From the Institut National de la Santé et de la Recherche
Médicale (INSERM) U 141, IFR6 Circulation Lariboisière,
Université Paris VII, Paris (K.M., D.H.), and IRIS, Courbevoie (P.S.,
D.G.), France.
Correspondence to D. Henrion, PhD, INSERM U 141, Hôpital Lariboisière, 41 Blvd de la Chapelle, 75475 Paris, Cedex 10, France. E-mail daniel.henrion{at}inserm.lrb.ap-hop-paris.fr
Abstract
Abstract—High sodium intake has been
associated with a higher blood pressure level. Resistance arteries are
the main determinants of blood pressure. They are largely regulated by
pressure (tensile stress)–induced tone (myogenic tone, MT) and by flow
(shear stress)–induced dilation (FD). Thus, we studied the effect of
NaCl (8%) intake for 8 weeks on FD and MT in mesenteric resistance
arteries of spontaneously hypertensive rats. Arteries were cannulated
and mounted in an arteriograph. Intraluminal diameter was measured
continuously. High NaCl intake increased mean arterial
pressure (186±5 to 217±6 mm Hg, P<0.01).
Passive arterial diameter ranged from 112±6 to 185±9
µm (pressure from 25 to 125 mm Hg, no effect of NaCl). MT
developed in response to pressure (tone from 89±1% to 83±3% of
passive diameter, 25 to 125 mm Hg). High NaCl intake
significantly decreased MT (89±1% versus 83±3% of passive diameter
when pressure was 125 mm Hg, P<0.023). High NaCl
intake also decreased FD (6.5±0.8 versus 10±1.3 µm dilation
under a pressure of 100 mm Hg and a flow rate of 160 µL/min,
P<0.012). Thus, high salt intake decreased both flow
(shear stress)–induced dilation and pressure (tensile stress)–induced
tone in mesenteric resistance arteries. These findings might reflect
attenuation by NaCl of flow and pressure mechanosensor processes.
Flow (shear
stress)–induced dilation and pressure (tensile stress)–induced tone
(myogenic tone) are two fundamental mechanisms for the control of
vascular tone. Shear stress is a potent stimulus for vascular
endothelial cells, triggering the release of vasoactive
agents such as nitric oxide (NO), cyclooxygenase
products, hyperpolarizing factors, and contracting
factors.1 2 3 4 5 6 7 Myogenic tone develops on
stretch8 9 and is generally independent of the
endothelium.8 It is opposed by
flow-induced dilation in vitro as well as in
vivo.1 2 3 4 5 6 7 High salt intake has been widely
involved in the genesis of hypertension.10 11 12 13
Previous studies have shown a specific sensitivity of flow-induced
dilation and myogenic tone to small changes in extracellular sodium
concentration.1 14 We hypothesized that
flow-induced dilation and myogenic tone might be selectively influenced
by high salt intake. We used mesenteric resistance arteries from
spontaneously hypertensive rats (SHR) submitted to high dietary salt
intake. Vessels were isolated in vitro in an arteriograph, and pressure
(myogenic)–induced tone and flow (shear stress)–induced dilation were
determined. Myogenic tone was determined compared with passive
arterial diameter, which depends on the structure of the
arterial wall.3 4 15 16
Methods
Two groups of 6-week-old SHR (n=19) were housed separately. One
group was fed a normal NaCl diet (0.4%, control group, n=9) while the
other group was fed a high NaCl diet (8%, high sodium group, n=10).
After 8 weeks, rats were anesthetized with pentobarbital (50
mg/kg IP), and the carotid artery was cannulated (ID, 0.6 mm) to
measure blood pressure (pressure transducer, Gould P10EZ). A segment of
mesenteric resistance artery (140 µm ID, 2 mm long) was
isolated and cannulated at both ends in an arteriograph (Living System
Instrumentation Inc) as described
previously.15 16 The segment was bathed in
physiological salt solution (in mmol/L): 135.0
NaCl, 15.0 NaHCO3, 4.6 KCl, 1.5
CaCl2, 1.2 MgSO4, 11.0
glucose, and 10.0 HEPES (pH was 7.4,
PO2 was 160 mm Hg, and
PCO2 was 37 mm Hg). The
pressure in both ends of the artery segment was monitored using
pressure transducers.15 16 Flow in the vessel
could be generated through the distal pipette with a peristaltic pump.
Pressure in the proximal end of the vessel was controlled by a
servo-controlled peristaltic pump (no recirculation of the perfusing
solution). When flow was applied and pressure increased, the difference
in pressure between distal and proximal ends of the vessel was changed
so that pressure could be increased without change in flow. This
assumes that the 2 pipettes provide the same resistance to flow;
therefore, pairs of pipettes were selected to satisfy the prerequisite.
