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© 1995 American Heart Association, Inc.
Articles |
Hormonal Dependence of the Effects of Metabolic Encephalopathy on Cerebral Perfusion and Oxygen Utilization in the Rat
From the Neuroradiology Section, University of California at San Francisco (E.K., T.P.L.R., Z.S.V., J.K.); the Department of Clinical and Applied Physiology, School of Medicine, Warsaw, Poland (E.K., M.O.); and the Department of Medicine, Geriatrics Section, Veterans Affairs Medical Center and University of California at San Francisco (A.I.A.).
Correspondence to Allen I. Arieff, MD, Department of Medicine, V.A. Medical Center (111G), 4150 Clement Street, San Francisco, CA 94121.
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Abstract Previous studies have demonstrated that in adult rats with chronic hyponatremia, both symptoms of encephalopathy and mortality largely depend upon the gender of the animal and the presence of elevated plasma levels of vasopressin (AVP). Since effects of AVP on blood vessels may be gender dependent, the present study was designed to compare the effects of chronic (4 days) hyponatremia on cerebral blood flow (CBF), cerebral oxygen consumption (CMRO2), and cerebral perfusion index (CPI) in adult male and female rats. CBF (intra-arterial 133Xe injection method) and CMRO2 (arteriovenous difference of cerebral oxygen contentxCBF) were measured in normonatremic and hyponatremic (hyponatremia induced with 140 mmol/L glucose and either AVP or desmopressin [dDAVP], plasma sodium=100 to 110 mmol/L) adult rats of both genders. The CPI was assessed from magnetic resonance imaging of the transit of magnetic susceptibility contrast agent through the brain. Female rats with AVP-induced chronic hyponatremia had a 36% decrease in CBF and a 60% decrease in CMRO2. In male animals, both parameters were not different from control values. AVP-induced hyponatremia resulted in a 45% decrease in CPI in female rats, but hyponatremia induced with dDAVP did not affect CPI in either male or female rats. Chronic (4 days) administration of AVP did not affect CPI in either male or female normonatremic rats. When rats with AVP-induced chronic hyponatremia were pretreated with estrogen, the CPI in males was not different from that in females. Our results demonstrate that during AVP-induced chronic hyponatremia in female rats, there is significant depression of both oxygen utilization and blood flow in the brain.
Key Words: cerebral blood flow • hyponatremic encephalopathy • vasopressin • estrogen • hyponatremia • brain oxygen utilization
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Introduction |
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Epidemiological and experimental evidence indicates that several steroid hormones, including estrogen, have important cardiovascular effects. This may in part explain the different incidence of arteriosclerosis in men compared with premenopausal women and the increased risk of cardiovascular diseases in women taking oral contraceptives and men taking estrogen.1 2 Hyponatremia is one of the most common fluid and electrolyte abnormalities observed in hospitalized patients.3 4 5 Recent studies show that although the incidence of hyponatremia is similar in male and female patients,5 the risk of permanent brain damage is at least 25 times higher for premenopausal women than for either men or postmenopausal women.4 5
The reasons for the propensity of hyponatremic brain damage to occur in young, menstruant women are unclear. Some authors have pointed to a possible important role of vasopressin (AVP) in the pathogenesis of hyponatremic brain damage.6 The plasma levels of this peptide are elevated in virtually all hyponatremic patients,3 7 8 as well as those suffering from stroke or other lesions of the central nervous system.9 10 The elevations are primarily due to the effects of nonosmotic stimuli for the release of vasopressin.11
Our previous studies using the rat model of chronic AVP-induced hyponatremia are in general agreement with the above-described clinical observations.12 13 14 The mortality among female rats with chronic AVP-induced hyponatremia is above 60%, whereas that of male rats with AVP-induced hyponatremia and similar plasma sodium level is less than 30%.12 When hyponatremia is induced using a selective V2 vasopressin receptor agonist, desmopressin (dDAVP), instead of AVP, the mortality from hyponatremic encephalopathy is substantially decreased.13 14 These results suggest that an interaction between AVP, acting through V1 receptors, and female sex hormones plays an essential role in the course and consequences of hyponatremic brain damage in the rat model of hyponatremia. The AVP dependence of hyponatremic brain damage suggests the possibility of the impairment of the cerebral circulation in hyponatremic female rats due to the presence of vasopressin.
