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Na+ loading without Cl− fails to increase blood pressure in the DOCA model. We compared the changes in the total body (TB) effective Na+, K+, Cl−, and water (TBW) content as well as in intracellular (ICV) or extracellular (ECV) volume in rats receiving DOCA-NaCl, DOCA-NaHCO3, or DOCA-KHCO3. We divided 42 male rats into 5 groups. Group 1 was untreated, group 2 received 1% NaCl, and groups 3, 4, and 5 were treated with DOCA and received 1% NaCl, 1.44% NaHCO3, or 1.7% KHCO3 to drink. We measured mean arterial blood pressure (MAP) directly after 3 wk. Tissue electrolyte and water content was measured by chemical analysis. Compared with control rats, DOCA-NaCl increased MAP while DOCA-NaHCO3 and DOCA-KHCO3 did not. DOCA-NaCl increased TBNa+ 26% but only moderately increased TBW. DOCA-NaHCO3 led to similar TBNa+ excess, while TBW and ICV, but not ECV, were increased more than in DOCA-NaCl rats. DOCA-KHCO3 did not affect TBNa+ or volume. At a given TB(Na++K+) and TBW, MAP in DOCA-NaCl rats was higher than in control, DOCA-NaHCO3, and DOCA-KHCO3 rats, indicating that hypertension in DOCA-NaCl rats was not dependent on TB(Na++K+) and water mass balance. Skin volume retention was hypertonic compared with serum and paralleled hypertension in DOCA-NaCl rats. These rats had higher TB(Na++K+)-to-TBW ratio in accumulated fluid than DOCA-NaHCO3 rats. DOCA-NaCl rats also had increased intracellular Cl− concentrations in skeletal muscle. We conclude that excessive cellular electrolyte redistribution and/or intracellular Na+ or Cl− accumulation may play an important role in the pathogenesis of salt-sensitive hypertension.

The skin interstitium sequesters excess Na+ and Cl- in salt-sensitive hypertension. Mononuclear phagocyte system (MPS) cells are recruited to the skin, sense the hypertonic electrolyte accumulation in skin, and activate the tonicity-responsive enhancer-binding protein (TONEBP, also known as NFAT5) to initiate expression and secretion of VEGFC, which enhances electrolyte clearance via cutaneous lymph vessels and increases eNOS expression in blood vessels. It is unclear whether this local MPS response to osmotic stress is important to systemic blood pressure control. Herein, we show that deletion of TonEBP in mouse MPS cells prevents the VEGFC response to a high-salt diet (HSD) and increases blood pressure. Additionally, an antibody that blocks the lymph-endothelial VEGFC receptor, VEGFR3, selectively inhibited MPS-driven increases in cutaneous lymphatic capillary density, led to skin Cl- accumulation, and induced salt-sensitive hypertension. Mice overexpressing soluble VEGFR3 in epidermal keratinocytes exhibited hypoplastic cutaneous lymph capillaries and increased Na+, Cl-, and water retention in skin and salt-sensitive hypertension. Further, we found that HSD elevated skin osmolality above plasma levels. These results suggest that the skin contains a hypertonic interstitial fluid compartment in which MPS cells exert homeostatic and blood pressure-regulatory control by local organization of interstitial electrolyte clearance via TONEBP and VEGFC/VEGFR3-mediated modification of cutaneous lymphatic capillary function.

1. The objective of this study was to determine the influence of iodine (I) supplementation of feed, within the range of the European guidelines, on the performance of broiler chickens and I transfer into different organs and tissues, especially meat. The main emphasis was to assess whether broiler meat could be enriched and used as an I source in human nutrition. 2. Two experiments were performed, one with KI and the other with Ca(IO(3))(2). For each experiment, 288 d-old broiler chicks were divided into 4 groups (72 birds/group) and fed on diets with supplementations between 0 and 5 mg I/kg feed. The birds were reared to 35 d of age under standard conditions. Six birds per group were slaughtered at 35 d and samples of blood, thyroid gland, liver, pectoral and thigh meat taken. 3. Iodine treatment did not significantly affect the growth and slaughter performance of the broiler chickens. In all investigated parameters, I concentrations increased significantly with increasing I intake of the animals. The lowest I concentrations were measured in the meat, but they were considerably higher in blood serum, liver and thyroid gland. Since the I content of meat was still low in the highest supplemented group (highest median concentration: 67·8 µg I/kg thigh meat), there is no evidence that this could substantially improve I supply in human nutrition.

