Dahl-Iwai Salt-sensitive Rats Research Articles

Effects of a lysophosphatidic acid receptor 1 antagonist on hypertensive renal injury in Dahl-Iwai salt-sensitive rats

Lysophosphatidic acid (LPA) is a biologically active lysophospholipid, and acts on six types of LPA receptors (LPA1-LPA6). LPA-LPA1 signaling has been suggested as a therapeutic target for inflammatory and fibrotic disorders, including renal fibrosis.In this study, we investigated the effects of AM095, an LPA1 selective antagonist, on hypertensive renal injury in Dahl-Iwai salt-sensitive (DS) rats. We evaluated the preventive as well as therapeutic efficacy of AM095 in reducing proteinuria, and improving impaired renal function and renal fibrosis in the hypertensive DS rat.Preventive administration of AM095 suppressed proteinuria, renal function impairment and renal fibrosis in the hypertensive DS rats. In addition, therapeutic administration of AM095 reduced the levels of proximal tubular injury markers and suppressed renal fibrosis. Furthermore, combined administration of AM095 with an angiotensin-converting enzyme (ACE) inhibitor reduced the levels of proximal tubular injury markers and kidney weight increase, and suppressed renal fibrosis more effectively than administration of either agent alone, independent of the antihypertensive effect of the ACE inhibitor.These results provide the first evidence of the potential efficacy of LPA1 antagonist in suppressing renal injury in hypertensive DS rats, suggesting the promise of LPA1 antagonists as a novel therapeutic option for hypertensive renal injury.

Prepubertal angiotensin blockade exerts long-term therapeutic effect through sustained ATRAP activation in salt-sensitive hypertensive rats

We previously showed that the molecule interacting with Ang II type 1 receptor (AT1R), ATRAP, promotes AT1R internalization and attenuates AT1R-mediated pathological responses. In this study we examined whether the regulation of renal ATRAP expression is related to the development of salt-induced hypertension and renal injury as well as to the beneficial effects of AT1R blockade. Dahl Iwai salt-sensitive hypertensive and Dahl Iwai salt-resistant rats were divided into six groups for the administration of vehicle or olmesartan either continuously from 3 to 16 weeks, or transiently from weaning to puberty (3-10 weeks), and fed high salt diet from 6 to 16 weeks. In Dahl Iwai salt-sensitive rats, not only continuous, but also prepubertal olmesartan treatment improved hypertension at 15 weeks. Renal ATRAP expression was suppressed in vehicle-treated Dahl Iwai salt-sensitive rats, concomitant with up-regulation of renal oxidative stress, inflammation and fibrosis-related markers such as p22phox, TGF-β, fibronectin, monocyte chemotactic protein-1 and type 1 collagen. However, prepubertal as well as continuous olmesartan treatment recovered the suppressed renal ATRAP expression and inhibited the renal activation of p22phox, TGF-β, fibronectin, MCP-1 and type 1 collagen. In Dahl Iwai salt-resistant rats, such suppression of renal ATRAP expression or induction of renal pathological responses by salt loading was not observed. These results indicate that prepubertal transient blockade of AT1R signaling exerts a long-term therapeutic effect on salt-induced hypertension and renal injury in Dahl Iwai salt-sensitive rats, partly through a sustained enhancement of renal ATRAP expression, thereby suggesting ATRAP a novel molecular target in salt-induced hypertension and renal injury.

Continuous Antagonism of the Ghrelin Receptor Results in Early Induction of Salt-Sensitive Hypertension

Ghrelin is a hormone that mediates a variety of physiological roles, such as stimulating appetite, initiating food intake, and modulating energy metabolism. Although it has been reported that a bolus injection of ghrelin decreases blood pressure, the effect of continuous ghrelin administration on vasoregulation has yet to be determined. We examined the longitudinal effect of ghrelin on vasoregulation using Dahl-Iwai salt-sensitive rats. In this model, a high-salt diet induced high blood pressure and increased ghrelin levels but reduced food intake. In salt-sensitive hypertension, cumulative food intake decreased, while both ghrelin messenger RNA levels and plasma ghrelin content increased. Continuous administration of a ghrelin receptor agonist, growth hormone releasing peptide-6 (GHRP-6), for 2 weeks by mini-osmotic pump did not change blood pressure values although the cumulative food intake recovered. In contrast, continuous administration of a ghrelin receptor antagonist, [D-Lys³]-GHRP-6, induced early elevations in blood pressure without changes in heart rate. Quantitative RT-PCR revealed high expression levels of genes involved in the catecholamine biosynthetic pathway, tyrosine hydroxylase and dopamine-β-hydroxylase, after continuous [D-Lys³]-GHRP-6 administration. These results indicate that continuous antagonism of the ghrelin receptor results in early induction of salt-sensitive hypertension in this animal model and suggests that increases in autonomic nervous activity induced by ghrelin receptor antagonism are responsible, as indicated by the high expression levels of genes in the catecholamine biosynthetic pathway.

