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Heart and Circulation
Research Article
Gestational High-Salt Intake
Causes Cardiovascular
Dysfunction in Adulthood
Satomi Kagota1*, Kana Maruyama1, Bruce N Van Vliet2 and
Kazumasa Shinozuka1
Department of Pharmacology, School of Pharmacy and Pharmaceutical
Sciences, Mukogawa Women’s University, Japan
2
BioMedical Sciences Division, Faculty of Medicine, Memorial University,
Canada
1
*Corresponding author: Satomi Kagota,
Email: [email protected]
Received: 20 December 2016; Accepted: 24 January 2017; Published: 07
February 2017
Abstract
Objective: We have demonstrated that a maternal high-salt intake
administered throughout gestation and lactation causes cardiac and
vascular dysfunction in offspring of spontaneously hypertensive rats
(SHR). The objective of this study was to investigate the influence on
arterial and cardiac function of a maternal high-salt diet administered
during gestation alone versus during both gestation and lactation.
Materials & Methods: SHR were treated with either a maternal
6% NaCl diet or a control (0.3% NaCl) diet during the gestation and
suckling periods. A third group was exposed to a high-salt maternal diet
during gestation alone. After weaning, the offspring were fed control
diet or the high-salt diet for 8 weeks, and then their heart function and
vasodilation in aortas and mesenteric arteries were determined at 12
weeks of age by a Langendorff heart perfusion system and myograph
methods.
Results: Left ventricular systolic and diastolic functions were
significantly impaired in 12-week-old offspring of dams fed the highsalt diet during gestation and suckling, irrespective of post-weaning
salt intake. Left ventricular function was not altered when high-salt
was administered during gestation alone, i.e., restriction of salt intake
during suckling was associated with reduced impairment of ventricular
function. Offspring of dams fed the high-salt diet during gestation
alone had a decreased vasodilatory response to nitric oxide relative to
those of control diet-fed dams. The level of impairment was similar
to that triggered by a maternal high-salt diet during gestation and
lactation, and to that of post-weaning high-salt intake in offspring of
the normal diet-fed dams.
Conclusions: These results indicate that a maternal high-salt intake
during gestation alone is sufficient to trigger vascular dysfunction
in offspring, whereas restriction of salt intake during lactation can
attenuate the detrimental effects of a maternal high salt intake during
gestation on cardiac function.
Keywords: Cardiac function; Dietary salt; Fetal programming;
Prenatal nutrition physiology; Vascular function
Introduction
High-salt intake is widely accepted to be associated with
significantly increased risk of stroke and cardiovascular diseases
[1,2]. A recent systematic review has further added to the evidence of
associations of high sodium intake with blood pressure or adverse health
outcome including cardiovascular mortality, and supports the current
global recommendations for a reduction in dietary salt intake [3]. A
variety of mechanisms have been proposed to explain salt-induced
alterations of cardiovascular functions. Impairment of vasodilation in
Open Access
response to nitric oxide (NO) represents one of the potential underlying
mechanisms. Dysfunction of vasodilation via the NO pathway has
been shown in patients with salt-sensitive hypertension [4,5]. Oral
salt loading has been reported to suppress flow-mediated vasodilation
(presumably endothelial NO dependent) in healthy subjects [6], and to
reduce vascular NO bioactivity in young healthy normotensives [7].
Using experimental animals, high-salt intake (8%NaCl) was found to
impair vasodilation in response to NO in spontaneously hypertensive
rats (SHR) [8,9], and decreased production of or response to NO in Dahl
salt-sensitive hypertensive rats [10,11]. Increasing dietary salt loading
(4, 6 and 8% NaCl) in SHR promotes an increase in vascular resistance
independent of arterial pressure, leading to renal injury [12]. In contrast,
effects of high-salt intake on heart function has also been reported: oral
salt loading reduced left ventricular (LV) myocardial relaxation in young
healthy normotensives [7] and in young hypertensive patients [13],
and salt excess (8%NaCl) led to increased left ventricular mass,
myocardial fibrosis, and impairment of LV diastolic function in
SHR [14].
