Excess dietary salt is a major cause of hypertension. Nevertheless, the specific mechanisms by which salt increases arterial constriction and peripheral vascular resistance, and thereby raises blood pressure (BP), are poorly understood. Here we summarize recent evidence that defines specific molecular links between Na(+) and the elevated vascular resistance that directly produces high BP. In this new paradigm, high dietary salt raises cerebrospinal fluid [Na(+)]. This leads, via the Na(+)-sensing circumventricular organs of the brain, to increased sympathetic nerve activity (SNA), a major trigger of vasoconstriction. Plasma levels of endogenous ouabain (EO), the Na(+) pump ligand, also become elevated. Remarkably, high cerebrospinal fluid [Na(+)]-evoked, locally secreted (hypothalamic) EO participates in a pathway that mediates the sustained increase in SNA. This hypothalamic signaling chain includes aldosterone, epithelial Na(+) channels, EO, ouabain-sensitive α(2) Na(+) pumps, and angiotensin II (ANG II). The EO increases (e.g.) hypothalamic ANG-II type-1 receptor and NADPH oxidase and decreases neuronal nitric oxide synthase protein expression. The aldosterone-epithelial Na(+) channel-EO-α(2) Na(+) pump-ANG-II pathway modulates the activity of brain cardiovascular control centers that regulate the BP set point and induce sustained changes in SNA. In the periphery, the EO secreted by the adrenal cortex directly enhances vasoconstriction via an EO-α(2) Na(+) pump-Na(+)/Ca(2+) exchanger-Ca(2+) signaling pathway. Circulating EO also activates an EO-α(2) Na(+) pump-Src kinase signaling cascade. This increases the expression of the Na(+)/Ca(2+) exchanger-transient receptor potential cation channel Ca(2+) signaling pathway in arterial smooth muscle but decreases the expression of endothelial vasodilator mechanisms. Additionally, EO is a growth factor and may directly participate in the arterial structural remodeling and lumen narrowing that is frequently observed in established hypertension. These several central and peripheral mechanisms are coordinated, in part by EO, to effect and maintain the salt-induced elevation of BP.

Pallone, Thomas L., Zhong Zhang, and Kristie Rhinehart. Physiology of the renal medullary microcirculation. Am J Physiol Renal Physiol 284: F253-F266, 2003; 10.1152/ajprenal.00304.2002.-Perfusion of the renal medulla plays an important role in salt and water balance. Pericytes are smooth muscle-like cells that impart contractile function to descending vasa recta (DVR), the arteriolar segments that supply the medulla with blood flow. DVR contraction by ANG II is mediated by depolarization resulting from an increase in plasma membrane Cl Ϫ conductance that secondarily gates voltage-activated Ca 2ϩ entry. In this respect, DVR may differ from other parts of the efferent microcirculation of the kidney. Elevation of extracellular K ϩ constricts DVR to a lesser degree than ANG II or endothelin-1, implying that other events, in addition to membrane depolarization, are needed to maximize vasoconstriction. DVR endothelial cytoplasmic Ca 2ϩ is increased by bradykinin, a response that is inhibited by ANG II. ANG II inhibition of endothelial Ca 2ϩ signaling might serve to regulate the site of origin of vasodilatory paracrine agents generated in the vicinity of outer medullary vascular bundles. In the hydropenic kidney, DVR plasma equilibrates with the interstitium both by diffusion and through water efflux across aquaporin-1. That process is predicted to optimize urinary concentration by lowering blood flow to the inner medulla. To optimize urea trapping, DVR endothelia express the UT-B facilitated urea transporter. These and other features show that vasa recta have physiological mechanisms specific to their role in the renal medulla. vasa recta; perfusion; hypertension; oxygenation; urinary concentration; patch clamp; calcium; fura 2 THE MICROCIRCULATION OF THE kidney is regionally specialized. In the cortex, afferent and efferent arterioles govern the driving forces that promote glomerular filtration. A dense peritubular capillary plexus arising from efferent arterioles surrounds the proximal and distal convoluted tubules to accommodate enormous reabsorption of glomerular filtrate. In contrast, vasa recta serve needs specific to the medulla. Through the counterflow arrangement of descending (DVR) and ascending vasa recta (AVR), countercurrent exchange traps NaCl and urea deposited to the interstitium by collecting ducts and the loops of Henle. This is vital to maintain corticomedullary osmotic gradients but conflicts with the need to supply nutrient blood flow to medullary tissue. Metabolic substrates that enter the medulla in DVR blood diffuse to the AVR to be shunted back to the cortex. To deal with the threat of medullary hypoxia resulting from this process, the kidney has evolved a capacity to exert subtle control over regional perfusion of the outer and inner medulla. The details are far from clear, but much experimental evidence points to the complex interactions of many autocoids and paracrine agents to modulate vasomotor tone at various sites along the microvascular circuit. The goal of this review is to summarize ...

