Monosodium Glutamate Neurotoxicity: A Sex-Specific Impairment of Blood Pressure But Not Vasopressin in Developing Rats
Monosodium Glutamate Neurotoxicity: A Sex-Specific Impairment of Blood Pressure But Not Vasopressin in Developing Rats
Monosodium Glutamate Neurotoxicity: A Sex-Specific Impairment of Blood Pressure But Not Vasopressin in Developing Rats
A 0361-9230186
$3.00 + .OO
Monosodium glutamate Blood pressure Vasopressin Water balance Dorsal vagal complex
Paraventricular hypothalamic nuclei Supraoptic hypothalamic nuclei Median eminence
Obesity Sex differences Rats
Requests for reprints should be addressed to Celia D. Sladek, Department of Neurobiology and Anatomy, University of Rochester Medical
Center, Rochester. NY 14642.
51
5, CLOUGH. ARAVICH .4ND SLADEK
TABLE 2
WET WEIGHTOF POSTERlOR PITUITARY (PP). ANTERIOR PITUITARY (AP). GONADS (CON) AND
ADRENAL GLANDS (ADR) AT SACRIFICE
Control Female 4 1.08 2 0.14 12.13 ? 0.95 67.80 + 4.74 35.18 f 2.77
NaCl Female 9 1.17 k 0.11 10.50 i 0.44 66.13 I 4.29 38.64 5 2.27
MSG Female 8 0.75 T 0.14 4.97 -t 0.45* 30.94 + 7.07* 22.41 2 1.33*
Control Male 5 1.38 f 0.16 9.66 c 0.31 1.86 T!T0.07 30.32 2 2.26
NaCl Male 9 1.43 r 0.18 9.32 i 0.64 I .83 i 0.11 29.76 + 2.61
MSG Male 7 0.93 f 0.17 5.55 i 0 ._59 1.42 i- o.ot3* 25.10 + 2.25
Mean k S.E.M.
*p<o.os.
c(n = 6).
assayed for AVP as previously described [42]. The antiserum control adrenal weights @>0.05). In other studies, a statisti-
was generously provided by Drs. Jacques Durr and Marshall cally significant decrease in adrenal weight is reported in
Lindheimer (University of Chicago) [IS]. The assay has a both male and female rats administered MSG as neonates
minimum sensitivity of 0.25 pglassay tube and a cross reac- [29,40].
tivity with oxytocin of 0.001%. Interassay variation was Systolic blood pressure and heart rate of male and female
15.6%~ rats at 6, 9 and 12 weeks of age were measured (Fig. I). A
Tissue homogenate AVP content was determined utilizing two-way ANOVA revealed a significant group difference in
a different RIA. The antiserum used in this assay was devel- SBP in female rats, F(3,18)=12.15, p<O.O005. Further
oped in conjunction with Arnel Laboratories (New York, analysis of this main effect indicated that these values in the
NY), and has been described previously 1421. This assay has MSG-treated female rats were significantly (p<O.OS) reduced
a minimum sensitivity of I .O pg/assay tube and a cross reac- relative to the control and NaCl-treated groups. There also
tivity with oxytocin of less than 0.02%. Hypothalamic tissue was a significant overall age effect in the female rats,
homogenates (VH-SON, DH-PVN, ME) were diluted 100 F(2,36):= 17.18, p<O.OOOS, but no group-by-age interac-
fold, PPs were diluted 10,000 fold and DM-DVC blocks were tion effect @>O.OS). Thus, while female rats had reduced
not diluted. For all samples, duplicate 100 or 200 ~1 and SBP compared with controls, all groups exhibited a progres-
single 25 or 50 ru;laliquots were assayed. Due to a microcen- sive increase in SBP with age. In contrast to the female rats,
trifuge malfunction, some of the brain homogenate samples a two-way ANOVA of SBP in male rats was not associated
were lost prior to assay. The specific number of subjects with a reliable group effect Q>O.OS), although there was an
included in the various assay treatment conditions is shown overall age effect across groups. F(2,36)=5.02, p<O.O5,
in the figures. which was similar to that seen across the female group. Male
rats also did not show a group by age interaction effect
@>0.05). Hence. unlike the female MSG-treated rats,
RESULTS
neonatal MSG administration failed to produce a consistent
Male and female body weight and unilateral gonadal fat reduction in SBP in male rats. Finally, no significant differ-
pad weight were measured (Table 1). The MSG-treated rats ences in heart rates were found across age or treatment
exhibited a significant degree of obesity as determined by groups in either sex @>0.05).
gonadal fat pad weight relative to body weight (female, Ad lib daily water intake was measured (Fig. 2). In abso-
F(2,18)= 16.58; male, F(2,18)=4.9, p<O.Ol). Despite the ap- lute amounts, the male MSG-treated rats consumed slightly,
pearance of obesity at sacrifice, MSG-treated animals of though significantly, less water than the control rats,
both sexes were lower in overall body weight than either of F(2,8)=7.2; p<O.Ol. However, no significant differences
the control animal groups (female, F(2,18)=8.38; male, @>0.05) were observed between MSG-treated and control
F(2,18)=40.27, pcO.01). Signi~cant divergence of body rats when basal water intake was expressed as a function of
weight by MSG-treated animals from the control levels was body weight. In addition, there were no reliabfe differences
apparent as early as day 32 after birth (data not shown). between groups in plasma osmolalities or hematocrits at the
Endocrine gland weights at sacrifice were measured in time of sacrifice (Table 3).