Androgens drive divergent responses to salt stress in male versus female rat kidneys

Dahl-Iwai (DI) salt-sensitive rats were studied using microarrays to identify sex-specific differences in the kidney, both basal differences and differences in responses to a high-salt diet. In DI rat kidneys, gene expression profiles demonstrated inflammatory and fibrotic responses selectively in females. Gonadectomy of DI rats abrogated sex differences in gene expression. Gonadectomized female and gonadectomized male DI rats both responded to high salt with the same spectrum of gene expression changes as intact female DI rats. Androgens dominated the sex-selective responses to salt. Several androgen-responsive genes with roles potentiating the differential responses to salt were identified, including increased male expression of angiotensin-vasopressin receptor and prolactin receptor, decreased 5α-reductase, and mixed increases and decreases in expression of Cyp4a genes that can produce eicosanoid hormones. These sex differences potentiate sodium retention by males and increase kidney function during gestation in females.

N-methylethanolamine attenuates cardiac fibrosis and improves diastolic function: inhibition of phospholipase D as a possible mechanism

Purpose: Ventricular fibrosis is promoted by many effectors that chronically activate phospholipase D (PLD), and induces cardiac dysfunction and heart failure in cardiovascular diseases. Since ethanolamine is a product of PLD, we hypothesized that an administration of an analogue of ethanolamine, N-methylethanolamine (MEA), decreases PLD activity through a negative feedback mechanism, suppresses collagen accumulation, and prevents organ dysfunction. Methods and Results: In human fibroblasts 1-butanol inhibited collagen synthesis and enhanced collagenase production, but iso-butanol did not. These indicate crucial roles of PLD in collagen synthesis and degradation. In fibroblasts, MEA dose-dependently decreased PLD activity, inhibited collagen synthesis and enhanced collagenase production. In a hypertensive heart failure (HHF) model using Dahl-Iwai salt-sensitive rats, PLD activity increased with progressive ventricular fibrosis, leading to myocardial stiffening and overt heart failure. Long-term administration of MEA did not significantly decrease blood pressure, however, decreased PLD activity and collagen content with inhibited gene expression of collagens, leading to prevention of myocardial stiffening and hemodynamic deterioration. MEA also attenuated ventricular hypertrophy, another detrimental structural alteration. Conclusion: MEA may exert therapeutic effects on cardiac disorders due to ventricular fibrosis through suppression of PLD activity and modulation of fibrosis pathway even without a release from mechanical stress.

N-methylethanolamine attenuates cardiac fibrosis and improves diastolic function: inhibition of phospholipase D as a possible mechanism.

Ventricular fibrosis is promoted by many effectors that chronically activate phospholipase D (PLD), and induces cardiac dysfunction and heart failure in cardiovascular diseases. Since ethanolamine is a product of PLD, we hypothesised that an administration of an analogue of ethanolamine, N-methylethanolamine (MEA), decreases PLD activity through a negative feedback mechanism, suppresses collagen accumulation, and thus prevents organ dysfunction. In human fibroblasts 1-butanol inhibited collagen synthesis and enhanced collagenase production, but iso-butanol did not. These indicate crucial roles of PLD in collagen synthesis and degradation. In fibroblasts, MEA dose-dependently decreased PLD activity, inhibited collagen synthesis and enhanced collagenase production. In a hypertensive heart failure model using Dahl-Iwai salt-sensitive rats, PLD activity increased with progressive ventricular fibrosis, leading to myocardial stiffening and overt heart failure. Long-term administration of MEA did not significantly decrease blood pressure, however, but decreased PLD activity and collagen content with inhibited gene expression of collagens, leading to the prevention of myocardial stiffening and haemodynamic deterioration. MEA also attenuated ventricular hypertrophy, another detrimental structural alteration. MEA may exert therapeutic effects on cardiac disorders due to ventricular fibrosis through suppression of PLD activity and modulation of the fibrosis pathway even without relief from mechanical stress.

