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PubMed1986

Aortic calcium uptake and efflux in spontaneously hypertensive and inbred Dahl rats.

Calcium uptake and efflux were studied in aortic tissues of three inbred rat strains; spontaneously hypertensive rats (SHR), inbred Dahl salt-sensitive rats (S/JR) and inbred Dahl salt-resistant (R/JR) rats. Previously, we showed that a single genetic locus (Hyp-2 locus) controls vascular smooth muscle responses to ionic cobalt (Co2+) among these three strains. Spontaneously hypertensive rats carry an allele at the Hyp-2 locus mediating high blood pressure, but S/JR and R/JR both carry an allele at this locus for low blood pressure. In the present work, resting Ca2+ uptake in aortic tissue was found to be increased in SHR and S/JR relative to R/JR. It was concluded that resting aortic Ca2+ uptake and genotypes at the Hyp-2 locus are not concordant among strains and that the increased Ca2+ uptake of the hypertensive strains must, therefore, be mediated by a mechanism other than the Hyp-2 locus. Resting aortic Ca2+ uptake was shown also to be increased in hypertension-resistant R/JR rats by the extreme treatment of unilateral nephrectomy plus 8% NaCl diet which induces hypertension in R/JR rats. The high resting vascular smooth muscle calcium-uptake seen in the hypertensive strains is, therefore, not a unique primary genetic cause of hypertension since it can also be induced by environmental manipulation. High resting aortic Ca2+ uptake is either a consequence of hypertension or a final common physiological pathway by which genetic and environmental factors influence blood pressure.

Animals↗
PubMed1994

Cosegregation of the endothelin-3 locus with blood pressure and relative heart weight in inbred Dahl rats.

OBJECTIVE: To determine whether the endothelin-1 or endothelin-3 genes are genetically linked with blood pressure and relative heart weight in segregating rat populations, in the context of an elevated dietary sodium chloride intake. METHODS: Endothelin-1 and endothelin-3 genotypes of rats in segregating populations, derived from crosses of Dahl salt-sensitive (SS/Jr) rats with contrasting inbred strains, including Lewis rats, spontaneously hypertensive rats and Dahl salt-resistant (SR/Jr) rats, were determined using restriction fragment length polymorphisms. Segregating populations were fed a high (8%)-sodium chloride diet. Linkage of genotype with blood pressure or relative heart weight was determined by analysis of variance. Chromosomal location of the rat endothelin-3 gene was determined by genotyping a panel of recombinant inbred strains. RESULTS: Two alleles for the endothelin-1 gene and three alleles for the endothelin-3 gene were identified. The endothelin-1 locus did not cosegregate with blood pressure or relative heart weight. The endothelin-3 locus cosegregated with blood pressure and relative heart weight in an SS/Jr x F1 (SS/Jr x SR/Jr) population, but not in populations containing a higher percentage of genes from the SR/Jr strain. The endothelin-3 and seminal vesicle protein-1 loci were linked and located on rat chromosome 3. CONCLUSION: The endothelin-3 gene is, or is linked to, a locus on chromosome 3 that regulates blood pressure and relative heart weight in inbred Dahl rats, and these effects were strongly dependent on the genetic background.

Animals↗
PubMed2000

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.

Age Factors↗
PubMed1987

Release of atrial natriuretic factor from heart-lung preparations of inbred Dahl rats.

Isolated heart-lung preparations from hypertensive inbred Dahl salt-hypertension sensitive (S) and normotensive inbred Dahl salt-hypertension resistant (R) rats were perfused using 15% washed rat red blood cells in Krebs-Ringer bicarbonate buffer. Atrial pressures were increased by increasing venous return (preload) or by increasing the arterial resistance (afterload). Increases in preload at a constant afterload produced increases in the right and left atrial pressures equivalent between S and R strains. Atrial natriuretic factor (ANF) release was linearly related to right atrial pressure (RAP) or left atrial pressure (LAP) in either strain, but S released more ANF at each level of preload, and the slope of the line relating ANF release to RAP was significantly greater in S than R. When the heart-lung preparations were subjected to changes in afterload at a constant preload, LAP was significantly increased in R but not in S rats, and concomitantly ANF increased in R but not in S. In the afterload experiments, as in the preload studies, S released more ANF than R for comparable LAP. It is concluded that 1) at any atrial pressure, hearts of hypertensive S rats release more ANF than hearts of normotensive R rats, 2) this strain difference is probably a consequence of hypertension, and 3) the observed relationships between ANF release and atrial pressures support the contention that atrial distention stimulates the release of ANF.