In these conditions, the average pressure between distal and proximal
pressures can be assumed to be representative of lumen
pressure.15 16 Thus, pressure and flow rate could
be changed independently.15 16
Arterial diameter was measured and recorded
continuously17 using a video monitoring system
(Living System Instrumentation Inc).
Equilibrium diameter changes were measured for intraluminal pressure
set at 25, 50, 75, 100, and 125 mm Hg (no flow). Pressure was
then set at 100 mm Hg, and flow was increased by steps from 3 to
160 µL/min. Arterial diameter was measured at each step
at the equilibrium (plateau). This was subsequently repeated after
addition of either
NG-nitro-L-arginine (L-NAME,
10 µmol/L) or indomethacin (10 µmol/L) to
the perfusion and superfusion solutions. At the end of each experiment,
arteries were perfused and superfused with a
Ca2+-free physiological salt
solution containing EGTA (2 mmol/L) and sodium nitroprusside
(100 µmol/L) to determine the passive diameter of the
arterial segments under the different levels of pressure
used (25 to 125 mm Hg). Data was collected using a Biopac MP 100
data acquisition system. Results are given in micrometers
for flow-induced dilation and as percentage of passive diameter for
myogenic tone.15 The integrity of the
endothelium was assessed by testing the vasodilator
effect of acetylcholine (1 µmol/L) after preconstriction with
phenylephrine (0.01 µmol/L) under an intraluminal
pressure of 50 mm Hg. The procedure followed in the care and
euthanasia of the study animals was in accordance with the European
Community standards on the care and use of laboratory animals
(authorization 00577).
Statistical Analysis
Drugs
Results
Mean arterial blood pressure significantly increased
in rats fed a high NaCl diet (186±5 versus 217±6 mm Hg,
P<0.01). High NaCl decreased body weight (284±10 to
265±10 g, P<0.01) and increased the ratio of heart weight
to body weight (3.45±0.09 to 4.36±0.13 mg/g, P<0.01).
Figure 1
The integrity of the endothelium was assessed by
testing the vasodilator effect of acetylcholine (1 µmol/L) after
a preconstriction with phenylephrine (0.01 µmol/L).
Phenylephrine (0.01 µmol/L) induced a contraction in
mesenteric resistance arteries from SHR (diameter from 100±5 to
19±6 µm) and in SHR fed a high NaCl diet (109±15 to 12±8
µm; no significant difference between groups). Acetylcholine (1
µmol/L) induced vasodilation of phenylephrine (0.01
µmol/L)–induced contraction in SHR (diameter from 19±6 to
103±4 µm) and in SHR fed a high NaCl diet (12±8 to
113±14 µm; no significant difference between groups).
Discussion
The major finding of the present study is that high NaCl
intake decreased both flow-induced dilation and myogenic tone in
SHR.
That high salt intake increased blood pressure and heart weight and
decreased body weight in SHR is in agreement with previous
studies.18 High salt intake causes an exaggerated
development of hypertension in rats genetically predisposed to
hypertension, such as SHR.18 It should be noted
that this sensitivity to NaCl may not apply to other strains of rats or
to nonsensitive subjects in other species.
Flow-induced dilation in SHR was resistant to NO synthase and
cyclooxygenase inhibition, which is
consistent with our previous studies.3 4
High salt intake decreased flow-induced dilation. A decreased response
to flow after sodium load has been previously shown in Dahl
rats.19 In addition, high sodium intake lowers
endothelium-dependent vasodilation to
acetylcholine18 and decreases NO synthase
activity in rats.20 Nevertheless, in SHR neither
NO nor cyclooxygenase derivatives are efficiently
involved in flow-induced dilation in mesenteric arteries, as shown in
the present and in previous studies.3 4 Thus,
the decreased flow-induced dilation found in the present study
after high sodium intake may not involve a change in NO synthase or
cyclooxygenase activity. In addition to the
possibilities given below, one explanation could be that contracting
agents released on flow stimulation were increased by the high NaCl
diet.21 Indeed, endothelin-1 is released by
flow,6 and its production increases after
high salt intake.21 22
In resistance arteries, myogenic tone decreased after high salt intake.