Pathophysiological roles of vascular 11β-hydroxysteroid dehydrogenase and aldosterone

Mineralocorticoid receptor (MR) binding is tightly regulated by the enzyme 11β-hydroxysteroid dehydrogenase type 2 (11β-HSDII) which selectively metabolizes glucocorticoids to inactive metabolites, thus allowing for MR activation by aldosterone. To examine whether this enzyme is involved in the pathophysiology of salt-sensitive hypertension, 11β-HSDII activity and messenger RNA (mRNA) levels were determined in blood vessels of Dahl Iwai salt-sensitive (DS) and salt-resistant (DR) rats. Decreased 11β-HSDII activity and mRNA levels in mesenteric arteries were observed in 8-week-old DS rats on a high-salt diet, indicating that 11β-HSDII may play a significant role in salt sensitivity and hypertension. It has been suggested that mineralocorticoids act on blood vessels, leading to increased vasoreactivity and peripheral resistance. We present direct evidence that blood vessels are aldosteronogenic. The production of aldosterone in blood vessels was compared between stroke-prone spontaneously hypertensive rats (SHRSP) and Wistar-Kyoto (WKY) rats. Vascular aldosterone and CYP11B2 mRNA levels were significantly increased in 2-week-old SHRSP versus WKY rats. However, the vascular aldosterone levels in 4- and 9-week-old SHRSP and WKY rats were similar. High sodium intake further increased both blood pressure and vascular aldosterone synthesis in the SHRSPs. Both the local renin–angiotensin–aldosterone system (RAAS) and the vascular 11β-HSDII level are critically important in the pathophysiology of cardiovascular disorders.

Myocardial stiffness is determined by ventricular fibrosis, but not by compensatory or excessive hypertrophy in hypertensive heart.

Diastolic dysfunction that determines symptoms and prognosis in patients with systolic dysfunction causes heart failure even in the absence of systolic dysfunction. Our recent studies have suggested that myocardial stiffening is likely to play a crucial role in triggering deleterious cardiac disorder. This study investigated differential contribution of left ventricular (LV) hypertrophy and fibrosis to myocardial stiffening in the pressure-overloaded heart. Dahl-Iwai salt-sensitive rats fed on high-salt diet since 7 weeks transit to congestive heart failure at 20 weeks following development of hypertension, LV hypertrophy and fibrosis, and 20 such rats were divided into three groups: rats treated with angiotensin II type 1 receptor antagonist from 8 weeks (n=7), rats treated with calcineurin inhibitor from 8 weeks (n=6), and untreated rats (n=7). Administration of angiotensin II type 1 receptor antagonist and calcineurin inhibitor did not affect blood pressure and allowed the development of compensatory hypertrophy. However, in contrast to the untreated rats, additive and excessive LV hypertrophy was not observed in either of the treated rats. The blockade of angiotensin II kept LV hydroxyproline content, a ratio of type I to type III collagen mRNA levels, collagen solubility and myocardial stiffness constant at the normal level; however, the calcineurin inhibition failed. Myocardial stiffening may be attributed to progressive collagen accumulation, collagen phenotype shift and enhanced collagen cross-linking, but not to either compensatory LV hypertrophy or LV hypertrophy that progresses from the compensatory stage.

The role of nitric oxide and the renin-angiotensin system in salt-restricted Dahl rats