On the other hand, cardiovascular structure and function and the
risk of developing cardiovascular disease are also influenced by the
maternal environment during development, including the maternal diet
[15,16]. Fetal exposure to both inadequate maternal diet and maternal
over-nutrition have been clearly shown to influence cardiovascular
health in later life, and a growing literature points to a similar influence
of a maternal high-salt intake [16]. It has been known that increased
preference for salt develops during pregnancy in women [17,18]. Our
previous study demonstrated that offspring of SHR fed a high-salt diet
during gestation and lactation have impaired LV systolic and diastolic
dysfunctions and vasodilation in response to NO independent of postweaning salt intake, compared with offspring of SHR fed a control
diet. A high-salt intake during pregnancy and lactation has also been
demonstrated to increase fibrosis of the arterial wall and decrease
expression of soluble guanylyl cyclase (sGC), leading to impairment
of vasodilation in response to NO, in aortas of offspring in SpragueDawley rats [19]. In contrast, maternal salt during gestation alone
has been found to affect to development of heart structures, probably
mediated by the renin-angiotensin system [20,21], but there is very
limited information about the effects of maternal high-salt intake on
heart function [22]. Furthermore, very few studies have investigated the
role of the timing of the exposure to a maternal high-salt diet during
gestation and/or lactation. For instance, a high-salt diet neither during
conception to lactation nor lactation alone affect heart rates in the
borderline hypertensive rat offspring [22], and a high-salt diet during
pregnancy alone increased vascular contractility in Sprague-Dawley rat
offspring [23].
Therefore, in this study, we compared the degree of the cardiac
and arterial dysfunction induced in SHR offspring by a maternal highsalt intake administered during gestation alone with that administered
during both gestation and lactation. The findings of the current study
may provide insight regarding the most salt sensitive periods of
development, and the periods in which salt restriction may provide the
greatest protection against development of the cardiac and vascular
dysfunction in offspring.
Materials & Methods
Animals and experimental designs
As shown in Figure 1, SHR dams were fed a control (NN, 0.3% NaCl)
or high-salt (HH, 6% NaCl) diet ad libitum from 1 week before mating
Copyright © 2017 The Authors. Published by Scientific Open Access
Journals LLC.
Volume 1, Issue 1
Kagota et al.
Determination of
cardiovascular functions
(12 weeks of age)
Weaning
(4 weeks of age)
1 week
before
mating
Gestation
Lactation
After weaning
Male offspring
N
Heart Circ 2017; 1:007
N
N
14
n
h
n
h
NN_n group
NN_h group
(n = 7)
HN_n group
HN_h group
(n = 7)
(n = 7)
(n = 7)
H
H
n
h
HH_n group (n =
HH_h group (n =
7)
7)
N and n; a standard diet containing 0.3% NaCl
H and h; a high salt diet containing 6% NaCl
Figure 1: Experimental protocol for salt loading. SHR dams and offspring were given a standard diet containing 0.3% NaCl (N and n) or a
high-salt diet containing 6% NaCl (H and h).
until weaning at 4 weeks of age. A second experimental group of dams
(HN) was fed a high-salt from 1 week before mating until birth, and
was then switched to the normal salt diet until weaning. Weaned male
offspring were received from Japan SLC, Inc. (Hamamatsu, Japan) at 4
weeks of age, and they were divided into two groups of the same body
weight. Offspring were given a standard diet containing 0.3% NaCl
(n) or a high-salt diet containing 6% NaCl (h) for 8 weeks, leading to
a total of 6 experimental groups: NN_n, NN_h, HN_n, HN_h, HH_n,
HH_h group (n = 7 each). Diets were based on a standard rodent chow
(MF diet, Oriental Yeast Co., Tokyo, Japan; 7.9% moisture, 23.1%
crude protein, 5.1% crude fat, 5.8% crude ash, 2.8% crude fiber,
55.3% nitrogen free extract, supplemented with vitamins and minerals
including Ca 1.07 % and K 0.9 %).