We showed recently that mononuclear phagocyte system (MPS) cells provide a buffering mechanism for salt-sensitive hypertension by driving interstitial lymphangiogenesis, modulating interstitial Na + clearance, and increasing endothelial NO synthase protein expression in response to very high dietary salt via a tonicity-responsive enhancer binding protein/vascular endothelial growth factor C regulatory mechanism. We now tested whether isotonic saline and deoxycorticosterone acetate (DOCA)-salt treatment leads to a similar regulatory response in Sprague-Dawley rats. Male rats were fed a low-salt diet and received tap water (low-salt diet LSD), 1.0% saline (high-salt diet HSD), or DOCA+1.0% saline (DOCA-HSD). To test the regulatory role of interstitial MPS cells, we further depleted MPS cells with clodronate liposomes. HSD and DOCA-HSD led to Na + accumulation in the skin, MPS-driven tonicity-responsive enhancer binding protein/vascular endothelial growth factor C–mediated hyperplasia of interstitial lymph capillaries, and increased endothelial NO synthase protein expression in skin interstitium. Clodronate liposome MPS cell depletion blocked MPS infiltration in the skin interstitium, resulting in unchanged tonicity-responsive enhance binding protein/vascular endothelial growth factor C levels and absent hyperplasia of the lymph capillary network. Moreover, no increased skin endothelial NO synthase protein expression occurred in either clodronate liposome–treated HSD or DOCA-salt rats. Thus, absence of the MPS-cell regulatory response converted a salt-resistant blood-pressure state to a salt-sensitive state in HSD rats. Furthermore, salt-sensitive hypertension in DOCA-salt rats was aggravated. We conclude that MPS cells act as onsite controllers of interstitial volume and blood pressure homeostasis, providing a local regulatory salt-sensitive tonicity-responsive enhancer binding protein/vascular endothelial growth factor C–mediated mechanism in the skin to maintain normal blood pressure in states of interstitial Na + and Cl − accumulation. Failure of this physiological extrarenal regulatory mechanism leads to a salt-sensitive blood pressure response.

The idea that an osmotically inactive Na+ storage pool exists that can be varied to accommodate states of Na+ retention and/or Na+ loss is controversial. We speculated that considerable amounts of osmotically inactive Na+ are lost with growth and that additional dietary salt excess or salt deficit alters the polyanionic character of extracellular glycosaminoglycans in osmotically inactive Na+ reservoirs. Six-week-old Sprague-Dawley rats were fed low-salt (0.1%; LS) or high-salt (8%; HS) diets for 1 or 4 wk. At their death, we separated the tissues and determined their Na+, K+, and water content. Three weeks of growth reduced the total body Na+ content relative to dry weight (rTBNa+) by 23%. This “growth-programmed” Na+ loss originated from the bone and the completely skinned and bone-removed carcasses. The Na+ loss was osmotically inactive (45–50%) or osmotically active (50–55%). In rats aged 10 wk, compared with HS, 4 wk of LS reduced rTBNa+ by 9%. This dietary-induced Na+ loss was osmotically inactive (≈50%) and originated largely from the skin, while ≈50% was osmotically active. LS for 1 wk did not reduce skin Na+ content. The mobilization of osmotically inactive skin Na+ with long-term salt deprivation was associated with decreased negatively charged skin glycosaminoglycan content and thereby a decreased water-free Na+ binding capacity in the extracellular matrix. Our data not only serve to explain discrepant results in salt balance studies but also show that glycosaminoglycans may provide an actively regulated interstitial cation exchange mechanism that participates in volume and blood pressure homeostasis.