Pflügers Archiv

Motor nerve terminals in mouse and frog display behavior consistent with an appreciable permeability of the nerve terminal membrane to chloride. In mouse diaphragm, in the presence of 15 mM K+ and 2 mM or 8 mM Ca2+, replacement of Cl− by NO 3 − , Br− or acetate causes a transient increase in the quantal release of acetylcholine, measured as the frequency of spontaneously occurring miniature end plate potentials (FMEPP); a rapid rise in FMEPP is followed by a slow decline, with a half-time of about 4 min, to an equilibration level close to the control level. After equilibration in a solution in which the Cl− is replaced by another anion, return to Cl−-containing solution causes a transient decrease in FMEPP with a subsequent slow recovery. The data are consistent with transient nerve terminal depolarization or hyperpolarization, reflecting a nerve terminal permeability to anions in the sequence Cl−>Br−>NO 3 − >acetate. In 5 mM K+, changes in nerve terminal excitability, determined using focal stimulation, are also consistent with alteration of nerve terminal membrane potential as a consequence of anion substitution. The time course of relaxation of FMEPP after a change from Cl− to an anion of lower permeability, or vice versa, is considerably slower than that expected if Cl− permeability of nerve terminals is similar to that of skeletal muscle fibres, and if the nerve terminal behaves as a single compartment. In frog cutaneous pectoris, transient changes in FMEPP produced by substitution of anions in the bathing solution were similar to those produced in mouse diaphragm, but more rapid in time course.

 In order to examine the nature and potential mechanisms of action of extracellular sodium on human proximal tubule growth and transport, quiescent primary cultures of human proximal tubule cells (PTC) were incubated for 24 h in serum-free, growth-factor-free culture media containing low (130 mmol/l), control (140 mmol/l) or high (150 mmol/l) Na+. Compared to control conditions, cells exposed to a high Na+ concentration demonstrated stimulated thymidine incorporation (121.8 ± 7.6%, P < 0.05) and increased cellular protein content (139.7 ± 9.9%, P < 0.05); the latter arising from suppressed protein degradation ([3H]valine release 72.3 ± 2.5%, P < 0.01) and unchanged protein synthesis ([3H]valine incorporation 98.5 ± 2.6%, P > 0.1). Substitution of choline chloride for NaCl did not replicate these effects. Conversely, cells incubated in low-Na+ media showed reduced thymidine incorporation (77.2 ± 4.4%, P < 0.05), reduced protein synthesis (60.6 ± 4.3%, P < 0.01), reduced protein degradation (79.5 ± 1.8%, P < 0.01) and an unaltered protein content (102.4 ± 8.8%). A role for apical Na+/H+ exchange (NHE) activity in mediating Na+-dependent alterations in PTC growth was suggested by the findings of increased apical, ethylisopropylamiloride- (EIPA)-sensitive 22Na+ uptake in the presence of a high Na+ concentration (159 ± 19% of control, P < 0.05) and concentration-dependent inhibition of cellular growth by EIPA at levels corresponding to those producing inhibition of apical NHE. Conditioned media from low Na+, control or high Na+ PTC contained comparable amounts of platelet-derived growth factor-AB (1.19 ± 0.23, 1.14 ± 0.22 and 1.28 ± 0.20 ng/mg protein, P > 0.1) and transforming growth factor-β1 (1.76 ± 0.32, 1.73 ± 0.33 and 1.45 ± 0.28 ng/mg protein, P > 0.1), and did not exhibit autocrine growth factor activity on separate PTC following adjustment of Na+ concentrations to 140 mmol/l by dialysis. Similarly, low-Na+, control or high-Na+ media did not modify the mitogenic responsiveness of PTC to insulin-like growth factor-I (IGF-I) or alter the affinity or number of PTC IGF-I binding sites. The results confirm that physiological increases in extracellular Na+ concentration directly stimulate human proximal tubule growth and Na+ transport. Such stimulation does not appear to be mediated by altered PTC secretion of, or responsiveness to, cytokines known to affect tubule growth and transport.

Mechanotransduction refers to the conversion of mechanical forces into biochemical or electrical signals that initiate structural and functional remodeling in cells and tissues. The heart is a kinetic organ whose form changes considerably during development and disease, requiring cardiac myocytes to be mechanically durable and capable of fusing a variety of environmental signals on different time scales. During physiological growth, myocytes adaptively remodel to mechanical loads. Pathological stimuli can induce maladaptive remodeling. In both of these conditions, the cytoskeleton plays a pivotal role in both sensing mechanical stress and mediating structural remodeling and functional responses within the myocyte.