At 11 weeks of age, offspring systolic blood pressure and heart rate
were measured using a photoplethysmographic tail-cuff system (Model
MK-2000; Muromachi Kikai Co. Ltd., Tokyo, Japan) without heating,
as described previously [24]. At 12 weeks of age, body weight was
measured under anesthesia (sodium pentobarbital, 60 mg/kg, i.p.), and
then hearts and arteries were removed from each rat. All procedures
were performed in accordance with the guidelines for the Care and Use
of Laboratory Animals at Mukogawa Women’s University.
Measurement of heart function using isolated heart by
Langendorff methods
Using an isolated Perfused Heart, Working Heart & Langendorff
system (IPH-L2A, Primetech Co., Tokyo, Japan), heart function was
determined as described previously [24]. Briefly, hearts removed from
each rat were immediately perfused with Krebs-Henseleit solution
(in mM: NaCl 118.4, KCl 4.7, MgSO4 1.2, CaCl2 2.5, NaHCO3
25, KH2PO4 1.2, and glucose 11.1) saturated with 95% O2 and 5%
CO2. A collapsed latex balloon was inserted into the LV cavity and
connected to a pressure monitoring kit (SAFTI, Kawasumi Lab., Inc.,
Tokyo, Japan) coupled to a recorder (8K21, NEC San-Ei, Tokyo,
Japan). Hearts were allowed to beat spontaneously at sinus rhythm,
and LV developed pressure (LVDP) and the maximum rate of LV
pressure decline (-dP/dt) were determined as indices of systolic and
diastolic function, respectively. Coronary flow was determined from
the Langendorff perfusion system with hearts provided with a constant
perfusion pressure of 80 mmHg.
Measurement of vasodilation in isolated aortas and
mesenteric arteries by myograph methods
Vasodilatory function was assessed as described previously [24].
Briefly, aortas and mesenteric arteries removed from each rat were
immediately placed in oxygenated Krebs–Henseleit buffer, described
above. Ring preparations were contracted by addition of 0.1–1
µM phenylephrine to generate approximately 80% of the maximal
contraction. After a stable contraction was obtained, relaxation was
elicited using nitroprusside (0.1 nM–1 µM). Individual concentrationresponse curves were analyzed by nonlinear curve fitting of relaxationdrug concentration relationships to determine the negative log EC50
using Graph Pad Prism software (ver. 5.0 for Mac, San Diego, CA,
USA).
Data analysis
Data are expressed as the mean ± SEM. Statistical analysis was
carried out with a one-way ANOVA followed by Bonferroni’s post-hoc
test (GraphPad Prism software). The results were considered significant
when P-values were < 0.05.
Results
Offspring blood pressure, heart rate, body weight, and
heart weight
The detailed protocol for salt loading is shown in Figure 1. As
shown in Table 1, at 11 weeks of age, one week before determination
of vascular and heart functions, systolic blood pressure in offspring
of dams fed high-salt diet during gestation and lactation (HH_n) was
lower than that in offspring of the control diet-fed dams (NN_n), but did
not differ in offspring of dams fed high-salt diet during gestation alone
(HN_n). A post-weaning high-salt intake was associated with increased
blood pressure in the offspring of dams fed a control diet (NN_h vs.
NN_n), but not in the offspring of dams fed high-salt diets (HN_h vs.
HN_n or HH_h vs. HH_n). There were no significant differences in
heart rate of conscious offspring among the 6 groups.
On the day of the determination of cardiac and vascular functions
(at 12 weeks of age, 8 weeks after weaning), there were no significant
differences in body weight among the 6 groups (Table 1). There were no
significant differences in heart weight-to-body weight ratio in offspring
fed the control diet (NN_n vs. HH_n and HN_n). In contrast, postweaning high-salt intake increased offspring heart weight (h vs. n).
However, this effect was significantly smaller in offspring of dams fed
a maternal high salt diet throughout gestation and lactation (HH_h vs.
NN_h, Table 1).
