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(Hypertension. 1997;30:64-70.)
© 1997 American Heart Association, Inc.
Articles |
The Sympathetic Nervous System Is Involved in the Maintenance but Not Initiation of the Hypertension Induced by N
-Nitro-L-Arginine Methyl Ester
From the Division of Cardiology, Molecular Cardiology Laboratories, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas.
Correspondence to Ronald G. Victor, MD, Molecular Cardiology Laboratories, Room NB11.200D, UT Southwestern Medical Center, 6000 Harry Hines Blvd, Dallas, TX 75235-8573. E-mail victor{at}ryburn.swmed.edu
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Abstract |
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Abstract Studies in anesthetized animals have advanced the theory that there is an important neurogenic component to the hypertension caused by pharmacological inhibition of nitric oxide, but studies in conscious animals have produced conflicting evidence for and against this theory. To try to reconcile the seemingly contradictory data, we hypothesized that the neurogenic component of this hypertension is time dependent such that the sympathetic nervous system is involved primarily in the maintenance, rather than the initiation, of the hypertension. We measured intra-arterial pressure in conscious, unrestrained rats with and without guanethidine-induced sympathectomy during varying durations of intravenous N
-nitro-L-arginine methyl ester
(L-NAME). The major new finding is that sympathectomy
had no effect on the hypertensive response to bolus injections of
L-NAME but in the same rats it produced a greater than 50% attenuation
in the hypertension seen after 6 days of continuous L-NAME (change in
mean arterial pressure, 23±4 versus 55±4 mm Hg,
P<.01, sympathectomy versus control). Using
8-hour infusions of L-NAME, we found that 60 minutes was the minimum
time required for detecting a sympathectomy-sensitive
component of L-NAME–induced hypertension. Furthermore, we demonstrate
that the magnitude of this component increases further between 8 hours
to 6 days of continuous L-NAME: it accounted for only 18% of the total
hypertensive response at 8 hours but 61% after 6 days. From these
experiments, we conclude that the importance of the sympathetic system
in the pathogenesis of L-NAME–induced hypertension accrues slowly over
hours and days, and thus its importance can be overlooked by focusing
on the initial phase of the hypertension.
Key Words: nitric oxide • sympathetic nervous system • sympathectomy • L-NAME • endothelin
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Introduction |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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It has been firmly established that pharmacological inhibition of NO synthesis produces acute and chronic hypertension in many animal species,1 2 3 4 5 6 but the underlying mechanisms mediating the hypertension are incompletely understood. Although this hypertension at first was attributed solely to inhibition of endothelial NO,5 7 8 an emerging body of literature suggests that inhibition of neuronal NO also may be involved.9 10 11 12 13 14 15 16 17 18
Acute studies in anesthetized animals provide the conceptual framework for hypothesizing a major neurogenic component to the hypertensive response evoked by NO inhibition. Administration of methyl arginine inhibitors of NO synthesis by intravenous injection,10 17 by intracisternal injection,11 16 or by their direct injection into the nucleus tractus solitarius12 or rostral ventrolateral medulla9 15 evokes acute increases in both renal sympathetic nerve activity and BP. These results, together with those from brain stem slice preparations,14 18 have been interpreted to suggest that neuronal NO is a part of the signal transduction pathways involved in the tonic restraint of sympathetic vasoconstrictor outflow from the brain stem. Removal of such restraint by NO synthesis inhibitors is postulated to cause sympathetic activation, which contributes to hypertension.
