physiology and Biophysics, the University of Mississippi Medical Center, Jackson.
Correspondence to Joey P. Granger, PhD, Department of Physiology and Biophysics, University of Mississippi Medical Center, 2500 North State St, Jackson, MS 39216-4505. E-mail jpg@fiona.umsmed.edu.
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Abstract |
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Abstract Recent studies suggest that enhanced renal sympathetic nervous activity plays an important role in mediating the renal hemodynamic and electrolyte excretion changes associated with acute inhibition of NO synthesis. The purpose of this study was to determine the importance of renal nerves in mediating the long-term hypertensive and renal actions of NO synthesis blockade. To achieve this goal, we infused NG-nitro-L-arginine methyl ester (L-NAME) at a rate of 25 µg/kg per minute for 2 weeks in control dogs and in bilaterally renal-denervated dogs. NO synthesis blockade in control dogs increased arterial pressure by 18%, from 94±3 to 111±4 mm Hg, and decreased heart rate from 74±4 to 57±4 beats per minute (bpm). L-NAME also decreased renal plasma flow from 195±18 to 166±18 mL/min while having no effect on glomerular filtration rate (67±7 versus 63±6 mL/min). In the renal-denervated dogs, inhibition of NO synthesis increased arterial pressure by 14%, from 92±4 to 105±5 mm Hg, and decreased heart rate from 80±4 to 65±5 bpm. Renal plasma flow in this group decreased from 195±20 to 165±20 mL/min, whereas glomerular filtration rate remained unchanged (66±6 versus 64±6 mL/min). In addition, renal excretion of sodium and water in response to L-NAME was similar in each group. The results of this study indicate that the long-term hypertensive and renal effects of NO synthesis inhibition in the dog are not dependent on activation of the renal sympathetic nervous system.
Key Words: endothelium • renal hemodynamics • kidney • nitric oxide • dog
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Introduction |
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TopAbstractIntroductionMethods Results Discussion References |
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Nitric oxide (NO) is synthesized from L-arginine by a family of enzymes called NO synthases.1 2 These enzymes are present in various cells of the body, such as endothelial, vascular smooth muscle, renal tubular, and neuronal cells.1 2 3 4 5 6 7 8 NO has been proposed to play an important role in a variety of physiological and pathophysiological cardiovascular processes.1 2 3 We and others have previously reported that long-term administration of NO synthesis inhibitors in the dog produces a sustained elevation in arterial pressure.9 10 11 12 Several lines of evidence indicate that the chronic hypertension induced by NO synthesis inhibition occurs as a result of a reduction in the ability of the kidneys to excrete sodium and water.9 10 11 12 13 Long-term administration of arginine analogues such as NG-nitro-L-arginine methyl ester (L-NAME) decreases renal plasma flow (RPF), increases filtration fraction and plasma renin activity, and causes a hypertensive shift in the pressure-natriuresis relationship.9 10 11 12 13 Although various direct mechanisms such as increased basal renal vascular resistance or renal tubular reabsorption and indirect mechanisms such as enhanced renal sympathetic nervous activity and renin release have been proposed to be involved, the quantitative importance of each of these factors in mediating the reduction in renal excretory function and hypertension in response to long-term NO synthesis inhibition is unclear.
The existence of NO synthase in specific areas of the brain such as the nucleus tractus solitarii and rostral ventrolateral medulla has led to the hypothesis that NO may produce a tonic restraint on sympathetic outflow to various organs of the body, including the kidney.14 15 Results from experiments in the rat showing that acute NO synthesis inhibition enhances renal sympathetic nerve activity despite large increases in arterial pressure support this concept.16 Since activation of the renal sympathetic nerves is known to reduce renal excretory function and produce hypertension, it is possible that the chronic renal and hypertensive effects of long-term NO synthesis inhibition may be mediated in part by the renal nerves. Whether such a mechanism plays a role in mediating the renal and hypertensive effects of L-NAME described previously in the dog is uncertain, since recent findings indicate that the effect of NO synthesis inhibition on sympathetic outflow may be species dependent.12 17 Therefore, the purpose of this study was to determine the importance of the renal nerves in mediating the long-term renal and hypertensive effects of chronic inhibition of NO synthesis in the dog. To achieve this goal, we examined the renal hemodynamic, electrolyte excretion, and arterial pressure responses to L-NAME over a 2-week period in normal dogs and in bilaterally renal-denervated dogs.