To elucidate the role of nitric oxide (NO) and renin-angiotensin system (RAS) in the development of salt-sensitive hypertension, we investigated the pressor responses and renal histologic changes after long-term inhibition of endogenous NO synthesis in Dahl-Iwai salt-sensitive (DS) and salt-resistant (DR) rats under salt-restricted conditions that exaggerate RAS activation. Male DS and DR rats (6 weeks old) were fed with a low-salt (0.3%) diet for 5 weeks. N G-nitro- l-arginine (L-NA; dissolved in 60 mg/L deionized water), an arginine analogue acting as a NO-inhibitor, was also administered for 5 weeks. L-NA administration induced a gradual increase in systolic blood pressure (SBP) in both strains, and the pressor response in DS rats was apparently more enhanced relative to that in DR rats. Urinary nitrate plus nitrite (u-NOx) excretion was decreased by L-NA, with a significant negative correlation between SBP and u-NOx excretion in DS rats but not in DR rats. Plasma renin activity and urinary aldosterone level were significantly increased in L-NA–treated DS rats on week 5. Marked histologic changes with glomerular sclerosis and increased proteinuria and urinary N-acetyl-β-glucosaminidase excretion were found in L-NA–treated DS rats but not DR rats. Competitive RT-PCR of mRNA extracted from the glomeruli revealed that angiotensin II type 1 receptor (AT 1R) mRNA level was significantly lower in DS rats than in DR rats at week 2, and that L-NA administration significantly reduced glomerular AT 1R level of DS rats at week 5, possibly because of downregulation. Our results showed that, even under sodium restriction, the pressor response and renal injury induced by chronic NO inhibition were markedly more enhanced in DS rats than in DR rats, which indicates that depletion of NO participates in both the development of hypertension and glomerular injury in DS rats through a potential activation of RAS irrespective of sodium loading. These data suggest that endogenous NO is an essential determinant of salt-sensitive hypertension in DS rats.

Local neurohumoral regulation in the transition to isolated diastolic heart failure in hypertensive heart disease: absence of AT1 receptor downregulation and 'overdrive' of the endothelin system.

Although isolated diastolic heart failure with preserved left ventricular (LV) systolic function frequently occurs, regulation of local neurohumoral factors in the transition from diastolic dysfunction without signs of heart failure to diastolic failure, a target for therapeutic strategy, remains to be clarified, partly because of a lack of animal models. Our laboratory recently demonstrated that Dahl-Iwai salt-sensitive (Dahl-S) rats fed on a high-salt diet since 7 weeks of age develop hypertension followed by compensated LV hypertrophy at 13 weeks and transition to isolated diastolic heart failure at 19 weeks. Gene expression of the components of the renin-angiotensin system, endothelin (ET) system and natriuretic peptide system in the left ventricle was investigated in the transition to isolated diastolic heart failure in this model. The compensated ventricular hypertrophy was associated with slight increases in angiotensin-converting enzyme (ACE) and angiotensin II type-1a (AT1a) receptor mRNA levels. Although preproET-1 (ppET-1) and ET-converting enzyme-1 (ECE-1) mRNA levels were not increased, mRNA levels of ET type-A (ETA) and ET type-B (ETB) receptors were increased. Atrial natriuretic peptide (ANP) mRNA level increased, but not brain natriuretic peptide (BNP) mRNA level. At the decompensated failing stage (at 19 weeks), ACE mRNA level further increased without downregulation of ATla receptor mRNA level. The mRNA levels of ppET-1 and ECE-1 increased with persistent upregulation of mRNA levels of ETA and ETB receptors, and immunohistochemical staining for ET-1 was found at endothelial cells and myocytes. BNP mRNA level increased with a further increase in ANP mRNA level. The transition to isolated diastolic heart failure in hypertrophied hearts was associated with preserved gene expression of the renin-angiotensin system and 'overdrive' of gene expression of the ET system. BNP gene expression is likely to be activated by the progression of diastolic failure rather than by LV hypertrophy alone.

The kinetics of Na +-H + antiporter activity in platelets of Dahl-Iwai salt sensitive rats.

The kinetics of Na +-H + antiporter activity in platelets of Dahl-Iwai salt sensitive rats.

Angiotensin II receptors in cardiac left ventricles of Dahl rats.

1. Dahl Iwai salt-sensitive (DS) rats have been reported as becoming hypertensive with left ventricular hypertrophy (LVH) and heart failure when on a high-salt diet. Their circulating renin-angiotensin system (RAS) has been reported to be suppressed. To evaluate the role of angiotensin II (AngII) type 1 and type 2 receptors (AT1 and AT2, respectively) in LVH, we compared cardiac AT1 and AT2 receptors in 10-week-old DS rats and Dahl Iwai salt-resistant (DR) rats. 2. Seven pairs of 6-week-old male DS and DR rats were fed either a low- or high-salt diet (0.3 or 8% NaCl, respectively) for 4 weeks. Left ventricular AngII receptors were measured by radioligand binding assays using [125I]-[Sar1,Ile8]-AngII in plasma membrane fractions from these four groups. The AT1 and AT2 receptors were distinguished using their specific antagonists CV 11974 and PD 123319, respectively. 3. The high-salt diet increased blood pressure and the left ventricle:bodyweight ratio in DS rats. However, neither Bmax for AT1 and AT2 receptors nor Kd for [125I]-[Sar1,Ile8]-AngII differed between the groups. These results are different from those of other reports of pressure-overload LVH, such as spontaneously hypertensive rats or renovascular hypertension rats, in which AT1 and AT2 receptors were reported to be up-regulated.

