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PubMed1997

Hpa II polymorphism of the atrial natriuretic peptide gene and the blood pressure response to salt intake in normotensive men.

OBJECTIVE: To test the hypothesis that the Hpa II variant of the atrial natriuretic peptide gene (ANP), which has been reported to be more common among black hypertensives than it is among normotensive controls, is related to the response of blood pressure to salt intake in normotensive Caucasians. METHODS: One hundred and three young (aged 19-35 years) male volunteers were fed a low-salt diet (20 mmol NaCl/day) for 2 weeks and a supplement of either 200 mmol NaCl/day (slow sodium) or placebo for 1 week each in a randomized double-blind cross-over order. Salt sensitivity was defined as a significant (P < 0.05) decrease in resting mean arterial blood pressure by > 3 mmHg under the low-salt diet. The genotype was determined by amplification of genomic DNA extracted from peripheral leukocytes and subsequent digestion of the amplicon with Hpa II restriction enzyme. RESULTS: According to the above definition, 27 subjects were salt sensitive. There were no significant differences in age, body-mass index and waist:hip ratio between the salt-sensitive and salt-resistant groups. Only salt-sensitive subjects displayed a significantly higher blood pressure under the high-salt diet (increase in mean arterial pressure 5.6 +/- 2.4 mmHg, P < 0.001). The prevalence of the ANP-Hpa II wild-type (w) allele did not differ between the salt-sensitive (qw = 1.0, qm = 0) and the salt-resistant group (qw = 0.96, qm = 0.04). Furthermore, the salt-induced response of blood pressure did not differ between homozygotes (ww) and heterozygotes (wm). CONCLUSIONS: Our findings do not support the hypothesis that the ANP-Hpa II polymorphism is a marker for salt sensitivity in young Caucasian normotensives.

Adult↗

PubMed1974

The regulation of corneal hydration by a salt pump requiring the presence of sodium and bicarbonate ions.

1. The use of polyacrylamide gel salt bridges enables trans-membrane potentials to be measured to an accuracy of 20 muV over long periods.2. The technique is applied to measure electrical potentials across corneal endothelia of rabbits.3. In de-epithelialized corneas which translocate water, a spontaneous potential of 550 muV is found across the endothelium (tissue resistance 20 Omega cm(2)).4. This electrical potential (and water translocation) is reduced to zero when sodium is absent from the Ringer, and by about 80% when bicarbonate ions are absent. Removal of chloride has no such effect.5. Under a variety of conditions, the potential correlates with the observed translocation of fluid across corneal endothelium. The translocated fluid is shown to be isotonic with sodium in the Ringer and therefore the potential correlates with ;active' sodium transport.6. The potential and water translocation are abolished in the presence of ouabain at concentrations greater than 10(-5)M.7. The potential (lens-side negative) is of the wrong polarity to explain the net sodium transport (into the lens-side) by a sodium ion ;pump'.8. The current does not equal the net sodium flux under short circuit conditions. They differ in magnitude and polarity.9. A model is proposed where the endothelium ;pumps' salt out of the corneal stroma into the aqueous humour.10. Flux equations are derived for a condition where the membrane (corneal endothelium) separates an ion exchanger (corneal stroma) from free solution (aqueous humour), where the usual relationship for free-free solutions Deltapi = c(s)Deltamu(s) does not apply.11. The model is of use only when the stroma is well stirred. It may be used in whole corneas retaining their epithelium but it may not be used in de-epithelialized corneas.12. The model predicts that the presence of an ;active' salt flux out across the endothelium would create passive water and salt fluxes. The passive water flux would also travel out of the stroma across the endothelium; the passive salt flux would travel, in the opposite direction, into the stroma across the endothelium.13. The kinetics of the passive water efflux, as a swollen cornea reverts to physiological hydration (the temperature reversal phenomenon) are predicted extremely well if the ;active' salt flux is chosen at 3.3 x 10(-7) m-mole. cm(-2) sec(-1).14. The value of the active salt flux which cannot be measured directly is extrapolated to be somewhat greater than 2.8 x 10(-7) m-moles. cm(-2) sec(-1); in good agreement with that required by the model to explain the temperature reversal phenomenon.15. The model is further used to calculate the salt concentration difference across the endothelium (which drives salt passively into the stroma) at various stromal hydrations.16. When an appropriate salt concentration is applied across the endothelium of de-epithelialized cornea, it generates a potential of the same polarity and similar magnitude to that found across the endothelium of equilibrated whole cornea. The endothelium acts like a cation exchange membrane.17. Additionally the calculated salt concentration difference across the endothelium correlates well with the measured transendothelial potentials in whole cornea as the corneal hydration varies.18. It is concluded that the model of an endothelial neutral salt ;pump' regulating corneal hydration is self consistent. The spontaneous potential found across the endothelium could be caused by the consequential passive flux of salt in the opposite direction.