Citation: Kagota S, Maruyama K, Vliet BNV, et al. Gestational High-Salt Intake Causes Cardiovascular Dysfunction in Adulthood. Heart Circ
2017; 1:007.
Volume 1, Issue 1
Kagota et al.
Heart Circ 2017; 1:007
Table 1: Changes in offspring blood pressure and heart rate measured using a tail-cuff system at 11 weeks of age and body and heart weights at
12 weeks of age on the day of determination cardiovascular functions in the offspring of dams fed a standard diet containing 0.3% NaCl (N and n)
or a high-salt diet containing 6% NaCl (H and h).
Systolic blood pressure
(mmHg)
Heart rate
(beats/min)
Body weight
(g)
Heart weight
(mg/g body weight)
Ventricular heart weight
(mg/g body weight)
NN_n
HN_n
HH_n
NN_h
HN_h
HH_h
175 ± 5
176 ± 4
157 ± 5*
192 ± 5
183 ± 6
172 ± 8
395 ± 15
370 ± 11
331 ± 22
387 ± 16
338 ± 10
361 ± 14
298 ± 3
296 ± 6
305 ± 9
318 ± 5
291 ± 5
290 ± 5
4.03 ± 0.08
4.19 ± 0.07
4.09 ± 0.06
4.78 ± 0.11#
4.56 ± 0.07#
4.44 ± 0.07#*
3.74 ± 0.06
3.85 ± 0.06
3.76 ± 0.05
4.44 ± 0.09#
4.22 ± 0.06#
4.07 ± 0.07#*
#
Results are expressed as the mean ± SEM. n = 7 each group. *P<0.05, NN vs. HN and HH in offspring fed a standard or high-salt diet (effects of
mother salt); #P<0.05, n vs. h in each mother (effects of offspring salt). See Figure 1 for detailed protocol for salt loading.
B
155
*
55
_n
NN
_n
HN
_n
HH
_h
NN
_h
HN
500
_n
NN
D
10
5
_n
NN
_n
NH
_n
HH
_h
NN
_h
NH
_h
HH
*
1000
_h
15
*
1500
HH
20
*
2000
_n
HN
_n
HH
_h
NN
_h
HN
_h
HH
300
Heart beat (beats/min)
Coronary flow (mL/min)
2500
105
5
C
*
*
-dP/dt (mmHg/sec)
LVDP (mmHg)
A
200
100
0
_n
NN
_n
NH
_n
HH
_h
NN
_h
NH
_h
HH
Figure 2: Changes in left ventricular cardiac function (A, left ventricular systolic function and B, maximum rate of left ventricular pressure
decline), coronary flow (C), and heart beat (D) in Langendorff perfused heart of the offspring of dams fed a high or normal salt diet at 12 weeks
of age. Results are expressed as the mean ± SEM. n = 7 each group. *P<0.05. See Fig. 1 for detailed protocol for salt loading.
Offspring cardiac function determined by a Langendorff
heart perfusion system
LV contractile function (Figure 2A) and diastolic function (Figure
2B) were unchanged in the offspring of dams fed a high-salt diet
during gestation alone (HN_n), but were significantly decreased in the
offspring of dams fed a high-salt diet during both gestation and lactation
(HH_n). Post-weaning high-salt intake did not itself significantly
affect cardiac functions in the offspring of either control diet-fed dams
or the high-salt diet-fed dams (n vs. h, Figure 2A and 2B). There were
no significant differences in coronary flow or in spontaneous heart rate
of the isolated hearts among the 6 groups (Figure 2C and 2D).
Offspring vasodilatory
myograph methods
function
determined
by
Figure 3A and Table 2 shows endothelium-independent
nitroprusside-induced relaxations for the thoracic aortas of offspring.
The sensitivity to nitroprusside was decreased by maternal dietary salt
during gestation only (NN_n vs. HN_n), and the degree of the decrease
was the same in offspring of the high-salt diet-fed dams during both
gestation and lactation (HH_n). A decrease was also observed in
response to a post-weaning high-salt intake in offspring of the normal
diet-fed dams (NN_n vs. NN_h). In contrast, post-weaning high-salt
intake was not altered in offspring of dams fed the high-salt diet during
gestation alone (HN_n vs. HN_h) or during gestation and lactation
(HH_n vs. HH_h).
