Am J Physiol Regul Integr Comp Physiol 288: R638-R644, 2005.
First published November 4, 2004; doi:10.1152/ajpregu.00525.2004
0363-6119/05 $8.00
WATER AND ELECTROLYTE HOMEOSTASIS
Role of angiotensin in body fluid homeostasis of mice: effect of losartan on water and NaCl intakes
Emily C. Crews and
Neil E. Rowland
Department of Psychology, University of Florida, Gainesville, Florida
Submitted 4 August 2004
; accepted in final form 31 October 2004
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ABSTRACT
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It is known that mice injected peripherally with ANG II do not show a drinking response but that cFos immunoreactivity (ir) is induced in brain regions similar to those in rats. We now show in Crl:CD1(ICR) mice that peripheral injection of the ANG II type 1 receptor antagonist losartan was sufficient to prevent this induction of Fos-ir in the subfornical organ (SFO). Injection of ANG II into the lateral cerebral ventricle produced a robust water intake in mice and induced Fos-ir in SFO, as well as in median preoptic (MnPO) and paraventricular (PVN) nuclei. Peripheral injection of losartan blocked this drinking response and prevented the induction of Fos-ir in each of these brain regions. Hypovolemia produced by polyethylene glycol (PEG) produced a robust water intake but no evidence of sodium appetite, and it induced Fos-ir in SFO, MnPO, and PVN. Peripheral injection of losartan did not affect this drinking response. Fos-ir induced by PEG in SFO and MnPO was reduced by treatment with losartan, while that induced in the PVN was further increased by losartan. Sodium depletion with furosemide and low-sodium diet produced a strong sodium appetite and induced Fos-ir in SFO and MnPO. Treatment with losartan completely blocked the sodium appetite, as well as the induction of Fos-ir in these brain regions. These data indicate that endogenous production of ANG II and action at forebrain receptors is critically involved in depletion-related sodium appetite in mice. The absence of an effect of losartan on PEG-induced drinking suggests the critical involvement of other factor(s) such as arterial or venous baroreceptor input, and we discuss how this factor could also explain why peripheral ANG II is not dipsogenic in mice.
hypovolemia; sodium depletion; subfornical organ; baroreceptors; Fos immunoreactivity
THE RENIN-ANGIOTENSIN CASCADE has important signaling functions in many tissues, including an integrative role in the regulation of hydromineral homeostasis by the brain (4, 5). Most of the studies that have led to this knowledge, especially in regard to neural mechanisms, have been performed in a few strains of rats. Contemporary interest in the use of mouse transgenic models has made it important to understand whether and how this rat-based model applies to mice. In particular, studies from this laboratory (12), as well as others (1, 4, 18), performed over a decade ago suggested that mice of several strains did not use ANG II as a signal molecule in precisely the same way as rats. Most prominent among the findings was that mice drank neither water nor NaCl solution when injected peripherally with ANG II (6, 12, 14, 18).
There are two general classes of potential explanations for that finding. The first is that ANG II is not dipsogenic because it does not have a role in fluid regulation in mice. This would be an extremely surprising conclusion because ANG II has been shown to have a dipsogenic action in all vertebrate groups except amphibians (4). A more likely explanation is that ANG II does play a role in fluid balance in mice, but that the protocols adapted from rats are inappropriate or not optimal in mice. In two recent papers, we have presented evidence in favor of the latter position. We showed (14) that peripheral injections of ANG II, although not dipsogenic, did induce the transcription factor cFos in brain regions similar to those in rats (see Ref. 10 for review), including the subfornical organ (SFO), a principal region at which circulating ANG II crosses into the mammalian brain because it lacks a tight blood-brain barrier. We further showed that sodium depletion in mice treated with furosemide or hypovolemia after injection of polyethylene glycol (PEG) not only activated the endogenous circulating renin-angiotensin system but also induced cFos in the SFO and other brain regions (11, 14). Interestingly, although peripheral injection of ANG II does not cause drinking in mice, PEG is a strong dipsogen and furosemide induces a sodium appetite (6, 11, 12, 14).
These findings suggest that the Fos immunoreactivity (Fos-ir) expressed in the brain during hypovolemia and/or sodium depletion in mice may be caused at least in part by circulating ANG II reaching the SFO or other brain regions lacking a tight blood-brain barrier. In the present work, we tested that hypothesis directly using the ANG II type 1 receptor (AT1) antagonist losartan to probe for involvement of ANG II. In particular, we asked whether losartan can block both fluid intake and the induction of cFos in brain after several challenges to body fluid homeostasis.
