(Hypertension. 2000;35:609.)
© 2000 American Heart Association, Inc.
Scientific Contributions |
Role of 
2-Adrenergic Receptor Subtypes in the Acute Hypertensive Response to Hypertonic Saline Infusion in Anephric Mice
From the Hypertension and Atherosclerosis Section of the Department of Medicine, Boston University School of Medicine, Boston, Mass.
Correspondence to Haralambos Gavras, MD, Hypertension and Atherosclerosis Section, Boston University School of Medicine, 715 Albany St, Boston, MA 02118. E-mail hgavras{at}bu.edu
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Abstract |
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Abstract—Experimental evidence suggests that the acute hypertensive response induced in anephric animals by infusion of a hypertonic saline solution is mediated by disinhibition of the presynaptic sympathoinhibitory
2-adrenergic receptors (2-AR) of the
central nervous system. The purpose of the present
experiments was to dissect the role of the 3 distinct
2-AR subtypes (2A-, 2B, -
and 2C-AR) in this response. Groups of genetically
engineered mice deficient in each one of these 2-AR
subtype genes were submitted to bilateral nephrectomy followed by a
0.4-mL infusion of 4% saline over a 2-hour period, with constant
direct blood pressure (BP) monitoring. The
2A-AR–deficient and 2C-AR–deficient
mice responded with significant BP elevations (by 11.8±2.5 and
16.7±1.7 mm Hg, respectively), and so did their wild-type
counterparts (17.8±2.5 and 11.8±2.0 mm Hg, respectively) and
the wild-type 2B +/+ (13.1±2.4 mm Hg). However,
the 2B-AR–deficient mice were unable to raise their BP
and had a slightly lowered BP (by -3.0±4.0 mm Hg) at the end of
the infusion period. All 6 groups exhibited elevated plasma
norepinephrine levels ranging between 0.8 and 1.8 ng/mL at
the end of the infusion. In all cases, the
2-AR–deficient groups tended to have higher
norepinephrine levels than their wild-type counterparts.
Surprisingly, this difference was significant only in the
2B-AR–deficient mice, which, despite the elevated
norepinephrine, were unable to raise their BP. The data
suggest that a full complement of the 2B-AR is needed to
mediate the hypertensive response to acute saline load, even though its
absence does not prevent the release of norepinephrine
under these conditions.
Key Words: receptors • genes • hypertension, experimental
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Introduction |
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It is well established that short-term and long-term salt loading raises blood pressure (BP), but the precise underlying mechanism(s) remain unclear. A number of experimental data support the view that sodium loading elicits a pressor response mediated in the early stages by an increase in the release of arginine vasopressin (AVP) and maintained by increased sympathetic nervous system (SNS) activity.1 Indeed, previous studies from our laboratory2 3 and others4 5 have demonstrated that in anephric rats, hypertonic saline infusion induced an increase in BP that was mediated partly by AVP release and partly by activation of the SNS.3 Furthermore, it has been shown previously that hypertonic saline administration directly into the cerebral ventricles6 or into the nucleus tractus solitarii (NTS),7 8 which is one of the major centers for cardiovascular control, resulted in a sharp elevation in BP accompanied by increased sympathetic activity. There is evidence indicating that the hyperadrenergic state that accompanies the later stages of salt-induced hypertension results from a centrally diminished sympathoinhibition, leading to increased peripheral sympathetic outflow and vasoconstriction.9
Experimental evidence suggests that the salt-induced sympathetic
activation is mediated by centrally located presynaptic
2-adrenergic receptors
(2-ARs).9 10 11 Although the
precise mechanism by which salt affects the
2-ARs has not been fully elucidated, data from
in vitro12 and in vivo13 studies suggest that
sodium decreases the affinity of 2-ARs for
naturally occurring agonists, resulting in sympathetic disinhibition
and increase in systemic BP. Three well-characterized
2-AR subtypes (2A,
2B, and 2C) have been
isolated,14 but to date, ligands with high subtype
selectivity have not yet become available.15 Recently,
however, the availability of genetically engineered mice lacking the
2A-AR,16
2B-AR,17 or
2C-AR18 subtype gene has provided
a useful tool that can be used to clarify the
physiological function of each one of these
2-AR subtypes. The present experiments
were designed to explore the contribution of each of the 3 subtypes in
a model of acute hypertonic saline–induced hypertension, with the use
of anephric genetically engineered mice with altered
2A-AR, 2B-AR, or
2C-AR subtype gene.