Journal Article↗

PubMed2002

High salt intake impairs vascular nitric oxide/cyclic guanosine monophosphate system in spontaneously hypertensive rats.

In aortas of spontaneously hypertensive rats (SHRs), excessive dietary salt causes down-regulation of soluble guanylate cyclase (sGC) followed by decreased cyclic GMP production, which leads to impairment of the vascular relaxation response to nitric oxide (NO). The present study aimed to elucidate whether this impaired NO/cyclic GMP system results secondarily from increased blood pressure or from an effect of the salt itself. The antihypertensive drug nifedipine was used on 4-week-old SHRs that received a normal-salt diet or a high-salt diet for 4 weeks. Treatment with nifedipine (30 mg/kg/day, p.o.) reduced the increased blood pressure of SHRs fed the high-salt diet to the level of SHRs fed the normal-salt diet. In aortic rings from SHRs fed the high-salt diet, not only endothelium-dependent relaxations but also endothelium-independent relaxations were significantly impaired. However, these impairments were not alleviated by treatment with nifedipine. Furthermore, nifedipine did not prevent the increase in protein levels of endothelial NO synthase and the decrease in the protein levels of sGC in aortas from SHRs fed the high-salt diet. These alterations by high salt intake were restored after replacement with the normal-salt diet for 4 additional weeks. These results indicate that in SHRs given excessive dietary salt, normalization of salt intake but not blood pressure reduction can ameliorate alterations in the NO/cyclic GMP system. High salt intake may directly affect the vascular smooth muscle and cause impairment of the relaxation response to NO.

Animals↗

PubMed1991

Quantitative skin prick and bronchial provocation tests with platinum salt.

Occupational asthma due to platinum salts is a frequent disease in platinum refineries. The diagnosis is based upon a history of work related symptoms and a positive skin prick test with platinum salts. Bronchial provocation tests have not been performed in epidemiological studies because the skin test is believed to be highly specific and sensitive. As no reliable data about this issue currently exist, this study assesses the use of skin prick and bronchial provocation tests with methacholine and platinum salt in platinum refinery workers. Twenty seven of 35 workers, who were referred to our clinic with work related symptoms and nine control subjects with bronchial hyperreactivity underwent a skin prick test and bronchial provocation with methacholine and platinum salt. For skin prick and bronchial provocation tests with platinum salt a 10(-2)-10(-8) mol/l hexachloroplatinic acid solution, in 10-fold dilutions was used. Four of the 27 subjects and all controls showed neither a bronchial reaction nor a skin reaction. Twenty three subjects were considered allergic to platinum salt; 22 of these showed a fall of 50% or more in specific airway conductance after inhalation of the platinum salt solution. Four workers experienced a positive bronchial reaction despite a negative skin prick test. No correlation of responsiveness to methacholine with responsiveness to platinum salt was found, but the skin prick test correlated with the bronchial reaction to platinum salt (rs = 0.50, p less than 0.023, n = 22). One dual reaction was seen in bronchial provocation tests. Side effects of both skin tests and bronchial provocation tests with platinum salt were rare and were not encountered in workers without a skin reaction to platinum salt. It is concluded that bronchial provocation tests with platinum salts should be performed on workers with work related symptoms but negative skin tests with platinum salts.

Adult↗

PubMed2006

Salt loading produces severe renal hemodynamic dysfunction independent of arterial pressure in spontaneously hypertensive rats.