An important unresolved issue is the extent to which these findings can be extrapolated to the pathogenesis of hypertension caused by systemic administration of NO synthase inhibitors in the conscious state. The large number of studies published to date have shown that pharmacological blockade of the sympathetic nervous system in conscious animals both has no effect on19 20 21 22 23 24 25 and causes a substantial attenuation and/or reversal of26 27 28 the hypertensive response to pharmacological inhibition of NO synthesis. Those studies vary considerably in many respects, including the species studied, specific NO inhibitors used, and methods used to produce adrenergic blockade. Even when all these factors are identical, seemingly contradictory results have been reported from different laboratories. In conscious rats, for example, the severe hypertension caused by L-NAME was both completely unaffected by guanethidine-induced sympathectomy in a study by Zhang et al19 and greatly attenuated by the same form of sympathectomy in a recent study from our laboratory by Sander et al.26
Although the experimental details in these two studies are identical in many respects, they differ considerably in the duration of L-NAME administration: less than 1 hour in the study by Zhang et al,19 which found no effect of sympathectomy on L-NAME–induced hypertension, and 1 week in the study by Sander et al,26 which found a large effect of sympathectomy. This led us to hypothesize that the sympathetic nervous system is involved primarily in the maintenance, rather than the initiation, of L-NAME–induced hypertension. To test this hypothesis, we performed a longitudinal study in which we compared effects of guanethidine-induced sympathectomy on the acute versus the chronic phase of L-NAME–induced hypertension in the same rats.
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Methods |
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The methods used were in accordance with institutional guidelines. All protocols were approved by the Institutional Animal Care and Research Advisory Committee at the University of Texas Southwestern Medical Center.
Chronic Sympathectomy
Chronic sympathectomy was induced by repeated
daily subcutaneous injections of guanethidine (50 mg/kg) to newborn
Sprague-Dawley rats (Harlan Sprague Dawley, Inc, Indianapolis, Ind)
from day 5 through day 27 after birth.29 This procedure
causes irreversible immunological destruction of postganglionic
sympathetic nerves.30 31 32 In each rat, the efficacy of
sympathectomy was documented by the attenuated response
to intravenous tyramine (250 µg/kg). With tyramine, MAP
increased by 13±2 mm Hg (-9 to +27 mm Hg) in
guanethidine-treated rats versus 54±2 mm Hg (+43 to +75
mm Hg) in control rats (P<.01). None of the
guanethidine-treated rats needed to be excluded from study on the basis
of a large pressor response to tyramine. Rats were matched for weight,
sex, and age. All experimental protocols were performed on rats 7 to 16
weeks of age weighing 132 to 344 g.
Surgical Procedures
Survival surgery was performed using intramuscular injections of
a mixture of ketamine (40 mg/kg) and xylazine (7 mg/kg). For
intravenous injections and measurement of
arterial pressure, the left jugular vein and carotid artery
were cannulated, the tubing was exteriorized at the neck, and the
patency was maintained with heparin. For continuous administration of
L-NAME, we subsequently implanted osmotic pumps (Alzet 2ml1, Alza Corp)
(subcutaneously on the back) for intravenous administration
(jugular vein catheter) or intraperitoneal
administration.
Recording of Arterial Pressure in
Conscious Rats
A minimum of 5 days was allowed for complete recovery after
surgery. All recordings were done with the rats in individual
cages in a quiet room. Carotid artery catheter extensions were placed
on a counterweighted lever system, allowing the rats to move freely,
and were connected to a P23XL pressure transducer (Viggo-Spectramed)
for continuous pressure recordings (RS3600, Gould Inc). At
least 30 minutes was allowed for acclimation before measurements began,
and baseline BPs were then obtained for 60 minutes before any
intervention. MAP was calculated from the phasic arterial
pressure tracing as diastolic pressure plus one third of
pulse pressure.
Drugs
Xylazine (Gemini SA) was obtained from Burns Veterinary Supply
Inc, and ketamine (Ketaset) was from Fort Dodge Laboratories
Inc. Endothelin(1-39) was obtained from either ICN Pharmaceuticals Inc
or Sigma Chemical Co. All other drugs used were obtained from
Sigma.
Experimental Protocols
Protocol 1
In protocol 1, the effects of sympathectomy on
the hypertensive response to bolus intravenous L-NAME
versus 6 days of continuous intravenous L-NAME were
compared (n=12 rats with sympathectomy plus 13 control
rats). The aim of this protocol was to compare effects of
sympathectomy on the initiation versus
maintenance of L-NAME–induced hypertension in the same rats.
Arterial pressures were measured during two different time
courses of L-NAME administration. Only rats that completed both parts
of the L-NAME protocol (below) were included in the
analysis.
