(Hypertension. 1996;27:626-630.)
© 1996 American Heart Association, Inc.
Articles |
Renal Sympathetic Neural Mechanisms as Intermediate Phenotype in Spontaneously Hypertensive Rats
From the Department of Internal Medicine, University of Iowa College of Medicine and Veterans Administration Medical Center, Iowa City, Iowa.
Correspondence to Gerald F. DiBona, MD, Department of Internal Medicine, University of Iowa College of Medicine, Iowa City, IA 52242. E-mail gdibona@blue.weeg.uiowa.edu.
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Abstract |
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Abstract The borderline hypertensive rat, the F1 of a cross between a hypertensive spontaneously hypertensive rat (SHR) and a normotensive Wistar-Kyoto (WKY) rat, is a NaCl-sensitive model of genetic hypertension. In addition to hypertension, borderline hypertensive rats fed 8% NaCl develop characteristic alterations in the regulation of efferent renal sympathetic nerve activity and the neural control of renal function that are similar to those observed in the SHR parent. Like the normotensive WKY rat parent, borderline hypertensive rats fed 1% NaCl remain normotensive and do not exhibit these alterations in renal sympathetic neural mechanisms. These renal sympathetic neural mechanisms constitute a complex quantitative trait that may represent an intermediate phenotype. They have a plausible pathogenetic role in hypertension and are different between SHR and WKY rats. This study evaluated two aspects of this complex quantitative trait, enhanced renal sympathoexcitation with air-jet stress and enhanced renal sympathoinhibition with guanabenz, as a candidate intermediate phenotype. As neither of these aspects was observed in two-kidney, one clip Goldblatt-hypertensive rats, this suggests that the trait is not secondary to hypertension from an acquired cause. In a backcross population (F1xWKY) fed 8% NaCl for 12 weeks, both enhanced renal sympathoexcitation with air-jet stress and enhanced renal sympathoinhibition with guanabenz cosegregated with the hypertension. These results support renal sympathetic neural mechanisms as an intermediate phenotype in SHR.
Key Words: neural mechanisms, sympathetic, renal • rats, inbred strains • phenotype
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Introduction |
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TopAbstractIntroductionMethods Results Discussion References |
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As described by Sanders and Lawler,1 the BHR is the F1 of a cross between a hypertensive SHR and a normotensive WKY rat. Exposure of BHRs to either environmental stress or increased dietary NaCl intake (8% NaCl) produces sustained hypertension (BHR-8%); in the absence of these interventions, the BHR remains normotensive (BHR-1%). BHRs subjected to prior renal denervation exhibit an attenuated increase in arterial pressure compared with BHRs with intact renal innervation.2 This finding suggests an important role for ERSNA in the development of hypertension in BHR.
We have examined the influence of increased dietary NaCl intake
on aspects of the regulation of ERSNA and the neural control of renal
function in
BHR.3 4 5 6 7 8 9 10 11 12 13 14 15 16 17
For comparison, the hypertensive
(SHR) and the normotensive (WKY) parents were studied concurrently. The
findings, ie, phenotypic features, are observed in both the
hypertensive SHR parent and the hypertensive BHR-8% but are not seen
in the normotensive WKY parent and the normotensive BHR-1%. In
addition to the development of hypertension, there is an exaggerated
natriuresis to volume expansion that is dependent on the concurrent
exaggerated inhibition of ERSNA.3 6 14
Arterial baroreflex control of ERSNA is reset to the higher
level of arterial pressure.17 Cardiac
baroreflex control of ERSNA is augmented, and this accounts for the
exaggerated inhibition of ERSNA during volume
expansion.3 18 AJS responses, in terms of increases
in
MAP, HR, and ERSNA and decreases in urinary flow rate and sodium
excretion, are
increased.4 5 7 8 10 12 13 14 15 19
The
inhibition of ERSNA after ICV administration of the
2-adrenoceptor agonist guanabenz is
enhanced.11 16 These phenotypic features are seen in
SHR
and BHR-8% but not in WKY rats or BHR-1%.
The possibility that the features that deal with renal sympathetic neural mechanisms represent a complex quantitative trait that may serve as an intermediate phenotype was considered. In the current study, two of these features were chosen for initial analysis: augmented increases in ERSNA in response to AJS and enhanced decreases in ERSNA in response to ICV guanabenz.
