Age-dependent salt hypertension in Dahl rats: fifty years of research

Fifty years ago, Lewis K. Dahl has presented a new model of salt hypertension - salt-sensitive and salt-resistant Dahl rats. Twenty years later, John P. Rapp has published the first and so far the only comprehensive review on this rat model covering numerous aspects of pathophysiology and genetics of salt hypertension. When we summarized 25 years of our own research on Dahl/Rapp rats, we have realized the need to outline principal abnormalities of this model, to show their interactions at different levels of the organism and to highlight the ontogenetic aspects of salt hypertension development. Our attention was focused on some cellular aspects (cell membrane function, ion transport, cell calcium handling), intra- and extrarenal factors affecting renal function and/or renal injury, local and systemic effects of renin-angiotensin-aldosterone system, endothelial and smooth muscle changes responsible for abnormal vascular contraction or relaxation, altered balance between various vasoconstrictor and vasodilator systems in blood pressure maintenance as well as on the central nervous and peripheral mechanisms involved in the regulation of circulatory homeostasis. We also searched for the age-dependent impact of environmental and pharmacological interventions, which modify the development of high blood pressure and/or organ damage, if they influence the salt-sensitive organism in particular critical periods of development (developmental windows). Thus, severe self-sustaining salt hypertension in young Dahl rats is characterized by pronounced dysbalance between augmented sympathetic hyperactivity and relative nitric oxide deficiency, attenuated baroreflex as well as by a major increase of residual blood pressure indicating profound remodeling of resistance vessels. Salt hypertension development in young but not in adult Dahl rats can be attenuated by preventive increase of potassium or calcium intake. On the contrary, moderate salt hypertension in adult Dahl rats is attenuated by superoxide scavenging or endothelin-A receptor blockade which do not affect salt hypertension development in young animals.     

Alpha1 Na,K-ATPase and Na,K,2Cl-cotransporte/D3mit3 loci interact to increase susceptibility to salt-sensitive hypertension in Dahl S(HSD) rats

BACKGROUND: Essential (multigenic) hypertension is a complex multifactorial disease whose genetic etiology has not been unraveled on a major locus-effect investigative paradigm. As with other complex genetic diseases, applying an interacting loci paradigm could be critical in the elucidation of genetic determinants. Having defined the alpha1 Na,K-ATPase (alpha1NK) as a hypertension susceptibility gene in Dahl salt-sensitive (Dahl S) rats, we determined whether alphaINK interacts with another renal epithelial Na transporter to increase susceptibility to salt-sensitive hypertension. We focused on alpha1NK and Na,K,2Cl-cotransporter (NKC) as an a priori candidate interacting gene pair because they comprise a functionally linked Na transport system in renal thick ascending limb of Henle (TALH) epithelial cells and exhibit altered function in prehypertensive Dahl S rats in contrast to Dahl salt-resistant normotensive (Dahl R) rats. MATERIAL AND METHOD: Cosegregation analysis of alphaNK and NKC loci was done in a (Dahl S x Dahl R) F2 cohort characterized for blood pressure by radiotelemetry using the D2mghII microsatellite marker in the alpha1NK gene and the D3mit3 microsatellite marker close to the NKC gene (NKC/D3mit3 locus). Single locus and digenic analyses were performed to establish the individual and interactive genetic contribution to salt-sensitive hypertension. Molecular analysis was then done to support the NKC gene as the likely candidate gene interacting with alpha1NK in Dahl salt-sensitive hypertension pathogenesis. RESULTS: Compared with respective single locus analysis, digenic analysis of 96 F2 (Dahl S x Dahl R) hybrid male rats revealed cosegregation of alpha1NK and NKC/D3mit3 loci as interacting pair with salt-sensitive hypertension with markedly increased significance for systolic (one-way ANOVA p = 10(-6)), diastolic (p = 10(-5)), and mean arterial (p = 10(-6)) blood pressures. Concordantly, two-way ANOVA detected interaction between alpha1NK and NKC loci in determining the levels of systolic (p = 0.004), diastolic (p = 0.008), and mean arterial (p = 0.006) pressures. To unravel potential NKC molecular dysfunction(s) involved in hypertension pathogenesis, we investigated putative differences between Dahl S and Dahl R rats in nucleotide sequence and isoform gene expression of the renal-specific Na,K,2Cl-cotransporter. Molecular analysis revealed an inversion of alternatively spliced NKC-isoform ratios (4B:4A:4F) between Dahl S and Dahl R prehypertensive kidneys supported by four mutations in intron-3 immediately upstream to alternatively spliced exons 4B, 4A, and 4F. No nucleotide changes were detected within the aminoacid encoding exons of NKC. CONCLUSIONS: Altogether, these current data and previous characterization of the role of the Q276L alpha1NK molecular variant in Dahl S hypertension provide cumulative compelling evidence that alpha1NK and NKC/D3mit3 loci interact to increase susceptibility to hypertension in Dahl S rats and that NKC is the likely candidate gene that interacts with alpha 1NK. More importantly, the data substantiate gene interaction as an operative mechanism in multigenic hypertension.     