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Methods |
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Animals
Six groups of male mice, 9 to 11 weeks old, weighing 24 to 27 g, were used in these experiments. Two groups of homozygous knockout (-/-) mice for the
2A-AR (n=9) and
the 2C-AR subtype gene (n =10) and 1 group of
heterozygous (+/-) 2B-AR subtype
gene–deficient mice (n=9) were compared with an equal number of their
appropriate wild-type (+/+) counterparts. The receptor
phenotype of the 2A -/- mice has
been confirmed in brain membranes by saturation binding with
3H-RX8221002, a nonselective
2-AR antagonist, concurrently with
competitive binding with yohimbine. The pattern of displacement of
3H-RX8221002 by yohimbine confirmed that the
residual 2-AR in these mice is not of the
2A-AR subtype.16 The
phenotype of 2B -/- has been
confirmed in kidney membranes from the pattern of
3H-yohimbine saturation-binding analysis,
competed with unlabeled prazosin.17 The
2C-AR -/- phenotype has been
ascertained by the markedly reduced
3H-rauwolscine binding in the caudate putamen and
other brain regions normally expressing 2C-AR
binding sites.18 However, homozygous
2B -/- gene knockouts were not available in
sufficient numbers because they do not breed well. Heterozygous
2B-AR gene–deficient mice were deemed
acceptable because they have been shown to have a lower level of
expression of the 2B-AR protein17
and have demonstrated an attenuated hypertensive response to long-term
salt loading aided by subtotal nephrectomy.19 The animals
were housed in the animal quarters and given free access to food
(Purina Certified Rodent Chow, 5002) and distilled water.
Genotypes were confirmed by polymerase chain reaction from DNA
isolated from the tail or spleen of the animals as described
elsewhere.19 20 All experiments were conducted in
accordance with the Institutional Guidelines for the Care and Use of
Animals approved by the Boston University Medical Center.
Surgical Protocol: BP Recording
All mice were submitted to right nephrectomy through a flank
incision under anesthesia induced by sodium pentobarbital
(50 mg/kg IP). The animals were then returned to their cages and
allowed a 5- to 7-day recovery period. Subsequently,
arterial and venous catheterization was
performed under anesthesia in all animals. Briefly, a
modified polyethylene PE-50 catheter was introduced into the right
iliac artery for direct BP recording and a silastic tubing was
placed into the right iliac vein for hypertonic saline infusion. Both
catheters were tunneled subcutaneously and exteriorized at the back of
the animal’s neck, filled with heparin in 0.9% saline solution, and
sealed with heat. After surgery the animals were returned to their
cages and allowed an overnight recovery period. On the following day
the remaining left kidney was removed under anesthesia
induced by isoflurane inhalation delivered by a face mask (2%
isoflurane, 100% oxygen). Five to 6 hours after the completion of left
nephrectomy, the arterial catheter was connected to a BP
transducer attached to a recorder (model 220S, Gould, Inc) for
direct BP monitoring. The venous catheter was connected to a Harvard
infusion pump for hypertonic (4%) saline infusion. The solution,
containing 0.68 mEq NaCl/mL, was infused over a period of 2 hours at a
rate of 0.0033 mL/min for a total of 0.4 mL, which represents a
10% increase in blood volume. Direct arterial pressure was
continuously recorded during the control period and throughout the
2-hour saline infusion period. At the end of the infusion, blood was
drawn from the arterial line for determination of plasma
catecholamine levels.
Plasma Catecholamine Level Determination
For assay of plasma catecholamine levels, 100 µL
of blood was drawn slowly from the arterial line, and
norepinephrine and epinephrine levels were measured
with the use of the BioTrak Catecholamine Research Assay
System TRK 995 (Amersham Life Sciences), as described
elsewhere.20
Statistical Analysis
All data are presented as mean±SEM. Student’s
t tests for paired and unpaired data were used as
appropriate. The Mann-Whitney rank sum test was used for
nonparametric data. Differences at a level of
P<0.05 were considered to be significant. Each group of
genetically engineered mice was compared with a group of wild-type mice
from the same parent strain because small but significant variations
exist between wild-type strains.
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Results |
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Figure 1 shows the time course of BP changes during the 2-hour hypertonic saline infusion in all 6 groups of mice. Panel A presents BP changes in
2A-AR
+/+ (n=9) and 2A-AR -/- (n=9) mice and shows
that in both groups BP increased significantly at the end of the 2-hour
infusion period (paired t test). Panel B shows BP changes in
2B-AR +/+ (n=9) and
2B-AR +/- (n=9) mice. Hypertonic saline
infusion induced a significant BP elevation in the
2B-AR +/+ animals (paired t test).
