Published online before print December 23, 2002, doi: 10.1161/01.HYP.0000048193.85814.78
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(Hypertension. 2003;41:657.)
© 2003 American Heart Association, Inc.
Scientific Contributions |
Gender Differences in ET and NOS Systems in ETB Receptor–Deficient Rats
Effect of a High Salt Diet
From the Department of Pharmacology and Toxicology (T.A.T., J.S.P.), Vascular Biology Center (D.M.P., J.S.P.), and Department of Surgery (D.M.P.), Medical College of Georgia, Augusta, Ga; and the Department of Pediatrics, University of Michigan (C.E.G.), Ann Arbor.
Correspondence to Jennifer S. Pollock, Vascular Biology Center, Medical College of Georgia, Augusta, GA 30912. E-mail jpollock{at}mail.mcg.edu
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Abstract |
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The purpose of this study was to determine if rats lacking the ETB receptor have altered renal endothelin (ET) production and NO synthase (NOS) activity in response to high salt and if female rats are better able to control blood pressure through higher NOS activity in rats heterozygous (sl/+) and homozygous (sl/sl) for ETB receptor deficiency. On normal salt (0.4% NaCl; NS), male sl/sl rats had higher systolic blood pressures compared with male sl/+ and female sl/+ and sl/sl rats. On a high salt diet (10% NaCl; HS), blood pressure in male sl/+ rats was significantly higher than female sl/+ rats. However, ETB receptor deficiency caused much larger increases in blood pressure in male and female rats. On NS, urinary ET excretion was not different between male and female of either genotype. HS significantly increased ET excretion in male and female sl/+ rats, but the increase was significantly less in sl/sl compared with sl/+. Homogenates of inner medullary collecting duct tissue were separated into particulate and cytosolic fractions and total NOS activity measured by conversion of [3H]L-arginine to [3H]L-citrulline. Female rats had significantly greater cytosolic NOS activity compared with male rats on NS. On HS, cytosolic NOS activity was lower in all groups compared with NS rats, whereas particulate NOS activity was significantly greater in male and female sl/+ rats compared with male and female sl/sl rats. These data support our hypothesis that NOS protects against rises in blood pressure in female rats and ETB receptors prevent further increases in blood pressure due to increases in renal ET production and NOS activity.
Key Words: gender • hypertension, renal • sodium, dietary • nitric oxide synthase • receptor, endothelin
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Introduction |
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Nitric oxide (NO) and endothelin (ET) have been shown to play an important role in renal hemodynamics and tubular function. Each of the three NO synthase (NOS) enzyme isoforms, NOS1 (neuronal NOS), NOS2 (inducible NOS), and NOS3 (endothelial NOS), have been localized to various parts of the kidney, with the greatest amount of activity found in the inner medullary collecting duct (IMCD).1,2 The highest amount of immunoreactive ET in the body is found in the renal medulla.3 The IMCD synthesizes 10 times more ET than any other site along the nephron,4 and renal ETB receptors are highly concentrated in IMCD cells.5
In the kidney, both NO and ET have been shown to inhibit tubular sodium reabsorption.6–8 In the thick ascending limb, there is evidence that ETB receptors serve to inhibit chloride reabsorption through an NO-dependent pathway.9 A preliminary study has also shown that ET directly stimulates NO production in IMCD cells, possibly contributing to the paradoxical natriuretic properties of ET.10 Additionally, rats treated chronically with an ETB receptor antagonist have elevated arterial pressures compared with control animals, and this increase in blood pressure was much greater in rats given a high salt diet compared with a low salt diet.11 Urinary ET excretion is increased in rats given a high salt diet, suggesting that renal ET synthesis is elevated in response to a salt load.11,12