Plasma 24,25-dihydroxyvitamin D concentration of Dahl salt-sensitive rats decreases during high salt intake

Dahl salt-sensitive rats, but not salt-resistant rats, develop hypertension in response to high salt intake. We have previously shown an inverse relationship between plasma 25-hydroxyvitamin D (25-OHD) concentration and blood pressure of Dahl salt-sensitive rats during high salt intake. In this study, we report on the relationship between high salt intake and plasma 24,25-dihydroxyvitamin D (24,25-(OH)(2)D) concentration of Dahl salt-sensitive and salt-resistant rats. Rats were fed a high salt diet (8%) and sacrificed at day 2, 7, 14, 21, and 28. Plasma 24,25-(OH)(2)D concentrations of salt-sensitive rats were reduced to 50% of that at baseline at day 2-when blood pressure and plasma 25-OHD concentration were unchanged, but 25-OHD content in the kidney was 81% of that at baseline. Plasma 24,25-(OH)(2)D concentration was reduced further to 10% of that at baseline from day 7 to 14 of high salt intake, a reduction that was prevented in rats switched to a low salt (0.3%) diet at day 7. Exogenous 24,25-dihydroxycholecalciferol (24,25-(OH)(2)D(3)), administered at a level that increased plasma 24,25-(OH)(2)D concentration to five times normal, did not attenuate the salt-induced hypertension of salt-sensitive rats. Plasma 24,25-(OH)(2)D concentration of salt-resistant rats was gradually reduced to 50% of that at baseline at day 14 and returned to baseline value at day 28 of high salt intake. We conclude that the decrease in plasma 24,25-(OH)(2)D concentration in salt-sensitive rats during high salt intake is caused by decreased 25-OHD content in the kidney and also by another unidentified mechanism.     

Superoxide dismutase and oxidative stress in Dahl salt-sensitive and -resistant rats

The roles of oxidative stress and renal superoxide dismutase (SOD) levels and their association with renal damage were studied in Dahl salt-sensitive (S) and salt-resistant (R)/Rapp strain rats during changes in Na intake. After 3 wk of a high (8%)-Na diet in S rats, renal medullary Cu/Zn SOD was 56% lower and Mn SOD was 81% lower than in R high Na-fed rats. After 1, 2, and 3 wk of high Na, urinary excretion of F(2)-isoprostanes, an index of oxidative stress, was significantly greater in S rats compared with R rats. Plasma F(2)-isoprostane concentration increased in the 2-wk S high Na-fed group. After 3 wk, renal cortical and medullary superoxide production was significantly increased in Dahl S rats on high Na intake, and urinary protein excretion, an index of renal damage, was 273 +/- 32 mg/d in S high Na-fed rats and 35 +/- 4 mg/d in R high Na-fed rats (P < 0.05). In conclusion, salt-sensitive hypertension in the S rat is accompanied by marked decreases in renal medullary SOD and greater renal oxidative stress and renal damage than in R rats.     

