The Na+/Ca2+ exchanger, an ion transport protein, is expressed in the plasma membrane (PM) of virtually all animal cells. It extrudes Ca2+ in parallel with the PM ATP-driven Ca2+ pump. As a reversible transporter, it also mediates Ca2+ entry in parallel with various ion channels. The energy for net Ca2+ transport by the Na+/Ca2+ exchanger and its direction depend on the Na+, Ca2+, and K+ gradients across the PM, the membrane potential, and the transport stoichiometry. In most cells, three Na+ are exchanged for one Ca2+. In vertebrate photoreceptors, some neurons, and certain other cells, K+ is transported in the same direction as Ca2+, with a coupling ratio of four Na+ to one Ca2+ plus one K+. The exchanger kinetics are affected by nontransported Ca2+, Na+, protons, ATP, and diverse other modulators. Five genes that code for the exchangers have been identified in mammals: three in the Na+/Ca2+ exchanger family (NCX1, NCX2, and NCX3) and two in the Na+/Ca2+ plus K+ family (NCKX1 and NCKX2). Genes homologous to NCX1 have been identified in frog, squid, lobster, and Drosophila. In mammals, alternatively spliced variants of NCX1 have been identified; dominant expression of these variants is cell type specific, which suggests that the variations are involved in targeting and/or functional differences. In cardiac myocytes, and probably other cell types, the exchanger serves a housekeeping role by maintaining a low intracellular Ca2+ concentration; its possible role in cardiac excitation-contraction coupling is controversial. Cellular increases in Na+ concentration lead to increases in Ca2+ concentration mediated by the Na+/Ca2+ exchanger; this is important in the therapeutic action of cardiotonic steroids like digitalis. Similarly, alterations of Na+ and Ca2+ apparently modulate basolateral K+ conductance in some epithelia, signaling in some special sense organs (e.g., photoreceptors and olfactory receptors) and Ca2+-dependent secretion in neurons and in many secretory cells. The juxtaposition of PM and sarco(endo)plasmic reticulum membranes may permit the PM Na+/Ca2+ exchanger to regulate sarco(endo)plasmic reticulum Ca2+ stores and influence cellular Ca2+ signaling.

https://www.physiology.org/doi/pdf/10.1152/physrev.1999.79.3.763

Sodium/Calcium Exchange: Its Physiological Implications

An attempt is made to elucidate the cellular mechanisms which may account for the well-documented correlation between sodium metabolism and peripheral vascular resistance. As a starting point, the ...

https://www.physiology.org/doi/pdf/10.1152/ajpcell.1977.232.5.C165

Sodium ions, calcium ions, blood pressure regulation, and hypertension: a reassessment and a hypothesis

Cation Selective Glass Electrodes and their Mode of Operation

Skeletal regeneration is accomplished by a cascade of biologic processes that may include differentiation of pluripotential tissue, endochondral ossification, and bone remodeling. It has been shown that all these processes are influenced strongly by the local tissue mechanical loading history. This article reviews some of the mechanobiologic principles that are thought to guide the differentiation of mesenchymal tissue into bone, cartilage, or fibrous tissue during the initial phase of regeneration. Cyclic motion and the associated shear stresses cause cell proliferation and the production of a large callus in the early phases of fracture healing. For intermittently imposed loading in the regenerating tissue: (1) direct intramembranous bone formation is permitted in areas of low stress and strain; (2) low to moderate magnitudes of tensile strain and hydrostatic tensile stress may stimulate intramembranous ossification; (3) poor vascularity can promote chondrogenesis in an otherwise osteogenic environment; (4) hydrostatic compressive stress is a stimulus for chondrogenesis; (5) high tensile strain is a stimulus for the net production of fibrous tissue; and (6) tensile strain with a superimposed hydrostatic compressive stress will stimulate the development of fibrocartilage. Finite element models are used to show that the patterns of tissue differentiation observed in fracture healing and distraction osteogenesis can be predicted from these fundamental mechanobiologic concepts. In areas of cartilage formation, subsequent endochondral ossification normally will proceed, but it can be inhibited by intermittent hydrostatic compressive stress and accelerated by octahedral shear stress (or strain). Later, bone remodeling at these sites can be expected to follow the same mechanobiologic adaptation rules as normal bone.