Animals↗
PubMed1991

Pressure natriuresis and cortical and papillary blood flow in inbred Dahl rats.

The present study examined whether alterations in papillary blood flow, renal interstitial pressure (RIHP), and the pressure-natriuretic (PN) response are associated with the development of hypertension in inbred Dahl salt-sensitive (Dahl-S) rats. The PN responses were compared in 18- to 20-wk-old, Inactin-anesthetized, inbred Dahl salt-sensitive (S/Jr) and salt-resistant (R/Jr) rats fed a low-(0.3%) and a high- (8.0%) sodium chloride diet. Cortical and papillary blood flows were measured using laser-Doppler flowmetry. Neural and hormonal influences on the kidney were controlled by renal denervation and by fixing plasma norepinephrine, vasopressin, corticosterone, and aldosterone levels by intravenous infusion. The slope of the PN relationship in S/Jr rats maintained on a low-salt diet was 62% lower than that observed in R/Jr rats; however, whole kidney, cortical, and papillary blood flows and RIHP were not significantly different at any perfusion pressure studied. Glomerular filtration rate (GFR) was 25% lower in S/Jr rats than in R/Jr animals maintained on a low-salt diet. The slopes of the PN responses were similar in S/Jr and R/Jr rats exposed to a high-salt diet, but the entire relationship was shifted toward higher pressures by 20 mmHg in the S/Jr rats. Control cortical and papillary blood flows measured at control mean arterial pressures of 126 +/- 3 and 167 +/- 5 mmHg in R/Jr and S/Jr rats, respectively, were not significantly different. However, cortical and papillary blood flows were 25% lower in the S/Jr than in the R/Jr rats exposed to a high-salt diet when compared at equivalent renal perfusion pressures.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

Inheritance of salt-dependent hypertension in the inbred Dahl rat.

The mode of inheritance of salt-dependent hypertension in the inbred Dahl salt-sensitive rat strain was examined by genetic crosses with the corresponding salt-resistant strain. The blood pressure responses to ingestion of a high NaCl (8%) diet defined three phenotypes: early onset (within 17 days) of systolic hypertension, defined as greater than or equal to 140 mm Hg, the parental salt-sensitive phenotype; late onset of systolic hypertension requiring 50 to 60 days in males and more than 200 days in females, characteristic of the F1 progeny; and normotension, less than 140 mm Hg, the parental salt-resistant phenotype. The frequencies of the phenotypes observed among 91 F2 progeny and 45 progeny of the backcross to parental salt-sensitive animals agree well with values predicted by a model in which two autosomal, unlinked, allelic loci, termed alpha and beta, determine the inheritance. For F2 male progeny, the predicted frequencies of early-onset hypertension, late-onset hypertension, and normotension are 0.1875, 0.5625, and 0.25, respectively, and the corresponding observed frequencies were 0.156, 0.50, and 0.34 (X2 = 0.48, P > .50). F1 progeny of reciprocal parental crosses were maintained on the 8% NaCl diet for 255 days. Male F1 rats developed systolic hypertension sooner than did females. From 60 to 200 days, the average blood pressure value within each group remained approximately stable; the male values exceeded those for females (P < .01); and the direction of the parental cross significantly influenced (P < .05) the levels in males and females, suggestive of genomic imprinting.

Analysis of Variance↗
PubMed1997

Endogenous inhibitor of Na-K-Cl cotransport system in inbred Dahl rats.