Bolus intravenous injections of L-NAME. Arterial pressures were measured at baseline and during stepwise intravenous bolus injections of L-NAME (0.5+0.5+1.5+2.5 mg/kg at 5-minute intervals), with the last measurement performed after a total of 30 minutes had elapsed. Additional experiments were performed using D-NAME (0.5+0.5+1.5+2.5 mg/kg at 5-minute intervals, n=4) to demonstrate the stereospecificity of the response to L-NAME.
Six days of continuous intravenous infusion of L-NAME. In the same rats, arterial pressures were measured 2 days later, as a new baseline, and again after a subsequent 6 days of continuous administration of L-NAME (50 mg/kg per day) by osmotic pumps.
Protocol 2
Protocol 2 measured the latency in the onset of the
sympathectomy-sensitive component of L-NAME–induced
hypertension (n=13 rats with sympathectomy plus 13
control rats). To determine the minimum time required to detect the
sympathectomy component of L-NAME–induced
hypertension, arterial pressures were measured at baseline
and during an 8-hour continuous intravenous infusion of
L-NAME. A dose of 2.1 mg/kg per hour was chosen because this is
equivalent to the dose of 50 mg/kg per day used in protocol 1.
In additional experiments (rats with sympathectomy, n=6; control rats, n=8), continuous intravenous infusion of D-NAME (2.1 mg/kg per hour) was used to demonstrate the stereospecificity of the response to L-NAME. Furthermore, experiments were performed to control for time (8 hours, n=7) and volume (1 mL/kg per hour of normal saline, n=6).
To compare the effects of sympathectomy on the hypertensive response to continuous intravenous infusion of L-NAME at three separate times (hour 1, hour 8, and day 6), in a subset of 6 control rats and 10 rats with sympathectomy, measurements were also performed after 6 days of continuous treatment (with osmotic pumps implanted on the day of the 8-hour infusion).
Protocol 3
Protocol 3 determined differential effects of
sympathectomy on the hypertensive responses evoked by
L-NAME versus endothelin-1 (n=8 rats with sympathectomy
plus 8 control rats). To examine the specificity of effects of chronic
sympathectomy on the hypertensive response to L-NAME,
arterial pressures were measured at baseline and during an
8-hour continuous intravenous infusion of big endothelin-1
[endothelin(1-39)] (2.4 nmol/kg per hour; volume, 1 mL/kg per hour),
which was used as an internal vasoconstrictor control. These data were
compared with those of protocol 2.
In all, we studied 52 control rats (18 male, 34 female) and 39 sympathectomized rats (17 male, 22 female).
Data Analysis
For comparisons within or between groups with two measurements
in each rat, Student's t test for nonpaired data or paired
data was used. For comparisons with more than two measurements on each
rat, three-factor (sex, sympathectomy, dose/time)
univariate ANOVA, with repeated measures on one factor
(dose/time), was used. Where relevant, multiple comparisons were
performed with contrast analysis using the Bonferroni
adjustment for the significance level, which was set at a value of
P<.05. Results are expressed as mean±SE.
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Results |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Sympathectomy Attenuates the Maintenance but Not Initiation of L-NAME–Induced Hypertension
There were no statistical differences in baseline MAP values between rats with sympathectomy versus control rats (104±3 versus 106±3 mm Hg, P=NS).
Bolus intravenous injections of L-NAME produced
dose-dependent increases in arterial pressure that, for
each dose, were comparable in rats with sympathectomy
versus control rats (Fig 1
, top) (
MAP: 11±1 versus
8±2 mm Hg; 20±2 versus 19±4; 40±3 versus 33±4; and 56±4
versus 47±4 increases from baseline after 0.5, 1.0, 2.5, and 5.0 mg/kg
L-NAME, respectively; P=NS, ANOVA). There were no sex
differences in the responses to bolus L-NAME. Thus, after 5.0 mg/kg
L-NAME, MAP in male (n=6) versus female (n=6) rats with
sympathectomy was 56±5 versus 56±7 mm Hg
(P=NS, ANOVA), and MAP in male (n=7) versus female (n=6)
control rats was 51±5 versus 43±5 mm Hg (P=NS,
ANOVA). Unlike L-NAME, bolus intravenous injections of
D-NAME (n=4) did not produce acute changes in BP. MAP values were
104±3, 103±2, 99±1, 100±1, and 104±1 mm Hg at baseline and
after 0.5, 1.0, 2.5, and 5.0 mg/kg D-NAME, respectively
(P=NS, ANOVA).