Vasopressin is a potent endogenous vasoconstrictor, and it has been demonstrated that exogenous AVP, when given in large doses, may result in the V1 receptor–dependent constriction of cerebral blood vessels.15 16 17 18 Much of the data on the cerebrovascular effects of vasopressin has been collected from studies performed in male animals, assuming that there were no sex-dependent differences in the responsiveness of cerebral circulation to vasopressin. There is, however, increasing evidence that such differences exist in peripheral blood vessels. According to these data, sex hormones modulate constriction of peripheral arterioles to vasopressin and norepinephrine.19 20 21 22 The present study was designed to investigate cerebral perfusion in the rat model of chronic hyponatremia in relation to gender and vasopressin effects.
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Materials and Methods |
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The experimental protocol was approved by the Animal Studies Subcommittee, Veterans Affairs Medical Center, and by the Committee on Animal Research, University of California at San Francisco.
Experiments were performed on male and female adult Sprague-Dawley rats weighing 220 to 280 g. The animal groups comprised normonatremic controls (group A, n=37), hyponatremic with AVP (group B, n=45), hyponatremic with dDAVP (group C, n=13), normonatremic with AVP (group D, n=11), normonatremic treated for 6 weeks with estrogen (group E, n=23), hyponatremic with AVP after 6 weeks of estrogen treatment (group F, n=13), normonatremic treated for 6 weeks with testosterone (group G, n=6), hyponatremic treated for 6 weeks with testosterone (group H, n=10), normonatremic with hypocapnia (group I, n=5), and hyponatremic with AVP plus hypocapnia (group J, n=5).
Chronic hyponatremia was induced in groups B, F, and H over a 4-day period by the twice-daily administration of either subcutaneous vasopressin in oil (200 µU/100 g) or the vasopressin analog 1-deamino-8-D-arginine vasopressin (desmopressin [dDAVP], 60 ng/100 g) subcutaneously (group C) in conjunction with 140 mmol/L glucose/H2O (8% body weight, IP). Group D received AVP (200 µU/100 g) twice daily subcutaneously over the same period of time as group B.
In groups E and F, prepubertal rats were continuously treated for 6 weeks with estrogen. At the age of 5 days, these rats received subcutaneous implants of continuously releasing estrogen pellets (17ß-estradiol, 0.5-mg pellets, 21-day release; Innovative Research of America) under local (lidocaine) analgesia. The pellets were reimplanted every 21 days during chronic studies in adult rats.
In groups G and H, prepubertal rats were continuously treated for 6 weeks with testosterone. At the age of 5 days, these rats received subcutaneous implants of continuously releasing testosterone pellets (testosterone propionate, 1.5-mg pellets, 21-day release; Innovative Research of America) under local (lidocaine) analgesia. The pellets were reimplanted every 21 days during chronic studies in adult rats.
Adaptation to hyponatremia was assessed by measuring brain water and electrolyte content. An index of cerebral perfusion (CPI) was assessed, using magnetic resonance imaging (MRI).23 In addition, cerebral blood flow (CBF) and cerebral metabolic rate for oxygen (CMRO2) were determined in female and male rats from groups A and B.
The animals had free access to water and commercial chow pellet until the day of the study. During the experiment, they were anesthetized with chloral hydrate (36 mg/100 g body weight, IP), paralyzed with pancuronium (0.05 mg/100 g body weight, IV), and mechanically ventilated with 30% O2/70% N2O. Body temperature was controlled and maintained at 37°C with a heating pad. A femoral artery was cannulated to allow continuous measurements of mean arterial blood pressure (MABP) and arterial blood sampling for blood gas analysis (PaO2, PaCO2, pH). Another catheter was placed in a femoral vein for the administration of magnetic susceptibility contrast agent and supplementation of anesthesia and muscle relaxant. The animals were kept normocapnic by appropriate adjustment of ventilatory parameters, as necessary. The PaO2 was maintained above 95 mm Hg. In groups I and J, arterial hypocapnia was induced by increasing the tidal volume to achieve a PCO2 of 30 mm Hg or less.
