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PubMed2004

Genetic linkage of albuminuria and renal injury in Dahl salt-sensitive rats on a high-salt diet: comparison with spontaneously hypertensive rats.

Our aim was to study the effects of high-salt diet on the genetics of albuminuria and renal injury in the Dahl salt-sensitive (SS) rat. We compared SS with salt-resistant spontaneously hypertensive rats (SHR) and with genetically related salt-sensitive stroke-prone SHR (SHRSP). Moreover, we performed genome-wide linkage analysis to identify quantitative trait loci (QTL) contributing to salt-induced renal injury in an F2 population derived from SS and SHR (n = 230). In response to high-salt diet SS and SHRSP developed a striking increase in systolic blood pressure, urinary albumin excretion (UAE), and renal damage indices compared with SHR. Both SHRSP and SS developed severe glomerulosclerosis, whereas microangiopathy, tubulointerstitial fibrosis, and inflammation were more pronounced in SHRSP. We detected two QTL with significant linkage to UAE on rat chromosomes (RNO) 6 and 19. Comparison with the recently identified salt-independent UAE QTL in young animals revealed that the UAE QTL on RNO6 is unique to high-salt conditions, whereas RNO19 plays a significant role during both low- and high-salt conditions. Some F2 animals demonstrated severe microangiopathy and tubulointerstitial injury, which exceeded the degree observed in the parental SS strain. Three loci demonstrated suggestive linkage to these phenotypes on RNO3, RNO5, and RNO20, whereas no linkage to glomerular damage was found. Further analyses at these loci indicated that the severity of renal injury was attributable to the SHR allele. Our data suggest that the SHR genetic background confers greater susceptibility for the development of microangiopathy and tubulointerstitial injury in salt-sensitive hypertension than the SS background.

Albuminuria↗
PubMed1989

Dissociation of renal nerve and excretory responses to volume expansion in prehypertensive Dahl salt-sensitive and Dahl salt-resistant rats.

Prehypertensive Dahl salt-sensitive rats on low sodium diet have impaired baroreceptor and cardiopulmonary receptor function as compared with Dahl salt-resistant control rats. We tested whether these abnormalities influenced the ability of conscious prehypertensive Dahl salt-sensitive rats to excrete a moderate intravenous isotonic saline volume load (0.9% NaCl, 3% body weight i.v.). During control, 30-minute volume expansion, and 2-hour recovery periods, arterial blood pressure and heart rate did not change. Glomerular filtration rate and renal plasma flow remained stable throughout control and recovery. The amount of the volume load excreted as either water or sodium was the same for Dahl salt-sensitive and Dahl salt-resistant rats with either denervated or innervated kidneys. The time course of water and sodium excretion was similar in Dahl salt-sensitive and Dahl salt-resistant rats. Renal sympathetic nerve activity, however, showed different patterns. Although the initial decrease in renal sympathetic nerve activity during volume expansion was similar for both groups, Dahl salt-sensitive rats exhibited a prompt return of renal sympathetic nerve activity to control levels, whereas renal sympathetic nerve activity in Dahl salt-resistant rats remained decreased throughout the recovery period. The rapid recovery of renal sympathetic nerve activity to control levels after volume expansion in Dahl salt-sensitive rats supports the concept of impaired cardiopulmonary receptor function in these rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

Dual hemodynamic mechanisms for salt-induced hypertension in Dahl salt-sensitive rats.