Dahl salt-sensitive (DS) rats seem characterized by a ubiquitous increase in Na-K-Cl cotransport activity. Here, an endogenous inhibitor of the Na-K-Cl cotransport system (cotransport inhibitory factor, CIF) was investigated in inbred Dahl salt-sensitive (DS) and salt-resistant (DR) rats. The animals were orally loaded for 10 days with 2% NaCl. Plasma from salt-loaded DS rats inhibited cotransport with a 50% inhibition concentration value (IC50) of 6.4 +/- 0.6% (% plasma concentration, vol/vol) vs. 24.2 +/- 2.2% in DR rats (P < 0.0001). In urine, IC50 for cotransport inhibition was constantly lower in DS before and all during the whole salt-loading period (after 10 days of salt loading, IC50 was 2.59 +/- 0.11% and 6.00 +/- 0.24% in DS and DR rats, respectively; P < 0.0001). After 3 days of salt loading, higher salt appetite in DS rats magnified the differences in urinary CIF excretion. In erythrocytes from DS rats, increased cotransport activity was strongly correlated with urinary CIF excretion (r = 0.967). In conclusion, DS rats present increased plasmatic and urinary CIF levels. This can be a compensatory phenomenon to reduce cotransport hyperactivity and increased NaCl reabsorption at the thick ascending limb of Henle's loop.

Animals↗
PubMed1994

Angiotensin II induced alteration of cyclic adenosine 3',5'-monophosphate generation in the hypertrophic myocardium of Dahl salt-sensitive rat on a high-salt diet.

The objective of this study was to explore the action of angiotensin II (AII) on cardiac contractility and cyclic AMP (cAMP) generation by forskolin and isoproterenol in the hypertrophic myocardium of the salt-sensitive Dahl rat. Inbred Dahl S and Dahl R rats that had been on a diet supplemented with 6% NaCl were studied. The functional effects of the interaction of AII and forskolin on cardiac contractility were assessed in the isolated heart preparation. The effect on the cAMP signal transduction pathway was assessed in cardiomyocytes isolated from hearts of Dahl S and R rats. Dahl S rats developed cardiac hypertrophy on a high-salt diet, whereas Dahl R rats did not. Forskolin increased cardiac contractility, which was differently affected by AII, depending on whether the heart was from hypertrophied Dahl S rat or from the control Dahl R rat. AII accentuated forskolin-induced increases in cardiac contractility in hypertrophic hearts but diminished forskolin-induced increases in contractility in the nonhypertrophied hearts. This response was reflected in the cAMP response to forskolin, in that AII decreased forskolin-induced increases in cAMP in the nonhypertrophic heart. AII had the reverse effect in cardiomyocytes from hypertrophied hearts, as AII increased forskolin-induced cAMP production. This was shown to be due to an AII receptor mediated effect, as it was antagonized by the AII receptor antagonist saralasin. The same effects of AII were found on isoproterenol-induced increases in cAMP. Similar results occurred in the presence of the phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine (IBMX), suggesting that the effect was on cAMP production rather than cAMP degradation. This was attributed to an inhibitory G protein (Gi) mechanism, as the muscarinic agonist carbachol, which acts through Gi, produced the same effects as AII. Furthermore, the effects of AII were abolished by pertussis toxin, which inactivates Gi. These data indicate a reversal of control by AII in the hypertrophic Dahl S heart in response to forskolin, which activates adenylyl cyclase directly on the catalytic subunit, converting the substrate, ATP, to cAMP, independent of the guanine nucleotide activated protein, and in response to isoproterenol, which activates adenylyl cyclase through G protein mechanisms. All accentuated the forskolin-induced increase in cardiac contractility and cAMP generation in the hypertrophied ventricle but decreased both contractility and cAMP generation in nonhypertrophied hearts, suggesting that the process of cardiac hypertrophy in salt-sensitive Dahl rat may compensate for the reduction in intracellular cAMP by altering its regulatory control by AII.

1-Methyl-3-isobutylxanthine↗
PubMed1995

Nerve growth factor, vessel innervation and hypertensive progression in the inbred Dahl SS/Jr and SR/Jr rats.

1. To test whether the inbred Dahl salt-sensitive hypertensive rat strain shares disturbed vessel innervation with the spontaneously hypertensive rat (SHR) model, highly innervated and sparsely innervated tissues from the SR/Jr and SS/Jr strains at several ages were assayed for tissue norepinephrine (NE) content and nerve growth factor (NGF). 2. Only two significant differences were found: (i) 1 week old SS/Jr rat kidneys had more NGF than SR/Jr kidneys; and (ii) six week old mesenteric arteries from SS/Jr contained significantly more NE than those in the SR/Jr animals. 3. The differences are in the expected direction for vessel hyperinnervation as a consequence of high vessel NGF, but the data do not support the hypothesis of a central role for vessel NGF and innervation in the hypertensive progression of the Dahl strain. The vessels of young Dahl inbred rat strains do not display the same degree of vessel hyperinnervation associated with hypertension as found in the young SHR compared to WKY strains. 4. The Dahl strain may lack the disturbed NGF metabolism of the SHR. This might suggest that the Dahl inbred strains and the SHR represent two distinct genetic mechanisms that predispose to hypertension via essentially independent processes and that all forms will evidence at least mildly altered vessel innervation.