CBF was measured using the intracarotid 133Xe injection technique as described by Hertz et al.24 The catheter for 133Xe injection was placed centripetally in the external carotid artery after ligation of the pterygopalatine artery and small branches of the external carotid artery on the side of isotope injection. For CBF measurement a bolus of 133Xe was injected in a volume of 15 to 50 µL of 154 mmol/L NaCl solution. The radioactivity of 133Xe was detected by a well-collimated scintillation crystal attached to a photomultiplier mounted over the ipsilateral temporoparietal region. CBF was calculated from the initial slope (15 seconds) of the semilogarithmically displayed clearance curve and expressed in mL/100 g per minute.
The CMRO2 was calculated from arteriovenous oxygen difference (arterial versus sagittal sinus blood) using the Fick principle and expressed in mL/100 g per minute. To allow access to the sagittal sinus blood, a 1-mm-diameter needle was mounted with dental cement in a hole bored out in the cranium 3 mm anterior to the lambda suture. Cerebral vascular resistance (CVR) was calculated as the ratio of MABP to CBF and expressed in mm Hg · 100 g · minutes per milliliter.
MRI was performed on a 2-T Omega CSI system (Bruker Medical Systems) equipped with Acustar S-150 self-shielded gradients (20 G/cm, 15 cm internal diameter). The rats were positioned with their heads inside a 40-mm–internal diameter RF excitation/detection coil. The image slice plane was chosen as a 3-mm coronal section at approximately the level of the optic chiasma. The CPI was estimated using high-speed echo planar imaging (EPI) as previously described.23 EPI was performed following intravenous injection of a bolus of magnetic susceptibility contrast agent DyDTPA-BMA (0.25 mmol/kg, Sprodiamide injection; Nycomed Salutar Inc) to obtain a series of 32 images acquired at 1-second intervals.
Variations in the integrated signal intensity across the entire slice
during transit of the contrast agent were transformed into plots of
R2* (the change in effective transverse relaxation rate)
versus time according to the relation R2*(t)=-ln
[S(t)/S(0)]/TE, where S(t) is the signal intensity at time t,
integrated over the slice, and TE is the image echo time. S(0) is the
precontrast baseline signal intensity. The quantity R2*
appears to be directly proportional to the regional concentration of
magnetic susceptibility contrast agent25 26 and thus
allows construction of the concentration-time curve which
represents the passage of the bolus of the contrast through the
tissue. CPI was calculated as the reciprocal of the full width at half
height (FWHH) of the concentration-time curve. Blood gas analysis
was performed during each measurement of CBF or CPI.
At the end of experiments in subgroups of A and B, the head of the animal was guillotined and the brain immediately removed. Brain water was determined by measuring the weight of fresh brain tissue placed in preweighed crucibles. The tissue was dried for 72 hours at 105°C and weighed again. The percentage water of the brain tissue was calculated from the difference between the wet and dry weights.27 The dry tissue was then pulverized and extracted for 24 hours in 1N HNO3.The supernatant was analyzed to determine brain content of sodium and potassium by flame photometry.27 Trunk blood was collected for the measurement of plasma sodium concentration by flame photometry.
In subgroups of normonatremic rats (group A; 6 females and 6 males) and rats with chronic AVP-induced hyponatremia (group B; 8 females and 6 males) which underwent identical treatment (anesthesia, ventilation, surgery) as did the rats used in the MRI experiments, the plasma vasopressin level was measured in trunk blood using radioimmunoassay.28 Plasma estrogen and testosterone levels were measured in rats from groups A, E, F, and H.
Statistics
All data are presented as mean±SEM unless otherwise
indicated. Data were subjected to statistical analysis using post
hoc Dunnett's t test significance testing, using
STATVIEW IV (Abacus Software) on a Macintosh computer. A
two-tailed probability value of less than 0.05 was considered
significant.