Cardiac output, blood volume, total peripheral resistance, and renal blood flow were measured in awake salt-sensitive and salt-resistant Dahl rats on normal rat chow (1% NaCl) and on high salt (8% NaCl) diets. Rats were studied after 4, 8, and 46 weeks on a 1% NaCl diet and after 4 and 8 weeks on an 8% NaCl diet. Salt-sensitive rats on 8% NaCl for 4 weeks developed systolic hypertension; by 8 weeks they developed greater systolic and also diastolic hypertension. Salt-resistant rats on 8% NaCl remained normotensive throughout the studies, although renal resistance decreased (p less than 0.05). At 4 weeks, hypertension in salt-sensitive rats on 8% NaCl was caused by increased blood volume and cardiac output (p less than 0.05), with normal total peripheral resistance. At 8 weeks, hypertension was due to increased total peripheral resistance (p less than 0.05); cardiac output was below normal despite persistent elevation of blood volume (p less than 0.05). Salt-sensitive rats on 1% NaCl for 46 weeks were hypertensive, with elevated total peripheral resistance (p less than 0.05); cardiac output decreased (p less than 0.05), whereas blood volume remained unchanged. Salt-resistant rats on 1% NaCl remained normotensive with no charges in hemodynamics. Salt-sensitive rats on 8% NaCl for 4 weeks had an increase in renal vascular resistance but no significant change in nonrenal resistance or total peripheral resistance. The increased total peripheral resistance in salt-sensitive rats on 8% NaCl for 8 weeks and on 1% NaCl for 46 weeks was a reflection of increases of both renal and nonrenal vascular resistance.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

Insulin levels are similar in obese salt-sensitive and salt-resistant hypertensive subjects.

Evidence supports the hypothesis that hyperinsulinemia, especially in obesity, contributes to salt-sensitive hypertension by enhancing sodium retention and blunting the normal reduction of sympathetic drive and vascular resistance that occurs during a high versus low NaCl diet. To address these issues, we studied 18 obese (body mass index, > 27 kg/m2) subjects younger than 45 years old with mild hypertension to determine if the salt-sensitive versus salt-resistant subset had higher insulin levels, retained more volume, and failed to suppress sympathetic drive and vascular tone normally on a high (approximately 200 mEq/d) versus low (20 mEq/d) NaCl diet for 7 days each. Six obese subjects were salt sensitive, with an 8.4 +/- 2.1 (SEM) mm Hg increase of ambulatory mean blood pressure on the high versus low NaCl diet. Ten obese subjects were salt resistant, with a 7.1 +/- 0.9 mm Hg reduction of ambulatory mean blood pressure on high versus low NaCl. The salt-sensitive and salt-resistant groups had similar values, respectively, for the insulin area under the curve during an oral glucose tolerance test on low (14.6 +/- 1.8 versus 14.0 +/- 1.4 mU x min/dL, P = NS) and high (10.6 +/- 1.5 versus 10.6 +/- 1.0, P = NS) salt diets. Although insulin levels were similar, insulin raised calf blood flow in salt-resistant subjects (P < .05) but not in salt-sensitive subjects on the high NaCl diet.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1997

Lipid metabolism and renal protection by chronic cicletanine treatment in Dahl salt-sensitive rats with salt-induced hypertension.

We investigated the role of lipid metabolism in renal protection by chronic cicletanine treatment in Dahl salt-sensitive (Dahl S) rats with salt-induced hypertension. Forty-four 6-week old Dahl S rats were divided into four groups: (1) low-salt (0.3% NaCl) control group: (2) high-salt (4% NaCl) control group; (3) low-dose (10 mg/kg/day) cicletanine (CICL)-treated group given a high-salt diet; and (4) high-dose (30 mg/kg/day) cicletanine-treated group given a high-salt diet. The rats were treated for 6 weeks; blood pressure was measured by the tail-cuff method. Cicletanine significantly reduced the systolic blood pressure in a dose-dependent manner (223 mmHg in the high-salt controls vs 195 mmHg in the high-dose, high-salt group, p < 0.01). Cicletanine treatment did not affect plasma concentration of total cholesterol or triglyceride or free fatty acid; in contrast, it significantly decreased low-density lipoprotein (LDL) cholesterol and increased high-density lipoprotein (HDL) cholesterol. Morphological examination demonstrated that glomerulosclerosis in the kidney was significantly improved by 15% with high-dose cicletanine (p < 0.01). Multivariate analysis revealed that glomerular sclerosis was determined independently by LDL cholesterol levels and arterial injury score, but not by total cholesterol or HDL cholesterol levels or blood pressures. LDL cholesterol was also an independent predictor of urinary excretion of protein. Thus, it is suggested that cicletanine treatment lowers the levels of LDL cholesterol in Dahl salt-sensitive rats, and that besides blood pressure reduction, this decrease in LDL cholesterol level contributes, in part, to regression of glomerular injury in salt-induced hypertension.