However, the 2B-AR +/- mice failed to develop
a similar BP rise and the hypertonic saline infusion resulted in a
small BP decrease at the end of the 2-hour infusion period. This
difference in BP changes between the 2 groups was evident by the first
hour of infusion but attained significance after 90 minutes of
infusion. Panel C presents BP changes in
2C-AR +/+ (n=10) and
2C-AR -/- (n=10) mice and shows that both
groups exhibited significant BP elevations (paired t test)
at the end of the 2-hour infusion period.
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, Wild-type mice; •, genetically altered mice. A,
Figure 2 summarizes mean differences in
BP (
BP) from control to the end of the 2-hour hypertonic saline
infusion in each group of mice studied. A lesser BP was observed in
the 2A-AR -/- mice compared with their
wild-type (+/+) counterparts (11.1±0.8 vs 17.8±2.5 mm Hg,
respectively, P=0.02), mainly because the knockouts started
at a somewhat higher baseline, as both groups attained the same end
point BP. Mean BP from control was also different between the
2B-AR +/- and 2B-AR
+/+ mice (-3.0±4.0 vs 13.1±2.9 mm Hg, respectively,
P<0.01). Mean BP was not different in the
2C-AR -/- versus the
2C-AR +/+ mice (16.7±1.7 vs 11.8±2.0
mm Hg, respectively).
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Figure 3 summarizes plasma
catecholamine levels obtained at the end of the 2-hour
hypertonic saline infusion in all 6 groups of mice. Panel A
presents plasma norepinephrine and epinephrine
levels in 2A-AR +/+ and
2A-AR -/- mice and shows that both
norepinephrine and epinephrine levels tended to be
higher in the 2A-AR -/- mice compared with
their wild-type +/+ counterparts, but this difference was not
significant. Paradoxically, as shown in panel B, plasma
norepinephrine levels were significantly higher in the
2B-AR +/- mice, which failed to respond with
a BP increase, than in the 2B-AR +/+ mice,
whose BP did increase to the same extent as all other groups.
Epinephrine levels were not different between the 2 groups.
Thus, although 2B-AR +/- mice did exhibit
elevated plasma norepinephrine levels in response to
hypertonic saline infusion, this was not accompanied by a BP rise.
Panel C presents plasma catecholamine levels in
2C-AR +/+ and 2C-AR
-/- mice and shows that plasma norepinephrine levels
tended to be higher in the 2C-AR -/- group,
though not significantly so, whereas plasma epinephrine levels
were similar in both groups.
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Discussion |
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A large number of experimental studies indicate that salt-induced hypertension is characterized by increased peripheral vascular resistance. It has been proposed that salt loading in the initial phase acts on the paraventricular hypothalamic region to stimulate the release of AVP, which modulates central SNS activity, resulting in excessive sympathetic outflow and peripheral vasoconstriction.1 Many studies have implicated the
2-ARs in this centrally
mediated, diminished sympathetic inhibition,21 but the
subtype(s) involved in this process have not been clarified as yet.
The major finding in the present set of experiments is the
inability of the 2B-AR–deficient anephric
mice to raise their BP in response to an acute hypertonic saline
stimulus. In all other groups of anephric mice, hypertonic saline
infusion elicited a significant elevation in BP, whereas in the
2B-AR–deficient group BP remained essentially
unchanged during the 2-hour infusion period. The results of the
present experiments are consistent with our previous
studies19 20 in which subtotally nephrectomized
2B-AR +/- mice had an attenuated BP elevation
in response to long-term dietary salt loading, whereas animals with a
complete lack of the 2C-AR or the
2A-AR subtype gene developed hypertension to
the same extent as their wild-type counterparts. Data from recent
studies suggest that central sympathetic outflow is predominately
regulated by the 2A-AR
subtype,16 22 although one or both of the other subtypes,
in particular the centrally located 2B-AR
subtype in the NTS, locus ceruleus, and other regulatory areas of the
brain stem,23 do contribute to a lesser extent to this
function. There is also evidence that the
2B-AR subtype is involved in the initial
vasoconstrictive effect of intravenously
administered 2-AR agonists.17 Our
results would be in keeping with these studies because they show that
the 2B-AR–deficient mice were unable to raise
their BP despite a more-than-adequate release of
norepinephrine triggered by salt loading. Therefore the
salt-induced BP elevation is either directly or indirectly mediated by
the 2B-AR subtype by a mechanism that remains
to be defined.
