Acutely elevated vasopressin increases circulating concentrations of cortisol and aldosterone in fasting northern elephant seal (Mirounga angustirostris) pups
1 Department of Biology, University of California, Santa Cruz, 95064,
USA
2 Neuroendocrinology Laboratory, Division of Life Science, NASA Ames
Research Center, Moffett Field, CA 94035, USA
* Corresponding author at present address: Department of Physiology SL-39, Tulane University Health Sciences Center, New Orleans, LA 70112, USA (e-mail: rortiz1{at}tulane.edu)
Accepted 12 May 2003
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Summary |
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Key words: aldosterone, cortisol, corticotropin-releasing factor, glomerular filtration rate, natriuresis, osmotic clearance, northern elephant seal, Mirounga angustirostris
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Introduction |
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The primary action of VP is to facilitate the reabsorption of solute-free
water from the collecting duct of the kidney, and this action may be
associated with the reabsorption of urea
(Klein et al., 1997). A number
of studies provide compelling evidence that tubular water resorption is
mediated via VP in seals. Fasting northern elephant seal pups infused
with hypertonic saline exhibited chronically elevated plasma VP
concentrations. Furthermore, excreted [VP] was elevated and negatively
correlated with free water clearance
(CH2O), and positively correlated
with excreted cAMP levels, suggesting that VP mediated tubular water
reabsorption (Ortiz et al.,
2002b
). The intravenous infusion of pitressin in a water-loaded
harbor seal Phoca vitulina resulted in an immediate decrease in urine
flow, which was associated with a concomitant increase in urinary electrolyte
concentrations (Bradley et al.,
1954
). Pitressin infusions also increased urine osmolality and
osmotic clearance (Cosm), suggesting that free water
reabsorption was increased (or CH2O
was reduced) (Page et al.,
1954
). Under force-fasted conditions, Baikal (P.
sibirica) and ringed (P. hispida) seals exhibited an increase in
excreted [VP] associated with a concomitant decrease in urine output and
increase in urine osmolality (Hong et al.,
1982
). A positive and significant correlation between urine
osmolality and excreted [VP] was also observed, further suggesting that the
increase in urine osmolality was attributed to an increase in tubular water
reabsorption via VP stimulation
(Hong et al., 1982
). In
force-fasted grey seals Halichoerus grypus, plasma osmolality and
[VP] increased in conjunction with an increase in urine osmolality
(Skog and Folkow, 1994
).
In addition, VP interacts dynamically with other physiological systems in
mammals. Aside from its role in tubular resorption of water, VP has also been
implicated in elevating glomerular filtration rate (GFR) in rats
(Bouby et al., 1996;
Roald et al., 2000
) and
Na+ excretion in dogs (Bie et
al., 1984
; Buckalew and Dimond,
1976
; Chan and Sawyer,
1961
; Johnson et al.,
1979
; Kompanowska-Jezierska et
al., 1998
; Smith et al.,
1979
; Sondeen and Claybaugh,
1989
). Although infusion of hypertonic saline in fasting northern
elephant seal pups induced a chronic (24 h) elevation in plasma [VP], GFR and
Na+ excretion, the contribution of elevated [VP] to an increase in
GFR and Na+ excretion could not be ascertained
(Ortiz et al., 2002b
).
Previous studies of pitressin infusions in seals suggest that VP possesses an antidiuretic function; however, those studies did not describe other hormonal or renal effects of the infusion. Therefore, to reconcile some of the previously observed effects of the hypertonic saline-induced elevation in [VP] as well as to describe the effects of VP on peripheral physiological systems, we quantified hormonal and renal responses of fasting northern elephant seal pups to infused VP.