As shown in Figure 3B and Table 2, impairment of vasodilatory
responses in response to a maternal dietary high-salt diet was also
observed in mesenteric arteries of offspring of the high-salt diet-fed
dams during either gestation only or during gestation and lactation.
Discussion & Conclusion
We have previously demonstrated that a maternal high-salt (4%
NaCl) diet throughout gestation and lactation causes dysfunction of
post-weaning cardiac and vascular functions in SHR [24]. The present
study compared these functions in offspring exposed to a maternal
high-salt (6% NaCl) diet during gestation alone versus throughout
both gestation and lactation. The data of this study confirmed the
ability of a maternal high-salt diet during gestation and lactation to
impair cardiac and vascular dilator function. In addition, however,
the data also demonstrate that exposure to the maternal high-salt diet
during gestation alone was sufficient to impair vascular NO-dependent
dilation. Furthermore, the effects of maternal exposure to a high-salt
Citation: Kagota S, Maruyama K, Vliet BNV, et al. Gestational High-Salt Intake Causes Cardiovascular Dysfunction in Adulthood. Heart Circ
2017; 1:007.
Volume 1, Issue 1
Kagota et al.
A
B
100
80
NN_n
HN_n
HH_n
60
40
NN_h
HN_h
HH_h
20
0
-10
*
-log EC50
-9
-8
-7
Nitroprusside (logM)
-6
Relaxation (%)
100
Relaxation (%)
Heart Circ 2017; 1:007
80
NN_n
HN_n
HH_n
60
40
NN_h
HN_h
HH_h
20
0
-10
-9
-8
-7
Nitroprusside (logM)
*
-log EC50
-6
Figure 3: Changes in the vasodilatory response to nitroprusside in isolated aorta (A) and mesenteric artery (B) in the offspring of dams fed
a high or normal salt diet at 12 weeks of age. Results are expressed as the mean ± SEM. n = 7 each group. *P<0.05. See Fig. 1 for detailed
protocol for salt loading.
Table 2: Changes in the vasodilatory response to nitroprusside in thoracic aorta and mesenteric artery measured by myograph methods in the
offspring of dams fed a standard diet containing 0.3% NaCl (N and n) or a high-salt diet containing 6% NaCl (H and h) at 12 weeks of age.
Thoracic aorta
Mesenteric
artery
-Log EC50
Emax
-Log EC50
Emax
NN_n
8.38 ± 0.07
87.9 ± 1.2
7.78 ± 0.03
92.3 ± 1.3
HN_n
8.10 ± 0.08*
85.1 ± 1.5
7.49 ± 0.06*
89.2 ± 1.7
HH_n
8.09 ± 0.02*
89.2 ± 1.0
7.51 ± 0.06*
88.6 ± 4.3
NN_h
8.02 ± 0.08#
88.3 ± 1.3
7.33 ± 0.06#
88.1 ± 1.6
HN_h
7.90 ± 0.07
91.9 ± 1.4
7.38 ± 0.05
85.2 ± 2.9
HH_h
8.09 ± 0.03
93.2 ± 1.0
7.50 ± 0.04
90.8 ± 2.1
Results are expressed as the mean ± SEM. n = 7 each group. *P<0.05, NN vs. HN and HH in offspring fed a standard or high-salt diet (effects of
mother salt); #P<0.05, n vs. h in each mother (effects of offspring salt). See Figure 1 for detailed protocol for salt loading.
diet throughout gestation and lactation on cardiac function appeared
to be greater than those caused by exposure during gestation alone
(e.g. comparing LV functions for HN_n with HH_n in Figure 2). This
suggests that the harmful effects of a maternal high-salt diet during
gestation on cardiac function can be reduced by salt restriction during
the subsequent period of lactation.