Mechanobiology of skeletal regeneration

IN 1963, Okamoto and Aoki introduced a new model of experimental hypertension that required no physiological, pharmacological, or surgical intervention. This spontaneously hypertensive rat (SHR) was developed by meticulous genetic (brother-to-sister) inbreeding that uniformly resulted in 100% of the progeny having naturally occurring hypertensive disease (Okamoto and Aoki, 1963; Okamoto et al., 1966a). Since then, several expert panels have reported that the SHR is an excellent model of experimental hypertension that could serve as a counterpart for clinical essential hypertension (Undenfriend and Spector, 1972; ILAR, 1976). In this discourse we take the affirmative position that the SHR is, indeed, an excellent model for the study of essential hypertension. We do so, however, with four important caveats. First, we recognize that it is unlikely that both forms of naturally occurring hypertension (man and rat) are identical expressions of genetically determined hypertensive disease. Second, we take the position that both forms of hypertension are polygenic in origin and that both are influenced by environmental factors. Thirdly, since the control of normal arterial pressure in both man and rat is multifactorial, it follows that certain pressor mechanisms might well operate in one form of genetic hypertension that do not necessarily occur in the other (although in both, some similar factors could be involved). This same reasoning also may be applied to hypertensive in-

Similarities of genetic (spontaneous) hypertension. Man and rat.

Red blood cells incubated in a physiological medium in which Li replaces Na (LiPSS) gain Li in exchange for Na and K. The rate of Li uptake is modestly but significantly increased in the spontaneously hypertensive rat (SHR) at 37 degrees C and at 22 degrees C. The slow rate of Na gain and K loss during cooling at 2 degrees C was about doubled in unmodified whole blood samples from the SHR.

Increased erythrocyte permeability to Li and Na in the spontaneously hypertensive rat.

Morphological assessment of vasoconstriction and vascular hypertrophy in sustained hypertension in the rat

The exchange of Na+ and K+ in rat red cells at 40% hematocrit incubated in a physiological salt solution containing 1 mM ouabain was monitored with ion-specific glass electrodes. Because this syste...

Glass electrode measurement of net Na+ and K+ fluxes in erythrocytes of the spontaneously hypertensive rat.

SummaryAn increase in total Na, due in large part to an increase in cell Na, was measured in the freshly excised rat tail artery during the course of DOCA-saline treatment. Since this change was associated with a fall in cell K, was first observed at 2 weeks, coincident with the rise in blood pressure, and was not sustained during subsequent immersion of the artery at zero pressure, it probably reflects the high in vivo intravascular pressure. In the incubated artery, cell Na is significantly reduced early n the course of treatment, while cell K falls late. Thus, Na transport in the artery is under direct attack from the start, but it is suggested that this leads to hypertrophy rather than to vasoconstriction.

Cell Na and K in the rat tail artery during the development of hypertension induced by desoxycorticosterone acetate.

Uninephrectomized rats were treated with DOCA-saline for 3 weeks. Active Na transport activity was assessed in the rat tail artery in three separate ways. In the first method, Na–K exchange was expressed in terms of steady-state values in normal and ouabain-blocked arteries. In the second method, the relation of free cell Na to [Na]0 was measured after equilibration in media in which [Na]0 varied from about 25 to 140 mM. In the third method, the relation of cell K to [K]0 was measured with glass electrodes during the reestablishment of normality following prolonged K depletion. All methods yielded evidence of enhanced net active transport activity in the incubated artery (zero intraluminal pressure) in steady state.

Miyoshi Nakashima

Papers

Increased erythrocyte permeability to Li and Na in the spontaneously hypertensive rat.

Morphological assessment of vasoconstriction and vascular hypertrophy in sustained hypertension in the rat

Glass electrode measurement of net Na+ and K+ fluxes in erythrocytes of the spontaneously hypertensive rat.

Cell Na and K in the rat tail artery during the development of hypertension induced by desoxycorticosterone acetate.

Evidence for enhanced Na transport in hypertension induced by DOCA in the rat