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Methods |
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TopAbstractIntroductionMethods Results Discussion References |
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This study was conducted in 12 mongrel dogs that were conditioned before the study. Surgical procedures were performed under pentobarbital anesthesia (30 mg/kg IV) and with aseptic techniques. The experimental procedures were performed according to the guidelines of the National Institutes of Health and in conformance with the Animal Welfare Act. The experimental protocols were approved by the Institutional Animal Care and Use Committee of the University of Mississippi Medical Center.
All animals underwent surgery for implantation of chronic vascular catheters in both femoral arteries and veins. The catheters were tunneled subcutaneously and exteriorized into the upper back for easy sampling and infusions and to allow continuous monitoring of arterial pressure. In one group of dogs, renal denervation of both right and left kidneys was performed as previously described.18 19 Briefly, flank incisions were made on both sides and the renal vessels were exposed, stripped of all the visible renal nerves, and subsequently painted with 10% phenol in absolute ethanol for approximately 20 minutes. This procedure markedly depleted the renal tissue norepinephrine to less than 5% in both kidneys.
After at least 1 week of recovery from surgery, all dogs were housed in individual metabolic cages in an air-conditioned room with an adjusted temperature and humidity and a 12-hour light/dark cycle. Isotonic saline was continuously infused with the use of a roller pump (Wiz Pumps) that delivered a fixed amount of saline at a rate of approximately 450 mL/d. Intravenous lines were mounted with disposable filters (0.22 µm, Cathivex, Millipore Corp) to prevent contaminants, microorganisms, and air bubbles from entering the infusion lines. These filters were changed frequently throughout the study period. Arterial pressure was recorded with a pressure transducer that was mounted at the level of the heart. Transducer cables and intravenous lines were protected by a flexible vacuum hose attached to a harness that was covered by a jacket worn by the dog. Blood pressure signals were continuously recorded and the analogue signals were sent to a digital computer to be analyzed. The computer was adjusted to take samples each minute and calculate the average mean arterial pressure and heart rate during the period from 2 PM to 8 AM. Daily care of the dogs was performed between 8 AM and 2 PM.
During the entire study period, dogs were placed on a sodium-deficient diet (H/D, Hills Pet Products) that provided approximately 6 to 7 mmol of sodium and 65 mmol of potassium. In addition, dogs were supplemented with 10 mL of a multivitamin preparation (VAL syrup, Dodge Labs) each day. Sodium intake was fixed at approximately 75 to 80 mmol/d including the saline infused and sodium provided in the food.
Experimental Protocol
A period of 1 week was allowed to
achieve stable
hemodynamic measurements and a state of sodium balance.
After obtaining a 1-week period of stable control measurements, L-NAME
was infused at a rate of 25 µg/kg per minute for 14 days in control
dogs and in bilaterally renal-denervated dogs.
Glomerular filtration rate (GFR) and RPF were determined
from the clearances of 125I-iothalamate (Glofil,
Isotex Diagnostics) and 131I-iodohippurate
(Hippuran, Syntex), respectively, with the use of the single injection
technique as previously described.20 Renal
hemodynamics were determined on days 3 and 7 of the
vehicle infusion period as well as during the 1st, 8th, and 14th days
of L-NAME infusion.