It has been shown in both humans13 and animals14 that vascular NO production is greater in female than male subjects and that renal NOS3 mRNA and protein levels are higher in kidneys from female subjects than from male subjects,15,16 though there was no gender difference in urinary nitrite/nitrate excretion.14,15 Furthermore, it has been shown that male rats are more susceptible to proteinuria during chronic NOS inhibition compared with female rats,16 leading to renal injury. Gender differences are not limited to the NO/NOS pathway but are found within the ET system as well. Studies by Ergul and colleagues17 that used isolated human saphenous veins found that ET-1 produced a greater vasoconstriction in vessels from men than from women and a ratio of ETA to ETB receptors of 3:1 in men, whereas the ratio of ETA to ETB receptors was just 1:1 in women, suggesting differential vascular regulation due to gender. Recently, Kellogg et al18 have demonstrated gender differences in the response of the vascular endothelin system in the human forearm circulation. They found that an ETB receptor selective antagonist caused skin vasodilation in men, whereas in women, the antagonist caused skin vasoconstriction. Thus, it was concluded that under basal vascular tone, men have ETB receptor–mediated vasoconstrictor tone, whereas women have ETB receptor–mediated vasodilator tone.18
The spotting lethal rat carries a natural 301-bp deletion in the ETB receptor gene that abrogates expression of functional ETB receptors. Rats homozygous (sl/sl) for this mutation have coat color spotting and a lethal phenotype of congenital intestinal agangliosis. In 1998, Gariepy et al19 used a dopamine–ß-hydroxylase promoter to direct transgenic ETB receptor expression only in the enteric nervous system, thus "rescuing" the rats from the intestinal defect. ETB receptor–deficient rats are subject to hypertension when fed a high salt diet that can be reversed when the rats are given the sodium channel inhibitor amiloride.20 Additionally, rats homozygous for the deletion have elevated levels of circulating ET and have augmented ET-1 arterial contraction though with increased ETA receptor expression.20,21 Because of the evidence supporting the role of ETB receptors activating the NO/NOS pathway, the aim of this study was to determine whether the absence of a functional ETB receptor in the inner medulla of male and female rats reduces NOS activity, NOS expression, and ET excretion in response to a high salt diet.
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Methods |
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Tail-Cuff Measurements and Metabolic Cage Studies
Experiments were performed in accordance with the Medical College of Georgia Committee for Animal Use in Research and Education, with the use of male and female heterozygous (sl/+) and homozygous (sl/sl) rats deficient of ETB receptors (n=9 to 16) that were obtained from our local breeding colony (8 to 12 weeks of age). Rats were placed on either normal salt (0.4% NaCl) or a high salt diet (10% NaCl) for 3 weeks along with tap water ad libitum; after 3 weeks, tail-cuff pressure was measured as an estimate of systolic arterial pressure as previously described.22
After tail-cuff measurements were recorded, rats were housed in metabolic cages (Nalgene) to allow quantitative measurement of food and water intake along with urine collection over a 24-hour period. Under sodium pentobarbital anesthesia (65 mg/kg IP), a terminal blood sample was obtained, centrifuged, and plasma frozen at -80°C. Kidneys were excised, dissected, and immediately frozen in liquid nitrogen and stored at -80°C.
Urine and Plasma Analysis
Urinary ET levels were determined by RIA (Amersham Pharmacia). Plasma ET concentrations were measured by ELISA (QuantiGlo, R&D Systems). Urinary protein excretion was determined by Bradford protein assay (BioRad). Urinary sodium analysis was determined by ion-selective electrodes (Beckman EL-ISE).
Protein Isolation and NOS Activity Assay
Renal inner medulla were homogenized (weight-to-volume ratio, 1:7), centrifuged, separated into cytosolic and particulate fractions, and subjected to NOS activity assay as previously described.23 Total NOS activity is defined as the conversion of [3H]L-arginine to [3H]L-citrulline that is inhibited by LNNA (1 mmol/L). Protein concentration was determined by Bradford assay (BioRad).