Animals↗
PubMed2000

Resistance to myocardial ischemia in five rat strains: is there a genetic component of cardioprotection?

There is a need to develop new and more consistent animal models of cardioprotection. Traditionally, outbred dogs, rabbits, and rats have been studied. We determined resistance to ischemia in isolated hearts from inbred strains of rats. Hearts from inbred rats: SS/Mcw (Dahl S, Dahl salt-sensitive), DA/Hsd (Dark Agouti), LEW/Hsd (Lewis), and BN/SsN/Mcw (Brown Norway); and from an outbred rat: Hsd:WIST (Wistar) were subjected to 27 min of global, no-flow ischemia, followed by 3 h of reperfusion. Infarct size in the Brown Norway rat was 2.5 times less than that observed in the Dahl S rat, with the Dark Agouti, Lewis, and Wistar rats intermediate in response. Hearts from Brown Norway rats were also most resistant to ischemia in terms of postischemic enzyme leakage and contractile and vascular function compared with other strains. The average polymorphism rate between strains revealed that such strains were genetically diverse. This study demonstrates strain differences in resistance to myocardial ischemia, suggesting these rats could be used to study a genetic and/or environmental basis for these differences and to provide new animal models for the physiological study of cardioprotection.

Animals↗
PubMed1985

Lack of effects of maternal salt intake on blood pressure of offspring in Dahl salt-sensitive rats.

Inbred Dahl salt sensitive (S/JR) and salt resistant (R/JR) rats were used to look for effects of varying maternal intake of salt (NaCl) on the blood pressure of the offspring. Neither the blood pressure at weaning nor the blood pressure response to postweaning high salt diet of S/JR or R/JR rat pups was affected whether their mothers had eaten high salt (8% NaCl) or low salt (0.15% NaCl) diet during gestation. Similarly, maternal salt intake during lactation had no effect on the blood pressure of the offspring at weaning or the blood pressure response to salt feeding after weaning. Na+ was higher and K+ was lower in milk of S/JR compared to R/JR mothers during the last half of the lactation period, but dietary salt intake did not influence milk Na+ or K+. Previous cross-fostering experiments show that this strain difference in milk electrolytes does not influence S pups blood pressure. It is concluded that neither maternal salt intake nor the existing changes in milk Na+ have any influence on the blood pressure of Dahl salt sensitive rat pups in contrast to the marked effects of salt intake in these rats after weaning.

Age Factors↗
PubMed2004

Identification of salt-sensitive genes in the kidneys of Dahl rats.

OBJECTIVE: Inherited differences in renal function underlie the effect of high salt diets on blood pressure in Dahl rats. We probed the kidneys of inbred Dahl SS/Jr and SR/Jr for anonymous and candidate genes whose expression was regulated by dietary sodium. METHODS: mRNA quantitation of both candidate genes implicated in sodium excretion and anonymous gene products found by differential hybridization in the kidneys of salt-resistant (SR) and salt sensitive (SS) inbred Dahl rats on high and low salt diets for 21 days. RESULTS: Differential screening revealed a cDNA clone (H1) that showed increased dietary salt-dependent expression only in SS rats. Sequencing of the H1 cDNA showed it was the Dahl rat homologue to a perchloric acid soluble protein expressed in liver and kidney. Among candidate genes, transcript levels of arginosuccinate synthetase (AS) and arginosuccinate lyase (AL) were higher in SS on low salt diets, and AS mRNA increased in response to a high salt diet in SR. Renal mRNA for the ANP-A and the vasopressin type II receptors did not differ by strain or dietary conditions. CONCLUSIONS: Three new salt-sensitive genes were detected in the kidneys of inbred Dahl rats. Two genes encode enzymes in the biosynthesis of L-arginine. The upregulation of these genes by dietary salt indicates increased demand and biosynthesis of L-arginine in Dahl SS rats. A third gene encodes a small acid-soluble protein thought to influence the transcription/translation of numerous genes. Further studies will be needed to determine the nature of the association of these genes with salt-sensitivity and blood pressure.