Analysis Procedures
Urinary and serum sodium and potassium
were determined by flame
photometry (model IL-943, Instrumentation Laboratory). Concentrations
of 125I-iothalamate and
131I-iodohippurate in plasma were determined by a
gamma counter (model 1185, Searle). At the end of the experiment, the
dogs were euthanatized with intravenous potassium chloride
under pentobarbital anesthesia, and the kidneys were
examined for any gross pathological changes. The kidneys were then
immediately removed, homogenized with 0.1M perchloric acid,
and centrifuged; then the supernatant was stored at -70°C
until assayed. Renal tissue norepinephrine concentration
was determined by high-performance liquid
chromatography with electrochemical detection using the
method of Moyer.21
Statistics
Data are expressed as mean±SEM. Comparisons
of control data
with those from the period after L-NAME were analyzed using
one-way ANOVA for repeated measures; subsequently, Dunnett's
t test for simultaneous comparisons within
groups and the Bonferroni t test for
nonsimultaneous comparisons between groups were used. A
value of P<.05 was accepted as statistically
significant.
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Results |
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TopAbstractIntroductionMethods Results Discussion References |
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Intravenous infusion of L-NAME for 14 days increased mean arterial pressure and decreased heart rate in the control dogs and in the renal-denervated dogs (Fig 1
).
Mean arterial pressure in the control dogs increased from
94±3 to 111±4 mm Hg on day 1 of L-NAME infusion and averaged
111±6
and 111±4 mm Hg for the first and second weeks of the L-NAME infusion
period, respectively. Mean arterial pressure in the
renal-denervated dogs averaged 92±4 mm Hg during the control
period and increased to 111±8 mm Hg on day 1 of L-NAME infusion and
averaged 105±5 and 104±5 mm Hg during the first and second weeks
of
the L-NAME infusion period, respectively. The increases in mean
arterial pressure in response to L-NAME were not
significantly different between the control (18%) and
renal-denervated (14%) groups of dogs. Heart rate in the control
dogs decreased from 74±4 to 58±5 bpm on day 1 of L-NAME infusion
and
averaged 57±4 and 68±6 bpm during the first and second weeks of
the
L-NAME infusion period, respectively. Heart rate in the
renal-denervated dogs averaged 80±4 bpm during the control period,
decreased to 58±4 bpm on day 1 of L-NAME infusion, and averaged
65±5
and 72±6 bpm during the first and second weeks of the L-NAME infusion
period, respectively. The decreases in heart rate between the control
and renal-denervated groups of dogs were also not significantly
different.
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Fig 2 illustrates that intravenous infusion of
L-NAME for 14 days decreased RPF and had no effect on GFR in the
control and renal-denervated dogs. RPF in the control dogs
decreased from 195±18 to 170±10 mL/min on day 1 of L-NAME
infusion
and averaged 166±18 and 168±20 mL/min on days 8 and 14 of the
L-NAME
infusion period, respectively. RPF in the renal-denervated dogs
averaged 195±20 mL/min, decreased to 157±19 mL/min on day 1 of
L-NAME
infusion, and averaged 165±20 and 163±20 mL/min on days 8 and 14
of
the L-NAME infusion period, respectively. The decreases in RPF in
response to L-NAME were not significantly different between the control
and renal-denervated dog groups.
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GFR in the control dogs averaged 67±7 mL/min during the 7 days of saline infusion and 64±6, 63±6, and 61±6 mL/min on days 1, 8, and 14 of the L-NAME infusion period, respectively. GFR in the renal-denervated dogs averaged 66±6 mL/min during the 7 days of saline infusion and 57±6, 64±6, and 61±7 mL/min on days 1, 8, and 14 of the L-NAME infusion period, respectively.