Mechanisms of salt-sensitive hypertension: role of inducible nitric oxide synthase

The goal of this study was to determine the role of inducible nitric oxide synthase (iNOS) in the arterial pressure, renal hemodynamic, renal excretory, and hormonal changes that occur in Dahl/Rapp salt-resistant (R) and salt-sensitive (S) rats during changes in Na intake. Thirty-two R and S rats, equipped with indwelling arterial and venous catheters, were subjected to low (0.87 mmol/day) or high (20.6 mmol/day) Na intake, and selective iNOS inhibition was achieved with intravenous aminoguanidine (AG, 12.3 mg. kg(-1). h(-1)). After 5 days of AG, mean arterial pressure increased to 121 +/- 3% control in the R-high Na AG rats compared with 98 +/- 1% control (P < 0.05) in the R-high Na alone rats, and S-high Na rats increased their arterial pressure to 123 +/- 3% control compared with 110 +/- 2% control (P < 0.05) in S-high Na alone rats. AG caused no significant changes in renal hemodynamics, urinary Na or H(2)O excretion, plasma renin activity, or cerebellar Ca-dependent NOS activity. The data suggest that nitric oxide produced by iNOS normally helps to prevent salt-sensitive hypertension in the Dahl R rat and decreases salt sensitivity in the Dahl S rat.     

Vascular eicosanoid production in experimental hypertensive rats with different mechanisms

This study investigated the release of prostacyclin (PGI2) and thromboxane A2 (TXA2) from the aortic walls of various experimental hypertensive rats, e.g. spontaneously hypertensive rats (SHR), Dahl salt-sensitive (Dahl S) rats, deoxycorticosterone (DOCA)-salt hypertensive rats and renovascular (2-kidney, 1-clip (2K1C) and 1-kidney, 1-clip (1K1C] hypertensive rats. The PGI2 generation was increased significantly in these hypertensive models, irrespective of the hypertensive mechanisms, when they developed established hypertension. Dahl S rats, having an impaired PGI2 production on a low salt diet, restored PGI2 generating capacity to the control level of Dahl salt-resistant rats when they were fed a high salt diet and developed salt-induced hypertension. On the other hand, the TXA2 generation in the vascular walls was enhanced particularly in rat models for genetic hypertension, and this system was unaltered in the models for secondary hypertension, e.g. DOCA-salt and renovascular hypertension. Thus, it is suggested that the elevation of blood pressure is associated with an increase in vascular PGI2 production, and that the increased vascular TXA2 production is a characteristic feature of genetic hypertension.     

Potassium turnover and norepinephrine sensitivity in the thoracic aorta of the Dahl rat

This in vitro study evaluated the basal 42K turnover and response to norepinephrine (NE) in the thoracic aorta removed from Dahl salt-sensitive (S) and salt-resistant (R) rats. Five-week-old S and R rats were placed on either a high-salt (HS) or low-salt (LS) diet. After 5 weeks of the diet, systolic blood pressure, aortic weight/length ratio, and the cellular pool of K+ were elevated in the S-HS group only. In contrast, the steady state turnover of 42K, the NE ED50, and the response to a supramaximal dose of NE were the same in both groups of salt-sensitive and salt-resistant rats. These results suggest that, despite the presence of a greatly elevated systolic blood pressure and evidence of aortic hypertrophy, the intrinsic electrolyte metabolism of the vascular smooth muscle in the Dahl hypertensive rat is the same as that of the Dahl normotensive rat.     

High-resolution mapping of the blood pressure QTL on chromosome 7 using Dahl rat congenic strains

It was previously shown using Dahl salt-sensitive (S) and salt-resistant (R) rats that a blood pressure quantitative trait locus (QTL) was present on rat chromosome 7. In the present work, this QTL was localized to a region less than 0.54 cM in size on the linkage map using a series of congenic strains. This region was contained in a single yeast artificial chromosome that was 220 kb long. This small segment still contained the primary candidate locus Cyp11b1 (11beta-hydroxylase), but the adjacent candidate genes Cyp11b2 (aldosterone synthase) and Cyp11b3 were ruled out. It is concluded that 11beta-hydroxylase, through its known genetic variants altering the production of 18-hydroxy-11-deoxy corticosterone, is very likely to account for the blood pressure QTL on chromosome 7 in the Dahl rat model of hypertension. This QTL accounts for about 23 mm Hg under the condition of 2% NaCl diet for 24 days.     

