Salt-sensitive Type Research Articles

Effect of Salt Supplementation on Sympathetic Activity and Endothelial Function in Salt-Sensitive Type 2 Diabetes.

Lower sodium intake is paradoxically associated with higher mortality in type 2 diabetes (T2D). To determine whether sympathetic nervous system (SNS) activation and endothelial dysfunction contribute to these observations, we examined the effect of salt supplementation on these systems in people with T2D with habitual low sodium. We hypothesized that salt supplementation would lower SNS activity and improve endothelial function compared to placebo. We conducted a randomized, double-blinded, placebo-controlled crossover trial. The study took place in a tertiary referral diabetes outpatient clinic. Twenty-two people with T2D with habitual low sodium intake (24-hour urine sodium <150 mmol/24h) were included. Salt supplementation (100 mmol NaCl/24h) or placebo for 3 weeks was administered. The primary outcome of SNS activity and endothelial function was assessed as follows: Microneurography assessed muscle sympathetic nerve activity (MSNA), pulse amplitude tonometry assessed endothelial function via reactive hyperemic index (RHI), and arterial stiffness was assessed via augmentation index (AI). Secondary outcomes included cardiac baroreflex, serum aldosterone, ambulatory blood pressure monitoring (ABPM), heart rate variability (HRV), and salt sensitivity. Compared to placebo, salt supplementation increased MSNA (burst frequency P = .047, burst incidence P = .016); however, RHI (P = .24), AI (P = .201), ABPM (systolic P = .09, diastolic P = .14), and HRV were unaffected. Salt supplementation improved baroreflex (slope P = .026) and lowered aldosterone (P = .004), and in salt-resistant individuals there was a trend toward improved RHI (P = .07). In people with T2D and low habitual sodium intake, salt supplementation increased SNS activity without altering endothelial function or blood pressure but improved baroreflex function, a predictor of cardiac mortality. Salt-resistant individuals trended toward improved endothelial function with salt supplementation.

Abstract 107: Role of Nox4 in the Control of ENaC Activity in Dahl SS Rats During the Development of Salt-induced Hypertension and Diabetic Nephropathy

Dahl salt sensitive (SS) rat is a well-established model for studying salt-induced hypertension and associated kidney injury. We and others have previously shown that salt-sensitive hypertension is accompanied by increased renal production of reactive oxygen species (ROS) and excessive activity of ENaC in the distal nephron. To investigate role of ROS, and specifically NADPH oxidase 4 (Nox4), a primary source of ROS in the kidney, involved in the regulation of ENaC activity during the development of SS hypertension and type 1 diabetes, we performed patch clamp analysis in the cortical collecting ducts of Dahl SS rats and SS rats lacking Nox4 (Nox4 -/- ). We found that SS rats fed a 4% NaCl diet have significantly elevated ENaC activity even 3 days post diet change. ENaC activity (NP o ) was 0.57±0.08, 1.32±0.3 and 1.69±0.06 before, 3 days and 3 weeks after high salt diet, respectively. In contrast, ENaC activity was not significantly different in SS Nox4-/- animals after high salt diet. To study the role of Nox4 in hyperglycemic conditions, diabetes was induced in 6 weeks old male wild type or Nox4 -/- rats with a single i.p. injection of STZ. We found that ENaC activity in the animals that were hyperglycemic for 11 weeks was elevated compared to control rats (0.71±0.10 and 1.27±0.2; p&lt;0.05) and this effect was mediated via changes in channel open probability. Nox4 deficiency blunts the effect of hyperglycemia on ENaC activity (in STZ-treated animals open probability significantly increased from 0.43±0.06 to 0.86±0.07 in WT rats, but in the Nox4 -/- group did not change: P o was 0.51±0.06 and 0.51±0.07, respectively) that delineates the importance of Nox4-mediated ROS production for regulation of ENaC open probability. Taken together, our data indicate that ENaC activity in Dahl SS rats is elevated following a change of salt diet (3 days and 3 weeks at high salt) and after the development of type 1 diabetes. Furthermore, Nox4 plays a crucial role in these effects of high salt and hyperglycemia on ENaC activity.

