Peter Dietsch

Macrophages regulate salt-dependent volume and blood pressure by a vascular endothelial growth factor-C–dependent buffering mechanism

In salt-sensitive hypertension, the accumulation of Na+ in tissue has been presumed to be accompanied by a commensurate retention of water to maintain the isotonicity of body fluids. We show here that a high-salt diet (HSD) in rats leads to interstitial hypertonic Na+ accumulation in skin, resulting in increased density and hyperplasia of the lymphcapillary network. The mechanisms underlying these effects on lymphatics involve activation of tonicity-responsive enhancer binding protein (TonEBP) in mononuclear phagocyte system (MPS) cells infiltrating the interstitium of the skin. TonEBP binds the promoter of the gene encoding vascular endothelial growth factor-C (VEGF-C, encoded by Vegfc) and causes VEGF-C secretion by macrophages. MPS cell depletion or VEGF-C trapping by soluble VEGF receptor-3 blocks VEGF-C signaling, augments interstitial hypertonic volume retention, decreases endothelial nitric oxide synthase expression and elevates blood pressure in response to HSD. Our data show that TonEBP–VEGF-C signaling in MPS cells is a major determinant of extracellular volume and blood pressure homeostasis and identify VEGFC as an osmosensitive, hypertonicity-driven gene intimately involved in salt-induced hypertension.

Sodium-, potassium-, chloride-, and bicarbonate-related effects on blood pressure and electrolyte homeostasis in deoxycorticosterone acetate-treated rats

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-NaHCO(3), or DOCA-KHCO(3). 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% NaHCO(3), or 1.7% KHCO(3) 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-NaHCO(3) and DOCA-KHCO(3) did not. DOCA-NaCl increased TBNa(+) 26% but only moderately increased TBW. DOCA-NaHCO(3) led to similar TBNa(+) excess, while TBW and ICV, but not ECV, were increased more than in DOCA-NaCl rats. DOCA-KHCO(3) 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-NaHCO(3), and DOCA-KHCO(3) 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-NaHCO(3) 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.

Extrarenal Na+ Balance, Volume, and Blood Pressure Homeostasis in Intact and Ovariectomized Deoxycorticosterone-Acetate Salt Rats

Water-free Na+ storage may buffer extracellular volume and mean arterial pressure (MAP) in spite of Na+ retention. We studied the relationship among internal Na+, K+, water balance, and MAP in Sprague-Dawley rats, with or without deoxycorticosterone-acetate (DOCA) salt, with or without ovariectomy (OVX). The rats were fed a low-salt (0.1% NaCl) or high-salt (8% NaCl) diet for 5 weeks. DOCA salt increased MAP (161±14 versus 123±4 mm Hg; P<0.05), and DOCA-OVX salt increased MAP further (181±22 mm Hg; P<0.05). DOCA salt increased the total body Na+ by ≈40% to 45%; however, water-free Na+ retention by osmotically inactive Na+ storage and by osmotically neutral Na+/K+ exchange allowed the rats to maintain the extracellular volume close to normal. DOCA-OVX salt rats showed similar Na+ retention. However, their osmotically inactive Na+ storage capacity was greatly reduced and only partially compensated by neutral Na+/K+ exchange, resulting in greater volume retention despite similar Na+ retention. For every 1% wet weight total body water gain, MAP increased by 2.3±0.2 mm Hg in DOCA salt rats and 2.5±0.3 mm Hg in DOCA-OVX salt rats. Because water-free Na+ retention buffered total body water content by 8% to 11% wet weight, we conclude that this internal Na+ escape buffered MAP. Extrarenal Na+ and volume balance seem to play an important role in long-term volume and MAP control.

New Approaches to Pathogenesis and Management of Hypertension

# Catheter-based renal sympathetic denervation for resistant hypertension: A multicenter safety and proof-of-principle cohort study. Lancet 373: 1275–1281, 2009 {#article-title-2} 1886 1888 Upon the initiative of Smithwick and Thompson (1) of the Massachusetts General Hospital, resection of the splanchnic nerves through a posterior infradiaphragmatic approach plus removal of the sympathetic chain from the level of the eighth dorsal ganglion to the second lumbar ganglion had been used with relative frequency in cases of desperate hypertension at the time when antihypertensive medication was not yet available. In the hands of other investigators, the results were spectacular in a minority of patients but not quite satisfactory in many patients (2,3). Despite improvement of headache, reversal of papilledema in malignant hypertension, etc. , the long-term reduction of BP was quite variable and the 5-yr mortality remained approximately 40% (2). A 10-yr follow-up compared 100 patients who were subjected to thoracolumbar sympathectomy with 1500 patients who received symptomatic therapy. Lasting BP reduction was seen only in one third of the patients (4). Whereas the average BP levels were reduced, occasional BP spikes were not. The average difference of preoperative to postoperative systolic BP values was 21 mmHg. The authors saw reduction of cerebrovascular accidents and less progression of proteinuria and renal dysfunction, but 10-yr mortality was still 41%. Against this background, once effective antihypertensive medication was available, this relatively crude procedure fell out of favor and remained a sleeping beauty. With todays better insight into the role of sympathetic activity in the genesis of hypertension and particularly the role of the kidney in sympathetic activation, there has been a renaissance in the interest of the renal sympathetic nervous system, including its role in primary hypertension—apart from its undoubted role in the hypertension of chronic kidney disease (5–10). Renal disease and, in animal experiments, even minor renal tissue damage such as injection of minute volumes of phenol, trigger afferent signals that ascend via …

Hypertension, sodium retention, calcium excretion and osteopenia in Dahl rats.

Background Salt-sensitive hypertension in the Dahl rat is associated with abnormalities in both calcium (Ca2+) and sodium (Na+) homeostasis. Objective To test the hypothesis that salt-induced abnormal Ca2+ handling in Dahl salt-sensitive (DSS) rats is associated with negative Ca2+ balance and bone disease. Methods Ca2+ excretion in acute and chronic Na+ loading and electrolyte and water balance were determined by balance studies in Dahl salt-resistant (DSR) and salt-sensitive (DSS) rats fed 8 or 0.1% NaCl for 4 weeks. A dry ashing procedure was used to determine Na+, Ca2+, and water content and their association with blood pressure in the rats. Results When fed 8% NaCl, DSS rats initially maintained a positive Ca2+ balance and showed decreased natriuresis compared with DSR rats. During the course of Na+ loading, DSS rats increased natriuresis and calciuresis. After 4 weeks of salt loading, cumulative Na+ balance was greater and cumulative Ca2+ balance was less in DSS than in DSR rats. In addition, DSS rats developed osteopenia. Bone mineral content correlated inversely with blood pressure in DSS rats. Acute saline volume expansion in DSS rats demonstrated their ability to excrete the Na+ load fully, but led to an exaggerated renal loss of Ca2+ compared with DSR rats. Conclusion DSS, but not DSR, develop Ca2+ loss and ostopenia during chronic Na+ loading. We speculate that Na+ retention in DSS rats fed a high Na+ diet may be in part a compensatory mechanism to maintain Ca2+ balance.