The localization of aquaporin-1 water channels (AQP-1) in nephron and vascular structures in rat kidney were characterized, because vascular bundles are known to play a key role in urinary concentration. Immunohistochemistry and immunoelectron microscopy were applied on thin cryosections or ultrathin Lowicryl sections, using an optimized freeze-substitution method. Within the vascular bundles, AQP-1 is localized in descending thin limbs (DTL) of short nephrons in apical and basolateral membranes. The expression in DTL of short nephrons is considerably lower compared with the expression in long nephrons, consistent with the known lower osmotic water permeability of this segment. Furthermore, DTL of short nephrons expressing AQP-1 continue abruptly into a thin limb segment without AQP-1. This suggests the existence of a novel thin limb epithelium in the outer medulla. Extensive expression of AQP-1 is observed in apical and basolateral membranes of DTL of long nephrons, which are localized in the periphery of the vascular bundles. The expression decreases along the axis of long nephron DTLs in correlation with the known water permeability characteristics of thin limb segments. DTLs of both short and long nephrons continue abruptly into thin limb segments without AQP-1 expression, revealing an abrupt cell-to-cell transition. In vasa recta, AQP-1 is selectively localized in the nonfenestrated endothelium of descending vasa recta, whereas the fenestrated endothelium of ascending vesa recta and peritubular capillaries do not express AQP-1. AQP-1 is localized in both apical and basolateral plasma membranes, which is logical for transendothelial water transport. Isolated perfused descending vasa recta display high water permeability, and, unlike sodium permeability, diffusional water permeability is partly inhibited by mercurials, thus substantiating the presence of mercurial-sensitive water channels in descending vasa recta. Thus AQP-1 is localized in DTL and descending vasa recta within vascular bundles, and AQP-1 expression in DTL segments is in exact concordance with the known water permeability characteristics, strongly supporting that AQP-1 is the major constitutive water channel of the nephron.

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Using nystatin perforated-patch whole cell recording, we investigated the role of Cl(-) conductance in the modulation of outer medullary descending vasa recta (OMDVR) pericyte membrane potential (Psi m) by ANG II. ANG II (10(-11) to 10(-7) M) consistently depolarized OMDVR and induced Psi m oscillations at lower concentrations. The Cl(-) channel blockers anthracene-9-decarboxylate (1 mM) and niflumic acid (10 microM) hyperpolarized resting pericytes and repolarized ANG II-treated pericytes. In voltage-clamp experiments, ANG II-treated pericytes exhibited slowly activating currents that were nearly eliminated by treatment with niflumic acid (10 microM) or removal of extracellular Ca(2+). Those currents reversed at -31 and -10 mV when extracellular Cl(-) concentration was 152 and 34 mM, respectively. In pericytes held at -70 mV, oscillating inward currents were sometimes observed; the reversal potential also shifted with extracellular Cl(-) concentration. We conclude that ANG II activates a Ca(2+)-dependent Cl(-) conductance in OMDVR pericytes to induce membrane depolarization and Psi m oscillations.