Variation in Salt Tolerance of Wheat Cultivars: Role of Glycinebetaine and Ethylene

Four wheat (Triticum aestivum L.) cultivars 711, PBW343, 3765 and WH542 were screened for studying variations in glycinebetaine (GB) content and plant dry mass under 100 mmol L−1 NaCl stress. A tolerance index was calculated using plant dry mass data to select salt-tolerant and salt-sensitive types and find association between tolerance index and GB content. Tolerance index has been used as a good criterion to select the tolerant types under high salinity stress. Further, physiological differences in salt-tolerant cultivar 711 and salt-sensitive cultivar WH542 were examined. The salt-tolerant cultivar exhibited greater GB content, which was found correlative with ethylene. The cultivar also showed higher nitrogen (N) content and nitrate reductase activity, reduced glutathione and higher redox state resulting in maximal protection of plant dry mass than the salt-sensitive type. Thus, the content of GB may be considered as important physiological criteria for selecting salt-tolerant wheat types.

Salt and Cardio-Renal Connection

In all animal models examined whose blood pressure (BP) is sensitive to changes in salt intake, glomerular BP indeed proved elevated. In fact, we quantitatively estimated glomerular BP elevated in this type of hypertension. We also showed that BP failed to fall during night in patients with salt sensitive type of hypertension, and they manifested as non-dippers. In addition, high cardiovascular event rates were recognized in salt sensitive patients than in non-salt sensitive patients.

Salt sensitivity and circadian rhythm of blood pressure: the keys to connect CKD with cardiovasucular events

In healthy subjects, blood pressure (BP) drops by 10-20% during the night. Conversely, in patients with the salt-sensitive type of hypertension or chronic kidney disease, nighttime BP does not fall, resulting in an atypical pattern of circadian BP rhythm that does not dip. This pattern is referred to as the 'non-dipper' pattern. Loss of renal functional reserve, due to either reduced ultrafiltration capacity or enhanced tubular sodium reabsorption, induces the salt-sensitive type of hypertension. When salt intake is excessive in patients with salt-sensitive hypertension, the defect in sodium excretory capability becomes evident, resulting in elevated BP during the night. This nocturnal hypertension compensates for diminished natriuresis during the daytime and enhances pressure natriuresis during the night. Nocturnal hypertension and the non-dipper pattern of circadian BP rhythm cause cardiovascular events. When excess salt intake is loaded in patients who are in a salt-sensitive state, glomerular capillary pressure is also elevated, resulting in glomerular sclerosis and eventual renal failure. In this way, salt sensitivity and excess salt intake contribute to both cardiovascular and renal damage at the same time. We propose that salt sensitivity of BP and excess salt intake have important roles in the genesis of the cardiorenal connection. Salt sensitivity and circadian rhythm of BP are the keys to understanding the connections between cardiovascular and renal complications.

Renal and vascular oxidative stress and salt-sensitivity of arterial pressure.

Oxidative stress occurs in a tissue or in the whole body when the total oxidant production exceeds the antioxidant capacity. Recent studies in human essential hypertension indicate that free radical production is increased and antioxidant levels are decreased, and more than one-half of these hypertensives have a salt-sensitive type of hypertension with progressive renal damage. Increased oxidative stress may also play a critical role in animal models of salt-sensitive hypertension. The stroke-prone spontaneously hypertensive rats (SHRSP) exhibits salt-sensitivity, vascular release of superoxide is increased, and total plasma antioxidant capacity is decreased. The superoxide release in the SHRSP rats inactivates nitric oxide, and superoxide dismutase (SOD) administration returns the bioactive nitric oxide levels to normal. The deoxycorticosterone acetate (DOCA)-salt hypertensive rat is salt-sensitive, aortic superoxide production is increased, and renal inflammation is significant. Treatment of the DOCA-salt rats with apocynin, an NADPH oxidase inhibitor, decreased aortic superoxide production and decreased arterial pressure. The Dahl salt-sensitive (S) rat has increased mesenteric microvascular and renal superoxide production and increased plasma levels of H2O2. The renal protein expression of SOD is decreased in the kidney of Dahl S rats, and long-term administration of Tempol, a superoxide mimetic, significantly decreased arterial pressure and renal damage. In conclusion, both human hypertension and experimental models of salt-sensitive hypertension have increased superoxide release, decreased antioxidant capacity and elevated renal damage.