We have previously shown that salt excess has adverse cardiac effects in spontaneously hypertensive rats (SHR), independent of its increased arterial pressure; however, the renal effects have not been reported. In the present study we evaluated the role of three levels of salt loading in SHR on renal function, systemic and renal hemodynamics, and glomerular dynamics. At 8 wk of age, rats were given a 4% (n = 11), 6% (n = 9), or 8% (n = 11) salt-load diet for the ensuing 8 wk; control rats (n = 11) received standard chow (0.6% NaCl). Rats had weekly 24-h proteinuria and albuminuria quantified. At the end of salt loading, all rats had systemic and renal hemodynamics measured; glomerular dynamics were specially studied by renal micropuncture in the control, 4% and 6% salt-loaded rats. Proteinuria and albuminuria progressively increased by the second week of salt loading in the 6% and 8% salt-loaded rats. Mean arterial pressure increased minimally, and glomerular filtration rate decreased in all salt-loaded rats. The 6% and 8% salt-loaded rats demonstrated decreased renal plasma flow and increased renal vascular resistance and serum creatinine concentration. Furthermore, 4% and 6% salt-loaded rats had diminished single-nephron plasma flow and increased afferent and efferent arteriolar resistances; glomerular hydrostatic pressure also increased in the 6% salt-loaded rats. In conclusion, dietary salt loading as low as 4% dramatically deteriorated renal function, renal hemodynamics, and glomerular dynamics in SHR independent of a minimal further increase in arterial pressure. These findings support the concept of a strong independent causal relationship between salt excess and cardiovascular and renal injury.

Albuminuria↗

PubMed2003

Effects of high salt intake on brain AT1 receptor densities in Dahl rats.

To assess effects of dietary salt on brain AT1 receptor densities, 4-wk-old Dahl salt-sensitive (Dahl S) and salt-resistant (Dahl R) rats were fed a regular (101 mumol Na/g) or high (1,370 mumol Na/g)-salt diet for 1, 2, or 4 wk. AT1 receptors were assessed by quantitative in vitro autoradiography. AT1 receptor densities did not differ significantly between strains on the regular salt diet. The high-salt diet for 1 or 2 wk increased AT1 receptor binding by 21-64% in the Dahl S rats in the subfornical organ, median preoptic nucleus, paraventricular nucleus, and suprachiasmatic nucleus. No changes were noted in the Dahl R rats. After 4 wk on a high-salt diet, increases in AT1 receptor binding persisted in Dahl S rats but were now also noted in the paraventricular nucleus, median preoptic nucleus, and suprachiasmatic nucleus of Dahl R rats. At 4 wk on the diet, intracerebroventricular captopril caused clear decreases in blood pressure only in the Dahl S on the high-salt diet but caused largely similar relative increases in brain AT1 receptor densities in Dahl S and R on the high-salt diet versus regular salt diet. These data demonstrate that high salt intake rapidly (within 1 wk) increases AT1 receptor densities in specific brain nuclei in Dahl S and later (by 4 wk) also in Dahl R rats. Because the brain renin-angiotensin system only contributes to salt-induced hypertension in Dahl S rats, further studies are needed to determine which of the salt-induced increases in brain AT1 receptor densities contribute to the hypertension and which to other aspects of body homeostasis.

Animals↗

PubMed1996

High-salt diet upregulates kininogen and downregulates tissue kallikrein expression in Dahl-SS and SHR rats.

Tissue kallikrein cleaves low-molecular-weight (low-M(r)) kininogen to produce the vasoactive kinin peptide. It has been suggested that hypertensive patients with low urinary kallikrein excretion may have a defect in sodium handling. In this study, we examined the effect of a high-salt diet on the expression of tissue kallikrein and kininogen genes in Dahl salt-sensitive rats (Dahl-SS), spontaneously hypertensive rats (SHR), and normotensive Sprague-Dawley rats (SD) by Northern and Western blot analysis and radioimmunoassay. Control and experimental groups received normal and high-salt diets containing 0.4% and 8% NaCl, respectively, for 6 wk. High-salt diet induced a significant time-dependent increase of blood pressure in both strains of hypertensive rats and a slight but significant increase of blood pressure in normotensive SD rats. Hepatic kininogen mRNA levels of both Dahl-SS and SHR on a high-salt diet increased 2.4-fold and 2.0-fold, respectively, while alpha 1-antitrypsin mRNA levels were not changed in rats receiving high-salt diet. Immunoreactive total kininogen and low-M(r) kininogen (58 kDa) levels in sera increased in response to high-salt diet in both strains of hypertensive rats. In SD rats, the low-M(r) kininogen level in sera was unaltered, whereas total kininogen increased in response to high-salt diet. Tissue kallikrein mRNAs in the kidney and salivary glands of Dahl-SS, SHR, and SD rats were reduced, whereas beta-actin mRNA was not altered by high-salt diet. Similarly, immunoreactive intrarenal kallikrein levels were reduced in these rats in response to high-salt diet. These studies show that increases in blood pressure after salt loading in Dahl-SS and SHR are accompanied by increases in low-M(r) kininogen. Tissue kallikrein gene expression in hypertensive Dahl-SS and SHR and normotensive SD rats is suppressed after salt loading. These findings show that reduced renal kallikrein expression and increased kininogen expression is regulated at the transcriptional level during salt loading.