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Results |
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Cardiovascular parameters along with blood gas analysis and plasma sodium data are presented in Tables 1
and 2. After 4 days of hyponatremia both male
and female rats had significantly reduced serum sodium levels compared
to control rats (P<.001), with no differences between
hyponatremic males and females. There were no significant differences
in MABP and blood gas parameters between normonatremic and hyponatremic
males and females in all the groups in which CPI was studied (Table 2).
The slight decrease in MABP in the group in which CBF and
CMRO2 were measured was significant (P<.05) but
not different between males (from 116±5 to 94±7 mm Hg) and females
(from 122±2 to 96±8 mm Hg) (Table 1). All animals were normocapnic
and had PaO2 values within the normal
range.
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Basal normonatremic CBF, CMRO2, and CVR values were
not different between male and female rats (Table 1
, Fig 1). However, CBF and CMRO2 were reduced
(P<.01) and CVR was increased (P<.01) in female
rats with AVP-induced hyponatremia (plasma sodium=110±2 mmol/L)
when compared with either male rats with the same severity of
hyponatremia (plasma sodium=115±4 mmol/L) or normonatremic
animals.
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Similar results were also obtained using MRI. The CPI in normonatremic
female brain was not statistically different from that in normonatremic
male brain (Fig 2, Table 2). However, it was
significantly impaired (P<.01) in chronic hyponatremic
females compared with males with the same duration and degree of
hyponatremia (Fig 2). A decrease in CPI was observed in female rats
during AVP-induced hyponatremia, but not when hyponatremia of the same
severity was induced with dDAVP (Table 2). The CPI in female rats with
dDAVP-induced hyponatremia was 0.25±0.02, a value which was
significantly greater than that in female rats with AVP-induced
hyponatremia (0.14±0.02, P<.025) but not significantly
different from the value in either control female (0.31±0.03,
P=.07) or male (0.28±0.03, P=.4) rats.
Similarly, chronic administration (4 days) of the same dose of
vasopressin as that which was administered to induce hyponatremia, but
without IP hypotonic fluid, did not affect CPI in either normonatremic
female or male rats (Table 2).
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Although the CPI was significantly decreased in AVP-induced
hyponatremic female versus male rats, it was not clear whether this was
a function intrinsic to genetic females or a particular hormone, such
as estrogen. We therefore evaluated the CPI in rats with AVP-induced
hyponatremia which had been previously treated for 8 weeks with
estrogen or testosterone. Treatment of normonatremic male and female
rats with estrogen for 8 weeks did not affect CPI. The CPI in
estrogen-treated females was 0.29±0.4 (serum sodium=141±1 mmol/L,
n=5), and in estrogen-treated males it was 0.28±0.03 (serum
sodium=134±3 mmol/L, n=6). In female estrogen-treated rats with
AVP-induced hyponatremia (serum sodium=111±6 mmol/L), the CPI was
0.20±0.04, which was not different from the value in female rats with
AVP-induced hyponatremia which had not received estrogen (0.14±0.02,
P=.25). However, in male estrogen-treated rats with
AVP-induced hyponatremia (serum sodium=109±4 mmol/L), the CPI was
0.19±0.04, a value that was significantly less than that in male rats
with AVP-induced hyponatremia which had not received estrogen
(0.30±0.03, P<.01) (Fig 2). However, testosterone
pretreatment did not prevent the development of cerebral perfusion
abnormalities present in female rats with AVP-induced hyponatremia.
In testosterone-pretreated females with AVP-induced hyponatremia, the
CPI was 0.20±0.03, not significantly different from that in
hyponatremic females not receiving testosterone (0.14±0.02,
P=.3). In male rats with AVP-induced hyponatremia which had
been pretreated with testosterone for 8 weeks (serum sodium=114±5
mmol/L, n=10), the CPI in males was 0.27±0.02, not significantly
different from that in hyponatremic males not pretreated with
testosterone.