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METHODS
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Animals.
Male mice of the Crl:CD1(ICR) strain (Charles River, Newton, MA) between 3 and 9 mo of age were used in these studies. This strain was used to be consistent with our previous work and because they are not known to have atypical physiological or behavioral traits for which some strains have been inbred. For at least 1 wk before and throughout the studies, mice were housed individually in polycarbonate tub cages (13 x 10 x 10 cm) with stainless steel wire mesh lids. Sani-Chips bedding of 1- to 2-cm depth (Teklad-Harlan, Madison, WI) was present in each cage and was changed before each experiment. The vivarium was maintained at 23 ± 1°C with a 12:12-h light-dark cycle (on 0600–1800). Food (Purina 5001 Chow pellets) and tap water were available ad libitum, except as noted for 1–3 h before and during all acute tests. Mice were handled frequently before studies to minimize nonspecific stress responses to injection. All experiments conformed to the American Physiological Society's guidelines on the care and use of animals and were approved by the University of Florida's Institutional Animal Care and Use Committee.
Drinking studies.
Tests were performed in the home cages from which food was removed for the duration of acute tests. Mice were given a specific treatment and either immediately or after a delay given access to tap water, NaCl solution, or both. These fluids were contained in short cylinders graduated to an accuracy of 0.1 ml and fitted with a metal sipper tube. Tubes were inserted through the slots in the cage lid, and intakes were measured volumetrically.
Brain Fos-ir.
At a designated interval after treatment, during which neither food nor fluid was available, except as noted, mice were deeply anesthetized (pentobarbital sodium 200 mg/kg) and perfused intracardially with heparinized saline followed by 4% paraformaldehyde. Their brains were then removed and stood in paraformaldehyde solution overnight. On the following day, the brains were sliced coronally (75 µm) using a vibratome. Free-floating sections were first treated with borohydride to destroy endoperoxidases and then were incubated with primary antibody against cFos (SC-52; Santa Cruz Biotechnology, 1:20,000) at 4°C for 48 h. Next, secondary antibody (Zymed Labs) and ABC (Vector Labs) treatment were applied, and the slices were stained using diaminobenzidene as described before (13). Sections were mounted on gelatin-coated slides and examined by microscope. The numbers of Fos-ir cells in specific brain regions were counted by two condition-blind observers, and their results were averaged. For regions that spanned more than one section, the slide with the most Fos-ir cells was included for statistical analysis. Fos-positive cells were counted in the subfornical organ (SFO), median preoptic nucleus (MnPO), supraoptic (SON) and paraventricular (PVN) hypothalamic nuclei and, in some studies, organum vasculosum laminae terminalis (OVLT). The parvocellular and magnocellular regions of the PVN were invariably coactivated, so they were combined for analysis.
Statistics.
All data were analyzed using SigmaStat (SPSS) software. Group comparisons were made using 1-way ANOVAs with post hoc Newman-Keuls tests. Significance value was set at P < 0.05.
Effect of peripheral losartan on Fos-ir induced by peripheral ANG II.
The purpose of this experiment was to determine whether peripheral injection of losartan affects expression of brain Fos-ir induced by peripheral injection of ANG II. The result of this study formed the basis for the doses of losartan in subsequent experiments. Because peripherally injected ANG II is not dipsogenic in mice, there was no behavioral component to this study.
Fifteen mice were injected subcutaneously with ANG II (0.2 mg/kg; Sigma, St. Louis, MO); 10 were additionally injected with losartan (10 or 20 mg/kg sc; n = 6 and 4) immediately after ANG II injections, and five were injected subcutaneously with saline. Losartan potassium was a gift from Dr. R. Smith of DuPont-Merck Research & Development Division; it was dissolved in saline for use. After 1 h, during which neither food nor water was present, mice were anesthetized and perfused; brains were removed and sliced for Fos-ir.
Effect of losartan on drinking and Fos-ir induced by central ANG II.
In our 1988 paper (12), we cited a pilot study in which mice did not consume water after intracerebroventricular injection of ANG II. However, in more recent work in our lab, as well as in other labs (6, 7), intracerebroventricular ANG II does appear to be dispogenic in mice. The purpose of this study was to test whether drinking and Fos-ir were inhibited by peripheral injection of losartan.