Rapp20 set forth criteria for a complex quantitative trait as an intermediate phenotype: (1) the trait should have a plausible pathophysiological role in hypertension; (2) there should be evidence for a difference in the trait in progenitor hypertensive and normotensive strains that would implicate the trait in the pathogenesis of hypertension; (3) the difference in the trait should not be secondary to the hypertension; and (4) the difference in the trait should cosegregate with arterial pressure in F2 or backcross populations. For the first criterion, alterations in ERSNA, with their well-established effects on renal vascular resistance, sodium handling, and renin release have a plausible pathophysiological role in hypertension.21 Second, the differences in the renal sympathetic neural mechanisms between the hypertensive SHR parent and the normotensive WKY parent noted above would implicate alterations in ERSNA in the pathogenesis of hypertension.
Criteria three and four are the subject of the current investigation. The responses of ERSNA to AJS and ICV guanabenz were investigated in a nongenetic acquired model of hypertension, the 2K,1C Goldblatt rat, to examine whether these ERSNA alterations are secondary to hypertension. A backcross population (F1xWKY) was created to see whether the ERSNA alterations cosegregated with hypertension.
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Methods |
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TopAbstractIntroductionMethods Results Discussion References |
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Animals
Adult male Sprague-Dawley rats, female SHR, and male WKY rats were purchased from Taconic Farms (Germantown, NY). Female SHR were bred with male WKY rats to produce BHR. BHRs of both sexes were bred with WKY rats of the opposite sex to produce the backcross population. Backcross-population rats of both sexes were weaned at 4 weeks of age and fed 8% NaCl with tap water drinking solution ad libitum until age 16 weeks, when they were studied. Sprague-Dawley rats were fed standard laboratory rat chow (1% NaCl) with tap water drinking solution ad libitum. All animal procedures were in accordance with the guidelines of the University of Iowa Animal Care and Use Committee.
Anesthesia
The rats were anesthetized with methohexital
(Brevital,
20 mg/kg IP supplemented with 10 mg/kg IV as needed; Eli Lilly).
Procedures
2K,1C Goldblatt Hypertension
Via a
right-flank incision, a 0.2-mm silver clip was placed
on the right renal artery of 6-week-old Sprague-Dawley
rats. The rats were studied 4 weeks later. Control rats were subjected
to similar surgery, but a clip was not placed on the right renal
artery.
Catheterization
The rats were instrumented
with polyethylene catheters in the
right jugular vein and right carotid artery for infusion of isotonic
saline (0.05 mL/min maintenance) and the measurement of MAP and
HR. The catheters were tunneled to the dorsum of the neck, where they
were exteriorized and plugged.
Renal Sympathetic Nerve
Activity Recording
Electrode19
The left kidney was exposed through a
left-flank incision
via a retroperitoneal approach. With the use of a dissecting microscope
(25x), a renal nerve branch from the aorticorenal ganglion was
isolated and carefully dissected free. The renal nerve branch was then
placed on a bipolar platinum wire (Cooner Wire Company) electrode.
ERSNA was amplified (50 000x) and filtered (low, 30 Hz; high, 3000
Hz) with a high-impedance probe and preamplifier (Grass HIP 511 and
P511, respectively; Grass Instrument Co). The output of the amplifier
was channeled to a Tektronix 5113 oscilloscope for visual evaluation
and an audio amplifier/loudspeaker (Grass Instrument Co model AM 8
audio monitor) for auditory evaluation. The quality of the ERSNA signal
was assessed by its pulse-synchronous rhythmicity and by examining
the magnitude of decrease in recorded ERSNA during sinoaortic
baroreceptor loading with an IV bolus injection of
norepinephrine (3 µg). The ERSNA remaining after maximum
inhibition pursuant to norepinephrine administration was
within 5% of the background noise observed approximately 30 minutes
postmortem or pursuant to hexamethonium 30 mg/kg IV
(ICN Pharmaceuticals)22 ; this background noise value was
subtracted from all experimental values of ERSNA. When an optimal ERSNA
signal (pulse-synchronous rhythmicity, abolition by
norepinephrine-induced arterial pressure
increase) was observed, the recording electrode was fixed to
the renal nerve branch with a silicone cement (Wacker Sil-Gel 604,
Wacker-Chemie). The electrode cable was then secured in position by
suturing it to the abdominal trunk muscles and further tunneled to the
dorsum of the neck, where it was exteriorized. The flank incision was
closed in layers.
Cerebroventricular
Cannulation11 16
The rat was placed in a
stereotaxic
apparatus for placement of a stainless steel cannula into
the right lateral cerebral ventricle. The coordinates used for cannula
placement were derived from the rat brain atlas of Paxinos and
Watson.23
Experimental Protocol
To avoid potential carryover effects,
the ERSNA responses to AJS
and ICV guanabenz were studied in separate groups of 2K,1C
Goldblatt-hypertensive rats and backcross-population rats. All
rats were studied on the day after the above-described chronic
instrumentation in the conscious, unrestrained state. In the
backcross-population rats, a 1-hour period of continuous
recording of basal arterial pressure was made
before beginning either the AJS or ICV guanabenz protocols.