Animals↗
PubMed2005

Assessment of the microRNA system in salt-sensitive hypertension.

Most animal microRNAs are imperfectly complementary to their mRNA targets and inhibit protein synthesis through an unknown mechanism. MicroRNAs have been reported to play important roles in a number of biological processes. We assessed the microRNA system in Dahl salt-sensitive rats in order to investigate possible roles of microRNA in salt-sensitive hypertension. We constructed microRNA libraries from the kidneys of Dahl salt-sensitive and Lewis rats taking normal or high-salt diets (4 groups), and identified 91 previously reported and 12 new microRNAs expressed in the kidney. We then used Northern blotting to assess the expression levels of 118 microRNAs in the kidneys and heart ventricles. No significant differences in microRNA expression profiles were observed among the 4 groups. Thus, the microRNA system seemed to be unlikely to contribute to salt-sensitive hypertension in Dahl salt-sensitive rats.

Animals↗
PubMed2006

Angiotensin II sensitivity of anterior hypothalamic area neurons is enhanced in both spontaneously hypertensive rats and Dahl salt-sensitive rats.

We have previously demonstrated that some neurons in the anterior hypothalamic area (AHA) are tonically activated by endogenous angiotensins. Furthermore, we have demonstrated that intracerebroventricular injection of hypertonic saline increases the firing rate of AHA angiotensin II-sensitive neurons via angiotensins and that the central sodium-induced activation of AHA neurons is enhanced in spontaneously hypertensive rats (SHR) and Dahl salt-sensitive (Dahl S) rats. In this study, we examined whether sensitivities of AHA angiotensin II-sensitive neurons to angiotensin II are enhanced in SHR and Dahl S rats as compared with their respective controls. Male 15- to 16-week-old SHR and age-matched Wistar Kyoto rats (WKY), and male 15- to 16-week-old Dahl S rats and Dahl R rats were anesthetized and artificially ventilated. Extracellular potentials were recorded from single neurons in the AHA. In SHR, pressure application of angiotensin II (3 x 10(-9) to 3 x 10(-8) M) onto AHA angiotensin II-sensitive neurons increased their firing rate in a concentration-dependent manner. In WKY, only the highest concentration of angiotensin II increased the firing rate, while the lower concentrations of angiotensin II did not affect it. In Dahl S rats, pressure application of angiotensin II (10(-8) and 3 x 10(-8) M) onto AHA neurons increased their firing rate, while angiotensin II (3 x 10(-9) M) did not affect it. In Dahl R rats, the highest concentration of angiotensin II increased the firing rate, while the lower concentrations of angiotensin II did not affect it. These findings indicate that the sensitivity of AHA neurons to angiotenisn II is enhanced in SHR and Dahl S rats as compared with their respective controls.

Action Potentials↗
PubMed2005

Increased number of aldosterone-sensitive NTS neurons in Dahl salt-sensitive rats.

Dahl salt-sensitive rats develop severe hypertension during a high-sodium diet, but the basis of their salt-sensitive phenotype is not completely understood. A subset of neurons in the nucleus tractus solitarius (NTS) are uniquely sensitive to the adrenal steroid hormone aldosterone, which is critically involved in sodium homeostasis, due to their expression of the enzyme 11-beta-hydroxysteroid dehydrogenase type 2 (HSD2). The number of HSD2 neurons in the NTS was counted in prehypertensive 7-week-old Dahl salt-sensitive rats and compared with two control strains: Dahl salt-resistant and Sprague-Dawley rats. Dahl salt-sensitive rats had more HSD2 neurons than age-matched Dahl salt-resistant and Sprague-Dawley rats (24% and 21%, respectively). Cell counts were also made in spontaneously hypertensive rats (SHR) and Wistar-Kyoto (WKY) rats; the number of HSD2 neurons in both of these strains was similar to the values obtained for Sprague-Dawley rats. The increased number of HSD2-immunoreactive neurons counted in Dahl salt-sensitive rats suggests that they may have a greater number of aldosterone-sensitive NTS neurons. Alternatively, an increase in HSD2 expression in Dahl salt-sensitive rats could increase the overall immunoreactivity, permitting detection of more of these neurons. In either case, the roughly 20% increase in HSD2 neurons in the NTS of prehypertensive Dahl salt-sensitive rats is a novel factor associated with their salt-sensitive phenotype. These neurons may play a role in regulating sodium appetite, which is abnormally suppressed in Dahl salt-sensitive rats.