An indwelling cannula was aimed to end just above the right lateral cerebral ventricle. Mice were anesthetized with a solution containing ketamine (
4 mg) and xylazine (1 mg) and then secured in a Kopf stereotaxic instrument. The skull was exposed by midline incision, and a guide cannula was lowered using standard stereotaxic procedures. Cannulas (Plastics One, Roanoke, VA) were made of 28-gauge stainless steel, cut to a 2-mm length below a Teflon screw cap. Skull coordinates with respect to bregma were –0.06 mm caudal and –0.16 mm lateral. The cannula was secured to the skull with cyanoacrylate and dental acrylic, and 5–7 days were allowed for recovery. Mice were then screened for cannula patency by injection of ANG II [50 ng/5 µl intracerebroventricularly (icv)] using an injector needle that extended 1 mm beyond the implanted guide. Mice that consumed <0.5 ml of water within 1 h were excluded or used as controls for Fos-ir studies.
In the behavioral study, mice were injected with losartan (20 mg/kg sc; n = 7) or saline (n = 11). ANG II (50 ng/5 µl icv) was administered 30 min later, and water was made available immediately thereafter. Intake was measured after 1 h. The same mice were subsequently used in the Fos-ir study. Mice received losartan (20 mg/kg sc, n = 7) or saline (n = 6), and 30 min later, they received ANG II (50 ng/5 µl icv) but no water. Control mice were injected intracerebroventricularly with 5 µl saline (n = 4). Mice were anesthetized 1 h later and perfused, as above, and the brains were removed, sliced, and processed for Fos-ir.
Effect of losartan on drinking and Fos-ir induced by hypovolemia.
Subcutaneous injection of the hyperoncotic colloid PEG causes hypovolemia and drinking in mice, although the time course appears to be more rapid than in rats (14, 16). Unlike in rats, we have been unable to find any evidence of a sodium appetite with this agent. PEG injection causes large elevations in plasma renin activity (PRA) in mice, indicative of the generation of circulating ANG II, and induction of Fos-ir in brain regions consistent with this hypothesis (14). The purpose of the present experiment was to determine, using losartan, whether endogenously generated ANG II contributes to the dipsogenic response and whether regional brain Fos-ir is antagonized. Because a total dose of 40 mg/kg losartan had proven ineffective against PEG-induced thirst in our work in rats (15), we included a still higher dose (100 mg/kg) in the design of this study.
In both behavioral and Fos-ir studies, PEG (formula wt > 20,000; Fisher Scientific) was injected subcutaneously using an 18-gauge needle (1 ml per mouse of a 40% wt/vol solution in distilled water). The PEG bolus was gently palpated to spread from the site of injection in the nape of the neck. Control mice received no injection. Losartan (10 or 100 mg/kg sc injected in the flank), or saline was administered immediately before the PEG injection. For the behavioral studies, 28 mice were divided randomly into four experimental groups. The same animals were used in two behavioral tests. In the first test, mice were given immediate access to distilled water for 2 h after PEG injection. In the second test, conducted 1 wk later, mice were given immediate access to saline (0.15 M) for 2 h after injections.
For the Fos-ir study, a separate group of 16 mice was divided randomly into four groups. As in the behavioral tests, groups received PEG and saline vehicle, PEG, and losartan (10 or 100 mg/kg sc), or no injection. After treatments, food and water were removed from the cages. Mice were anesthetized 2 h later and perfused; then brains were removed for Fos-ir processing. Blood was collected in capillary tubes immediately before perfusion for the determination of plasma protein concentration (Atago hand refractometer).
Effect of losartan on sodium appetite and Fos-ir after sodium depletion.
The loop diuretic furosemide causes a robust natriuresis in mice, and combined with subsequent access to a low-sodium food, it is suitable for demonstrating a sodium appetite under both acute and chronic conditions (1, 11, 12, 14). This treatment is associated with elevated PRA and induction of Fos-ir in the SFO. The purpose of the present experiment was to determine, using losartan, whether endogenously generated ANG II contributed to this natriorexigenic response and whether regional brain Fos-ir was correspondingly antagonized.
In a behavioral study, mice received injections of furosemide (40 mg/kg sc) and were then placed on a low-sodium natural ingredient diet (Teklad TD90228, 0.08–0.2% sodium) and distilled water for 24 h (n = 21). Before the drinking test, seven mice were injected with losartan (10 mg/kg sc), seven with losartan (100 mg/kg), and seven with saline. Control mice (n = 7) received saline injections instead of furosemide. After a 1-h delay, mice were given access to both distilled water and saline (0.15 M) for 2 h.