The present study focused on the effects of maternal and offspring
salt intake on functional changes assessed in vitro in isolated hearts
and vascular segments. Our results point to important functional
effects on both the heart and vasculature in vitro. Nevertheless, it is
important to consider that these effects may be manifested differently
under the loading and neurohumoral conditions that prevail in the
intact animal. A recent study demonstrated that increased salt in the
maternal diet has lasting effects on offspring cardiovascular function
that were not only highly sex-dependent, but were also related to the
offspring’s stress-response [25]. Careful consideration will be required
to fully understand and explain the net effects of maternal salt intake
on cardiovascular function of the intact animal.
In salt-sensitive individuals or species, a high-salt intake leads to
an increase in blood pressure in the manner that we observed here in
the offspring of dams fed a standard diet (NN_n vs. NN_h group). In
contrast, a post-weaning high-salt intake did not affect blood pressure
in the offspring of dams fed a high-salt diet (e.g. HH_n vs. HH_h
group). It is not clear why a high maternal salt intake would reduce the
salt-sensitivity of offspring blood pressure, though it may reflect the
impairment of cardiovascular functions that we have observed to be
produced by maternal salt intake. In addition, the impairment could be
associated with decrease in blood pressure in the offspring of dams fed
a high-salt diet (HH_n vs. NN_n group). There have been few studies
investigating the effect of the period of maternal exposure to a high-salt
diet on blood pressure and heart functions of offspring. For example,
a maternal 8% NaCl diet from conception to weaning accelerated the
increase in post-weaning blood pressure of offspring, but maternal
high-salt intake during lactation period only was not altered in the
borderline hypertensive rat strain at 8 weeks of age [22]. In another
report, a maternal 3%NaCl diet during gestation and lactation was
found to not alter blood pressure of SHR offspring [26]. In contrast,
a maternal high-salt diet during gestation alone was reported to have
less of an effect on offspring blood pressure than exposure during both
gestation and lactation in female Brattleboro rats [27]. Furthermore,
in heart functions, neither a maternal 8% NaCl diet during gestation
nor during lactation alone was found to affect offspring heart rates in
the borderline hypertensive rats at 17 weeks of age [22]. The present
study indicates that decreases in blood pressure, unchanged heart rate,
and decrease in LV contractile and diastolic functions were observed
in SHR offspring of the 6% NaCl diet-fed dams during gestation
and lactation independent with a post-weaning high-salt diet (HH_n
groups). The extent of the dysfunction was approximately similar to
the degree induced by a maternal 4% NaCl diet during gestation and
lactation in our previous study [24]. Cardiac abnormalities, normal LV
contractile and impaired LV diastolic functions, were also described in
SHR exposed to a post-weaning 8% NaCl intake (a higher concentration
of NaCl compared to that we used) from 8 to 16 weeks of age [14]. This
suggests that a maternal high-salt intake has long-term consequences
for cardiac functions of offspring in later life, including effects that
may be similar to some of those of a post-weaning high-salt intake.
Concerning the mechanisms associated with cardiac dysfunction, we
previously demonstrated that a maternal high-salt diet reduces alphasmooth muscle-actin expression and phosphorylated phospholambanto-phospholamban ratio in SHR offspring myocardium, which would
be expected to lead to a reduced intracellular Ca2+ uptake into the
sarcoplasmic reticulum Ca2+-ATPase [28,29]. On the other hand, the
dysfunction was mild in offspring of the high-salt diet-fed dams only
during gestation (HN_n group) compared to that the effects of highsalt intake during gestation and lactation (HH_n group). These results
suggest that maternal exposure to a high-salt diet from gestation until
the early post-weaning period may be required for the full development
of cardiac dysfunction in offspring. In other words, restriction of salt
intake during lactation may be a significant approach to help reduce
cardiovascular dysfunction in offspring in later life.
The current study suggests that the period of gestation also plays
an important role in the effects of maternal high-salt intake on NOdependent vasodilation in offspring. When dams were fed with the
high-salt diet during gestation alone (HN_n group), this was sufficient
to impair the vasodilatory response to an NO-donor (nitroprusside) in
Citation: Kagota S, Maruyama K, Vliet BNV, et al. Gestational High-Salt Intake Causes Cardiovascular Dysfunction in Adulthood. Heart Circ
2017; 1:007.