To determine whether the cerebral vasoconstrictor effects of estrogen plus vasopressin in hyponatremic rats were specific effects of estrogen or vasoconstrictor responses to vasopressin, we next examined the effects of estrogen on arterial hypocapnia, which is another important cerebral vasoconstrictive stimulus. In normonatremic (serum sodium=141±1 mmol/L) female rats (plasma estrogen=21±3 pg/mL) with hypocapnia (PCO2=26±1 mm Hg), the CPI was 0.20±0.02, significantly less than the control value (0.31±0.03, P<.01). In female rats with AVP-induced hyponatremia (serum sodium=106±6 mmol/L, plasma estrogen=25±4 pg/mL) and hypocapnia (PCO2=25±3 mm Hg), the CPI was 0.13±0.02, significantly less than the value in both normonatremic female rats and those with hypocapnia (P<.01).
Brain water and electrolytes are shown in Table 3. In
rats with AVP-induced chronic hyponatremia, the brain tissue water was
increased by 9% to 10% above control values both in males and females
(P<.05) (Table 3). The brain sodium content was decreased
during AVP-induced chronic hyponatremia by 
24% below
normonatremic values, and the decrease was similar in males and
females (P<.01 versus controls). Brain potassium
concentration was decreased by 16% to 18% in comparison with male and
female normonatremic rats (P<.01 versus controls). There
was no significant difference between male versus female rats with
AVP-induced chronic hyponatremia with regard to brain water, sodium, or
potassium.
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Plasma AVP was measured in separate subgroups of control rats, postsurgical rats (placement of arterial lines), and rats with chronic hyponatremia. In awake normonatremic adult rats, the plasma AVP (5 males, 7 females) was <5 pg/mL, and after anesthesia plus surgery (placement of arterial lines), it was 6±1 pg/mL in females (n=6) and 16±2 pg/mL in males (n=5) (P<.05). In rats with chronic AVP-induced hyponatremia, the plasma AVP was 44±11 pg/mL in females (n=11) and 33±8 pg/mL in males (n=10) (P>.05).
Plasma estrogen was measured in control and experimental groups of male and female rats. The control value in normonatremic females (n=8) was 21±3 pg/mL, and in males (n=7) estrogen was 8.9±0.9 pg/mL (P<.01). In rats with AVP-induced hyponatremia, the plasma estrogen level in female rats was 23.2±2.2 pg/mL, and in males it was 6.6±0.4 pg/mL (P<.01). After 6 weeks of estrogen treatment, the plasma levels were 331±60 pg/mL in females (n=14) and 167±25 pg/mL in males (n=9). In rats pretreated with estrogen with AVP-induced hyponatremia, plasma estrogen was 192±47 pg/mL in females (n=7) and 162±45 pg/mL in males (n=6) (P>.1).
Plasma testosterone was measured in control and experimental groups of male and female rats. The control value in normonatremic females (n=8) was 0.1±0.01 ng/mL, and in males (n=7) testosterone was 2.3±0.2 ng/mL (P<.01). In rats with AVP-induced hyponatremia, the plasma testosterone level in female rats was 0.13±0.08 ng/mL, and in males it was 1.4±0.4 ng/mL (P<.01). After 6 weeks of testosterone treatment followed by AVP-induced chronic hyponatremia, plasma testosterone was 2.8±0.7 ng/mL in male rats and 0.05±0.01 ng/mL in females (P<.01).
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Discussion |
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The results of the present study demonstrate that CBF, CPI, and CMRO2 are decreased during chronic hyponatremia in female rats. However, decreased CBF and CMRO2 are observed only in the presence of increased levels of circulating vasopressin.
The cerebral effects observed in hyponatremic females seem to be a
consequence of a combination of low plasma sodium, estrogen, female
gender, and activation of V1 vasopressin
receptors.5 12 14 Such a combination of factors appears to
be essential because neither chronic administration of vasopressin to
normonatremic rats nor chronic hyponatremia induced with dDAVP, a
selective V2 receptor agonist, affected the cerebral
circulation in rats of either gender (Fig 2) or induced any mortality.
Furthermore, genetic male rats pretreated with estrogen for 6 weeks
prior to induction of AVP-induced chronic hyponatremia had
abnormalities of cerebral perfusion which were not quantitatively
different from those observed during AVP-induced hyponatremia in
genetic female rats.