Animals↗
PubMed1996

Adrenomedullin: changes in circulating and cardiac tissue concentration in Dahl salt-sensitive rats on a high-salt diet.

Adrenomedullin (AM), a novel hypotensive peptide, is suggested to be involved in defense mechanisms against hypertension, however, the detail mechanisms have not been clarified. To elucidate whether AM synthesis would be altered in a salt dependent hypertension, we have investigated the AM concentration and AM messenger RNA (mRNA) level in tissues of Dahl salt-sensitive rats on either low- or high-salt intake. The AM concentration in cardiac ventricle of the high-salt group was significantly higher than that of the low-salt group. The plasma AM concentration was also significantly higher in the high-salt group than in the low-salt group. Furthermore, the plasma AM concentration correlated well with the weight of left ventricle. RNA blot analysis revealed that the AM mRNA level in cardiac ventricle of the high-salt group was higher than that of the low-salt group. These results suggest that AM participates in the pathophysiology of salt dependent hypertension and plays a role in cardiac hypertrophy.

Adrenomedullin↗
PubMed1992

Sodium kinetics in salt-sensitive and salt-resistant normotensive and hypertensive subjects.

OBJECTIVE: To test the hypotheses that sodium kinetics are not affected by blood pressure, salt sensitivity, salt resistance or race, and that the kinetics of sodium balance are not a first-order process. DESIGN, PARTICIPANTS AND INTERVENTIONS: Two studies were conducted. In the first, 18 normotensive and 36 hypertensive men and women were given sodium at 120 mmol/day for 6 days, followed by 10 mmol/day for 8 days, then 400 mmol/day for 8 more days. Salt sensitivity was defined as an increase in diastolic blood pressure from the 10 to the 400 mmol/day intake. Salt resistance was defined as no increase, or a decrease in diastolic blood pressure with the increased sodium intake. In the second study, 12 white and 12 black normotensive men ingested sodium at 10, 200 or 400 mmol/day in random order, each for 7 days. All urine was collected in both protocols. SETTING: Metabolic ward at the University of Greifswald (Greifswald, Germany; study 1), and Clinical Research Center (Indiana University, Indianapolis, Indiana, USA; study 2). MAIN OUTCOME MEASURE: In addition to conventional statistics, a pharmacokinetic analysis was carried out to determine the elimination rate constant and half-life. RESULTS: In the Greifswald study, when the sodium intake was decreased, a longer half-life was determined for the salt-sensitive than the salt-resistant hypertensive subjects. The half-life for the normotensive salt-sensitive and salt-resistant subjects did not differ. When the sodium intake was decreased, a monoexponential equation fitted the data for all subjects; when the sodium intake was increased, only data for half the subjects could be fitted to the same equation. In the Indianapolis study, black race had a significant influence upon urinary sodium excretion. Furthermore, the half-life for sodium elimination was dependent upon sodium intake; namely, the greater the intake, the longer the elimination half-life. CONCLUSIONS: The time required to reach sodium balance may increase following salt-sensitive increases in blood pressure rather than precede them. Race influences the time required to achieve salt balance. Sodium kinetics are not a first-order process.

Adult↗
PubMed1987

Effect of alpha 1-adrenoceptor blockade on blood pressure and iliac vascular resistance in normotensive and Goldblatt hypertensive dogs; influence of dietary salt and DOCA-salt.

Instrumented normotensive and two-kidney, one clip Goldblatt hypertensive dogs were placed on normal salt, high salt and DOCA-salt regimens and the effect on mean arterial blood pressure (MAP) and iliac vascular resistance (IVR) determined. High salt and DOCA-salt did not alter these variables in the Goldblatt hypertensive group. DOCA-salt increased MAP in the normotensives by 12 mmHg; however, IVR was not significantly increased by this treatment. In order to determine the degree of sympathetic tone in the iliac vascular bed, the change in IVR evoked by the alpha 1-adrenoceptor antagonists, urapidil and prazosin, was assessed. There were similar reductions in MAP and IVR after alpha 1-blockade in both groups of dogs, regardless of the salt regimen. However, urapidil caused a greater decrease in MAP in the normotensives than in the hypertensives. Captopril administration after alpha 1-blockade caused further reductions in MAP and IVR in the hypertensives, and in the MAP of the normotensive dogs on normal or high salt, indicating that the renin-angiotensin system maintained blood pressure in these groups. These results suggest that sympathetic tone is not increased by high salt- or DOCA-salt in normotensive or Goldblatt hypertensive dogs for the 8-11 day duration of these treatments.