Ovariectomy Aggravated Sodium Induced Hypertension Associated With Altered Platelet Intracellular Ca 2 in Dahl Rats

Our purpose was to determine the effect of ovariectomy on intracellular Ca 2+ mobilization and platelet aggregation in sodium induced hypertension. At the age of 12 weeks ovariectomy or sham operation was performed in female Dahl-Iwai salt sensitive rats on a 0.3% NaCl diet. Four weeks later we assessed the effects of ovariectomy and an 8% NaCl diet on agonist induced intracellular Ca 2+ mobilization in fura-2 loaded platelets and platelet aggregation. Ovariectomy enhanced the increase of systolic blood pressure and heart to body weight ratio on an 8% NaCl diet. However, thrombin evoked intracellular Ca 2+ was not correlated with systolic blood pressure (r = −0.338, P = .17), and was lowered by sodium loading and ovariectomy (360 ± 23 to 285 ± 9, 296 ± 10 nmol/L, P < .05). Furthermore, the ionomycin induced intracellular calcium fraction in the absence of external Ca 2+ that reflected internal Ca 2+ discharge capacity was reduced in ovariectomized rats compared with sham operated rats on an 8% NaCl diet (648 ± 15 v 768 ± 35 nmol/L, P < .05). The internal Ca 2+ discharge capacity was inversely correlated with systolic blood pressure (r = −0.506, P = .03). In addition to the decreased internal Ca 2+ discharge capacity, intracellular Ca 2+-independent platelet aggregation by phorbol 12-myristate 13-acetate, a protein kinase C activator, was significantly enhanced in hypertensive rats. We concluded that ovariectomy enhanced sodium induced hypertension associated with the decreased internal Ca 2+ discharge capacity and increased platelet aggregation in Dahl-Iwai salt-sensitive rats.

Transition From Compensatory Hypertrophy to Dilated Failing Left Ventricle in Dahl-Iwai Salt-Sensitive Rats

Transition From Compensatory Hypertrophy to Dilated Failing Left Ventricle in Dahl-Iwai Salt-Sensitive Rats

Urinary Kallikrein in Dahl-Iwai Salt-Sensitive and -Resistant Rats

This study was designed to evaluate the differences between the renal kallikrein in newly established Dahl-Iwai rats under salt loading and that of Sprague-Dawley rats (SD). Urinary kallikrein quantity and activity was markedly lower in Dahl-Iwai rats than in SD even during the control period. Moreover, kallikrein quantity and activity in Dahl-Iwai salt-sensitive rats (SS) were clearly diminished in comparison with salt-resistant rats (SR). The kallikrein activity/ quantity ratio was also lower in SS and SR than in SD during the control period. After salt loading, systolic blood pressure increased only in SS. Kallikrein activity in SS and SR, and kallikrein quantity in SS were increased, whereas those in SD did not change. Although the kallikrein activity/quantity ratio in SR reached the same level in SD after salt loading, that in SS was lower throughout the experiment. These results suggest that Dahl-Iwai rats are less able hereditarily to produce renal kallikrein and that there may exist structurally abnormal kallikrein that may have a lower activity. Different kinetics of renal kallikrein between SS and SR by salt loading might be explained by kallikrein inhibitors or abnormal kallikrein or nonkallikrein kininogenase. These different kinetics of renal kallikrein may play some role on blood pressure elevation in SS.

