(Hypertension. 1996;27:573-577.)
© 1996 American Heart Association, Inc.
Articles |
Salt-Sensitive Hypertension in (mREN-2)27 Transgenic Rats
From the Departments of Physiology and Pharmacology and The Hypertension Center, Bowman Gray School of Medicine of Wake Forest University, Winston Salem, NC, and the Max Delbrück Center for Molecular Medicine, Berlin-Buchs, Germany.
Correspondence to Michael F. Callahan, PhD, Department of Physiology and Pharmacology, Bowman Gray School of Medicine of Wake Forest University, Winston Salem, NC 27157-1083. E-mail mcallahan@medcenter.wpmail.wfu.edu.
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Abstract |
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Abstract The (mREN-2)27 transgenic model of hypertension was developed to investigate the effect of genetic over activity of angiotensin II systems as a contributing factor in the development of arterial hypertension. In this model, transgene-positive rats demonstrate elevated renin-angiotensin system activity not only in the circulatory system but also in adrenal gland, reproductive organs, and brain. Since evidence indicates that angiotensin peptides and osmotic stimuli interact synergistically to produce exaggerated behavioral, endocrine, and cardiovascular effects, we examined the effect of salt consumption on arterial pressure, plasma vasopressin, and body fluid balance in male (mREN-2)27 transgene-positive and -negative rats. Four days of drinking 2% NaCl increased mean arterial pressure from 165±10 to 199±7 mm Hg in transgene-positive rats. In contrast, transgene-negative rats showed no change in arterial pressure (126±5 to 128±3 mm Hg). Plasma vasopressin levels were significantly elevated only in transgene-positive rats, whereas pituitary levels of vasopressin were significantly lower in transgene-positive rats compared with transgene-negative controls (18±3 and 118±14 ng, respectively). Although transgene-positive rats consumed significantly more 2% NaCl than did transgene-negative rats, during this period 24-hour sodium balance did not differ between the groups. Since fluid and electrolyte balance is similar between the two groups of rats, the data suggest that transgene-positive rats may be more sensitive to the effects of increased NaCl intake in terms of both endocrine and cardiovascular responses.
Key Words: vasopressins • drinking • heart rate • appetite • angiotensin • renin • water-electrolyte balance
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Introduction |
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A new animal model of hypertension that depends on the genetic expression of the RAS has been developed by the insertion of mouse submandibular Ren-2 gene into the rat genome.1 Hypertensive Tg(+) rats display normal or only slightly elevated plasma renin and Ang II compared with Tg(-) rats.2 3 However, the mREN-2 gene is expressed in a number of tissues,4 and levels of renin or angiotensin or both are elevated in several of these tissues, including adrenal gland and brain.1 5 6 7 Evidence indicates that the hypertensive process does not depend on adrenal hormones2 8 9 but may be mediated at least in part by CNS mechanisms. For example, Moriguchi and colleagues3 have demonstrated that intracerebroventricular injection of an antibody against Ang II10 or the Ang II antagonist losartan (unpublished observations, 1995) decreased arterial pressure in Tg(+) rats. Thus, elevations in central angiotensin peptides may be critical for the development of hypertension in Tg(+) rats.
It is well recognized that angiotensin peptides regulate arterial pressure and body fluid homeostasis through actions on the CNS. Centrally administered Ang II increases arterial pressure in part by activation of vasopressin release and also by sympathetic activation.11 12 Chronic CNS administration of angiotensin peptides leads to long-lasting increases in arterial pressure and water intake without significantly affecting either water or electrolyte balance.13 In addition, centrally administered Ang II increases salt appetite, especially in mineralocorticoid-treated rats.14
Recent work has indicated that angiotensin peptides and osmotic stimuli act in a synergistic manner to cause exaggerated pressor, dipsogenic, and endocrine responses in a number of animal models. Substitution of isotonic saline for drinking water led to a rapid increase in arterial pressure in dogs receiving long-term intracerebroventricular infusion of Ang II.15 Katahira et al16 found that intracerebroventricular NaCl and subpressor intravenous doses of Ang II increased arterial pressure and plasma aldosterone. Ando and colleagues17 reported that intravenous Ang II acted in a dose-dependent manner with dietary NaCl to increase blood pressure in rats. Likewise, intravenous infusion of hypertonic saline augmented the hypertension produced by chronic intracerebroventricular infusion of Ang II.18 This hypertensive response was independent of fluid intake or adrenal hormones. Thus, evidence suggests that the CNS is a site where osmotic and angiotensinergic stimuli are integrated to produce hypertensive responses.
We therefore examined whether rats that have elevated CNS expression of the mREN-2 gene and increased CNS angiotensin peptides would show increased salt appetite and greater increases in arterial pressure and plasma vasopressin in response to salt consumption. In addition, we examined whether the Tg(+) rats would show alterations in the ability to excrete this sodium challenge.