Animals↗

PubMed1999

Renal arteriolar Na+/Ca2+ exchange in salt-sensitive hypertension.

The present studies were performed to assess Na+/Ca2+ exchange activity in afferent and efferent arterioles from Dahl/Rapp salt-resistant (R) and salt-sensitive (S) rats. Renal arterioles were obtained by microdissection from S and R rats on either a low-salt (0.3% NaCl) or high-salt (8.0% NaCl) diet. On the high-salt diet, S rats become markedly hypertensive. Cytosolic calcium concentration ([Ca2+]i) was measured in fura 2-loaded arterioles bathed in a Ringer solution in which extracellular Na (Nae) was varied from 150 to 2 mM (Na was replaced with N-methyl-D-glucamine). Baseline [Ca2+]i was similar in afferent arterioles of R and S rats fed low- and high-salt diet. The change in [Ca2+]i (Delta[Ca2+]i) during reduction in Nae from 150 to 2 mM was 80 +/- 10 and 61 +/- 3 nM (not significant) in afferent arterioles from R rats fed the low- and high-salt diet, respectively. In afferent arterioles from S rats on a high-salt diet, Delta[Ca2+]i during reductions in Nae from 150 to 2 mM was attenuated (39 +/- 4 nM) relative to the Delta[Ca2+]i of 79 +/- 13 nM (P < 0.05) obtained in afferent arterioles from S rats on a low-salt diet. In efferent arterioles, baseline [Ca2+]i was similar in R and S rats fed low- and high-salt diets, and Delta[Ca2+]i in response to reduction in Nae was also not different in efferent arterioles from R and S rats fed low- or high-salt diets. Differences in regulation of the exchanger in afferent arterioles of S and R rats were assessed by determining the effects of protein kinase C (PKC) activation by phorbol 12-myristate 13-acetate (PMA, 100 nM) on Delta[Ca2+]i in response to reductions in Nae from 150 to 2 mM. PMA increased Delta[Ca2+]i in afferent arterioles from R rats but not from S rats. These results suggest that Na+/Ca2+ exchange activity is suppressed in afferent arterioles of S rats that are on a high-salt diet. In addition, there appears to be a defect in the PKC-Na+/Ca2+ exchange pathway that might contribute to altered [Ca2+]i regulation in this important renal vascular segment in salt-sensitive hypertension.

Animals↗

PubMed2006

Deoxycorticosterone acetate-salt rats: hypertension and sympathoexcitation driven by increased NaCl levels.

Using deoxycorticosterone acetate (DOCA)-salt rats, we tested the hypothesis that increased plasma NaCl concentration supports sympathetic activity and blood pressure (BP) during salt-sensitive hypertension. One day before experimentation, femoral catheters and an electrode for measurement of lumbar sympathetic nerve activity (LSNA) probe were surgically positioned in DOCA-salt and Sham-salt rats. DOCA-salt rats exhibited increased (P<0.05) BP and NaCl concentration (BP, 163+/-8 mm Hg; NaCl, 260.8+/-3.3 mEq/L [DOCA-salt]: BP, 106.3+/-4.2 mm Hg; NaCl, 254.3+/-1.7 mEq/L [Sham-salt]). After V1 vasopressin blockade (Manning compound, 5 microg IV), infusion (0.12 mL/min) of 5% dextrose in water decreased NaCl concentrations, BP (-28+/-7 mm Hg), and LSNA (-39+/-5%) in DOCA-salt but not Sham-salt rats. To explain how such small (approximately 2%) increases in plasma NaCl could underlie the hypertension, we hypothesized that DOCA augments the pressor and sympathoexcitatory actions of NaCl. To address this hypothesis, animals with equally elevated NaCl but no DOCA (Sham-1.7% salt) and animals with increased DOCA but normal NaCl levels (DOCA-water) were prepared and administered the infusion of 5% dextrose in water. BP and LSNA were not altered in DOCA-water rats. In the Sham-1.7% salt rats, BP fell (P<0.05), but not LSNA, and the responses were significantly smaller than that observed in the DOCA-salt animals. Collectively, these data suggest that increased NaCl levels contribute to sympathoexcitation and hypertension in DOCA-salt rats because of amplification of the NaCl signal by DOCA.