Dietary ?-Arginine Supplementation Normalizes Regional Blood Flow in Dahl-Iwai Salt-Sensitive Rats

We performed the present study to determine 1) whether different organs undergo similar increase in vascular resistance in Dahl-Iwai salt-sensitive (S) rats, and 2) the effects of chronic oral L-arginine supplementation on the regional hemodynamics in S rats. Male 6 week old S rats and Dahl-Iwai salt-resistant (R) rats were maintained on an 8% NaCl chow for 4 weeks. One group (S or R rats) was maintained on tap water and the other group (S/Arg) of S rats received tap water containing L-arginine at a concentration of 1.5%. Organ blood flow and cardiac output were measured with microspheres in the conscious condition. Concerning regional hemodynamics, the flow rate of the kidney was lower in S rats than in R rats, but there were no differences between S and R rats in the flow rates of the brain, heart, lung, liver, spleen, intestine, skeletal muscle and skin. The flow rate of the kidney in S/Arg rats was maintained at a higher level as compared to that of S rats. Urinary excretion of protein and albumin in S/Arg rats was significantly suppressed when compared to S rats. Thus, the supplementation of L-arginine normalized the abnormality of renal hemodynamics accompanying salt-induced hypertension. It is suggested that the disturbance in the production of nitric oxide may induce salt-sensitive hypertension and the abnormality of renal hemodynamics in the S rats.

Transition from compensatory hypertrophy to dilated failing left ventricle in Dahl-Iwai salt-sensitive rats*1

Transition from compensatory hypertrophy to dilated failing left ventricle in Dahl-Iwai salt-sensitive rats*1

Pressor and sympathetic responses to excitatory amino acids are not augmented in the ventrolateral medulla of Dahl salt-sensitive rats

We assessed the pressor and sympathetic responses to microinjection of excitatory amino acids (EAA) into the rostral ventrolateral medulla (RVLM) to see whether the response would be augmented in salt-induced hypertension. Seven-week-old Dahl-Iwai salt-sensitive rats were fed either a high- (8%, n=10) or a low- (0.3%, n=12) salt diet for 3 weeks. Then, l-glutamate (2 nmol), N-methyl- d-aspartate (NMDA; ionotropic EAA receptor agonist, 20 pmol) or (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid [(1S,3R)-ACPD; metabotropic EAA receptor agonist, 1 nmol] was microinjected into the RVLM of urethane-anesthetized, artificially ventilated rats. The rats fed a high-salt diet showed a significantly ( P<0.001) higher mean arterial pressure (123±3 mmHg) than those fed a low-salt diet (99±2 mmHg). We found similar increases in mean arterial pressure and splanchnic sympathetic nerve activity elicited by microinjection of l-glutamate into the RVLM in the high- (33±2 mmHg and 52±10%) and low- (35±3 mmHg and 46±8%) salt groups. Similarly, pressor and sympathoexcitatory responses to either NMDA or (1S,3R)-ACPD did not differ between the groups. Microinjections of the lower doses of l-glutamate, NMDA and (1S,3R)-ACPD also showed comparable pressor responses between the groups. These results indicate that salt-induced hypertension in Dahl salt-sensitive rats is not associated with enhanced responsiveness of the RVLM to EAA. This is in contrast with our previous findings that pressor and sympathetic responses to EAA are enhanced in spontaneously hypertensive rats.

Ovariectomy aggravated hypertension and enhanced platelet aggregation in dahl-iwai salt-sensitive rats

Ovariectomy aggravated hypertension and enhanced platelet aggregation in dahl-iwai salt-sensitive rats

Blunted pressure natriuresis in ovariectomized Dahl-Iwai salt-sensitive rats.

Our objective was to determine whether increased salt sensitivity after menopause precedes the development of overt hypertension. We investigated the effect of ovariectomy on pressure natriuresis in Dahl-Iwai salt-sensitive (DS) and salt-resistant (DR) rats by in vivo perfusion studies. Differences in the neural and hormonal backgrounds of the kidney were minimized by renal denervation and by holding plasma vasopressin, aldosterone, corticosterone, and norepinephrine levels constant by intravenous infusion. The pressure-natriuresis relationship was blunted in DS rats compared with DR rats (slope, 0.30 versus 0.63 mumol.min-1.g kidney wt-1.mm Hg-1, P < .01). The impaired pressure-natriuresis response of DS rats was further blunted by ovariectomy (from 0.30 to 0.14 mumol.min-1.g kidney wt-1.mm Hg-1, P < .05), and that of DR rats was not. The ovariectomized DS rats developed hypertension earlier than sham-operated DS rats by salt loading. These results show that ovariectomy enhances genetic salt sensitivity by blunting the pressure-natriuresis relationship, which precedes the development of overt hypertension in female DS rats.