males and females (Table 2). The posterior pituitary gland Absolute urinary output during the 48-hour water depri-
weights, although somewhat reduced, were not affected reli- vation period also was measured (Fig. 3). A two-way
ably by MSG treatment blO.05). On the other hand, the ANOVA revealed that both female (deprivation effect,
anterior pituitary glands (female, F(2,18)=46.9; male, F(2.16)~ 107.9, p<O.OOl) and male (deprivation effect,
F(2,17)=12.9) and gonads (female, F(2,18)=3l.l; male, F(2,16)- 178.2, p<O.OOl) rats progressively reduced urine
F(2,18)=6. I) of male and female MSG-treated rats were sig- output in response to increasing hours of water deprivation.
nificantly lower in weight than the control glands @<O.Ol). Within each sex, MSG treatment failed to influence differen-
The adrenal glands of female MSG-treated rats were smaller tially the effects of water deprivation on urine output
than those of the control rats, F(2,18)=18.79, p<O.Ol. The tnonsigni~cant group and group-by-depl-ivation effects).
adrenals of male MSG-treated rats, although tending to be Likewise, no differences were found between groups when
lower in weight, were not signi~~ntly different from the urine output was expressed as a function of body weight
CLOUGH. ARAVICH AND SLADEK
Female
D ..a Control
c---+ NaCl
- MSG
6 9 12
Age (weeks)
FIG. 1. Systolic blood pressure and heart rate of female and male rats at 6, 9 and t2 weeks of age. The number of animals per
group is: female controls, 4; female MSG, 8; female and male NaCl, 9; male control, 5: male MSG, 7. *There was a consistent
reduction (p<O.OS) in SBP in the female MSG rats across the various ages. Mean2S.E.M.
(data not shown). Therefore, the ability to reduce urine out- support the claim of Van Den Buuse et al. [46], that neonatal
put in response to water deprivation was not affected by MSG treatment produces higher levels of serum AVP in
MSG treatment. adult rats. Thus we conclude that, under basal conditions,
The AVP content in brain region homogenates and neither the magnocellular AVP projection system to the
serums from female and male rats were measured (Figs. 4 neurohypophysis nor the parvocellular AVP projection sys-
and 5, respectively). Statistical comparisons revealed no tem to the DM is altered by neonatal MSG treatment.
significant group differences (p>O.O5) within either sex in It is possible that the functional controf of AVP release
AVP content of the VH-SON, DH-PVN, PP, ME and the may be altered by neonatal MSG treatment, even though
DM-DVC. As with the various brain regions, serum AVP regional AVP content is unaffected under basal conditions.
levels did not differ between groups in either sex @>0.05). The circumventricular organs play an important role in the
regulation of AVP release [27, 28, 441 and are damaged by
neonatal MSG treatment 1241. Therefore, the functional
DISCUSSION
status of the vasopressinergic system was examined in the
This investigation confirms several previous findings of present experiment. Monosodium glutamate-treated rats
the MSG Obesity Syndrome [311 and provides new data demonstrated normal basal water intake and urine output,
regarding neurohypophyseal AVP and hemodynamic func- and displayed a normal capacity to decrease urine output in
tion. response to water deprivation. There was no indication of
We found that neonatal MSG-treatment resulted in obe- abnormalities in the antidiuretic response of MSG-treated
sity, judged by relative gonadal fat pad weights, hypo- rats to chronic dehydration. Plasma hematocrit and osmolality
gonadism, reduced anterior pituitary gland weights and also were found to be within normal limits at the time of sac-
reduced adrenal weights (in male rats, however, p>O.OS). rifice. These data support the conclusion that AVP release in
Thus, the animals in this experiment exhibited the classic response to dipsogenic stimuli such as hypertonic saline [25] or
features of the MSG toxicity syndrome [i, 6, 9, 19, 29, 36, water deprivation (present study) is not altered by neonatal
37, 401. MSG treatment. The selective effects of MSG on other
In contrast to MSGs effects on anterior pituitary function stimuli to AVP release [25] indicate that MSG-induced toxi-
129,401, the neurotoxin had no effect on the content of AVP city has differential effects on the varied mediators of AVP
in SON, PVN, DVC, PP, ME or serum. While this conclu- release.
sion is baaed on limited samples in some groups, the present Unlike the lack of effect of MSG on the AVP system,
regional microdissection results are consistent with previous female MSG-treated rats had significantly lower SBP com-
findings obtained from whole hypothalami and whole pitui- pared with the control and NaCI-treated groups. Although
tary homogenates [21]. The serum AVP analysis also is con- there appeared to be a transient reduction in SBP of male
sistent with the results of Knepel et ul. [21], but fails to rats at 9 weeks of age, male SBP was not statisticaHy altered
MSG, BLOOD PRESSURE AND AVP 55
TABLE 3
PLASMA OSMOLAL~TIES fPOsmf AND HEMATOCRITS (%Hct) IN
FEMALE AND MALE RATS
POsm
Group N mosmoVkg Hz0 % Hct
Mean 2 S.E.M.