Vasopressin is a potent vasoconstrictive agent in many vascular beds.29 Vasoconstrictor responses to exogenous vasopressin have also been reported in isolated cerebral blood vessels in vitro in several animal species and in humans.17 18 Vasoconstriction following vasopressin has also been demonstrated in vivo in the basilar artery and pial arterioles of the cerebrum in rats and cats.15 16 However, the effects of vasopressin on cerebral blood vessels appear to differ depending on the size of the blood vessel.30 There is dilation in larger blood vessels but constriction in smaller ones.30 Thus, effects of vasopressin on cerebral blood vessels are inconsistent, and vasopressin alone does not consistently lower CBF in normal animals over a wide range of plasma vasopressin levels15 30 31 32 33 and under different physiological conditions, including hemorrhage.31 However, vasopressin has been implicated in the pathogenesis of cerebral vasospasm and hemorrhagic brain edema.34 35 The vasoconstrictor effects of vasopressin seem to be mediated by V1 vasopressin receptors, since they are inhibited by the administration of selective V1 antagonists.16 18 34 35
Data concerning the effects of hyponatremia on the cerebral circulation are scanty. Published results suggest that an acute decrease of the extracellular sodium concentration results in a direct constriction of feline pial arteries in vivo36 and of the rabbit's middle cerebral and basilar arteries in vitro.37 Osmolarity was found to be one of the determinants of arteriolar resistance in the brain, because infusion of hypotonic solutions resulted in vasoconstriction and a reciprocal effect, vasodilatation, was observed when hypertonic solutions were infused.36 However, neither AVP alone nor hyponatremia induced with dDAVP appeared to have an overall effect on CBF and CPI in our experiments, and only a combination of AVP and hyponatremia resulted in a deterioration of the CPI in female rats or rats pretreated with estrogen.
It has been demonstrated that systemic administration of vasopressin
results in several effects on brain metabolism and function in the rat
which may or may not be secondary to the direct vasoconstrictive effect
of AVP. These effects include a decrease in intracellular pH,
impairment in synthesis of ATP, and movement of water into brain
without hyponatremia.12 38 39 These cerebral effects of
vasopressin are absent when hyponatremia is induced without
vasopressin.40 Vasopressin also has been reported to bind
to cerebral microvessels41 and to alter the permeability
of endothelium to certain brain nutrients42 43 that
potentially could result in a decrease of CMRO2 and,
secondarily, CPI. In this study, CMRO2 was reduced in
female rats with AVP-induced hyponatremia, suggesting a possible
primary role of the alterations of brain metabolism (decreased oxygen
utilization) in the observed decrease of CBF (Fig 1).
Thus, the decrease of CBF in females with AVP-induced hyponatremia may result from alterations of brain metabolism associated with hyponatremic encephalopathy, or it may be secondary to a direct vasoconstrictor effect of the decreased sodium and increased vasopressin levels in female rats.15 16 17 18 44
In the present study, both male and female rats were administered identical exogenous quantities of vasopressin. The plasma levels were not significantly different in hyponatremic male versus female rats. However, we could anticipate that in analogy with peripheral blood vessels, estrogen and hyponatremia may well result in greater reactivity of cerebral blood vessels to AVP. It has been demonstrated that AVP-associated vasoconstriction in peripheral blood vessels is modulated by estrogen and low sodium levels.20 21 22 45 46 In both isolated aorta in vitro and mesenteric vascular bed in vivo, constriction in response to vasopressin is greater in female than in male rats.20 45 Estrogen may be in part responsible for some of the differences in blood vessel contractility. A single administration of ß-estradiol results in enhanced vasoconstriction in the mesentery in response to vasopressin both in male and female rats.22 45 Moreover, when female rats are castrated three days before the administration of vasopressin the constriction observed following vasopressin is attenuated.