This may look paradoxical because salt loading increased blood
pressure. Nevertheless, myogenic tone may not be primarily responsible
for the increased blood pressure after a sodium load. Decreased
myogenic tone could reflect an adaptation to increased vascular tone
originating from other mechanisms responsible for the increased blood
pressure. In Dahl salt-sensitive rats, high NaCl intake impairs
myogenic tone in renal arterioles.23 Indeed, high
salt increases sympathetic activity.24 As
myogenic tone in resistance arteries is strongly potentiated by
sympathetic stimulation,25 a chronic
overstimulation of myogenic tone by norepinephrine might
downregulate myogenic tone. Another possibility is that such
downregulation results from an increased intracellular calcium
concentration after high salt intake.26 Such a
rise in intracellular calcium concentration might result from a
decrease in Na+/K+ ATPase
activity.27 An initial defect in renal function
would induce a rise in endogenous inhibitor(s)
of the pump (ouabain-like factors), which would in turn decrease
Na+/K+ exchanges and thus
increase vascular tone.27 28 29 It has been shown
that Na+/K+ ATPase blockade
with ouabain increases sarcoplasmic reticulum calcium filling and thus
increases vascular responsiveness to vasoconstrictor
agents.27 Indeed, calcium sequestration by the
sarcoplasmic reticulum increases in vascular cells from rats with a
high salt intake.24 Sarcoplasmic reticulum
calcium is also involved in endothelial cell response
to flow.5 29 Another possibility to explain a
decrease in both myogenic tone and flow-induced dilation is that high
salt intake could affect mechanosensors to flow and pressure, both
sensitive to small changes in extracellular sodium and probably located
in the extracellular matrix.1 30 Even without a
detectable change in the circulating level of sodium, the extracellular
glycosaminoglycanes might bind a larger amount of
cations, mainly sodium, and then increase the extracellular
concentrations in response to mechanical stimuli as they release the
cations on shear stress stimulation.1
In conclusion, chronic high salt intake in SHR decreased flow-induced
dilation and myogenic tone, reflecting a possible structural and/or
functional change in the signaling mechanisms in
endothelial and smooth muscle cells.
Acknowledgments
This work was supported in part by a grant from IRIS, Paris,
France. Khalid Matrougui is a fellow of the "Recherche et Partage"
Foundation, Paris, France.
Received January 30, 1998;
first decision February 22, 1998;
accepted April 7, 1998.
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© 1998 American Heart Association, Inc.
Third Workshop on Structure and Function of Large
Arteries: Part I
High Sodium Intake Decreases Pressure-Induced (Myogenic) Tone and Flow-Induced Dilation in Resistance Arteries From Hypertensive Rats
Key Words: myogenic tone • shear stress • blood vessels • resistance arteries • sodium
Results are expressed as mean±SE. Significance of the
differences between the different groups was determined by 1- or
2-factor ANOVA, or ANOVA for consecutive measurements when appropriate.
Values of P<0.05 were considered to be significant.
All reagents were purchased from Sigma Chemical Co. 
shows typical recordings
obtained in mesenteric resistance arteries isolated from SHR with
normal or high NaCl intake and mounted in vitro in an arteriograph.
Stepwise increases in flow induced a significant dilation in mesenteric
resistance arteries (Figures 1 and 2).
Flow-induced dilation was lower in rats with a high sodium intake
(Figure 2). In both groups, L-NAME (10 µmol/L) and
indomethacin (10 µmol/mL) did not significantly
change flow-induced dilation. For example, with a pressure of 100
mm Hg and a flow rate of 65 µL/min, the diameter was 152±7, 151±7
after L-NAME, and 152±8 µm after indomethacin
(group with 0.4% NaCl). In the group with 8% NaCl, the diameter was
167±7, 166±8 after L-NAME, and 165±6 µm after
indomethacin. Passive arterial diameter
ranged from 114±4 to 186±6 µm in rats fed a high NaCl and from
112±6 to 185±9 µm in control rats (no significant difference
between groups). Stepwise increases in pressure (25 to 125 mm Hg,
no flow) induced the development of myogenic tone that was
significantly lowered by the high NaCl diet (Figure 3). The addition of L-NAME (10
µmol/L) and indomethacin (10 µmol/L) had no
significant effect on myogenic tone in both groups (not shown).
View larger version (38K):
[in a new window]
Figure 1. Typical recordings show the changes in
diameter in response to increasing flow rates, under a pressure of
100 mm Hg, in resistance mesenteric arterial segments
isolated from spontaneously hypertensive rats with normal (A) or high
(B) sodium intake.
View larger version (24K):
[in a new window]
Figure 2. Flow (3 to 160 µL/min)-induced dilation in
resistance mesenteric arteries isolated from spontaneously hypertensive
rats with a normal (n=9) or high (n=10) salt intake. Data is expressed
as change in diameter in micrometers (mean±SE).
*P<0.001, high versus normal salt intake, 2-factor
ANOVA for repeated measures.
View larger version (22K):
[in a new window]
Figure 3. Myogenic tone determined in resistance mesenteric
artery segments isolated from spontaneously hypertensive rats with a
normal (n=9) or high (n=10) salt intake. Myogenic tone was expressed as
percentage of passive diameter (mean±SE). *P<0.001,
normal versus high salt intake, 2-factor ANOVA for repeated
measures.
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