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) and controls (n=13, 
). The hypertensive responses
to bolus injections of L-NAME were comparable in both rat groups.
Bottom, Individual and summary data (same rats as in top panel) showing
MAP at baseline and after 6 days of continuous L-NAME administered by
implanted osmotic pumps (50 mg/kg per day). *Significant difference
(P<.05) between the two groups. The hypertensive response
after 6 days of continuous L-NAME was greatly attenuated in
sympathectomized rats.
In contrast to the comparable dose-responses to bolus L-NAME, the
hypertensive response to 6 days of continuous L-NAME was greatly
attenuated in sympathectomized versus control rats (Fig 1
, bottom)
(MAP: 104±3 to 127±4 versus 106±3 to 161±4 mm Hg;
MAP: 23±4 versus 55±4 mm Hg, P<.01). This
difference was apparent for both female and male rats (MAP,
sympathectomized versus control rats: female, 23±6 versus 61±5
mm Hg, P<.01; male, 23±7 versus 49±6 mm Hg,
P<.01).
There was no difference between increases in BP produced by continuous
intravenous (n=6) versus
intraperitoneal (n=7) administration of L-NAME in
control rats (MAP: 61±5 versus 49±6 mm Hg, P=NS).
There also were no differences in increases in BP produced by
intravenous (n=6) versus
intraperitoneal (n=6) administration of L-NAME in
sympathectomized rats (MAP: 23±6 versus 23±7 mm Hg,
P=NS).
Latency in the Onset of the Sympathectomy-Sensitive
Component of L-NAME–Induced Hypertension Is 1 to 2 Hours
Baseline MAP values again were not significantly different in rats
with sympathectomy versus control rats (102±2 versus
106±2 mm Hg, P=NS).
Sympathectomy exerted a significant effect on the
increases in arterial pressure produced by 8 hours of
continuous intravenous infusion of L-NAME
(P<.01, ANOVA). During the initial 45 minutes of L-NAME,
arterial pressures increased comparably in both groups
(MAP at 45 minutes: 31±5 versus 33±5 mm Hg,
P=NS). However, during the second hour of L-NAME,
arterial pressure did not increase further in
sympathectomized rats but continued to increase in control rats (MAP
at 120 minutes: 25±5 versus 46±5 mm Hg, P<.01).
This difference in BP was maintained during the remainder of L-NAME
administration (Fig 2, top). Sex was not a significant
factor in the response to L-NAME (P=NS, ANOVA).
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Compared with L-NAME, D-NAME produced a slow and small increase in BP (P<.05, ANOVA) that was unaffected by sympathectomy. Thus, during the first 3 hours of D-NAME infusion, MAP was unchanged in both rat groups, whereas during hour 4 of infusion MAP increased by 10±4 mm Hg in sympathectomized rats and by 13±5 mm Hg in control rats (P=NS, ANOVA between groups).
In control rats, BPs were stable during 8 hours of continuous
measurement (MAP at 480 minutes: 5±3 mm Hg; P=NS,
ANOVA). In addition, BP was unchanged during intravenous
infusion (1 mL/kg per hour) of normal saline vehicle (MAP at 480
minutes: 4±3 mm Hg; P=NS, ANOVA).
Sympathectomy Does Not Attenuate the Hypertensive
Response to Endothelin-1
In contrast to the hypertensive response to 8 hours of L-NAME,
sympathectomy did not attenuate the hypertensive
response to 8 hours of intravenous big endothelin-1 (Fig 2, bottom). Rather, the increase in MAP caused by endothelin was slightly
greater in sympathectomized rats versus control rats
(P<.05, ANOVA), with the only differences occurring at 15
and 30 minutes. Increases in BP with big endothelin-1 were initially
larger and subsequently (at 6 to 8 hours) comparable to the increases
seen with L-NAME in the control rats.