Air-Jet Stress19
During two consecutive
10-minute control periods,
continuous recordings of arterial pressure, HR, and
ERSNA were made. Then acute environmental stress (AJS, continuous) was
begun; 5 minutes thereafter, two consecutive 10-minute experimental
periods were conducted, during which continuous recordings of
MAP, HR, and ERSNA were made. The AJS was stopped; 5 minutes
thereafter, two consecutive 10-minute recovery periods were conducted,
during which continuous recordings of MAP, HR, and ERSNA were
made. Then hexamethonium (30 mg/kg IV) was
administered, and the ERSNA remaining 15 minutes thereafter was taken
as the background noise.
AJS consisted of an air jet delivered continuously to the dorsum of the rat's head through a tube located 4 to 5 cm behind the rat. Repeated applications of AJS in the same rat resulted in similar increases in HR, MAP, and ERSNA, indicating reproducibility and lack of adaptation.4 5 7 8 10 12 13 14 15 19
ICV Guanabenz11 16
During
a 10-minute control period, continuous recordings
of MAP, HR, and ERSNA were made. Then 5 µg guanabenz in 1 µL
isotonic saline was injected ICV. Fifteen minutes was allowed for
equilibration, followed by a 10-minute experimental period. Then 25
µg guanabenz in 1 µL isotonic saline was injected ICV. Fifteen
minutes was allowed for equilibration, followed by a 10-minute
experimental period. Next 125 µg guanabenz in 5 µL isotonic saline
vehicle was injected ICV. Fifteen minutes was allowed for
equilibration, followed by a 10-minute experimental period.
Continuous recordings of MAP, HR, and ERSNA were made during
each of the experimental periods. It has been demonstrated
previously11 that the ICV injection of up to 7 µL
isotonic saline alone has no effect on MAP, urinary sodium excretion,
or renal sympathetic nerve activity. Finally, 30 mg/kg
hexamethonium IV was administered, and the ERSNA that
remained 15 minutes after hexamethonium administration
was taken as the background noise.
Analysis19
The amplified and filtered renal
neurogram was full-wave
rectified and integrated (Grass 7P3 resistance-capacitance
integrator, 20 ms time constant) and stored as ERSNA on videotape
(Vetter 4000A PCM; A.R. Vetter Co) along with the neurogram, MAP
(Statham 23Db pressure transducer; Statham-Gould), and HR (Grass 7P4
tachograph) signals for later off-line analysis.
With the use of an analog-to-digital converter (Data Translation 2801) and standard data acquisition software (LABTECH Notebook 7.3), the steady state ERSNA, MAP, and HR were sampled at 5 Hz and averaged over the duration of the control, experimental, and recovery periods in the AJS protocol and over the duration of the control and experimental periods in the ICV guanabenz protocol.
Statistics24
Statistical analysis was conducted
with one-way
ANOVA and Scheffé's test for pairwise comparisons among means
for the comparison of MAP and ERSNA responses to AJS and guanabenz (125
µg ICV dose) among 2K,1C Goldblatt-hypertensive rats, SHR, WKY
rats, BHR-1%, and BHR-8%. One-way ANOVA with repeated measures
and Scheffé's test for pairwise comparisons among means were
used for comparison of MAP, HR, and ERSNA responses to AJS and
guanabenz (5, 25, and 125 µg ICV) in the backcross population. In the
backcross population, the correlation coefficient values (r)
between basal MAP and MAP, HR, and ERSNA responses to AJS and guanabenz
(5, 25, and 125 µg ICV) were calculated. A value of P<.05
was considered significant. Data in text and figures are mean±SE.