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Materials and methods |
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Animals
Seven northern elephant seal pups Mirounga angustirostris Gill
1866 (99±4 kg; 4 males, 3 females), between 5 and 8 weeks postweaning,
were transported from Año Nuevo State Park (approximately 30 km north
of Santa Cruz, CA, USA) to Long Marine Laboratory, University of California,
Santa Cruz. Upon arrival at the marine laboratory, pups were weighed using a
hanging-load cell and placed in a sandpit overnight. The following morning, a
catheter was inserted into the extradural spinal vein after the pup had been
sedated with 0.01 ml kg-1 body mass tiletamine HCl and zolazepam
HCl (Telazol; Fort Dodge Animal Health, Fort Dodge, IA, USA). Following the
catheterization procedure, pups were allowed to recover for approximately 22 h
prior to the collection of control data. The catheter served as the sole route
by which materials were infused or blood was collected. Immediately following
the catheterization and every day (34 days) until the catheter was
removed, each pup received 1 g cefazolin sodium (Fort Dodge Animal Health,
Fort Dodge, IA, USA) to minimize the risk of a bacterial infection from the
catheter. The catheterized pup was then placed in a metabolic cage with a
urine collection pan underneath attached to a collection flask.
Control infusion
During the control infusion, pups received 220 ml of sterile isotonic
saline calculated to be the approximate volume of vehicle to be given on the
day of the hormone infusion. Control blood samples were collected prior to
(pre-infusion) and 15, 30, 60 and 120 min, and 24 h post-infusion, with
reference to the end of the infusion period. The 24 h sample also served as
the pre-infusion sample for the VP infusion trial.
Vasopressin infusion
On the day following the collection of control blood samples, pups were
infused with a bolus (20 ng kg-1 in 5 ml isotonic saline) of
arginine VP (AVP; Phoenix Pharmaceuticals, Belmont, CA, USA) followed by a
constant infusion of 0.6 ng kg-1 ml-1 for a 34 min
period in sterile, isotonic saline (225±16 ml). Based on a percentage
total body water (TBW) pool size of approximately 38%, determined empirically
for similarly sized pups (Ortiz et al.,
2002a,
2003
), the infused volumes
amounted to 0.60±0.02% of the pups' TBW pool. Post-infusion blood
samples were taken at 15, 30, 60 and 120 min, and at 24 h after the end of the
infusion period (as with the control sampling schedule).
Blood samples and plasma analyses
All blood samples were obtained from the indwelling catheter into 20 ml
syringes. Prior to the collection of each blood sample, a 3 ml sample was
drawn into a 20 ml syringe with 10 ml of sterile isotonic saline to clear the
catheter line of any residual blood that could potentially contaminate the
samples drawn. Blood was transferred into pre-chilled collection tubes
containing either lithium heparin or EDTA. After 30 s of gentle rocking,
duplicate samples of whole blood were removed in capillary tubes and spun in a
microcentrifuge to determine hematocrit (Hct) (%). The remaining blood was
centrifuged for 15 min (1500 g at 4°C), and plasma
collected and frozen at -20°C for later analyses.
All assays were conducted using commercially available radioimmunoassay
kits validated previously for use with northern elephant seal plasma (Ortiz et
al.,
2002a,b
,
2000
). Aldosterone (DPC, Los
Angeles, CA, USA), cortisol (DPC), VP (AVP; Phoenix Pharmaceuticals), and
angiotensin II (AII; Phoenix Pharmaceuticals) were analyzed from heparinized
plasma, and plasma renin activity (PRA; Dupont-NEN, MA, USA) was determined
from EDTA-treated plasma. Prior to being assayed, VP and AII were extracted
from the plasma using a C-18 column extraction procedure as previously
described (Zenteno-Savin and Castellini,
1998
). Final concentrations were not corrected for incomplete
extractions. All samples were run in duplicate in each assay. Hormone assays
displayed an intra-assay percentage coefficient of variation (%CV) of
79% and interassay %CV of 611% (including urinary hormones).
Electrolytes (Na+, K+, Cl-), creatinine,
blood urea-nitrogen and total proteins were analyzed from heparinized plasma
and were measured on a clinical auto-analyzer (Roche Diagnostics, Somerville,
NJ, USA). Osmolality was determined using a freezing point osmometer (Fiske,
Norwood, MA, USA).
Urine analyses
In each study, urine volume in the collection flask was measured after a 24
h collection period and a 3 ml portion was filtered and frozen for later
analyses. Urine samples were collected without the use of preservatives.
Because urine samples could only be collected as the pups naturally voided,
obtaining paired plasmaurine samples was not possible in our hands. In
order to maintain consistency in collection of urine, a cumulative 24 h sample
was therefore collected. Urine samples were analyzed for electrolytes
(Na+, K+, Cl-), creatinine, osmolality and
urea-nitrogen using the same techniques as with the plasma samples. The same
commercial assays used to measure the plasma hormones were used to measure the
extracted urinary hormones. Urinary VP, AII and urodilatin (Phoenix
Pharmaceuticals) were extracted as for the plasma, but in a volume of 0.5 ml.