Animals↗

PubMed2006

Surgical menopause increases salt sensitivity of blood pressure.

Salt sensitivity of blood pressure is associated with an elevated risk of developing hypertension (HTN) and is an independent risk factor for cardiovascular disease. The prevalence of HTN increases after menopause. The aim of this study was to investigate prospectively whether the loss of ovarian hormones increases the occurrence of salt sensitivity among healthy premenopausal women. We enrolled 40 normotensive, nondiabetic women (age 47.2+/-3.5), undergoing hysterectomy-oophorectomy for nonneoplastic processes and not on hormone replacement, to determine the effect of changes in sodium intake on blood pressure the day before and subsequently 4 months after surgical menopause. Salt loading was achieved using a 2-L normal saline infusion and salt depletion produced by 40 mg of intravenous furosemide. A decrease >10 mm Hg in systolic blood pressure between salt loading and salt depletion was used to define salt sensitivity. Before and after menopause, salt-sensitive women exhibited higher waist/hip and waist/thigh ratios (P<0.01). Although all of the women remained normotensive, the prevalence of salt sensitivity was significantly higher after surgical menopause (21 women; 52.5%) than before (9 women; 22.5%; P=0.01), because 12 (38.7%) salt-resistant women developed salt sensitivity after menopause. In summary, we demonstrated that the prevalence of salt sensitivity doubled as early as 4 months after surgical menopause, without an associated increase in blood pressure. Epidemiological studies indicate that development of HTN may not occur until 5 to 10 years after menopause. The loss of ovarian hormones may unmask a population of women prone to salt sensitivity who, with aging, would be at higher risk for the subsequent development of HTN and cardiovascular disease.

Blood Pressure↗

PubMed1992

Beneficial effects of a potassium- and magnesium-enriched salt alternative.

The effects on blood pressure and the development of cardiac hypertrophy of sodium chloride (regular salt) and a novel potassium-, magnesium-, and l-lysine-enriched salt alternative, which in a previous study prolonged the life span of hypertensive rats nearly threefold as compared with the animals receiving regular salt, were compared both in spontaneously hypertensive rats and their hypertension-resistant genetic controls. In particular, the possible protective effect of increased intakes of potassium, magnesium, and l-lysine during a high intake of sodium chloride was examined. Therefore, the salt alternative was added at 1.75 times higher levels to produce the same dietary levels of sodium chloride in the regular salt and the salt alternative groups. Regular salt produced a remarkable left ventricular hypertrophy in both rat strains, but as compared with the respective control groups, it induced an increase of blood pressure only in the spontaneously hypertensive rats. The salt alternative did not induce a rise in blood pressure in either of the rat strains, nor did it produce left ventricular hypertrophy in the hypertension-resistant rats and, in the spontaneously hypertensive animals, significantly less hypertrophy than regular salt. The salt alternative appeared to prevent the sodium chloride-induced volume load since plasma levels of atrial natriuretic peptide were increased in the regular salt groups but remained normal in the salt alternative groups. Therefore, potassium, magnesium, and/or l-lysine of the salt alternative produced a powerful protection against the harmful effects of sodium chloride.

Analysis of Variance↗

PubMed1994

Renal apical membrane sodium-hydrogen exchange in genetic salt-sensitive hypertension.