Aldosterone↗
PubMed2005

Enhanced central hypertonic saline-induced activation of angiotensin II-sensitive neurons in the anterior hypothalamic area of spontaneously hypertensive and Dahl S rats.

High dietary salt intake activates the brain renin-angiotensin system in spontaneously hypertensive rats (SHR) and Dahl S rats, resulting in sympathetic hyperactivity and hypertension. Increases of sodium concentration in cerebrospinal fluid (CSF) and/or enhanced responses to CSF sodium are considered to be involved in the high dietary salt-induced activation of central nervous system pathways in those rats. Previously we have demonstrated that intracerebroventricular injection of hypertonic saline increases the neural activity of angiotensin II-sensitive neurons trans-synaptically via endogenous angiotensins in the anterior hypothalamic area (AHA) of rats. In the present study, we examined whether the AHA angiotensin II-sensitive neuron response to hypertonic saline would differ in SHR and Dahl S rats from those of their controls. Male 15- to 16-week-old SHR and age-matched Wistar Kyoto rats (WKY), Dahl S rats and Dahl R rats and Wistar rats were anesthetized and artificially ventilated. Extracellular potentials were recorded from single neurons in the AHA. Intracerebroventricular injection of hypertonic saline increased the firing rate of AHA angiotensin II-sensitive neurons. The threshold sodium concentration for the central sodium-induced increase of neural firing was lower in SHR than those of WKY, Dahl S rats, Dahl R rats and Wistar rats. The increase in neural firing induced by hypertonic saline (250 mM) was greater in SHR than those of other four kinds of rats. Similarly, the threshold sodium concentration was lower in Dahl S rats than those of WKY, Dahl R rats and Wistar rats and the increase in neural firing induced by hypertonic saline (250 mM) was greater in Dahl S rats than those of WKY, Dahl R rats and Wistar rats. In SHR, intracerebroventricular injection of the amiloride-sensitive sodium channel blocker benzamil abolished the hypertonic saline (250 mM)-induced increase in neural firing, but the sodium channel blocker itself did not affect the basal firing of these neurons. These findings indicate that central sodium-induced activation of AHA angiotensin II-sensitive neurons is enhanced in SHR and Dahl S rats.

Action Potentials↗
PubMed2005

Corroboration of Dahl S Q276L alpha1Na,K-ATPase protein sequence: impact on affinities for ligands and on E1 conformation.

OBJECTIVE: Multifactorial analyses support the hypothesis that alpha1Na,K-ATPase is a hypertension susceptibility gene in Dahl S rats. However, two studies report non-detection of the A1079T transversion underlying the Q276L substitution in Dahl S alpha1Na,K-ATPase questioning the validity of ATP1A1 as a hypertension susceptibility gene. To resolve this discordance, we investigated the issue at the protein level. DESIGN AND METHODS: We employed protein blot analysis using Q276L- and Q276-specific; antipeptide-specific antibodies; tested differential chymotrypsin cleavage efficiency, measured differential Na and K affinities of alpha1Na,K-ATPases in Dahl S and Dahl R renal membranes and determined amino acid sequences of purified Dahl S alpha1Na,K-ATPase chymotryptic-digest peptides. RESULTS: We detected Q276L variant protein in Dahl S rats; and Q276 wild-type variant in Dahl R, spontaneously hypertensive (SHR), Lewis and Wistar-Kyoto (WKY) rat kidney membranes. Q276L variant exhibits less chymotrypsin cleavage efficiency than the Q276 wild-type variant, consistent with the substitution of hydrophobic L for hydrophilic Q. Kinetic studies of kidney membranes detect increased Na affinity and decreased K affinity in renal Dahl S alpha1Na,K-ATPase compared with Dahl R. Protein sequencing of high pressure liquid chromatography (HPLC)-purified chymotrypsin digested 77 kDa peptide confirms Q276L substitution in the Dahl S alpha1Na,K-ATPase. CONCLUSIONS: Data demonstrate the existence and functional significance of the Q276L variant in Dahl S rats.

Amino Acid Substitution↗