Statistical Analysis
Statistical differences in the mean values for all measurements were determined by ANOVA, and the Fisher protected least significant difference (PLSD) test was used to determine differences between individual means (StatView, Abacus Concepts Inc). Values are reported as mean±SEM, with a value of P<0.05 being considered significant.
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Results |
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Salt Diet and Gender Differences in Metabolic Cage Measurements
Results from male and female rats placed in metabolic cages for 24 hours are shown in the Table. All animals used in the study were between 8 and 12 weeks of age. Body weights of male sl/+ and sl/sl animals given NS and HS were higher than that of female sl/+ and sl/sl animals given either NS or HS. Since male animals had higher body weights, they also had higher food and water intake than female rats on either NS or HS diet, though all groups had higher water intake and urine output as a result of the HS. As expected, urinary sodium was increased in all groups exposed to HS compared with NS.
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ETB Receptor Deficiency, Salt Diet, and Gender Differences in Systolic Arterial Pressure
As shown in Figure 1A, systolic arterial pressure was significantly greater in male sl/sl rats given the NS diet compared with male sl/+ rats given the NS diet, similar to previous studies by Gariepy et al.20 There was no significant difference in systolic arterial pressure between female sl/+ and sl/sl animals given the NS diet or between male and female rats of the same genotype on NS diet. When placed on a HS diet, both groups of male sl/+ and sl/sl animals had significantly higher systolic arterial pressures compared with male animals given NS, with the male sl/sl animals given HS having significantly higher pressures than male sl/+ rats. Under NS conditions, female sl/+ rats had systolic arterial pressure similar to male sl/+ rats. When female sl/+ animals were placed on an HS diet, systolic arterial pressure rose slightly but was not significantly different than NS values, though when compared with male sl/+ rats given HS, the females had pressure measurements significantly lower compared with male sl/+ animals given HS. The female sl/sl animals, however, became severely hypertensive when given HS for 3 weeks and had significantly higher systolic arterial pressures not only compared with the female sl/+ given HS but male sl/sl animals given an HS diet as well.
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P<0.05 comparing salt diet, and #P<0.05 comparing gender are considered significant.
ETB Receptor Deficiency and Dietary and Gender Differences in Protein Excretion
Results of urinary protein excretion are shown in Figure 1B. Under NS conditions, male sl/+ and sl/sl rats excreted significantly more protein compared with female sl/+ and sl/sl animals, indicating that male rats are more susceptible to proteinuria and renal injury than are female rats. When animals were placed on an HS diet, all groups excreted more protein in the urine; however, male and female sl/sl animals for the ETB receptor excreted significantly greater amounts compared with male and female sl/+ animals.
ETB Receptor Deficiency and Dietary Differences in Urinary ET Excretion and Plasma ET Concentration
As shown in Figure 2A, urinary excretion of ET was not significantly different between male sl/+ and sl/sl animals given an NS diet. There was a small but significant elevation in urinary ET excretion from female sl/sl rats compared with female sl/+ rats given an NS diet. When rats were placed on an HS diet, all groups excreted significantly more ET compared with those given an NS diet, confirming previously published data from our laboratory implicating high salt diet as a stimulus for ET production.11,12 Under HS conditions, male sl/+ animals had significantly higher levels of urinary ET than male sl/sl rats and female sl/+ rats had significantly higher levels of urinary ET levels compared with female sl/sl rats. Thus, sl/sl animals were unable to increase renal ET production in response to a sodium load.
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The increase in urinary ET excretion in animals given HS is most likely due to an increased synthesis of renal tubular ET and not increased vascular ET production, since there is considerable evidence that plasma ET does not get excreted in urine. Even so, there was no significant difference in plasma ET levels comparing NS with HS treatments (Figure 2B). However, there does appear to be a significant elevation in circulating plasma ET levels caused by the ETB receptor deficiency, confirming previously published results.20 Under NS conditions, male sl/sl rats had higher plasma ET levels than sl/+ rats, and this same pattern was found in the female sl/sl and sl/+ animals. When the animals were placed on an HS diet, plasma ET levels were similar to those found under NS conditions, with male and female sl/sl animals having significantly higher circulating ET compared with their male and female sl/+ counterparts. Interestingly, female sl/sl animals given HS had significantly higher plasma ET concentrations compared with all other groups.