Effect of chronic administration of dexfenfluramine on blood pressure in salt-sensitive rats.

Chronic administration of dexfenfluramine, at a relatively low daily dose, slowed the development of salt-induced elevation of blood pressure in salt-sensitive (Dahl DS and Rapp SS) rats. This effect could not be accounted for by drug-related anorexia alone. Elevated serotonin activity, possibly in the brain, may underlie this antihypertensive action of dexfenfluramine.     

Defining the blood pressure QTL on Chromosome 7 in Dahl rats by a 177-kb congenic segment containing Cyp11b1

Previously we reported that there is a blood pressure quantitative trait locus (QTL) on rat Chromosome (Chr) 7 seen when comparing Dahl salt-sensitive (S) rats and Dahl salt-resistant (R) rats. Evidence was also presented that this QTL was due to genetic variants in the adrenal steroidogenic enzyme 11beta-hydroxylase ( Cyp11b1). A series of congenic strains supported this contention. In the present work we have constructed a final congenic substrain that retains a blood pressure effect and that has an introgressed congenic segment which includes Cyp11b1 and is < 177 kb in size. None of the other genes in the congenic region (eight known genes) have known biological functions for influencing blood pressure. We believe that we have reached the limit of resolution for congenic analysis of a QTL in a rodent animal model, and we conclude that Cyp11b1 causes the observed QTL on rat Chr 7 in Dahl rats.     

Mechanisms of salt-sensitive hypertension: role of renal medullary inducible nitric oxide synthase

The goal of this study was to determine the role of renal medullary inducible nitric oxide synthase (iNOS) in the arterial pressure, renal hemodynamic, and renal excretory changes that occur in Dahl/Rapp salt-resistant (R) and salt-sensitive (S) rats during high Na intake. Forty R and S rats, equipped with indwelling arterial, venous, and renal medullary catheters, were subjected to high (8%) Na intake, and selective iNOS inhibition was achieved with continuous intravenous or renal medullary interstitial infusion of aminoguanidine (AG; 3.075 mg. kg(-1). h(-1)). After 5 days of AG, mean arterial pressure increased to 132 +/- 2% control in the S rats with high Na intake and intramedullary AG compared with 121 +/- 4% control (P < 0.05) in the S rats with high Na intake alone and 121 +/- 2% control (P < 0.05) in the S rats with high Na intake and intravenous AG. AG did not change arterial pressure in R rats. AG also caused little change in renal hemodynamics, urinary Na, or H(2)O excretion or ACh-induced aortic vasorelaxation in R or S rats. The data suggest that during high Na intake, nitric oxide produced by renal medullary iNOS helps to prevent excessive increases in arterial pressure in the Dahl S rat but not the R rat.     

Baroreflex control of heart rate in young and adult salt hypertensive inbred Dahl rats

Baroreflex control of heart rate was studied in inbred salt-sensitive (SS/Jr) and salt-resistant (SR/Jr) Dahl rats that were subjected to chronic dietary sodium chloride loading (for 4 weeks) either in youth or only in adulthood, i.e. from the age of 4 or 12 weeks. Using phenylephrine administration to pentobarbital-anesthetized male rats we have demonstrated the decreased baroreflex sensitivity (lower slope for reflex bradycardia) in young prehypertensive SS/Jr rats fed a low-salt diet as compared to age-matched SR/Jr animals. High salt intake further suppressed baroreflex sensitivity in young SS/Jr but not in SR/Jr rats. Baroreflex sensitivity decreased with age in SR/Jr rats, whereas it increased in SS/Jr rats fed a low-salt diet. Thus at the age of 16 weeks baroreflex sensitivity was much higher in SS/Jr than in SR/Jr animals. High salt intake lowered baroreflex sensitivity even in adult SS/Jr rats without affecting it in adult SR/Jr rats. Nevertheless, baroreflex sensitivity was significantly lower in young SS/Jr rats with a severe salt hypertension than in adult ones with a moderate blood pressure elevation. It is concluded that the alterations of baroreflex sensitivity in young inbred SS/Jr rats (including the response to high salt intake) are similar to those described earlier for outbred salt-sensitive Dahl rats. We have, however, disclosed contrasting age-dependent changes of baroreflex sensitivity in both inbred substrains of Dahl rats.     