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Methods |
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The rats used in these studies were obtained from the breeding colony established at the Hypertension Center of Bowman Gray School of Medicine from breeding stock supplied by Dr D. Ganten (Berlin-Buchs, Germany). Rats included (mREN-2)27 Tg(+) and Tg(-) littermates produced by breeding male heterozygous Tg(+) rats with female rats from the Hannover Sprague-Dawley strain used to create the transgenic line. The genetic lineage of each rat was determined by the presence or absence of mREN transcript after polymerase chain reaction amplification of tissue samples. Phenotypic expression of the transgene was initially determined by measurement of blood pressure by tail-cuff plethysmography. All procedures used in this study were approved by the Bowman Gray School of Medicine Animal Care and Use Committee.
Male Tg(+) (465±9 g, n=8) and Tg(-) (528±17 g, n=10) rats, 3 to 5 months of age, were housed in Nalge metabolic cages. Arterial cannulas (drawn PE-50 with silicone elastomer tip) were placed in the common carotid artery with rats under xylazine:ketamine anesthesia (10:50 mg/kg IM). Food and water intakes stabilized at presurgery levels during a 5- to 7-day recovery period. Baseline measures of food and water intakes and urinary volume and sodium output were taken for 2 days. On the second day, the arterial catheter was connected to a length of PE-50 tubing that was exteriorized from the metabolic cage. The rats received a 0.5 mL injection of heparinized saline (50 U/mL of 0.9% NaCl) and were allowed 1 hour to stabilize. Direct arterial pressure and heart rate were determined. A 1.5-mL blood sample was taken for the determination of hematocrit and plasma vasopressin, and the rats received 1.5 mL heparinized saline to replace the blood lost. The rats were then given 2% NaCl in place of normal drinking water for 4 days. Indexes of body fluid and electrolyte balance were taken on each day. On the fourth day of 2% saline administration, direct arterial pressure and heart rate were determined, and the rats were killed by rapid decapitation. Trunk blood was collected for assay of vasopressin by radioimmunoassay.
Daily indexes of sodium balance were computed by subtracting urinary sodium excretion from total electrolyte intake (food plus 2% NaCl). Fecal electrolyte excretion was not determined because it represents only 1% to 2% of total sodium output over a range of intakes.19
Arterial pressure was measured with a physiograph (model 5/6H, Gilson Medical Electronics) and pressure transducers (model 156PC15GWL, Microswitch). Mean arterial pressure was calculated as diastolic pressure plus one third pulse pressure. Heart rate was calculated for 5-second periods. Vasopressin was assayed by a sensitive radioimmunoassay as previously described.20
Data were analyzed by ANOVA with repeated measures as
appropriate (SAS). The Student-Newman-Keuls test was used for
between-group post hoc analysis. Within-group
comparisons were analyzed by contrast transformation. A
significance level of P
.05 was used for all
analyses. All values are reported as mean±SE.
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Results |
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Tg(+) rats had significantly higher basal mean arterial pressure than Tg(-) rats (165±10 versus 126±5 mm Hg) and showed a significant increase in arterial pressure (34 mm Hg) after consuming 2% NaCl for 4 days (Fig 1
). Tg(-) rats showed no
significant change in arterial pressure in response to
sodium load; ie, mean arterial pressure increased only 2
mm Hg. Heart rate did not differ significantly between the two groups
[337±19 versus 320±19 beats per minute, Tg(-) versus
Tg(+)],
and the drinking of salt solution did not significantly affect
heart rate [339±20 versus 334±21 beats per minute,
Tg(-)
versus Tg(+)].
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Basal levels of plasma vasopressin were not significantly different
between Tg(-) and Tg(+) rats (Fig 2, left).
Drinking 2% NaCl for 4 days caused a significant increase in plasma
vasopressin (P<.002) that was greater in Tg(+) rats
(P<.01). On average, plasma vasopressin increased 4.5 pg/mL
in Tg(+) rats, whereas the increase was only 0.6 pg/mL in Tg(-)
rats. Additionally, after 4 days of a high salt intake, posterior
pituitary vasopressin content (Fig 2, right) was significantly
lower in
Tg(+) rats (P<.01).