Possible association but no linkage of the HSD11B2 gene encoding the kidney isozyme of 11beta-hydroxysteroid dehydrogenase to hypertension in Black people.

The HSD11B2 (HSD11K) gene encoding the kidney isozyme of 11beta-hydroxysteroid dehydrogenase is mutated in the syndrome of apparent mineralocorticoid excess, an autosomal recessive form of salt-sensitive hypertension. This gene is thus a logical candidate locus for risk of essential hypertension. Because hypertension in Black people tends to be of the low-renin, salt sensitive type, we genotyped independent sets of hypertensives of Afro-American (59 kindreds) and Afro-Caribbean (66 kindreds) origin using a highly polymorphic (heterozygosity index 0.84) CA repeat polymorphism in the first intron of HSD11B2. Linkage was assessed by the affected pedigree member method. No linkage of hypertension to this locus could be demonstrated, but statistically significant allelic associations were noted. HSD11B2 does not have a strong influence on the development of essential hypertension in Black people, but weaker effects on blood pressure cannot be ruled out.

Significance of sympathetic nervous system in sodium-induced nocturnal hypertension.

The purpose of this study was to investigate the effects of salt loading on circadian patterns of blood pressure (BP) and sympathetic nervous activity. Seventy-six patients with essential hypertension were hospitalized and placed on a low-salt diet (2 g/day) for 7 days followed by a high-salt diet (20-23 g/day) for another 7 days. On the last day of each salt diet, 24 h ambulatory BP, plasma noradrenaline concentrations, urinary noradrenaline excretion, plasma renin activity (PRA) and plasma aldosterone concentration (PAC) were measured. Patients whose average mean BP was increased by more than 10% by salt loading were assigned to the salt-sensitive (SS) group (n = 44); the remaining patients, whose mean BP was increased by less than 10%, were assigned to the non-salt-sensitive (NSS) group (n = 32). Salt loading converted the circadian pattern of BP from dippers, whose mean BP during the night-time was decreased by more than 10% from the daytime BP, to non-dippers in the SS group but not in the NSS group. A nocturnal decrease in plasma noradrenaline concentration was unaffected after salt loading in the NSS group but dampened in the SS group. The night-time/daytime ratio of urinary noradrenaline excretion, which was increased after salt loading in the SS group only, was greater in the SS group than in the NSS group under the high-salt diet. The salt-induced suppression rate of PRA and PAC was similar between the SS and NSS groups. BP fails to fall during the night under the high-salt diet in patients with the SS type of essential hypertension. This may be related to the lack of nocturnal decrease in sympathetic nervous activity.