Aldosterone and cortisol were extracted as previously described
(Ortiz et al., 1999). As with
the plasma extractions, final urinary concentrations were not corrected for by
incomplete extractions. Prostaglandin E2 (PGE2; Assay
Designs, Ann Arbor, MI, USA) was analyzed by enzymatic immunoassay following a
1:10 dilution of urine with assay buffer. The PGE2 kit displayed
significant cross-reactivity with the urinary elephant seal PGE2,
as indicated by the significant parallelism exhibited between the standards
and the diluted urine pool.
Calculations
For all variables, excretion values were calculated as urinary
concentration x daily urine volume. GFR was estimated by standard
creatinine clearance. Osmotic clearance (Cosm; ml
h-1) was calculated as:
![]() | (1) |
Fractional excretion (FE; %) was calculated as:
![]() | (2) |
Statistics
Means for plasma values during the post-infusion period were compared to
those during the control period by two-way analysis of variance (ANOVA)
adjusted for repeated measures over time. If significant group x time
interactions were not observed, means during the post-infusion period were
compared to pre-infusion values by one-way ANOVA adjusted for repeated
measures. Excretion values between control and post-infusion periods were
compared by paired t-test. Fisher's PLSD test was administered
post-hoc if significance was determined. Values (means ±
S.E.M.) were considered significantly different at
P<0.05. Statistical analyses of means were made using Statview
(SAS, 1998).
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Results |
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Vasopressin data
Plasma VP concentrations were not significantly altered during the control
sampling period; however, mean concentrations increased by approximately
13-fold after 15 min and threefold by 30 min post-infusion, remaining
significantly (P=0.0032) higher than control values for at least 120
min post-infusion (Fig. 1).
Total excreted [VP] increased 10.5-fold above control values following the
infusion (Fig. 1).
|
Plasma data
Plasma aldosterone and cortisol concentrations were elevated and PRA
reduced following the infusion (Fig.
2); however AII (12.9±2.6 and 15.2±2.8 pg
ml-1) was not significantly altered between control and
post-infusion periods (not shown). Plasma aldosterone returned to control
concentrations within 60 min while plasma cortisol and PRA returned to control
concentrations within 24 h (Fig.
2). Electrolytes (Na+: 155±1 and 153±1
mmol l-1; K+: 4.4±0.1 and 4.6±0.1 mmol
l-1; Cl-: 106±1 and 106±1 mmol
l-1), blood urea-nitrogen (1.9±0.1 and 1.9±0.1 mmol
l-1) and creatinine (74.5±3.3 and 71.4±1.6 µmol
l-1) were not altered between control and post-infusion periods,
respectively. During the control period the plasma urea:creatinine ratio (U:C)
was unchanged (26.1±0.8); however, following the infusion of VP, the
U:C ratio increased by 15% (P=0.0076) above pre-infusion levels
(24.5±1.6) after 120 min (28.1±1.8) and remained elevated after
24 h (27.7±1.8) (not shown).
|
Urine output and excretion data
Compared to the control values, following infusion of VP, urine output over
a 24 h period (162±17 and 278±36 ml day-1) and
osmotic clearance (698±64 and 884±95 ml day-1)
increased by 69±18% and 36±10%, respectively; however, free
water clearance (-533±53 and -602±72 ml day-1) and
GFR (80±5 and 78±7l day-1; not shown) were not
significantly altered between control and post-infusion periods, respectively
(Fig. 3). Electrolyte
(Fig. 4) and osmolal excretion
(212±21 and 277±29 mosmol day-1) as well as
fractional excretion of electrolytes were significantly increased 24 h
post-infusion (Table 1). Urea
excretion (46±5 and 41±7 mmol day-1) and fractional
excretion of urea (Table 1)
were not significantly altered following infusion of VP. Excreted cortisol and
urodilatin levels were elevated following the infusion of VP; however
aldosterone, AII and PGE2 levels were not significantly altered
(Table 2).