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Results |
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TopAbstractIntroductionMethods Results Discussion References |
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2K,1C Goldblatt-Hypertensive Rats
Fig 1
displays the baseline MAP and Fig 2 displays the ERSNA
responses to AJS and ICV guanabenz
of 2K,1C Goldblatt-hypertensive rats. For comparison, data are
shown for SHR, BHR-8%, BHR-1%, and WKY rats previously studied in our
laboratory under identical conditions.4 14 Baseline
MAP in
2K,1C Goldblatt-hypertensive rats was 191±5 mm Hg; baseline MAP in
control rats was 109±5 mm Hg. MAP in 2K,1C Goldblatt-hypertensive
rats was similar to that in SHRs and BHR-8% and higher than that in
BHR-1% and WKY rats (P<.01). However, despite a similar
magnitude of hypertension, 2K,1C Goldblatt-hypertensive rats
exhibited only an 18±3% increase in ERSNA with AJS; the increase in
ERSNA with AJS in control rats was 15±4%. In 2K,1C
Goldblatt-hypertensive rats, the renal
sympathoexcitatory response to AJS was lower
than those responses observed in SHR (77±6%) and BHR-8% (62±6%)
(P<.01 for both) and was in the range of those observed in
WKY (12±2%) and BHR-1% (17±5%). In 2K,1C
Goldblatt-hypertensive rats, AJS produced no significant change in
MAP (from 191±5 to 189±6 mm Hg) or HR (430±22 to
443±24 beats per
minute). Similarly, 2K,1C Goldblatt-hypertensive rats exhibited
only a 45±6% inhibition of ERSNA with the 125 µg dose of ICV
guanabenz; the response in control rats was 51±4%. This
inhibitory response is lower than those responses observed
in SHR (80±4%) and BHR-8% (86±4%) (P<.05 for both)
and
is in the range of those observed in WKY (52±3%) and BHR-1%
(48±2%). In 2K,1C Goldblatt-hypertensive rats, this dose of ICV
guanabenz did not significantly affect MAP (-3.2±3.7%) or HR
(-11.0±4.6%). Therefore, despite similar hypertensive levels of
MAP, 2K,1C Goldblatt-hypertensive rats did not exhibit augmented
ERSNA responses to either AJS or ICV guanabenz.
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Backcross Population
In the backcross-population rats, the
1-hour period of
continuous recording of arterial pressure before
beginning the AJS or ICV guanabenz protocols gave values of MAP that
were not significantly different from those derived from the
shorter-duration control periods in each of the respective
protocols. Of the 163 backcross-population rats studied, there were
83 male rats whose MAP was 138±2 mm Hg and 80 female rats whose MAP
was 141±2 mm Hg.
For each backcross rat, the MAP from the
preprotocol 1-hour
continuous monitoring period was plotted against the respective values
for the percent increase in ERSNA with AJS (Fig 3) and
the percent inhibition in ERSNA with 125 µg guanabenz ICV (Fig
4). In the 81 backcross rats in the AJS protocol, the
percent increase in ERSNA with AJS was correlated with the basal level
of MAP (r=.76, P<.001). Significant correlations
at lower correlation coefficient values were found with both the MAP
(r=.59, P<.001) and HR (r=.50,
P<.001) responses to AJS. In the 82 backcross rats in the
ICV guanabenz protocol, the percent inhibition in ERSNA with 125 µg
guanabenz ICV was correlated with the basal level of MAP
(r=.70, P<.001). Significant correlations at
lower correlation coefficient values were found with the ERSNA
responses to either the 5 (r=.49, P<.001) or 25
(r=.53, P<.001) µg ICV dose of guanabenz or
the MAP (range of r, .51 to .62; P<.001) and HR
(range of r, .48 to .57; P<.001) responses to
all three doses of ICV guanabenz.
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Discussion |
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TopAbstractIntroductionMethods Results Discussion References |
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The BHR (F1) inherits genetic information from a hypertensive SHR parent and a normotensive WKY parent. When BHRs ingest an 8% NaCl diet, they develop hypertension and exhibit aspects of regulation of ERSNA and the neural control of renal function that are similar to the hypertensive SHR parent. When BHRs ingest a 1% NaCl diet, they remain normotensive and exhibit aspects of regulation of ERSNA and the neural control of renal function that are similar to the normotensive WKY parent. These results suggest that increased dietary NaCl intake is able to induce or unmask the capabilities for these responses that are genetically conveyed to the BHR by the hypertensive SHR parent in latent forms.
The current study evaluated renal sympathetic neural mechanisms as a complex quantitative trait for suitability as an intermediate phenotype. Complex traits refer to phenotypes or intermediate phenotypes that do not exhibit classic mendelian inheritance attributable to a single gene locus. Variation in these traits may result from variation in multiple genes and environmental influences. Quantitative traits refer to continuous variables such as MAP, in contrast to discrete traits measured by a specific outcome, such as albino versus pigmented.