Regulation of DI Receptor Function in Spontaneous Hypertension

Although multiple genes may interact to initiate hypertension, the kidney is a primary locus for the genesis and maintenance of hypertension by its ability to influence sodium balance and produce hormones that can increase or decrease blood pressure. Most of the salt transport in the kidney occurs in the proximal tubule, and several studies have reported abnormalities in the renal regulation of sodium transport at this site in human as well as in animal models of genetic hypertension. The production of dopamine by renal proximal tubules and its effect on sodium transport in this nephron segment is regulated by sodium intake. During moderately increased sodium intake, dopamine, via D1-like receptors, acts as an intrarenal natriuretic factor. This renal paracrine–autocrine effect is lost during states of negative sodium balance. This chapter surmises that a defect in the regulation of dopamine and its effect on renal sodium transport may be important in the pathogenesis of spontaneous hypertension. Decreased renal production of dopamine has been reported in human essential hypertension, especially in those individuals with the salt-sensitive type. Those patients have also been reported to have an exaggerated natriuretic response to exogenous dopamine, although this natriuretic response may be related exclusively to the renal hemodynamic effect of D1 receptors. However, the defect in spontaneous hypertension is not because of a mutation of the D1A receptor gene. The mechanism of the uncoupling of the renal D1-like receptor from its effector proteins remains to be determined. Although, the uncoupling is akin to homologous desensitization, it is not because of agonist-induced desensitization.

Parathyroid Hypertensive Factor, a Circulating Factor in Animal and Human Hypertension

A new circulating hypertensive factor (parathyroid hypertensive factor; PHF) was shown to exist in the plasma of spontaneously hypertensive rats (SHR) but not in that of normotensive rats. PHF produced a delayed increase in blood pressure with a peak response at 45 min (bolus injection) or 60 to 90 min (continuous infusion). This increase in blood pressure was coupled with an in vitro increase in calcium uptake in rat tail artery with a similar time course. The involvement of calcium in the mechanism of action was supported by the inhibitory effect of calcium antagonists on the vascular action of PHF. Furthermore, PHF increased the intracellular free calcium concentration in cultured smooth muscle cells from rat tail artery. Parathyroidectomy and parathyroid transplant experiments indicated the parathyroid origin of PHF. A culture of parathyroid glands from SHR, but not from normotensive rats, produced in the medium a factor which has the same biological property and HPLC retention time as plasma PHF. A novel cell type was described in the parathyroid gland of SHR, but not normotensive rats, and the percent of these cells correlated significantly with plasma PHF level and blood pressure. In some hyperparathyroid patients, plasma PHF and hypertension were found, both of which disappeared after surgical removal of the parathyroid gland. In both animal models and human studies, PHF seems to be associated with low or normal plasma renin and salt-sensitive type of hypertension.

Studies on Osmophillic Yeasts

Influences of concentrations of sodium chloride and pH values of soy mash on the changes of microflora during the ripening process were investigated. The proportions of various yeasts in the soy mash were proved to be changed with the above two environmental factors. And it was shown that growth sequence of yeasts in soy mash was controlled according to their pH sensitivities at the hypertonic condition. From young soy mash (3 days’ old), the following yeasts were isolated: salt-tolerant type.…Saccharomyces rouxii Boutrpux, Torulopsis famata (Harrison) Lodder et Kregervan Rij, Candida polymorpha Ohara et Nonomura, Pichia farinosa (Lindner) Hansen, and Trichosporon behrendii Lodder et Kreger-van Rij ; salt-sensitive type.…Candida tropicalis (de Beurm., Gougerot et Vaucher) Ota and Candida rugosa (Anderson) Diddens et Lodder.

Studies on Osmophilic Yeasts

Influences of concentrations of sodium chloride and pH values of soy mash on the changes of microflora during the ripening process were investigated. The proportions of various yeasts in the soy mash were proved to be changed with the above two. environmental factors. And it was shown that growth sequence of yeasts in soy mash was controlled according to their pH sensitivities at the hypertonic condition. From young soy mash (3 days' old), the following yeasts were isolated: salt-tolerant type……Saccharomyces rouxii Boutroux, Torulopsis famata (Harrison) Lodder et Kregervan Rij, Candida polymorpha Ohara et Nonornura, Pichia farinosa (Lindner) Hansen, and Trichosporon behrendii Lodder et Kreger-van Rij; salt-sensitive type……Candida tropicalis (de Beurm., Gougerot et Vaucher) Ota and Candida rugosa (Anderson) Diddens et Lodder.