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Discussion |
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The extradural vein of the pups was catheterized, so that frequent serial
blood samples could be obtained in order to examine the acute peripheral
effects of VP. We recognize, however, that the collection of 24 h urine
samples only provides an opportunity to quantify the net effects of acutely
elevated [VP] on kidney function and does not provide an examination of more
acute and dynamic renal changes. Therefore, the renal responses to acutely
elevated [VP] are discussed in this context, especially since the 22 h period
between the 120 min and 24 h post-infusion blood samples probably represents a
refractory period in which kidney function was compensating for the peripheral
changes induced by acutely elevated [VP]. Although the 24 h post-infusion
period was characterized by a diuresis and natriuresis, the kidney may have
been in an antidiuretic state during the 2 h post-infusion period when [VP]
was significantly elevated. Nonetheless, the observed net diuresis is
consistent with previous studies, which have shown that acute infusion of VP
increases urine output as well as Na+ and K+ excretion
in mammals (MacFarlane et al.,
1967; Sondeen and Claybaugh,
1989
). The diuresis observed in the present study can be
attributed to an increase in solute excretion, or osmotic diuresis, and not to
an increase in free water clearance. We have previously shown that under a
chronic (24 h) state of hyperosmolality, circulating [VP] remained elevated
until the condition of hyperosmolality was rectified, during which time free
water clearance was reduced, indicating that VP mediated the tubular
resorption of water (Ortiz et al.,
2002b
). In the present study, the effect of acutely elevated [VP]
was no net change in free water clearance. This distinction between acutely
and chronically elevated circulating VP concentrations may be the underlying
factor responsible for the contrasting VP-related responses observed between
the two studies. Therefore, the antidiuretic function of VP in fasting seals
may depend on the duration of exposure of target tissues to VP. Thus, the
physiological functions of VP in fasting seals appear to be dynamic, depending
on whether the elevation in [VP] is chronic or acute.
Infused VP has been shown to induce natriuresis in a variety of terrestrial
mammals (Fejes-Tóth and Szenasi,
1981; Kompanowska-Jezierska et
al., 1998
; MacFarlane et al.,
1967
), which is consistent with the present study. However,
excreted K+ and Cl-, FEK+, and
FECl- were also elevated, suggesting that the actions of
VP on electrolyte handling are non-selective. Infusion of pitressin in the
harbor seal was also associated with an increase in excreted Na+
and K+ (Bradley et al.,
1954
). Despite the natriuretic effect of VP, the loss of
Na+ amounted to approximately 700 mg, or the amount of
Na+ in approximately 65 ml of seawater. Although the present study
reveals that VP may function as a natriuretic, this relatively small loss of
Na+ appears to be physiologically insignificant. However, over the
course of 23 months, acute elevations in [VP] may result in significant
loss of Na+. Therefore, under naturally fasting conditions, [VP]
may not increase over the course of the fast, as expected, in order to abate
the natriuretic actions of VP. Thus, the kidneys may be keenly sensitive to
low concentrations of VP, thereby maintaining both water and electrolyte
homeostasis.
Previously in fasting seal pups, following plasma volume expansion by
infusion of isotonic saline and hypernatremia induced by infusion of
hypertonic saline, circulating and excreted ANP concentrations were not
elevated (Ortiz et al.,
2002b), suggesting that another natriuretic mechanism is employed
in these seals. The kidney-derived natriuretic factor, urodilatin, has been
reported to possess greater natriuretic activity than ANP
(Drummer et al., 1996
;
Goetz et al., 1990
).
Therefore, in the present study, we examined the response of urodilatin
instead of ANP to VP stimulation. Excreted urodilatin was elevated
post-infusion, suggesting that the natriuretic function of VP may be mediated
via a physiological cascade incorporating urodilatin.
VP has been implicated in the elevation of GFR in rats
(Bouby et al., 1996;
Roald et al., 2000
), so we
hypothesized that creatinine excretion would increase in response to acutely
elevated [VP]. Although the net effect was no significant change in GFR
following infusion of VP, the significant increase in plasma U:C ratio, a
recognized indicator of altered filtration rate
(Duarte and Preuss, 1993
),
suggests that filtration rate may have been acutely elevated as a consequence
of the increase in [VP].