ETB Receptor Deficiency and Dietary and Gender Differences in NOS Activity
NOS activity (Figure 3) was determined in IM tissue by the conversion of [3H]L-arginine to [3H]L-citrulline in the presence of a nonselective NOS inhibitor, L-NNA (1 mmol/L). In addition, IM tissue was separated into cytosolic and particulate fractions as an initial assessment of cellular localization of NOS isoforms. The cytosolic fraction isolated from female sl/+ animals given NS had the highest amount of total NOS activity. Total cytosolic NOS activity from female sl/sl animals given NS was significantly less than the sl/+ counterpart. When given NS, male sl/sl animals had significantly less total NOS activity in the cytosol compared with male sl/+ rats. Under NS conditions, no significant differences were detected as the result of gender or ETB receptor deficiency in total NOS activity in the particulate fractions, though there was a trend for less NOS activity in animals lacking ETB receptors that did not reach statistical significance.
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When rats were given HS, total cytosolic NOS activity was significantly decreased in all groups, and there was a trend for lower NOS activity in animals without the ETB receptor that did not reach statistical significance. In the particulate fraction, total NOS activity in IM from male and female sl/+ animals fed HS was significantly greater than that of male and female sl/sl animals.
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Discussion |
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In this study, we demonstrated that male rats lacking functional ETB receptors have significantly higher systolic blood pressures and higher plasma ET levels while on a normal salt diet. In contrast, female ETB-deficient rats given an NS diet have similar systolic blood pressures compared with sl/+ control rats, yet with higher plasma ET levels. It would appear that the higher plasma ET levels in male rats may produce higher systolic blood pressures through the activation of ETA receptors; however, female animals had normal blood pressures despite elevated plasma ET levels, implicating a gender-specific protective mechanism. Male sl/+ and sl/sl ETB receptor–deficient rats had elevated protein in the urine when compared with female rats, though it was most likely not directly related to the elevated blood pressures.
Female sl/+ and sl/sl rats had significantly higher NOS activity when compared with the male groups. This is consistent with previously published reports of increased NOS mRNA and protein expression in renal tissue of female rats when compared with male rats.16 The lack of functional ETB receptors resulted in decreased cytosolic NOS activity regardless of gender. Interestingly, no differences were seen in particulate NOS activity from all groups given an NS diet. Further studies are needed to determine which NOS isoform(s) accounts for these changes in NOS activity. It is also interesting to note that there was a significant difference in urinary ET excretion between the sl/+ and sl/sl female but not male rats given an NS diet, although this difference was small and values were in the normal range for male rats. In sl/+ female rats given an NS diet, the NOS system may serve as a protective mechanism, since they have higher renal inner medullary NOS activity. Thus, the elevated systolic blood pressure in male sl/sl rats given an NS diet may be the result of a combination of gender, ETB receptor deficiency, and reduced NOS activity.
When animals were placed given an HS diet for 3 weeks, the lack of functional ETB receptors increased the severity of the hypertension, attenuated the increase in renal ET production, and increased proteinuria relative to animals with functional ETB receptors. These data suggest that the elevated systolic blood pressures after high salt treatment in sl/sl animals is due in part to an inability of the kidneys to promote salt excretion through ETB receptors and that unopposed ETA-mediated effects may contribute to renal injury, as evidenced by the changes in proteinuria.