Inbred Dahl/Rapp salt-sensitive and salt-resistant rats differ in their blood pressure response to dietary salt. We studied sodium-hydrogen (Na-H) exchanger kinetics in renal brush border membrane vesicles prepared from both strains on either a 1% or 8% NaCl diet. Kinetics measurements were made with the acridine orange fluorescence quenching technique in vesicles prepared at pH 6.0. The initial Na-H exchange rate was measured using preparations with similar initial quench values. The maximal transport rate (Vmax, fluorescence units per second per milligram protein [+/- SEM]) in salt-sensitive rats on a 1% NaCl diet was significantly lower than that in salt-resistant rats (36.9 +/- 4.4 versus 51.8 +/- 5.5, respectively, P < .0005). With the 8% NaCl diet for 1 week, the Vmax of salt-resistant rats decreased and became similar to that of salt-sensitive rats. The affinity for sodium (Km, millimoles per liter [+/- SEM]) was also lower in salt-sensitive rats than in salt-resistant rats while on a 1% NaCl diet (11.8 +/- 1.0 versus 19.6 +/- 2.3, respectively, P < .002). These values converged when both strains were fed an 8% NaCl diet for 1 week. Inhibition by 25 mumol/L amiloride was less in salt-sensitive rats than in salt-resistant rats on the 1% NaCl diet. These results show that salt-sensitive rats have lower renal apical membrane Na-H exchange activity than salt-resistant rats on a 1% NaCl diet.(ABSTRACT TRUNCATED AT 250 WORDS)

Amiloride↗

PubMed1995

Renal vasodilation with L-arginine. Effects of dietary salt.

Infusion of L-arginine, the substrate for nitric oxide synthase, causes renal vasodilation. Since dietary salt restriction blunts the renal vasoconstrictor response to inhibition of nitric oxide synthase, we investigated the hypothesis that dietary salt intake determines the renal vascular response to L-arginine. Bolus intravenous doses of L-arginine given to anesthetized Sprague-Dawley rats caused dose-dependent increases in renal blood flow and decreases in renal vascular resistance, whereas D-arginine was not effective. The response to L-arginine was prevented by pretreatment with NG-nitro-L-arginine methyl ester. Compared with rats adapted to a high salt diet, those adapted to a low salt diet were more sensitive to the reductions in blood pressure and renal vascular resistance (threshold dose of L-arginine for renal vascular resistance: low salt, 2.9 +/- 0.9 mumol . kg-1 versus high salt, 20.0 +/- 6.2; P < .025), but the maximal changes in renal vascular resistance were similar (low salt, -43 +/- 5% versus high salt, -34 +/- 5%; P = NS). Bolus doses of L-glycine also caused dose-dependent renal vasodilation, but the renal vasodilator responses were not affected by salt intake. Preinfusion of L-arginine augmented the renal vasoconstrictor response to NG-nitro-L-arginine methyl ester in low salt but not high salt rats; after L-arginine dietary salt no longer significantly affected the renal vasoconstrictor response to NG-nitro-L-arginine methyl ester. In conclusion, renal vasodilation is more sensitive to L-arginine during salt restriction. This effect is specific for L-arginine.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1999

Renal intramedullary infusion of L-arginine prevents reduction of medullary blood flow and hypertension in Dahl salt-sensitive rats.

A role for reduced renal nitric oxide production has been proposed as a mechanism responsible for hypertension in Dahl "salt-sensitive" rats. The present study had 2 goals: first, to determine the relationship between changes in mean arterial pressure and renal cortical and medullary blood flows in unanesthetized Dahl/Rapp salt-sensitive (S) and Dahl/Rapp salt-resistant (R) rats as daily salt intake was increased from 0.4% to 4.0%; second, to determine if delivery of L- or D-arginine into the renal medulla of Dahl S rats would change the responses to high salt. Optical fibers were implanted into the renal cortex and inner medulla for daily recording of cortical and medullary blood flows using laser-Doppler flowmetry. Indwelling aortic catheters were used to record arterial pressure. Increasing salt intake to 4.0% in Dahl S rats increased mean arterial pressure from 128+/-2.0 to 155+/-5.0 mm Hg by day 5 of high salt diet; medullary blood flow was reduced 13% by day 2, 24% by day 3 (P<0.05), and 31% by day 5 (P<0.05), whereas cortical blood flow was unchanged. In Dahl R rats, mean arterial pressure averaged 117+/-5 mm Hg during the 0.4% salt control period and remained unchanged (as did cortical and medullary blood flows) during 5 days of 4.0% salt intake. Dahl S rats that received medullary L-arginine (300 microg. kg-1. min-1) exhibited no changes of mean arterial pressure or regional renal blood flow during the 5 days of 4.0% salt intake. Medullary infusion of D-arginine (300 microg. kg-1. min-1) did not prevent the development of hypertension in Dahl S rats that received 4.0% salt. The results are consistent with the view that Dahl S rats have a reduced capacity to generate nitric oxide within the renal medulla under conditions of high salt, which the administration of L-arginine can normalize. Furthermore, early reductions of medullary blood flow in Dahl S rats with high salt intake probably contribute to the development of hypertension.