Kagota et al.
Volume 1, Issue 1
offspring, and the extent of the dysfunction was the same as in offspring
of the high-salt diet-fed dams during both gestation and lactation
(HH_n group). An impaired dilatory response to NO is likely to be key
contributor to vascular dysfunction, irrespective of whether endothelial
production of NO is reduced or not. Furthermore, the extent of the
vascular dysfunction caused by a maternal high-salt diet (HN_n and
HH_n group) was the same as in the high-salt diet-fed offspring of the
normal dams (NN_h group). In other words, the influence of a maternal
high-salt diet on vascular functions was approximately equivalent
to that of a post-weaning high-salt intake. This may be the reason
that post-weaning high-salt intake did not cause further impairment
in offspring of dams fed a high-salt diet. Concerning the underlying
mechanisms, impairment of sGC-related pathway in vascular smooth
muscle cells may be anticipated to play a role based on our previous
findings that both perinatal 4% NaCl diet [24] and post-weaning 8%
NaCl diet [8,30] decreased sGC expressions in SHR arteries. This
possibility is also consistent with a recent report that a 8% NaCl
maternal diet during gestation alone increased vascular contractility
in association with decreased sGC expression in Sprague-Dawley rat
offspring [23]. In that study, nitroprusside-induced increases in cGMP
were attenuated in the arteries of offspring of the high-salt diet fed
mothers. This mechanism could also explain the decreased response to
nitroprusside in aorta and mesenteric artery in the offspring of salt fed
mothers in the present study. Taken together, the findings indicate the
potential for exposure to high-salt to lead to vascular dysfunction as a
consequence of an impaired response to NO in vascular smooth muscle
cells, particularly in aorta. In mesenteric artery, a maternal high-salt
intake (4%NaCl diet) during pregnancy and lactation was also shown
to reduce NO-independent vasodilations in fetal offspring (day 18),
weanling offspring (day 21) and adult offspring (day 135) in SpragueDawley rats [31]. Since a number of factors contribute to vasodilation
in mesenteric arteries, further studies will be required to determine the
detailed mechanisms underlying the vascular dysfunction induced by
a maternal high-salt diet in this vessel. In addition, by comparing with
the data of the present study with our previous observation [24], the
extent of the dysfunction in offspring of a 6% NaCl diet-fed dams was
greater than that in the group fed 4% NaCl diet during gestation and
lactation, suggesting that the severity of the vascular dysfunction is
likely dependent on the amount of NaCl in the maternal diet. On the
other hand, several studies and a recent review have raised concern that
excessive maternal salt restriction during pregnancy could also lead to
development of disease in adult offspring [32]. Thus, in the future, it
will be important to further define the levels of maternal salt intake
that may trigger, or prevent, cardiovascular dysfunction in offspring.
In conclusion, the results of the present study suggest that
consumption of a maternal high-salt diet during gestation alone
is sufficient to impair the vascular dilatory response to NO in adult
offspring, to an extent that is comparable with that induced by
a post-weaning high-salt diet. Furthermore, our results indicate
that consumption of a maternal high salt diet during gestation and
lactation significantly impairs offspring cardiac function, and that
this impairment can be alleviated, at least in part, by salt-restriction
during the lactation period. It has been reported that preference for salt
increases during pregnancy in women [17,18]. The data of the present
study provides a contribution to our understanding of the time periods
in which maternal salt restriction may help prevent a disturbance in
cardiovascular function in offspring.
Acknowledgments
This research was partly supported by a grant from the Salt
Sciences Research Foundation (No. 1533, to S. Kagota) in Japan. The
authors greatly thank Ms. Iwata Saki, Ms. Shiori Koyanagi, Ms. Yuki
Fukao and Ms. Madoka Nagai for their technical support.
Heart Circ 2017; 1:007
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