Cardiovascular effects of the combination of levosimendan and valsartan in hypertensive Dahl/Rapp rats

Hypertension is the main risk factor for left ventricular hypertrophy and development of diastolic heart failure. There is no yet treatment, which can effectively reduce mortality in patients suffering from heart failure with preserved systolic function. We tested whether the calcium sensitizer levosimendan and the AT1-receptor antagonist valsartan could protect from salt-induced hypertension, cardiovascular mortality and heart failure in Dahl/Rapp salt-sensitive rats fed for 7 weeks with a high salt diet (8% NaCl). Levosimendan (1 mg/kg/day via drinking water) and valsartan (30 mg/kg in the food) monotherapies and their combination prevented mortality in Dahl/Rapp rats. The drug combination evoked an additive effect on blood pressure, cardiac hypertrophy, cardiomyocyte cross-sectional area, target organ damage and myocardial ANP mRNA expression. There was a close correlation between systolic blood pressure and cardiac hypertrophy, cardiac and renal damage. As compared to Dahl/Rapp controls kept on low-salt diet (NaCl 0.3%). The high salt rats exhibited impaired diastolic relaxation as assessed by isovolumic relaxation time. Levosimendan alone and in combination with valsartan, improved diastolic relaxation without significantly improving systolic function. Our findings are evidence for an additive effect between levosimendan and valsartan on blood pressure and a blood pressure-dependent protection against the development of salt-induced target organ damage. The present study also demonstrates that levosimendan, alone or in combination with valsartan, can correct diastolic dysfunction induced by salt-dependent hypertension.     

Alterations of vascular prostacyclin and thromboxane A2 in Dahl genetical strain susceptible to salt-induced hypertension

To assess the implications of vascular eicosanoids system in the hypertension of Dahl salt-sensitive (Dahl S) strain, we investigated the production of vascular vasodepressor and vasoconstrictor eicosanoids in Dahl S rats. 14-week-old Dahl S rats on a 0.11% NaCl diet (normotension) or a 0.3% NaCl diet (borderline hypertension) had a significantly lowered generation of vascular prostacyclin (PGI2), compared with Dahl salt-resistant (Dahl R) rats. The impairment of vascular PGI2 in Dahl S rats was restored to the normal level of Dahl R rats with the elevation of blood pressure induced by a high salt diet (4% NaCl). The production of vascular PGI2 was closely related to the height of blood pressure. The deterioration of vascular PGI2 was also found in 4-week-old Dahl S rats with normotension. Conversely, vascular thromboxane A2 (TXA2) was significantly enhanced in 14-week-old Dahl S rats in all of the feeding groups. Thus, it seems possible that the proved alterations of the vasodepressor and vasoconstrictor eicosanoids partially contribute to the genesis of salt hypertension. Although the exact mechanisms remain obscure, the adaptation of vascular PGI2 on a high salt diet may be suitable to compete with the high blood pressure and to protect against the vascular damage.     