Animals↗

PubMed1999

Pathophysiological roles of endothelin-1 in Dahl salt-sensitive hypertension.

The purpose of the present experiment was to study the pathophysiological roles of endothelin-1 (ET-1) in salt-sensitive hypertension with the use of Dahl salt-sensitive (DS) and salt-resistant (DR) rats. PreproET-1 mRNA expression was determined by reverse transcription-polymerase chain reaction. In the kidney, expression of preproET-1 mRNA was greater in DS rats on a normal salt diet compared with DR rats of the same age. In DS rats, the level of preproET-1 mRNA expression in kidney had a significant correlation with systolic blood pressure. The expression of preproET-1 mRNA in aorta and kidney was increased by 3-week high salt intake in DS rats but not in DR rats. Expression of preproET-1 mRNA and ET-1 levels in left ventricle was exaggerated by high salt intake in DS rats. However, there was no significant difference in plasma ET-1 levels between DS and DR rats regardless of salt intake. Pressor response curves for ET-1 in DS rats with or without high salt intake were significantly shifted to the left compared with those in DR rats. A single oral dose (3 to 10 mg/kg) of J-104132 (L-753 037), a potent, orally active mixed endothelin A and B (ET(A)/ET(B)) receptor antagonist, reduced blood pressure to normotensive levels in DS rats with high salt intake, and its action was maintained for >/=24 hours. In DS rats with normal salt intake, J-104132 (10 mg/kg) slightly but significantly decreased blood pressure. DR rats did not show obvious depressor responses to J-104132 (10 mg/kg) regardless of salt intake. These results suggest that ET-1 acts as one of the pathophysiological factors in the development and maintenance of salt-sensitive hypertension, and a mixed ET(A)/ET(B) receptor antagonist could be useful in the treatment for salt-sensitive hypertension.

Animals↗

PubMed2000

Renin-angiotensin system genetic polymorphisms and salt sensitivity in essential hypertension.

We evaluated the association between salt-sensitive hypertension and 3 different genetic polymorphisms of the renin-angiotensin system. Fifty patients with essential hypertension were classified as salt sensitive or salt resistant, depending on the presence or absence of a significant increase (P<0.05) in 24-hour ambulatory mean blood pressure (BP) after high salt intake. The insertion/deletion (I/D) angiotensin-converting enzyme (ACE) gene, the M235T angiotensinogen (AGT) gene, and the A1166C angiotensin II type 1 (AT1) receptor gene polymorphisms were determined with the use of standard polymerase chain reaction methods. Twenty-four (48%) patients with significantly increased (P<0.05) 24-hour mean BP with high salt intake (from 107.3+/-9.4 to 114.8+/-10.6 mm Hg) were classified as salt sensitive. In the remaining 26 patients (52%), high salt intake did not significantly modify 24-hour mean BP (from 107.6+/-10 to 107. 8+/-9 mm Hg), and they were classified as having salt-resistant hypertension. We did not find any significant association between either M235T AGT or A1166C AT1 receptor genotypes and the BP response to high salt intake. However, patients with essential hypertension homozygous for the insertion allele of the ACE gene (II) had a significantly higher BP increase with high salt intake (9. 8+/-8.1 mm Hg for systolic BP and 5.2+/-4.2 mm Hg for diastolic BP) than that observed in patients homozygous for the deletion allele (DD) (1.2+/-5.9 mm Hg for systolic BP; P=0.0118 and -0.2+/-4.2 mm Hg for diastolic BP; P=0.0274). Heterozygous patients (ID) exhibited an intermediate response. The prevalence of salt-sensitive hypertension also was significantly higher (P=0.012) in II (67%) and DI patients (62%) compared with DD hypertensives (19%). We conclude that a significant association exists between the I/D polymorphism of the ACE gene and salt-sensitive hypertension. Patients with II and DI genotypes have significantly higher prevalence of salt sensitivity than DD hypertensives.