L-NAME increased renal vascular resistance and filtration fraction in
the control and renal-denervated dogs (Fig 3). Renal
vascular resistance in the control dogs increased from 0.34±0.05 to
0.48±0.04 mm Hg/mL per minute on day 1 of L-NAME infusion and averaged
0.48±0.05 and 0.42±0.05 mm Hg/mL per minute on days 8 and 14 of
the
L-NAME infusion period, respectively. Renal vascular resistance in the
denervated dogs averaged 0.36±0.05 mm Hg/mL per minute during the
saline infusion period, increased to 0.47±0.04 mm Hg/mL per minute on
day 1 of L-NAME infusion, and averaged 0.42±0.04 and 0.41±0.04
mm
Hg/mL per minute on days 8 and 14 of the L-NAME infusion period,
respectively. Filtration fraction in the control dogs averaged
0.34±0.01 during the 7 days of saline infusion and 0.38±0.04,
0.38±0.02, and 0.36±0.01 on days 1, 8, and 14 of the L-NAME
infusion
period, respectively. Filtration fraction in the renal-denervated
dogs averaged 0.34±0.01 during the 7 days of saline infusion and
0.36±0.03, 0.37±0.02, and 0.37±0.01 on days 1, 8, and 14
of the
L-NAME infusion period, respectively. The increases in renal vascular
resistance and filtration fraction in response to L-NAME were not
significantly different between the control and renal-denervated
dogs.
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Infusion of L-NAME for 14 days had no significant effects on sodium and
water excretion in the control and renal-denervated dogs (Fig
4). Urinary excretion of sodium in the control dogs averaged
72±7 mmol/d during the vehicle infusion period and increased to 95 to
99 mmol/d on days 1 and 2 of L-NAME infusion, respectively.
Sodium excretion averaged 84±9 and 71±6 mmol/d for the first and
second weeks of the L-NAME infusion period, respectively. Sodium
excretion in the renal-denervated dogs averaged 70±9 mmol/d during
the 7-day vehicle infusion period and increased to 96 mmol/d on day 1
of L-NAME infusion. Sodium excretion averaged 80±12 and 76±10
mmol/d
for the first and second weeks of the L-NAME infusion period,
respectively. Water excretion in the control dogs averaged 1058±161
mL/d during the vehicle infusion period and remained constant
throughout the L-NAME infusion period. Water excretion averaged 919±79
and 913±76 mL/d for the first and second weeks of the L-NAME infusion
period, respectively. Water excretion in the renal-denervated dogs
averaged 978±69 mL/d during the 7-day vehicle infusion period. Water
excretion averaged 958±105 and 949±87 mL/d for the first and
second
weeks of the L-NAME infusion period, respectively. The changes in
sodium and water excretion in response to L-NAME were not significantly
different between the control and renal-denervated dog groups.
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Tissue norepinephrine concentration was determined from
renal tissue after completion of the experimental protocol in control
and renal-denervated dogs. Renal denervation resulted in
significant reductions in renal tissue norepinephrine
content as compared with kidneys of renal-denervated dogs. Renal
tissue norepinephrine content averaged 733±20 pg/mg in
control dogs and 37±6 pg/mg in renal-denervated dogs (Fig
5).
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Discussion |
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TopAbstractIntroductionMethods Results Discussion References |
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The present study confirms previous findings in the dog that long-term intravenous infusion of L-NAME, an inhibitor of NO synthesis, results in chronic increases in arterial pressure.9 10 12 The L-NAME–induced hypertension is associated with significant increases in renal vascular resistance, increases in renal filtration fraction, and decreases in RPF while having no effect on GFR. Maintenance of sodium balance despite elevations in arterial pressure also indicates that NO synthesis inhibition results in a hypertensive shift in the pressure-natriuresis relationship.22 Although most investigators attribute these effects of L-NAME to inhibition of NO synthesis within endothelial cells of the renal vasculature or renal tubular cells, other investigators have suggested that renal function may be altered through indirect mechanisms such as the renal sympathetic nervous system.16 23
Results from previous experiments in the rat showing that acute NO
synthesis inhibition enhances renal sympathetic nerve activity support
the possibility of a role for renal nerves.16 Since
activation of the renal sympathetic nerves is known to reduce renal
excretory function and produce hypertension, it is possible that part
of the chronic renal and hypertensive effects of L-NAME may be mediated
by the renal nerves. Whether such a mechanism plays a role in mediating
the renal and hypertensive effects of L-NAME in the dog is uncertain,
since recent studies suggest that the effect of NO synthesis inhibition
may be species specific.12 17 Hansen et
al17
recently reported that the NO synthesis inhibition of
NG-monomethyl-L-arginine
(L-NMMA) had no effect on sympathetic outflow in humans. In addition,
Manning et al12 reported that combined 
- and
ß-blockade in the dog had no effect on the short-term
effects of NO synthesis inhibition on renal function.