For the Fos-ir study, 13 mice received furosemide (40 mg/kg) and losartan (20 or 40 mg/kg) or saline (n = 5, 5, 3). Food and water were removed. Mice were anesthetized 3 h later and perfused; brains were processed for Fos-ir, as above.
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RESULTS
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Effect of peripheral losartan on Fos-ir induced by peripheral ANG II.
Peripheral injection of ANG II induced strong Fos-ir in the SFO (Fig. 1). In our previous work (14), as well as in the present experiments 3 and 4, untreated, or control, animals express only 10 Fos-ir cells in SFO. Losartan (10 and 20 mg/kg) significantly reduced the ANG II-induced Fos-ir in the SFO [F(2,14) = 5.98, P < 0.02; Fig. 1], suggesting that circulating losartan penetrates the SFO. Substantial numbers of Fos-ir cells were also observed in MnPO and PVN after ANG II, but these values were neither above basal (see Fig. 3) nor were they reduced by losartan (Fig. 1).
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Fig. 1. Mean ± SE numbers of Fos-immunoreactive (Fos-ir) cells per section in subfornical organ (SFO), median preoptic nucleus (MnPO), paraventricular hypothalamus (PVN) and supraoptic nucleus (SON) of mice killed 1 h after subcutaneous injection of ANG II (0.2 mg/kg) and either losartan (Los, 10 or 20 mg/kg) or saline. *P < 0.05 vs. saline + ANG II.
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Fig. 3. Mean ± SE numbers of Fos-ir cells per section in mice after intracerebroventricular injection of saline (control), or ANG II (50 ng) preceded by subcutaneous saline or losartan (20 mg/kg). Brain regions as in Fig. 1. *P < 0.05 vs. control. #P < 0.05, losartan inhibition of ANG II effect.
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Effect of losartan on drinking and Fos-ir induced by central ANG II.
Mice drank substantial amounts (2–3% of body weight) of water after intracerebroventricular ANG II (Fig. 2), and this drinking was inhibited significantly by peripheral administration of losartan. Intracerebroventricular ANG II induced Fos-ir in all brain areas investigated (Fig. 3) compared with vehicle-injected controls, and administration of losartan reduced Fos-ir in the MnPO, SFO, and PVN to control levels [SFO: F(2,16) = 36.01, P < 0.01; MnPO: F = 15.25, P < 0.01; SON: F = 12.48, P < 0.01; PVN: F = 8.07, P < 0.01].
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Fig. 2. Mean ± SE water intake in a 1-h test after intracerebroventricular injection of ANG II (50 ng) preceded by subcutaneous injection of either saline or losartan (20 mg/kg). *P < 0.01, losartan inhibition of ANG II-induced drinking.
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Effect of losartan on drinking and Fos-ir induced by hypovolemia.
Treatment with PEG stimulated water intake (Fig. 4) [F(3,23) = 5.16, P < 0.01]. Losartan did not inhibit PEG-induced water consumption at either 10 or 100 mg/kg dose. In the test of saline intake, untreated control mice consumed a mean of 0.8 ml, and intakes of the PEG groups were not different (means 0.6–1.0 ml). PEG treatment was associated with elevated Fos-ir in all brain areas investigated (Fig. 5) [SFO: F(3,15) = 15.49, P < 0.01; MnPO: F = 4.26, P < 0.03; SON: F = 65.78, P < 0.01; PVN: F = 31.65, P < 0.01]. We also examined the OVLT. Strong Fos-ir occurred in a band of cells over only a small anteroposterior extent, and a representative section (Fig. 6) was not obtained in every mouse. Thus we did not perform a quantitative analysis in OVLT. Losartan (10 or 100 mg/kg) reduced Fos-ir to baseline levels in the MnPO and SFO (Fig. 5) and clearly reversed it in OVLT (Fig. 6). In contrast, losartan further elevated Fos-ir in PVN compared with PEG alone (Fig. 5). Interestingly, while losartan reversed Fos-ir in the OVLT of PEG-treated mice, we found a striking induction of Fos in a small band of cells on the ventral surface of the brain just lateral to the OVLT (Fig. 6) in mice receiving losartan + PEG.