The Sympathectomy-Sensitive Component of
L-NAME–Induced Hypertension Increases Over Time
The increase in MAP in the subgroups of rats studied both during 8
hours and after 6 days of continuous L-NAME were as follows (MAP in
rats with sympathectomy versus control rats): at 45
minutes, 34±6 versus 30±6 mm Hg (P=NS); at 8 hours,
32±6 versus 39±4 mm Hg (P=NS); and at 6 days, 24±5
versus 52±7 mm Hg (P<.05). These average increases
correspond to a relative increase of the
sympathectomy-sensitive component of
L-NAME-hypertension from 0% of the total hypertensive response at 45
minutes to 18% at 8 hours and further to 61% after 6 days (Fig 3). Over the same time frame, the absolute magnitude of
the sympathectomy-resistant component of the
hypertension was largely unchanged, with a trend toward decreasing
between 8 hours and 6 days.
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significant difference (P<.05)
within the control group between 8 hours and 6 days of L-NAME. During
the first 45 minutes of L-NAME, MAP increased comparably in both
groups. During continued L-NAME, MAP did not increase further
in rats with sympathectomy but increased progressively
over time in control rats. |
Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Previous studies in conscious animals have led to seemingly contradictory conclusions as to whether the sympathetic nervous system plays an important role in mediating the severe hypertension caused by pharmacological inhibition of NO synthesis.19 20 21 22 23 24 25 26 27 28 33 34 35 36 The major new conclusion of the present study is that the importance of the sympathetic system in the pathogenesis of L-NAME–induced hypertension accrues slowly over hours and days, and thus its importance can be overlooked by focusing on the initial phase of the hypertension. Guanethidine-induced sympathectomy produced a greater than 50% attenuation in the maintenance of L-NAME–induced hypertension although the sympathectomy had no effect on the initiation of the hypertension in the same rats.
By focusing on the duration of NO inhibition, we were able to resolve two seemingly incongruous observations from previously published studies. First, by administering the L-NAME as intravenous boluses, we confirmed the observation of Zhang et al19 that sympathectomy has no effect on the rapid rise in arterial pressure produced by L-NAME. This was true over a large range of doses. Second, by administering the L-NAME intravenously for 8 hours or for 1 week via osmotic pumps, we replicated our own previous finding that sympathectomy causes a sizable attenuation of the hypertension seen after 1 week of oral L-NAME.26 This is noteworthy because the new intravenous experiments demonstrate that the interpretation of our previous observations using orally administered L-NAME is valid and not spuriously related to a possible effect of sympathectomy on gut absorption L-NAME, a substituted amino acid (eg, from protein losing enteropathy). We provided evidence that the long-term effects of L-NAME on the neural control of BP are specifically related to the ability of L-NAME to act as an NO synthase inhibitor, since sympathectomy had no effect on the small pressor response to D-NAME. We also provided evidence for the specificity of the sympathectomy-induced attenuation in the hypertensive response to L-NAME by showing that sympathectomy has no effect on the hypertensive response elicited by endothelin, used as an internal vasoconstrictor control. Thus, in the conscious rat, it is the maintenance, not the initiation, of L-NAME–induced hypertension that is sensitive to sympathectomy.