Adult↗

PubMed2001

Endothelial dysfunction in salt-sensitive essential hypertension.

The aim of this study was to evaluate endothelium-dependent and -independent vasodilation, as well as endothelium biochemical markers, in a group of essential hypertensive patients classified on the basis of salt sensitivity. Changes in forearm blood flow in response to acetylcholine, sodium nitroprusside, and N(G)-monomethyl-L-arginine (L-NMMA) infusion were determined by means of strain-gauge plethysmography. Moreover, plasma and urinary concentrations of nitrates, cGMP, and endothelin were measured during low (50 mmol/d) and high (250 mmol/d) salt intake. Salt-sensitive hypertension was diagnosed in 26 patients who exhibited a significant increase in 24-hour mean blood pressure assessed by ambulatory blood pressure monitoring after 1 week of high salt intake. Nineteen patients were considered salt resistant. Compared with salt-resistant hypertensives, salt-sensitive patients presented a significant lower (P=0.005) maximal acetylcholine-induced vasodilation (21+/-6.3 versus 28+/-7.5 mL. 100 mL(-1). tissue. min(-1)). On the contrary, maximal sodium nitroprusside-induced vasodilation did not significantly differ between groups (22.4+/-4.5 versus 23.9+/-5.3 mL. 100 mL(-1). tissue. min(-1)). The decrease in maximal acetylcholine-induced vasodilation promoted by the coadministration of L-NMMA was significantly more pronounced in salt-resistant compared with salt-sensitive patients (P=0.003). Finally, high salt intake promoted a significant decrease in 24-hour urinary nitrate excretion in salt-sensitive patients (from 443+/-54 to 312+/-54 micromol/d; P=0.033) compared with salt-resistant hypertensives (from 341+/-50 to 378+/-54 micromol/d). We conclude that salt-sensitive hypertension is associated with endothelial dysfunction characterized by a defective endothelium-dependent vasodilation. Impairment of the L-arginine-nitric oxide pathway may be responsible for this abnormal endothelial response.

Acetylcholine↗

PubMed1984

Mechanism of impaired baroreflex control in prehypertensive Dahl salt-sensitive rats.

Dahl salt-sensitive rats fed a low salt diet demonstrate functional impairment in baroreflex control of cardiovascular function prior to the development of hypertension. The purpose of this study was to identify the mechanism(s) responsible for impaired baroreflex control in prehypertensive Dahl salt-sensitive rats. To examine the central and efferent portions of the baroreflex arc, we electrically stimulated the aortic depressor nerve of urethane anesthetized Dahl salt-sensitive and Dahl salt-resistant rats while recording arterial pressure, heart rate, and sympathetic nerve activity. Aortic nerve stimulation produced equivalent responses in both groups, indicating that central and efferent mechanisms could not account for functional baroreflex impairment. In separate groups of Dahl rats, multifiber afferent aortic baroreceptor discharge was recorded while arterial pressure was increased with phenylephrine. Prehypertensive Dahl salt-sensitive rats demonstrated significantly less baroreceptor activation than Dahl salt-resistant rats, indicating that impaired baroreceptor discharge is the mechanism responsible for baroreflex abnormalities. Aortic arch distensibility was not different between Dahl strains, suggesting that impaired baroreceptor discharge in Dahl salt-sensitive rats is probably not due to abnormalities in vessel wall distensibility. Since arterial pressure of both Dahl strains was in the normotensive range and did not differ significantly between Dahl salt-sensitive and salt-resistant rats, baroreceptor impairment appears to be a primary defect in Dahl salt-sensitive rats, rather than being secondary to hypertension. We speculate that this impairment in baroreceptor function in Dahl salt-sensitive rats prior to any elevation in arterial pressure may contribute to the Dahl salt-sensitive rat's genetic propensity to develop hypertension.

Afferent Pathways↗