Adrenergic alpha-Antagonists↗
PubMed1995

[Role of renal thromboxane in salt-sensitive blood pressure rise in DOCA salt hypertension].

Urinary excretion and release of prostaglandins (PG) from isolated glomeruli and renal papilla of deoxycorticosterone acetate (DOCA)-treated rats fed with a normal salt (0.6% NaCl) diet and a high salt (4%NaCl) diet were determined. Mean blood pressure was significantly higher in the high salt diet group than in the normal salt diet group (146.2 +/- 2.3 vs 118.6 +/- 1.9 mmHg, p < 0.01). Urinary excretion of thromboxane (Tx) B2, stable metabolite of Tx A2, and 6-keto PG-F1 alpha, a stable metabolite of prostacyclin, increased significantly in the high salt diet group compared to the values of the normal salt diet group increased significantly by 104%, 55%, and 74% compared to those of the normal salt diet group, respectively. Release of 6-keto-PG F1 alpha from renal papilla of the high salt diet group decreased significantly, but there were no intergroup differences in the release of PG E2 and Tx B2. Stepwise multiple linear regression analysis showed that the significant contributory factors underlying the mean blood pressure were urinary excretion of Na (F = 14.187, p < 0.01) and release of Tx B2 from isolated glomeruli (F = 4.135, p < 0.05). These findings suggest that the manifestation of Tx synthesis in renal glomeruli has a predominant role in the salt sensitive pressor response of DOCA salt hypertension in rats.

Animals↗
PubMed1996

Adsorption of mixtures of bile salt taurine conjugates to lecithin-cholesterol membranes: implications for bile salt toxicity and cytoprotection.

Tauroursodeoxycholate (TUDC), a relatively hydrophilic bile salt, reduces disruption of cholesterol-rich membranes by more hydrophobic bile salts such as taurocholate (TC), taurochenodeoxycholate (TCDC), or taurodeoxycholate (TDC). We examined the interactions of these bile salts in adsorption to large unilamellar vesicles to determine whether TUDC may stabilize membranes by preventing adsorption of more toxic bile salts. Fractional adsorption was quantified by rapid ultrafiltration. Adsorption coefficient Ai was defined for each bile salt i as ([bound i]/[free i])/[lecithin]. Affinity of different bile salts for lecithin vesicles varied with their relative hydrophobicity, increasing in the order TUDC < TC << TCDC < or = TDC. Ai of each bile salt fell with its accumulation on membranes, reaching a minimum at bound bile salt/lecithin mole ratio (B:L) between 0.05 and 0.1, then increasing with formation of higher-affinity mixed micelles. Inclusion of cholesterol in vesicles reduced Ai of all bile salts. In heterologous binding studies at submicellar concentrations, Ai of each bile salt varied with total B:L but was independent of the specific bile salts present on the membrane. Addition of TUDC to TDC reduced binding of TDC to membranes only slightly and lowered the threshold TDC concentration associated with transition to mixed micelles. However, above this threshold, TUDC markedly altered the adsorption of TDC to lecithin-containing phases. We conclude that TUDC does not directly stabilize membranes; rather, reduced permeabilization and dissolution of cholesterol-rich membranes after addition of TUDC to TDC may result from effects on the formation and structure of simple and mixed micelles.

Adsorption↗
PubMed1997

[Threshold values of salt in instruction of salt-restricted diet for patients with heart disease].