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Fig. 4. Mean ± SE water intake of mice in a 2-h test after no treatment (control) or subcutaneous injection of polyethylene glycol (PEG; 1 ml 40%) either alone or with losartan (10 or 100 mg/kg). *P < 0.01 vs. untreated control; PEG groups did not differ from each other.
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Fig. 5. Mean ± SE numbers of Fos-ir cells per section in mice 2 h after either no treatment (control) or subcutaneous injection of PEG alone or with losartan (10 or 100 mg/kg). Brain regions as in Fig. 1. *P < 0.05 vs. control; #P < 0.05 vs. PEG alone.
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Fig. 6. Representative photomicrographs of the SFO (A and B) and the organum vasculosum laminae terminalis (OVLT) (C and D) of mice treated with PEG alone (A and C) or PEG plus 100 mg/kg losartan (B and D). PEG induced Fos-ir throughout the core region of the SFO and in the lateral walls of the OVLT, and this response was absent after pretreatment with losartan. Note the induction of Fos-ir in a band of cells just ventral and lateral to the OVLT in the losartan-treated sample (D). Scale: images were captured digitally at x40, then cropped and sized using Adobe Photoshop; each image represents 0.5 mm square of tissue.
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Regardless of whether they received losartan, mice that received PEG had elevated plasma protein levels (mean 8.56 g/dl) compared with controls (mean 6.72 g/dl).
Effect of losartan on sodium appetite and Fos-ir after sodium depletion.
Treatment with furosemide followed by a low-sodium diet for 1 day stimulated a robust salt appetite [F(3,26) = 12.4, P < 0.01]. Administration of losartan before the test inhibited this NaCl consumption (Fig. 7). No group consumed significant amounts of water (means < 0.1 ml). Fos-ir was elevated in SFO, MnPO, SON, and PVN after administration of furosemide and low-sodium diet, compared with basal or control values such as those observed in the foregoing PEG study (Fig. 8). Fos-ir was also induced in OVLT (Fig. 9). Losartan inhibited Fos-ir in the SFO at either the 20 or 40 mg/kg dose [F(2,12) = 6.79 P = 0.01] and in the MnPO at the higher dose [F(2,13) = 7.26, P = 0.01], and in representative sections of OVLT (Fig. 9).
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Fig. 7. Means ± SE of 0.15M NaCl intake by mice in a 2-h test conducted 24 h after injection of saline (control) or furosemide (Furo; 40 mg/kg) and overnight access to a low-sodium diet. Some mice received losartan (20 or 40 mg/kg) 1 h before the intake test. *P < 0.01 vs. control.
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Fig. 8. Mean ± SE numbers of Fos-ir cells per section in mice 3 h after subcutaneous injection of furosemide either alone or with losartan (20 or 40 mg/kg). Brain regions as in Fig. 1. *P < 0.05 vs. furosemide alone; #P < 0.05, higher dose of losartan differs from lower dose.
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Fig. 9. Representative photomicrographs of the SFO (A and B) and OVLT (C and D) of mice treated with furosemide alone (A and C) or furosemide plus 20 mg/kg losartan (B and D). Furosemide induced Fos-ir throughout the core region of the SFO and in the lateral walls of the OVLT, and this effect was abolished by losartan. Scale: same as for Fig. 6; each panel represents 0.5 mm square of tissue.
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DISCUSSION
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Fos-ir induced in mouse SFO by subcutaneous administration of ANG II was similar to that reported previously by our laboratory (14). The present demonstration that this Fos-ir can be reversed by losartan suggests that as in rats (8), this agent is able to access this brain region that has little or no blood-brain barrier. Alternatively, it is possible that the likely antagonism by losartan of the pressor action of peripheral ANG II could have diminished the access of ANG II itself to the SFO. The penetration of losartan into SFO was tested more directly in the second experiment in which ANG II was administered centrally. Peripherally administered losartan inhibited Fos-ir after intracerebroventricular ANG II, consistent with the penetration of losartan into SFO, and probably into other brain regions. Consistent with reports from other labs (6, 7), we found a reliable dipsogenic response in mice to a relatively high intracerebroventricular dose of ANG II, and this was inhibited by peripherally injected losartan. Compared with peripheral administration (Fig. 1; Ref. 14), intracerebroventricular ANG II at the dose used in this study induced more Fos-ir cells in MnPO, SON, and PVN (Fig. 3), values that were significantly elevated compared with intracerebroventricular vehicle control.