To determine the importance of the renal nerves in mediating the long-term renal and hypertensive effects of chronic inhibition of NO synthesis, in the present study we examined the long-term effects of L-NAME on renal function and arterial pressure regulation in normal dogs and bilaterally renal-denervated dogs. We found that the increases in arterial pressure in response to 2 weeks of L-NAME administration were similar in the control and renal-denervated dog groups. Arterial pressure increased by approximately 17% to 18% in the control dogs while increasing 13% to 14% in the renal-denervated dogs. The renal hemodynamic and excretory responses to L-NAME were also the same in both groups of dogs. RPF decreased similarly (by 15% to 16%) in the control and renal-denervated dog groups. L-NAME had no effect on GFR in either group of dogs.
During the first day of NO synthesis blockade, sodium excretion tended to increase in both control and renal-denervated dogs. Although L-NAME tended to increase sodium excretion initially, the fact that after 2 weeks of L-NAME administration, the dogs were in sodium balance at an arterial pressure 14% to 18% higher than normal indicates that NO synthesis inhibition resulted in a rightward shift in the pressure-natriuresis relationship. The findings that renal denervation did not alter the renal hemodynamic, sodium excretory, or arterial pressure responses to L-NAME indicate that activation of the renal sympathetic nervous system is not important in mediating these effects of long-term NO synthesis inhibition in the dog.
Since renal denervation had no effect on the renal or hypertensive effects of L-NAME in our dogs, this finding raises the question of the effectiveness of the denervation procedure. The technique used in this study has been used numerous times in our laboratory and has been shown to markedly deplete renal tissue norepinephrine content and to abolish the renal effects of splanchnic nerve stimulation.18 19 In the present study, renal tissue norepinephrine content was determined at the end of the study to be 720 pg/mg in control dogs and only 37 pg/mg in the denervated dogs, indicating effective renal denervation. We have also previously demonstrated that the renal-denervation procedure in dogs is effective in altering functional responses to chronic physiological stimuli.18 In a recent study, we demonstrated that bilateral renal denervation markedly attenuated the sodium retention and hypertension associated with obesity, a condition well known for enhanced sympathetic nervous activity.18
Although we did not find a role for renal nerves in mediating the chronic effect of L-NAME in dogs, a recent study by Matsuoka and colleagues23 demonstrated that L-NAME–induced hypertension in the rat may be mediated in part by or is at least dependent on the integrity of the renal nerves. It should be pointed out, however, that although they reported that renal-denervated rats had significantly lower systolic pressures than control rats after 4 weeks of L-NAME, direct measurement of arterial pressures did not confirm the systolic pressures as measured by the tail-cuff method. Direct measurements of arterial pressure indicated no difference in arterial pressure between denervated rats and control rats receiving L-NAME. It was also not evident that renal denervation altered renal hemodynamic responses to L-NAME in the rat because renal function was determined in that study.23
In summary, long-term NO synthesis blockade with L-NAME in control and renal-denervated dogs produced significant increases in arterial pressure, renal vascular resistance, and filtration fraction, and decreased RPF, but had no effect on GFR. The renal hemodynamic, excretion, and arterial pressure responses to 2 weeks of continuous administration of L-NAME were the same between control and renal-denervated dogs. These results indicate that the long-term hypertensive and renal effects of NO synthesis inhibition in the dog are not dependent on activation of the renal sympathetic nerves.
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Acknowledgments |
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This work was supported by grants HL-51971 and HL-33947 from the National Institutes of Health (NIH). Jacqueline Novak is the recipient of an NIH National Research Service Award (HL-09373). Christine Schnackenberg is the recipient of an Arthur C. Guyton Fellowship. The authors thank Kristi Pigg and Brett Tucker for excellent technical assistance and Susie Zuller for administrative assistance.
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References |
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