In our review of the literature, we found 10 studies (including that by Zhang et al19 ) arguing against a neurogenic component to the hypertensive response caused by NO inhibition in the conscious state.19 20 21 22 23 24 25 33 34 36 Although the species studied varied from rats and dogs to humans, in all those studies the NO inhibitor was administered as a rapid intravenous infusion. In light of our new data, in those studies the rather short observation periods may have led to underestimation of a neurogenic component to the hypertension. Indeed, in the previously published studies (including that by Sander et al26 ) that argue for a neurogenic component to L-NAME–induced hypertension in conscious rats, L-NAME was administered orally for a minimum of 1 week.26 27 28 35
A seminal observation of the present study is that 1 hour is the minimum time required for detection of a sympathectomy-sensitive component of L-NAME–induced hypertension in conscious rats. Recent studies indicate that 30 to 60 minutes is required for intravenous L-NAME to cross the blood-brain barrier and gain sufficient central nervous system concentration to inhibit more than 50% of neuronal NO synthase activity, as measured in brain homogenates.37 38 39 40 Thus, the rather slow active transport of L-NAME into the central nervous system via amino acid transporters41 42 43 is one likely factor contributing to the delay in the onset of the sympathectomy-sensitive component of L-NAME–induced hypertension in conscious rats. On the basis of recent neurophysiological studies in anesthetized animals, baroreflex activation is probably another contributing factor.17 18 44 With rapid intravenous L-NAME, the rapid rise in BP would be expected to increase the discharge of arterial baroreceptors, resulting in an initial reflex inhibition of sympathetic vasoconstrictor drive.44
A characteristic feature of L-NAME hypertension is that the severity increases progressively over days and weeks (before the development of irreversible target-organ damage).4 27 35 45 46 47 48 An important feature of our study is the suggestion that this progressive nature is sympathetically mediated. Although the sympathectomy-insensitive component of L-NAME–induced hypertension was stable over hours and days, the sympathectomy-sensitive component was considerably larger after 1 week of intravenous L-NAME than after 8 hours. This finding is provocative because with doses of intravenous L-NAME similar to those used in the present study, 2 to 6 hours is sufficient time to maximally inhibit neuronal NO synthase activity in all areas of the brain.37 38 39 40
The explanation for this additional slow increment in neurogenic hypertension is unknown and beyond the scope of this study. One possibility is that continued inhibition of NO synthase leads to induction of NO synthase mRNA in neurons,49 50 51 so that there is more NO synthase to inhibit. Another possible explanation is that chronic inhibition of NO synthase in neurons somehow activates or potentiates excitatory neural circuits that normally are not tonically (or are only minimally) active, or it leads to attenuation of inhibitory neural circuits. Some studies, for example, have found that L-NAME treatment is accompanied by a progressive attenuation in sinoaortic baroreflexes, which might contribute to neurogenic vasoconstriction and hypertension.52 53 However, in those studies it is unclear whether baroreflex attenuation is the cause or consequence of the hypertension, and others have found that L-NAME treatment is accompanied by normal15 54 or even augmented55 56 baroreflexes. The specific sites of NO inhibition leading to progressive neurogenic hypertension are unknown, but afferent, central, and efferent neural mechanisms all could be involved.9 12 13 15 52 57 58 59 60 61 62 63 64 65 66 67 68 69 70 71 72
Regardless of the precise neurophysiological mechanisms involved, the major new concept arising from the present work is that the sympathetic nervous system is one important mechanism responsible for the maintenance and progressive nature of L-NAME–induced hypertension, which previously was assumed to be caused entirely by inhibition of NO synthase in endothelial cells. We propose that in the conscious rat, L-NAME–induced hypertension is initiated via inhibition in endothelially derived NO and is maintained by inhibition of both endothelial and neuronal NO, the latter effect becoming increasingly dominant over hours and days.
Whether these findings can be extrapolated to human hypertension remains to be determined. Previous studies have suggested that impaired endothelial NO production is one mechanism contributing to human essential hypertension.73 74 75 76 On the basis of our present study in rats, we might speculate that impaired neuronal NO production may be an important mechanism contributing to the increased sympathetic nerve activity that accompanies human borderline77 78 and essential79 80 hypertension as well as hypertension in patients with chronic renal failure.81
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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This research was supported by funding to Dr Victor from the Baxter Healthcare Corp (Renal Division) and from a National Aeronautics and Space Administration Specialized Center of Research and Training (NAGW3582, C. Gunnar Blomqvist, Director), and to Dr Sander from the Fogarty Foundation (F05 TW05085) and the Michaelsen Foundation.
Received August 22, 1996; first decision September 9, 1996; accepted December 10, 1996.
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