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Over the 4-day period, consumption of the 2% NaCl solution was higher
than baseline water intake on all four days of treatment
(Table). Tg(+) rats showed significantly greater
(P.02) intake of the salt solution. However, there was no
significant interaction of genetic background and time
(P=.34). Although the Tg(+) rats consumed more saline,
there
was no significant effect of salt consumption on sodium balance
(P.07) and no significant difference between Tg(+) and
Tg(-) rats (P.4). There was no significant
interaction of genetic background and time on sodium balance. Drinking
2% NaCl had a significant effect (P<.001) on fluid balance
(intake-urine output), but there was no significant interaction
between genetic background and time and no difference between the
groups. Fluid balance was significantly lower on days 1 and 4 of salt
loading (Table). On day 4 this decrease in fluid balance was
significant only in the Tg(+) rats (P<.02). Hematocrit
showed a significant decline from baseline to day 4 of salt treatment
in Tg(+) (0.43±0.007 to 0.41±0.001) and Tg(-)
(0.42±0.005 to
0.39±0.002) rats, with no significant difference in the response of
the two groups.
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Discussion |
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The main finding of this study is that an increase in salt intake exacerbates the progression of hypertension in the (mREN-2)27 transgenic rat. Additionally, Tg(+) rats respond to the osmotic stimulus with a greater increase in plasma vasopressin. These effects do not appear to be related to changes in overall fluid balance because the pattern of fluid and electrolyte excretion was not different between the groups.
The current finding that arterial pressure in Tg(+) rats is salt sensitive supports work by Barrett and Mullins,21 who found that acute administration of furosemide combined with a low salt diet lowered diastolic arterial pressure (-55 mm Hg) in Tg(+) rats. Arterial pressure rose to pretreatment levels on reexposure to a normal salt diet, indicating that the regulation of arterial pressure is salt and/or volume dependent in Tg(+) rats. These findings of salt sensitivity in Tg(+) rats contrast with a report by Chung et al22 that Tg(+) rats show no change in arterial pressure when given an 8% NaCl diet for 10 days. However, in that study,22 arterial pressure (data not provided) was determined at unspecified times by tail-cuff plethysmography in anesthetized rats. Additionally, the mode of salt loading differed (dietary versus liquid), as did the total osmotic challenge administered to the rats. In recent work using 24-hour cardiovascular monitoring, we have observed that arterial blood pressure increases within 6 hours of giving Tg(+) rats access to 2% NaCl, further verifying the salt sensitivity in this model of hypertension.23
A major goal of the current study was to determine whether Tg(+) rats showed deficits in the excretion of a salt/volume challenge. Kreiger and colleagues24 showed that the increase in arterial pressure during simultaneous infusion of Ang II and hypertonic NaCl solution was associated with increases in total body water and intravascular volume. In our study, overall water balance and hematocrit were decreased by drinking 2% NaCl. These findings would suggest that drinking the hyperosmotic solution caused an overall net fluid loss that was accompanied by an increase in intravascular volume. An increase in intravascular volume would presumably be related to a dehydration of extravascular spaces. It is conceivable that a modest volume expansion, especially in the face of decreased vascular compliance, could lead to an increase in arterial pressure. Increases in intravascular volume as low as 5% were reported to increase arterial pressure in areflexive rats.25 However, whether such mechanisms are operative in animals with unimpaired volume- or pressure-sensitive reflexes and whether such a response is exaggerated in Tg(+) rats remain to be determined.
The present results provide no evidence for changes in sodium balance in the (mREN-2)27 transgenic rat model. However, other data show that Tg(+) rats display alterations in the renal handling of water and NaCl that may be related to the development of hypertension. For example, Tg(+) rats show greater depressor and natriuretic responses to furosemide, suggesting that sodium and volume retention may play a role in the maintenance of hypertension.26 In the current study, both Tg(+) and Tg(-) rats responded to a hypertonic saline challenge by remaining in sodium balance and entering a slight negative water balance. This is in agreement with a report that Tg(+) and Sprague-Dawley rats show no differences in sodium excretion when placed on a high NaCl diet.22 Furthermore, Tg(+) rats are able to rapidly excrete an oral isotonic saline load26 and show exaggerated natriuresis during intravenous isotonic saline infusion.27 It is possible that Tg(+) rats excrete a sodium load via a pressure-natriuresis mechanism. Pressure natriuresis/diuresis in an isolated perfused kidney preparation was reported to be similar in Tg(+) and Lyon hypertensive rats.26 However, Gross and colleagues28 found a blunted pressure-natriuresis/diuresis curve and decreased renal blood flow and glomerular filtration rate in Tg(+) rats compared with Sprague-Dawley controls. Thus, a higher pressure may be required for similar natriuretic responses. Indeed, in Tg(+) rats blockade of the RAS with captopril decreases arterial pressure, glomerular filtration rate, and sodium excretion.27
We now report that Tg(+) rats show elevated plasma vasopressin levels in response to consumption of 2% NaCl. The increased secretion of vasopressin is similar to that previously reported for other models of salt-sensitive hypertension, eg, Dahl salt-sensitive rats,29 and acute sinoaortic denervation.30 The increased sensitivity of the vasopressinergic neurohypophyseal axis to an osmotic challenge contrasts with a previous report that Tg(+) rats showed diminished release of vasopressin into CNS tissues but normal plasma responses.31 The source of this discrepancy could be the stimulus chosen (osmotic pressure versus Ang II), the source of the released peptide (pituitary versus intranuclear), sex of the rats, and/or presence of anesthesia.