The low-salt diet was basic means for therapeutic heart diseases. The salt threshold value represented individual's degree of salt taking or dietetic habit. The salt threshold value was measured in 60 patients with essential hypertension, 60 patients with congestive heart failure and 40 normal subjects. The salt threshold value revealed no significant difference in three groups (4.3% +/- 1.6%, 4.0% +/- 1.3% and 4.1% +/- 1.4%, P > 0.05). According to the salt threshold value, 120 patients were classed into three groups: high, middle and low salt threshold value group (n1 = 36, n2 = 74, n3 = 10). The patients were given selective and unitary low-salt diet with random before and after respectively. The results showed that acceptable level of patients to the diet in selective condition was significantly higher than that in unitary condition (81.7% vs 70.8%, P < 0.05). In conclusion, individualized selectivity restriction salt according to salt threshold value had advantage of no reducing appetite, patient's acceptance with ease and cooperative treatments.

Adolescent↗
PubMed1988

Effects of intestinal microbial bile salt sulfatase activity on bile salt kinetics in gnotobiotic rats.

Hepatic sulfation is thought to promote fecal excretion of lithocholate in humans by impairing the enterohepatic recirculation of the compound. Sulfatases produced by the gut flora may, at least in part, counteract this process. To investigate this interaction, female germfree rats, which are known to excrete considerable amounts of sulfated bile salts, were selectively associated with a bile salt desulfating flora. In these rats nearly all cecal, colonic, and fecal bile salt sulfate esters were hydrolyzed, resulting in a decrease of total fecal bile salt excretion of greater than 25% compared with gnotobiotic rats without a bile salt desulfating flora. Desulfation of allochenodeoxycholate, the major sulfated bile salt in germfree rats, led to an enhanced recirculation and 12 alpha-hydroxylation of the compound in the liver, resulting in an increased fecal output of allocholate. Microbial desulfation of intraperitoneally injected [24-14C]taurolithocholate-3-sulfate caused a fivefold decrease of the fecal plus urinary excretion rate of the isotope to approximately that found for unsulfated [24-14C]taurolithocholate. Coassociation of the gnotobiotic rats with a microflora that normalized the small intestinal transit time and cecal size led to a rise of total fecal bile salt excretion of greater than 30% and a twofold accelerated excretion of both sulfated and unsulfated injected [24-14C]taurolithocholate. We conclude that in rats the gut flora rapidly desulfates intestinal bile salt sulfates, enhancing the enterohepatic recirculation and subsequent hydroxylation of the desulfated bile salts. In addition, these data illustrate the importance of having a well-defined microflora to normalize intestinal transit time and cecal size of gnotobiotic animals when performing kinetic studies of enterohepatic circulating compounds.

Animals↗
PubMed1988

Adaptive regulation of hepatic bile salt transport. Effect of prolonged bile salt depletion in the rat.

Exposure of the liver to increased bile salt flux can increase the bile salt maximum secretory rate (SRm), presumably through the induction of new transport sites. The converse, i.e., the down-regulation of SRm upon bile salt deprivation, has not been demonstrated. We examined the effects of bile salt depletion for 24 h and 48 h on taurocholate SRm and bromsulphalein (BSP) SRm, and on [14C]taurocholate binding to isolated liver surface membranes in unrestrained external biliary fistula rats. Taurocholate SRm was significantly decreased by 35% and 51% in 24-h-depleted and 48-h-depleted rats, respectively, compared with control, sham-operated rats. Maximal taurocholate concentration in bile was also significantly lower in bile salt-deprived rats. In contrast, BSP SRm was not significantly different between depleted animals and controls. Bile salt depletion for 24 h and 48 h did not significantly alter liver surface membrane protein recovery and membrane enzyme specific activity, including Na+ + K+-ATPase. Specific [14C]taurocholate binding to liver surface membranes was significantly decreased by 25% in 24-h-depleted rats compared with control rats. In contrast to taurocholate SRm, bile salt depletion for 48 h did not result in further reduction of specific taurocholate binding sites. This study demonstrates that taurocholate SRm progressively decreased in 24-h- and 48-h-bile salt-depleted rats, this being consistent with adaptive down-regulation of hepatic bile salt transport.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1998

Bile salt hydrophobicity modulates subselection of biliary lecithin species in rats depleted of bile salt pool.