As we have reported before (14), PEG stimulated water but not NaCl consumption in mice. Losartan did not affect PEG-induced water consumption, but did reduce Fos-ir in the MnPO and SFO, as reported in rats (15). In contrast, Fos-ir in the PVN was further elevated with the addition of losartan to the PEG treatment. PEG has a very modest hypotensive action in rats (3, 16); presumably, the ANG II generated helps to prevent a drop in arterial pressure. Blood pressure during elevated renin states is reduced by losartan (19), so we infer that losartan should exacerbate hypotension in PEG-treated rodents. We know of no relevant blood pressure studies in mice or rats. However, if this is true, and given the present finding that losartan does inhibit intracerebroventricular ANG II-induced drinking, then the failure of losartan to affect PEG drinking suggests that the latter is independent of ANG II. The fact that PEG-induced Fos-ir in SFO and MnPO was inhibited by losartan, reflecting antagonism of ANG signaling, further shows that even though ANG II is stimulated in this model, it does not contribute significantly to drinking. Instead, it is likely that PEG-induced drinking is dependent upon afferent input from cardiopulmonary baroreceptors. Because the PVN receives baroreceptor input, the increase in Fos-ir in the PVN after losartan administration, in addition to PEG treatment compared with PEG treatment alone, may be due to exacerbation of hypotension in the presence of losartan. We also noted that combination of PEG and losartan produced Fos-ir in a distinctive band of cells on the ventral surface of the brain, just lateral to the OVLT or the ventral MnPO. It is possible that these cells also receive baroreceptor input, although we know of no relevant evidence in this regard.
In contrast to the result with PEG, furosemide stimulated a robust sodium appetite, and this was completely inhibited by losartan. Depletion-related, sodium-seeking behavior in mice thus appears to be highly dependent on ANG II signaling. Further, sodium depletion induced Fos-ir primarily in SFO and OVLT, and this was reduced by losartan. A previous investigation of the possible role for peripheral ANG II in salt appetite in mice (6) was unsuccessful insofar as combined treatment with furosemide and captopril did not induce salt intake in C57BL/6 mice. This discrepancy could be due to a strain difference, or to a difference between rats and mice in the actions of captopril; one such species difference has been reported previously (12).
The doses of losartan used in the present studies are relatively high, and we did not attempt dose-effect analyses. In studies not presented, doses of losartan in the range used here did not inhibit drinking induced by either fluid deprivation or hypertonic saline administration. The results of the present studies are, thus, not attributable to nonspecific behavioral effects of the doses of losartan used.
The present data show clearly that endogenously produced ANG II does contribute to fluid intake in mice and, in particular, to salt appetite. The previously reported failure of peripherally administered ANG II to stimulate drinking in mice may be due to a presumed ANG II-induced elevation in blood pressure (3, 9). Although water consumption in hypotensive rats is at least partly dependent upon ANG II (3, 5, 9, 17), water drinking in mice seems to be independent of ANG II. On the basis of the present finding that salt appetite is inhibited by losartan, salt appetite in mice is dependent upon AT1 receptor signaling. Thus, although hypotension-related drinking in mice may depend primarily on baroreceptor afferents (or other signal), salt appetite appears to be regulated by a separate ANG II-dependent pathway. Perhaps these pathways are not so clearly separated in rats, so that drinking and salt appetite are both regulated by ANG II and afferent baroreceptor input. It is important to note that although our studies indicate that AT1 receptors mediate intracerebroventricular ANG II-induced drinking, other studies indicate that AT2 receptor signaling additionally contributes to the behavioral response (7). Further investigation is necessary to determine the contribution of hypotension to drinking in mice and the specific roles of AT1 and AT2 receptors. Finally, our studies have used only one strain of mouse that we believe to be unexceptional. However, the possibility of strain differences in sensitivity to or contribution of ANG II to hydromineral homeostasis cannot be discounted at this time.
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FOOTNOTES
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Address for reprint requests and other correspondence: N. Rowland, Psychology, P.O. Box 112250, Univ. of Florida, Gainesville, FL 32611-2250 (E-mail: nrowland{at}ufl.edu)
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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M. J. McKinley, L. L. Walker, T. Alexiou, A. M. Allen, D. J. Campbell, R. Di Nicolantonio, B. J. Oldfield, and D. A. Denton
Osmoregulatory fluid intake but not hypovolemic thirst is intact in mice lacking angiotensin
Am J Physiol Regulatory Integrative Comp Physiol,
May 1, 2008;
294(5):
R1533 - R1543.
[Abstract]
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