The dissociation between plasma norepinephrine levels and
BP in the 2B-AR +/- mice was an unexpected
finding in these studies. In a previous set of
experiments19 we described the inability of
2B-AR +/- mice to develop
hypertension in response to long-term salt loading after subtotal
nephrectomy. We speculated on the possible mechanisms, including the
possibility of abnormal renal handling of sodium (ie, inability to
retain sodium) in the absence of a full complement of functional
2B-AR or inability to stimulate the release of
norepinephrine by central SNS neurones. The current
experiments effectively rule out both of these possibilities:
Accumulation of sodium in the extracellular space was equal in all
anephric animals, and stimulation of norepinephrine release
did occur in the 2B-AR +/-
heterozygotes, even more so than in their wild-type
counterparts. MacDonald et al15 have proposed that
activation of the 2B-AR subtype counteracts
the hypotensive effects of the activation of the
2A-subtype, that is, the
2B-AR has a hypertensive function, but these
investigators believe that the 2B-AR is
exclusively located in the vascular wall, and its effect can only be
that of direct vasoconstriction.15 17 However, in previous
experiments with in situ hybridization, we have detected
2B-AR mRNA throughout the rat brain and have
found particularly high density of this message in the areas of the NTS
and the locus ceruleus,23 that is, the centers of
baroreflex control. On the contrary, we were unable to detect
2B-AR in the arterial wall of
rabbits, whereas 2A-AR were abundant in
endothelial and smooth muscle cells.24
In the 2B-AR–deficient mice it is difficult
to attribute the lack of hypertension from excessive levels of
circulating catecholamines to inadequate
arterial constriction resulting from
2-AR deficiency because
catecholamine-induced vasoconstriction is mainly an
1-AR–mediated effect.25 One
plausible though speculative explanation for our findings is that the
2B-AR indeed has a hypertensive function but a
centrally mediated one. In other words, activation of the
2B-AR would oppose the hypotensive effect of
the 2A-AR in the central nervous system
centers of vascular tone regulation. In such a case, excessive levels
of circulating catecholamines in
2B-AR–deficient mice result in unopposed
activation of the central presynaptic 2A-AR
and therefore tend to further lower the systemic BP, which is precisely
what we found in these mice (Figure 1B). This interpretation is
not in conflict with the data of Link et al,17 although
these authors chose to interpret their findings differently. It is
notable that catecholamines also can activate
vasodilatory receptors on the vascular wall, such as the
ß2-adrenergic and dopaminergic receptors, so
that the vasomotor response is the sum of multiple constricting and
dilating influences.
A confirmatory but interesting finding in the present studies was
that the 2A-AR knockout animals, starting from
a higher baseline BP, exhibited a lesser increase in BP compared with
their wild-type (2A-AR +/+) counterparts in
response to the hypertonic saline infusion, although both groups
attained the same BP level at end point. This is in agreement with
recent reports suggesting that the 2A-AR
subtype, which appears to be the major subtype in brain areas involved
in cardiovascular regulation,23 plays a
critical role in regulating sympathetic outflow, since
2A-AR mutant mice22 or
2A-AR knockout mice16 were unable
to exhibit hypotension in response to 2-AR
agonists. Moreover, 2A-AR -/- mice have
higher control BP, heart rate, and plasma norepinephrine
levels compared with their wild-type (+/+) counterparts,20
which indicates that lack of the 2A-AR results
in loss of sympathetic restraint.
In conclusion, our present data indicate that a complete
expression of the 2B-AR subtype is required
for BP elevation in response to an acute hypertonic saline stimulus in
anephric animals and corroborate previous findings that an intact
2A-AR subtype is necessary to maintain tonic
sympathoinhibitory control. Our hypothesis that
adrenergically mediated hypertension is a function of the central
2B-AR subtype needs further confirmation. If
true, it would mean that selective blockade or inactivation of this
subtype may achieve dissociation of the hypotensive effect from the
side effects that are part of the pharmacological action of currently
used antihypertensive 2-AR agonists such as
clonidine (eg, sedation and impotence), which are believed to be
2A-AR mediated.
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Acknowledgments |
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These studies were supported in part by National Institutes of Health grant 1P50-HL-55001. The authors wish to thank Dr Brian K. Kobilka for providing the breeders of the mice used in these experiments.
Received July 15, 1999; first decision August 12, 1999; accepted September 23, 1999.
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