Localization of a blood pressure QTL to a 2.4-cM interval on rat chromosome 9 using congenic strains

A blood pressure (BP) quantitative trait locus (QTL) was previously found on rat chromosome 9 using Dahl salt-sensitive (S) and Dahl salt-resistant (R) rats. A congenic strain, S.R(chr9), constructed by introgressing an R chromosomal segment into the S background, previously proved the existence of a BP QTL in a large 34.2-cM segment of chromosome 9. In the current work congenic substrains were constructed from the progenitor congenic strain, S.R(chr9). BP and heart weight comparisons between these congenic substrains and their S control localized the BP QTL to a 4.6-cM interval. Two solute carrier (Na(+)/H(+) exchanger) genes, Nhe2 and Nhe4, were excluded as candidates based on their map locations. A second iteration of congenic substrains was used to localize the QTL further to a 2.4-cM interval. Another solute carrier (Cl(-)/HCO3- exchanger) gene, Ae3, is in this reduced interval and was sequenced for both S and R strains, but no coding sequence variations were found. Ae3 mRNA was not differentially expressed in the kidney of congenic compared to S rats. Although the identity of the QTL remains unknown its map location has been reduced from an interval of 34.2 to 2.4 cM.     

Aldosterone-induced abnormal regulation of ENaC and SGK1 in Dahl salt-sensitive rat

Aldosterone plays a crucial role in controlling mineral balance in our body. The mechanism of aldosterone has been reported to elevate renal Na+ reabsorption by stimulating expression of epithelial Na+ channel (ENaC) and also activate an ENaC-regulating protein kinase, serum and glucocorticoid-regulated kinase 1 (SGK1). However, it is unknown whether aldosterone shows its stimulatory action on ENaC and SGK1 under an abnormal, salt-sensitive hypertensive condition. To clarify this point, we studied how aldosterone regulates expression of ENaC and SGK1 in Dahl salt-sensitive (DS) rat that shows hypertension with high salt diet. RNA and protein were extracted from the kidney 6 h after application of aldosterone (1.5 mg/kg body weight) subcutaneously injected into adrenalectomized DS and Dahl salt-resistant (DR) rats. Aldosterone decreased mRNA expression of beta- and gamma-ENaC in DS rat unlike DR rat, while aldosterone increased alpha-ENaC mRNA expression in DS rat similar to DR rat. Further, we found that aldosterone elevated SGK1 expression in DR rat, but not in DS rat. These observations indicate that ENaC and SGK1 are abnormally regulated by aldosterone in salt-sensitive hypertensive rats, suggesting that disturbance of the aldosterone regulation would be one of factors causing salt-sensitive hypertension.     

Enhanced sympathoexcitatory and pressor responses to central Na+ in Dahl salt-sensitive vs. -resistant rats

An enhanced responsiveness to increases in cerebrospinal fluid (CSF) Na+ by high salt intake may contribute to salt-sensitive hypertension in Dahl salt-sensitive (S) rats. To test this hypothesis, sympathetic and pressor responses to acute and chronic increases in CSF Na+ were evaluated. In conscious young (5-6 wk old) and adult (10-11 wk old) Dahl S and salt-resistant (R) rats as well as weight-matched Wistar rats, hemodynamic [blood pressure (BP) and heart rate (HR)] and sympathetic [renal sympathetic nerve activity (RSNA)] responses to 10-min intracerebroventricular infusions of artificial CSF (aCSF) and Na+-rich aCSF (containing 0.2-0.45 M Na+) were evaluated. Intracerebroventricular Na+-rich aCSF increased BP, RSNA, and HR in a dose-related manner. The extent of these increases was significantly larger in Dahl S versus Dahl R or Wistar rats and young versus adult Dahl S rats. In a second set of experiments, young Dahl S and R rats received a chronic intracerebroventricular infusion of aCSF or Na+-rich (0.8 M) aCSF (5 microl/h) for 14 days, with the use of osmotic minipumps. On day 14 in conscious rats, CSF was sampled and BP, HR, and RSNA were recorded at rest and in response to air stress, intracerebroventricular alpha2-adrenoceptor agonist guanabenz, intracerebroventricular ouabain, and intravenous phenylephrine and nitroprusside to estimate baroreflex function. The infusion of Na+-rich aCSF versus aCSF increased CSF Na+ concentration to the same extent but caused severe versus mild hypertension in Dahl S and Dahl R rats, respectively. After central Na+ loading, hypothalamus "ouabain" significantly increased in Dahl S and only tended to increase in Dahl R rats. Moreover, sympathoexcitatory and pressor responses to intracerebroventricular exogenous ouabain were attenuated by Na+-rich aCSF to a greater extent in Dahl S versus Dahl R rats. Responses to air-jet stress or intracerebroventricular guanabenz were enhanced by Na+-rich aCSF in both strains, but the extent of enhancement was significantly larger in Dahl S versus Dahl R. Na+-rich aCSF impaired arterial baroreflex control of RSNA more markedly in Dahl S versus R rats. These findings indicate that genetic control of mechanisms linking CSF Na+ with brain "ouabain" is altered in Dahl S rats toward sympathetic hyperactivity and hypertension.     