The effect of sex hormones on the regulation of cerebral circulation
has not previously been evaluated. Data from the current study
establish that a combination of female gender (or estrogen
pretreatment) and vasopressin in hyponatremic rats has detrimental
effects on the cerebral circulation. However, vasopressin without
hyponatremia has not previously been observed to have such
effects.30 32 33 In the current study, chronic
administration of AVP in similar dosage as used for the induction of
hyponatremia did not affect CPI in either male or female rats. We can
assume that during chronic administration of AVP the plasma level of
the peptide should be similar to its plasma level during hyponatremia
in our model. It appears that the effects of vasopressin alone on the
cerebral circulation do not differ in normonatremic male versus female
rats. However, our results suggest that in the presence of AVP-induced
hyponatremia the cerebral circulation in female rats is more sensitive
to the effects of AVP than is that of male rats. The increased
sensitivity of the cerebral circulation appears to be due in large part
to the presence of circulating estrogen in blood. In genetic males with
AVP-induced hyponatremia which had been continuously treated for 6
weeks with estrogen, the CPI was not significantly different from that
in genetic females with AVP-induced hyponatremia (Fig 2). Thus,
estrogen pretreatment resulted in a "female" cerebral circulation
in genetic males.
It seems to be unlikely, however, that the increased sensitivity of cerebral perfusion to AVP in the presence of sex steroid hormones observed in both female rats and male estrogen-pretreated rats with AVP-induced hyponatremia can be extrapolated to a variety of vasoconstrictive stimuli. The effects on cerebral perfusion of estrogen plus AVP cannot be considered to be a generalized change in vascular responsiveness but rather an effect specific to the interplay of hyponatremia, estrogen, and vasopressin. In normonatremic rats, the addition of arterial hypocapnia, a very important stimulus for cerebral vasoconstriction, leads to a decrease in cerebral perfusion. When female rats with AVP-induced hyponatremia (and elevated plasma estrogen levels) are also rendered hypocapnic, there is an additional significant decrement of cerebral perfusion compared to normonatremic rats with hypocapnia. Thus, the cerebral perfusion abnormalities observed in female rats (and presumably in estrogen-treated male rats) with AVP-induced hyponatremia appear to be specific for effects of estrogen plus vasopressin-induced hyponatremia.
Although a decrease in CMRO2 will lead to a decrease in CBF, there is no known mechanism for increased vasoconstriction associated with vasopressin in the presence of estrogen. The studies of St. Louis and associates22 suggest that estrogen results in an increase in the density of vasopressin vascular receptors. Other studies reported an increase in the sensitivity of vascular smooth muscle cells to vasopressin when the activity of Na+,K+-ATPase is attenuated, which may be meaningful in view of data demonstrating that estrogen inhibits the Na+,K+-ATPase system in rat brain.47 48 49 On the other hand, hyponatremia results in an increase in the density of vasopressin vascular receptors and in a greater sensitivity of mesenteric blood vessels to vasoconstriction induced with vasopressin.46
The noninvasive estimate of CPI obtainable using the MRI approach
outlined above appears to be closely correlated with the
133Xe determination of CBF (Fig 3). As with
the 133Xe method, the MRI technique allows repeated
measurements (separated by a suitable washout period of about 20
minutes), suggesting that it might be a suitable method for studying
the time course of cerebral perfusion changes that accompany
hyponatremia. Perfusion-sensitive MRI offers the further advantage of
assaying regional variations in the cerebral microcirculation, which
may then be assessed longitudinally with changes in anatomy, or
pathophysiological phenomena such as cytotoxic edema.
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In summary, the present study demonstrates that hyponatremia results in the attenuation of cerebral perfusion and metabolism exclusively in the presence of elevated plasma vasopressin and in female rats or male rats treated with estrogen. The exact mechanism of this attenuation merits further investigation. Since the impairment of cerebral circulation in females during hyponatremia parallels decreased CMRO2 and symptoms of hyponatremic encephalopathy, these results suggest that activation of vasopressin V1 receptors, female sex hormones, and a decrement of cerebral perfusion play an important role in the pathogenesis of brain damage associated with hyponatremia.
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Acknowledgments |
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This work was supported by grant RO1-AG-08575 from the National Institute on Aging, Department of Health and Human Services, Bethesda, Md, and the Research Service of the Veterans Affairs Medical Center, San Francisco, Calif.
Received May 12, 1994; accepted November 23, 1994.
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