With regard to the criteria for complex quantitative traits as intermediate phenotypes, renal sympathetic neural mechanisms, through their multiple actions on various aspects of renal function,25 have a plausible pathophysiological role in the pathogenesis of hypertension (criterion 1). Increased ERSNA is known to increase renal vascular resistance, which, in view of the fraction of cardiac output delivered to the kidneys, may represent a substantial contribution to total peripheral vascular resistance. ERSNA at levels below the threshold for effects on renal blood flow or glomerular filtration rate directly increases renal tubular sodium and water reabsorption throughout the nephron. In this way, increased ERSNA opposes pressure diuresis and natriuresis, resulting in the need for a higher level of MAP to achieve the same level of water and sodium excretion (ie, a rightward shift of the renal function curve along the MAP axis).26 Graded increases in ERSNA produce graded increases in renin release, beginning at levels of ERSNA that are subthreshold for effects on renal blood flow, glomerular filtration rate, or renal tubular sodium and water reabsorption.
As noted above, the various renal sympathetic neural mechanisms differ substantially between SHR and WKY (criterion 2). Furthermore, the influence of dietary NaCl intake in the BHR (F1) is such that 8% NaCl intake results in the BHR resembling the hypertensive SHR parent in becoming hypertensive and exhibiting these features, whereas 1% dietary NaCl intake results in the BHR resembling the normotensive parent and not exhibiting these features.
In the current study, we have provided evidence that two aspects of this complex quantitative trait are not secondary to hypertension (criterion 3). Using an acquired or secondary model of hypertension, 2K,1C Goldblatt hypertension, we showed that despite hypertension of a magnitude similar to that seen in SHR and BHR-8%, the ERSNA responses to AJS and ICV guanabenz were not enhanced. The ERSNA responses of 2K,1C Goldblatt-hypertensive rats to AJS and ICV guanabenz were not different from control rats, BHR-1%, or WKY rats.
Using a backcross population (F1xWKY) fed 8% NaCl, we have demonstrated that the ERSNA responses to AJS and ICV guanabenz cosegregate with MAP (criterion 4). Higher levels of MAP were accompanied by greater renal sympathoexcitatory responses to AJS and greater renal sympathoinhibitory responses to ICV guanabenz.
Therefore, with respect to the complex quantitative trait of renal sympathetic neural mechanisms as reflected by enhanced increases in ERSNA with AJS and enhanced decreases in ERSNA with ICV guanabenz, these results support the view that this trait represents an intermediate phenotype for SHR.
It should be emphasized that cosegregation of a phenotypic defect with arterial pressure in an F2 or backcross population is evidence of an association of the defect with the pathogenesis of hypertension. However, used in this manner, such studies cannot determine directly whether the association is due to cause or effect (ie, secondary to the hypertension). There are several ways of overcoming this problem. One way is to use a longitudinal approach,27 ie, to look for the phenotypic defect before the onset of hypertension and determine whether it correlates with later development of hypertension. Harrap and Doyle28 studied groups of F2 WKY and SHR rats at different ages and demonstrated that although MAP was negatively correlated with glomerular filtration rate in 11-week-old rats, there was no such correlation in 16-week-old rats. These results were interpreted as indicating that MAP increased from 11 to 16 weeks to normalize glomerular filtration rate. Nørrelund et al29 used a longitudinal approach to follow individual F2 WKY and SHR rats and demonstrated that a narrowed lumen of distal afferent arterioles at 7 weeks (when MAP was not increased) was negatively correlated with MAP at 23 weeks. Another approach is to demonstrate that the phenotypic defect or trait occurs in a genetic model of hypertension but not in acquired (secondary) models of hypertension. In the current study, the two aspects of the complex quantitative trait of renal sympathetic neural mechanisms studied, enhanced ERSNA responses to AJS and ICV guanabenz, were observed in SHR but not in 2K,1C Goldblatt hypertension. Thus, if the trait were simply a secondary consequence of hypertension from any cause, it should have been present in the 2K,1C Goldblatt-hypertensive rats, whose level of MAP was similar to that observed in SHR.
These results suggest that the complex quantitative trait of renal sympathetic neural mechanisms is causally involved in hypertension and that it lies on the pathogenetic pathway at some point between the level of the gene(s) and the expression of hypertension in SHR. Thus, the complex quantitative trait of renal sympathetic neural mechanisms is an intermediate phenotype for SHR.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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This study was supported by grants DK-15843 and HL-44546 from the National Institutes of Health and grants from the Department of Veterans Affairs.
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References |
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G. F. DiBona, S. Y. Jones, and U. C. Kopp Renal Mechanoreceptor Dysfunction : An Intermediate Phenotype in Spontaneously Hypertensive Rats Hypertension, January 1, 1999; 33(1): 472 - 475. [Abstract] [Full Text] [PDF]
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O. Grisk and G. F. DiBona Cardiopulmonary Baroreflex in NaCl-Induced Hypertension in Borderline Hypertensive Rats Hypertension, January 1, 1997; 29(1): 464 - 470. [Abstract] [Full Text] [PDF]
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