Several laboratories including our own have hypothesized that renal ET production, ETB receptor activation, and NO release is required for a proper renal response to high salt intake. Our current findings are consistent with this hypothesis. ETB receptor–deficient animals given an NS diet had significantly less NOS activity in the renal inner medulla. One possible explanation for this observation is an increase of an endogenous inhibitor of NOS in the ETB receptor–deficient animals. Others have reported various proteins that regulate NOS activity that could influence NO generating ability in our assay protocol.1 It is possible that these proteins could be influenced by increased levels of ET seen in the ETB receptor–deficient animals, although this idea has yet to be investigated.
Gender differences in renal inner medullary NOS activity were observed in animals given an NS diet that were not present in animals given an HS diet. Placing rats on a high salt diet reduced cytosolic NOS activity in both male and female genotypes to a similar extent. Particulate NOS activity from animals given an HS diet demonstrated significant differences only with regard to genotype. Thus, the female sl/sl animals given an HS diet appear to lose the NO-generating ability that results in higher arterial pressure compared with sl/+ animals.
These studies confirm previously published results that male sl/sl rats, under conditions of normal salt intake, have higher resting blood pressures compared with sl/+ rats.20 Similar to our results, male sl/sl rats became more hypertensive when placed on a high salt diet compared with the male sl/+ animals. The authors also reported a similar blood pressure response to combined L-NAME and indomethacin infusion between wild-type and homozygous animals given an NS diet, suggesting no changes in endothelium-dependent vasodilatory function. However, these results are preliminary, and specific experiments addressing NO or prostaglandin release have not been conducted. Recently, Konishi et al24 reported that an acute infusion of Big ET-1 resulted in a blunted increase of intrarenal NOx levels in the ETB receptor–deficient rats compared with wild-type rats, consistent with ETB-mediated NO release in intact kidneys. In the current study, under normal and high salt conditions, ET excretion and total NOS activity were lower, along with an elevation in blood pressure in sl/sl rats compared with sl/+ rats, implying that the renal NO/NOS pathway is dysfunctional.
Thus, we can conclude from this study that under conditions of normal salt intake, gender and ETB receptor expression greatly influence the renal pressure natriuresis relation. Overall, female animals have higher amounts of cytosolic total NOS activity and less proteinuria compared with their male counterparts. Animals lacking ETB receptor expression have elevated plasma ET concentrations, lower cytosolic NOS activity, and attenuated ET excretion when placed on a high salt diet. Our findings are consistent with the hypothesis that activation of NOS protects against elevations in blood pressure, especially in female rats, and that ETB receptors prevent further increases in blood pressure through the increase in renal ET production and NOS activity.
Perspectives
We have hypothesized that an increase in sodium intake triggers renal production of ET and activation of NOS through the ETB receptors that results in inhibition of tubular sodium reabsorption. We can further speculate that inappropriate responses of the ET and NOS systems in the kidney contribute to salt-dependent hypertension. Thus, by studying animals that are deficient in ETB receptors, we can begin to explore these possibilities. The data presented in this study have demonstrated that the lack of functional ETB receptors reduces the ability of the kidney to handle the challenge of a high salt intake, which results in higher blood pressures. Although there remains much to be learned about the ETB-deficient rat, we have observed significant gender differences in the ET and NO systems in response to changes in dietary salt. Therefore, these studies provide a significant reason to focus future investigation on the influence of gender-specific mechanisms that may influence renal control of arterial pressure. Regardless of gender differences, it is clear that functional ETB receptors are of paramount importance when faced with a sodium challenge.
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Acknowledgments |
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This work was supported in part by research grants from the National Institutes of Health, HL60653 and HL64776, and by Scientist Development Grants from the American Heart Association. We thank Dr Masashi Yanagisawa for providing us with the breeders for our colony of ETB receptor–deficient animals. We thank Dr Jennifer Waller for help with statistical analysis. We also thank Jean Roscow and Janet Stewart for excellent technical assistance.
Received October 7, 2002; first decision October 25, 2002; accepted November 7, 2002.
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