Although bile salts play an important role in the secretion of biliary lipid, little is known about the relationship between bile salt hydrophobicity and the selection of lecithin species to be secreted into bile. We therefore investigated whether bile salts modulate the selection of biliary lecithin subspecies. Rats that were depleted of the bile salt pool were infused with taurocholate (50, 100, 200, and 400 nmol/min/100 g body weight), taurochenodeoxycholate (25, 50, 100, and 200 nmol/min/100 g body weight), tauroursodeoxycholate (100, 200, 400, and 800 nmol/min/100 g body weight), or taurobetamuricholate (100, 200, 400, and 800 nmol/min/100 g body weight). Bile was collected to analyze bile flow, bile acid output, cholesterol levels, and lecithin levels. The hydrophobic-hydrophilic balance of the bile salts and biliary lecithin species was assessed by determining the retention times during reverse-phase high-performance liquid chromatography. Biliary lecithin secretion rates correlated with the hydrophobicity index of the biliary bile salts administered. Thus, biliary lecithin hydrophobicity increased with increasing bile salt hydrophobicity, whereas the molar cholesterol-lecithin ratio in the bile decreased. In conclusion, bile salt hydrophobicity regulates the selection of biliary lecithin subspecies during biliary secretion and thereby modulates, at least in part, bile cholesterol metastability. Thus, bile salt hydrophobicity accounts for the physicochemical conditions determining bile lipid metastability.

Animals↗
PubMed2000

Importance of arginines 63 and 423 in modulating the bile salt-dependent and bile salt-independent hydrolytic activities of rat carboxyl ester lipase.

Previous studies using chemical modification approach have shown the importance of arginine residues in bile salt activation of carboxyl ester lipase (CEL) activity. However, the x-ray crystal structure of CEL failed to show the involvement of arginine residues in CEL-bile salt interaction. The current study used a site-specific mutagenesis approach to determine the role of arginine residues 63 and 423 in bile salt-dependent and bile salt-independent hydrolytic activities of rat CEL. Mutations of Arg(63) to Ala(63) (R63A) and Arg(423) to Gly(423) (R423G) resulted in enzymes with increased bile salt-independent hydrolytic activity against lysophosphatidylcholine, having 6.5- and 2-fold higher k(cat) values, respectively, in comparison to wild type CEL. In contrast, the R63A and R423A mutant enzymes displayed 5- and 11-fold decreases in k(cat), in comparison with wild type CEL, for bile salt-dependent cholesteryl ester hydrolysis. Although taurocholate induced similar changes in circular dichroism spectra for wild type, R63A, and R423G proteins, this bile salt was less efficient in protecting the mutant enzymes against thermal inactivation in comparison with control CEL. Lipid binding studies revealed less R63A and R423G mutant CEL were bound to 1,2-diolein monolayer at saturation compared with wild type CEL. These results, along with computer modeling of the CEL protein, indicated that Arg(63) and Arg(423) are not involved directly with monomeric bile salt binding. However, these residues participate in micellar bile salt modulation of CEL enzymatic activity through intramolecular hydrogen bonding with the C-terminal domain. These residues are also important, probably through similar intramolecular hydrogen bond formation, in stabilizing the enzyme in solution and at the lipid-water interface.

Animals↗
PubMedDate not supplied

Hydrophilic bile salts and liposomes inhibit hydrophobic bile salt-induced release of glycoprotein by guinea-pig gall-bladder.

Bile salts can be cytotoxic to mucosal surfaces, because of their detergent properties. This is not normally seen under physiological circumstances in the gall-bladder. To further study normal mucosal defence mechanisms, the present study was performed to examine the effects of liposomes and hydrophilic bile salts on hydrophobic bile salt-induced release of radiolabelled glycoproteins from explants of guinea-pig gall-bladder. Glycoprotein release was correlated with the degree of hydrophobicity of bile salts, as determined by the retention factor in reversed-phase high-performance liquid chromatography. Hydrophobic bile salt-induced release of glycoproteins was reduced by liposomes and hydrophilic bile salts. The inhibitory effect of liposomes was directly related to the degree of saturation of their fatty acyl chains, and that of hydrophilic bile salts was related to the degree of hydrophilicity. These findings suggest that vesicles and hydrophilic bile salts may play a cytoprotective role against membrane damage passively caused by hydrophobic bile salts in the biliary system, and that such damage may occur according to the quantitative and qualitative imbalance among these factors.

Animals↗