Atrial natriuretic factor in the spinal cord of normotensive and hypertensive rats

Atrial natriuretic factor (ANF) was investigated in the rat spinal cord and hypothalamus using two radioimmunoassays. ANF was also quantified in both tissues of Spontaneously Hypertensive Rats and Dahl rats. Spinal cord and hypothalamus were found to be immunoreactive to proANF and its near-NH2- or near-COOH-terminal fragments. A major part of the extracted ANF was a COOH-terminal peptide smaller than or the same as ANF (Ser99-Tyr 126). SHR had higher hypothalamic and spinal cord ANF concentrations than Wistar Kyoto rats, while the Dahl salt-sensitive animals exhibited an increase in spinal cord ANF when compared with the Dahl salt-resistant group. The data suggest that spinal cord may produce ANF locally with processing similar to that in hypothalamus. Changes in ANF concentrations occurring during the course of hypertension remain to be further investigated.     

Beyond vasodilation: the antioxidant effect of adrenomedullin in Dahl salt-sensitive rat aorta

We have investigated the antioxidant effect of adrenomedullin (AM) on endothelial function in the Dahl salt-sensitive (DS) rat hypertension model. Dahl salt-resistant (DR) and DS rats were fed an 8% NaCl diet. In addition, the DS rats were subcutaneously infused with either saline or recombinant human AM for 4 weeks. Although systolic blood pressures measured weekly in AM- and saline-infused rats did not significantly differ, aortic O2*- levels were significantly (P<0.01) higher in the latter. Likewise, both endothelial nitric oxide synthase (eNOS) mRNA and protein were significantly higher in saline-infused DS rats. Infusion of AM reduced both O2*- and eNOS expression to levels comparable to those seen in DR rats. AM infusion also upregulated the gene expression of guanosine-5'-triphosphate cyclohydrolase I and downregulated the expression of p22(phox), suggesting that AM increased the NOS coupling and bioavailability of NO. AM possesses significant antioxidant properties that improve endothelial function.     

Alterations of vascular prostacyclin and thromboxane A2 in Dahl genetical strain susceptible to salt-induced hypertension

To assess the implications of vascular eicosanoids system in the hypertension of Dahl salt-sensitive (Dahl S) strain, we investigated the production of vascular vasodepressor and vasoconstrictor eicosanoids in Dahl S rats. 14-week-old Dahl S rats on a 0.11% NaCl diet (normotension) or a 0.3% NaCl diet (borderline hypertension) had a significantly lowered generation of vascular prostacyclin (PGI₂), compared with Dahl salt-resistant (Dahl R) rats. The impairment of vascular PGI₂ in Dahl S rats was restored to the normal level of Dahl R rats with the elevation of blood pressure induced by a high salt diet (4% NaCl). The production of vascular PGI₂ was closely related to the height of blood pressure. The deterioration of vascular PGI₂ was also found in 4-week-old Dahl S rats with normotension. Conversely, vascular thromboxane A₂ (TXA₂) was significantly enhanced in 14-week-old Dahl S rats in all of the feeding groups. Thus, it seems possible that the proved alterations of the vasodepressor and vasoconstrictor eicosanoids partially contribute to the genesis of salt hypertension. Although the exact mechanisms remain obscure, the adaptation of vascular PGI₂ on a high salt diet may be suitable to compete with the high blood pressure and to protect against the vascular damage.