Female
Female
9
1 15
9
z
._
3
1C
f
B
Male
5
FIG. 2. Twenty-four-hour water intake in absolute terms and rela-
tive to body weight in female and male rats. The number of animals
per group is indicated over the co~esponding column. Male MSG-
treated rats consumed less water than NaCl or NaCi-treated rats in C
absolute terms @<O.OS) however when corrected for body weight
there were no significant differences. Mean+S.E.M. Solid column:
Male o- - -a Colltrd
control; striped column: NaCI; dotted column: MSG.
O--Q NaCl
O---O MSG
2c
T i
180
I
WJ
I40
120
loo
80
60
43
16
FIG. 4. AVP content of female ventral hypothalamic-supraoptic nuclei (VH-SON), dorsal hypothalamic-paraventricular
nuclei (DH-PVN), dorsal medulla-dorsal vagal complex (DM-DVC), median eminence (ME), posterior pituitary (PP)
homogenates and serum. The number of animals per group is indicated over the corresponding column. Mean2S.E.M.
Columns same as Fig. 2.
FIG. 5. AVP content of male ventral hypo~~amic-supraoptic nuclei (VH-SON), dorsal hypothalamic-p~ra~ent~cu~ar
nuclei (DH-PVN), dorsal medulla-dorsal vagai complex (DM-DVC), median eminence (ME), posterior pituitary (PP)
homogenates and serum. The numbers of animals per group is indicated over the corresponding column. Mean2S.E.M.
Colunks same as Fig. 2.
the AV3V region exhibits a variety of anatomical and neuro- been implicated in the pathogenesis of some forms of hyper-
chemical sex differences in rats [3,11]. Brainstem structures tension. Supporting this view, gonadectomy can red,uce
represent additional possible loci of the MSG effect on blood blood pressure in male hypertensive rats [lo]. Qespite the
pressure in females. There have been descriptions of MSG- fact that the male MSG-treated rats in the present study were
induced lesions in the DM [24,33], an area known to partici- hypogonadal and presumably had markedly reduced serum
pate in cardiovascular regulation [4If. While lesions of the testosterone concentrations 1301, they were not hy~ot~nsivc
AV3V, hypothalamus and DM may contribute to the ob- relative to controls. Thus, based on the available data, it
served hypotension in MSG-treated females, this effect ap- appears unlikely that the sex difference in MSG-induced
pears to be unrelated to changes in neural AVP. hypotension is a consequence of the effects of MSG on cir-
Circulating sex steroids have also been implicated in the culating gonadal steroids.
control of blood pressure in rats [lo]. However, the sex Finally, an alteration in the renin-angiotensin-aldosterone
steroids do not seem to have contributed to MSG-induced system (RAAS) also could contribute to the observed
hypotension in the female rats in the present study. While it hypotension in MSG-treated female rats. In the present
is clear that MSC-treated female rats exhibit severe ovarian study, overall adrenal gland weights were reduced reliably in
dysgenesis and maintain a greatly reduced serum estradiol female but not in male rats. Therefore, the RAAS may be
concentration compared to controls {30], gonadectomy in compromised in female rats. However, male adrenal gland
female hypertensive rats increases [I31 or has no effect ilOJ weights are consistently reduced in other MSG studies
on blood pressure. The androgens, on the other hand, have [29,40] and tended to be reduced in the present study. In
MSG, BLOOD PRESSURE AND AVP 51
addition, blockade of the RAAS in salt-repleted normotensive tain blood pressure at a lower level, and that this resetting of
animals does not, in and of itself, reduce blood pressure 1231. the baroreflex mechanism occurs independent of any central
In summary, the present investigation reveals that the or peripheral vasopressin changes.
AVP content of the posterior pituitary, hypothalamus and
lower brainstem is resistant to the neurotoxic effects of
neonatal MSG in rats, and that MSG has little influence on ACKNOWLEDGEMENTS
antidiuresis to chronic dehydration. In contrast, MSG exerts This work was supported by grants ROl-HL-28172 and
a sexually dimorphic hypotensive effect in female ROI-AM-19761 from the United States Public Health Service
Sprague-Dawley rats, which is not associated with a com- (C.D.S.), and by National Research Service Awards 1 F32 MH-
pensatory elevation in heart rate or circulating AVP concen- 09136 (R.W.C.) and 1 F32 MH-08872 (P.F.A.). We are grateful to
tration. These observations suggest that baroreflex mech- Ms. Carol Sterling for her laboratory assistance and to Dr. Michael
anisms have been reset in MSG-treated female rats to main- Mangiapane for his comments on the manuscript.
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