It is unlikely that the increase in circulating vasopressin in the Tg(+) rats is the cause of the increase in arterial pressure as it has been demonstrated that chronic infusion of vasopressin at doses designed to produce up to a fourfold elevation in circulating vasopressin levels did not affect arterial pressure.32 However intravenous or intrarenal infusion of a V1 vasopressin agonist chronically increased arterial pressure, whereas infusion of vasopressin was without effect.33 Additionally, it is possible that the balance between V1/V2 effects of vasopressin may be shifted in the Tg(+) rats such that vascular actions of endogenous vasopressin predominate in these rats. We have recently found that the arterial pressure increase in Tg(+) rats given 2% NaCl is accompanied by increases in plasma norepinephrine and epinephrine.23 Thus, consideration must also be given to the role of sympathetic activation in the cardiovascular response to salt loading demonstrated by Tg(+) rats.
In the current study, we also found that consumption of 2% NaCl was exaggerated in Tg(+) rats. Avrith and Fitzsimons34 reported that injection of pig renin or purified murine submandibular renin [ie, the source of the extra renin gene in the Tg(+) rats] into Wistar rats caused increased intake of NaCl. Injection of purified renin caused an initial positive sodium balance with a longer-lasting positive water balance. Our results demonstrate that the elevation of sodium intake was accompanied by maintenance of sodium/fluid balance. Since it has been reported that renal angiotensin peptides may allow Tg(+) rats to excrete a sodium challenge,27 it is possible that the renal RAS permits the normalization of electrolyte balance in the face of a sodium load in Tg(+) rats. Thus, elevated expression of the mREN gene, albeit in different tissues, could be responsible for both the increase in salt intake and its excretion.
The reason for enhancement of the sodium response in Tg(+) rats is likely to be related to changes in the brain RAS in these rats. There is strong evidence for CNS-mediated interactions between angiotensin peptides and osmotic stimuli. For example, injection of Ang II into the cerebral ventricles increased both blood pressure and salt appetite.35 In addition, the ability of circulating angiotensin to increase arterial pressure depends on the level of sodium intake.17 36 Also, the hypertensive response to intracerebroventricular Ang II is potentiated by NaCl load administered by intravenous infusion18 37 or in the diet.17 Likewise, hypertension could be produced by delivering the osmotic stimulus to the CNS (intracerebroventricularly) and Ang II into the circulation.16 Interestingly, the hypertension in these models does not depend on increased fluid intake or adrenal hormones38 but may depend on increased sympathetic nervous system activity.16 Work by Fink and colleagues39 indicated that the area postrema is necessary for Ang II–salt-induced hypertension. Work by Averill and colleagues40 shows that lesion of the area postrema substantially lowers arterial pressure in Tg(+) rats. The current study demonstrated that a genetically engineered increase in tissue RAS activity produces a substantial salt sensitivity of arterial pressure. It is possible that the ability of area postrema lesions to decrease arterial pressure in Tg(+) rats reflects the fact that normal rat chow has a high NaCl content and thus Tg(+) rats are demonstrating substantial salt sensitivity of arterial pressure on a regular diet. In recent studies, we found that paraventricular nucleus administration of antisense oligodeoxynucleotide directed against the type 1 Ang II receptor decreases arterial pressure in salt-loaded Tg(+) rats but has no effect on arterial pressure in non–salt-loaded Tg(+) rats. These findings would suggest that two CNS sites are critical for the integration of these two hypertensivogenic stimuli23 : the area postrema for the detection of elevated circulating levels of angiotensin peptides and the paraventricular nucleus for the integration of salt sensitivity.
In summary, the present data show that (mREN-2)27 transgenic rats are sensitive to chronic osmotic stimulation in terms of arterial pressure and vasopressin secretion. Our findings support the idea that interactions between osmotic and angiotensin stimuli are critical in the regulation of cardiovascular and endocrine function. In view of the interaction of central Ang II systems and osmotic stimuli in controlling sympathetic and body fluid and electrolyte status, further work is warranted on the sites and mechanisms of integration of these stimuli and the efferent pathways by which fluid and electrolyte homeostasis is maintained during these chronic osmotic challenges.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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This research was supported by grants from the American Heart Association, North Carolina Affiliate (NC93-GS-15), to Dr Callahan and the National Institutes of Health (HL-51952) to Dr Ferrario. The authors wish to thank Dr Gui Tsai and Cindy Barrett for expert technical assistance.
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