Vasopressin has been measured as an index of stress and can possess
secretory properties similar to that of corticotropin releasing hormone (CRH)
(Aguilera and Rabadan-Diehl,
2000; Brooks and Challis,
1989
; Kjaer, 1993
;
Zehnder et al., 1995
). As an
adrenocorticotropin (ACTH) secretogogue, VP may stimulate the release of
cortisol (Brooks and Challis,
1989
). In the present study, plasma cortisol concentration was
increased approximately 4.5-fold by 15 min post-infusion and remained nearly
double after 2 h, while plasma aldosterone concentration increased by
approximately 66% after 15 min, suggesting that VP possesses corticotropin
releasing factor-like action in northern elephant seal pups. Alternatively,
the increase in plasma aldosterone may have been in response to the increased
natriuresis resulting in the maintenance of plasma Na+
concentrations. During natural fasting conditions, plasma cortisol increases
linearly over the course of the fast (Ortiz et al.,
2001a
,b
)
despite the lack of an increase in [VP] (Ortiz et al.,
1996
,
2000
), suggesting that the
fasting-induced increase in cortisol is not VP mediated.
The reduction in plasma renin activity (PRA) following the infusion of VP
is consistent with that observed in terrestrial mammals
(Johnson et al., 1979;
Merrill and Cowley, 1986
;
Reid et al., 1983
); however,
the lack of a decrease in AII was unexpected since a decrease in renin may
also be associated with a decrease in AII
(Morton et al., 1982
). The
dissociation between renin and AII in the present study suggests that (1) the
production of AII is unaffected by the observed reductions in renin or (2) the
reduction in AII is delayed beyond the 24 h period examined in fasting
northern elephant seal pups. Also, under natural fasting conditions, PRA and
aldosterone are linearly increased over the first 5 weeks of the fast while VP
concentrations remain relatively low and unchanged
(Ortiz et al., 2000
). The
reninangiotensinaldosterone system (RAAS) probably contributes
significantly to the conservation of water and electrolytes during the fast,
so not increasing VP levels during the fast may be beneficial to the pups by
not attenuating the response of RAAS. This relationship between VP and PRA
provides another plausible explanation for fasting northern elephant seal pups
to have developed an increased sensitivity to low VP concentrations.
In mammals, VP stimulates urea transporters to enhance urea resorption into
the renal medulla and, thus decreases FEurea, while glucocorticoids
have been shown to downregulate VP-regulated urea transporters, resulting in
an increase in FEurea (Klein et
al., 1997). Despite the increase in circulating and excreted
cortisol, the elevated concentrations of VP may have been sufficient to
alleviate the glucocorticoidmediated downregulation of VP-regulated urea
transporters, resulting in no net alteration in FEurea.
In summary, the increase in plasma and excreted cortisol levels suggests
that VP may function as a potent CRF in these mammals, as in terrestrial
mammals. Plasma aldosterone may have increased acutely in response to the
natriuresis. The suppression of PRA by VP suggests that during the fast [VP]
is not elevated to alleviate the inhibition on renin because, under natural
conditions, PRA and aldosterone are concomitantly increased over the first 5
weeks of the fast (Ortiz et al.,
2000). Acutely elevated [VP] induced a net osmotic diuresis
accompanied by natriuresis, without affecting net free water clearance.
Although GFR measured 24 h post-infusion was not elevated, the increase in
plasma U:C ratio suggests that filtration rate may have been elevated during
the first 120 min post-infusion, when circulating [VP] was also increased.
Excretion of Na+, K+ and Cl- were all
elevated, suggesting that electrolyte excretion in response to VP is
non-selective in fasting seals. The increase in excreted urodilatin suggests
that the VP-induced natriuresis may have been mediated via this
natriuretic peptide. The functions of natriuretic peptides in marine mammals
warrant further investigation. In terrestrial mammals, VP is typically
elevated in response to an increase in plasma osmolality and a decrease in
blood volume resulting from water deprivation-induced dehydration. However,
fasting northern elephant seal pups maintain constant plasma osmolality and
blood volume, thereby precluding an increase in [VP]. Nonetheless, the
peripheral actions of acutely elevated [VP] observed in the present study are
consistent with those observed in terrestrial mammals, suggesting that VP is
as dynamic in fasting seals as in terrestrial mammals.
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Abbreviations |
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Acknowledgments |
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References |
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