A key question in hypertension is: How is long-term blood pressure controlled? A clue is that chronic salt retention elevates an endogenous ouabain-like compound (EOLC) and induces salt-dependent hypertension mediated by Na + /Ca 2+ exchange (NCX). The precise mechanism, however, is unresolved. Here we study blood pressure and isolated small arteries of mice with reduced expression of Na + pump α1 (α1 +/-) or α2 (α2 +/-) catalytic subunits. Both low-dose ouabain (1-100 nM; inhibits only α2) and high-dose ouabain (≥1 µM; inhibits α1) elevate myocyte Ca 2+ and constrict arteries from α1 +/-, as well as α2 +/-and wild-type mice. Nevertheless, only mice with reduced α2 Na + pump activity (α2 +/-), and not α1 (α1 +/-), have elevated blood pressure. Also, isolated, pressurized arteries from α2 +/-, but not α1 +/-, have increased myogenic tone. Ouabain antagonists (PST 2238 and canrenone) and NCX blockers (SEA0400 and KB-R7943) normalize myogenic tone in ouabain-treated arteries. Only the NCX blockers normalize the elevated myogenic tone in α2 +/-arteries because this tone is ouabain independent. All four agents are known to lower blood pressure in salt-dependent and ouabain-induced hypertension. Thus, chronically reduced α2 activity (α2 +/-or chronic ouabain) apparently regulates myogenic tone and long-term blood pressure whereas reduced α1 activity (α1 +/-) plays no persistent role: the in vivo changes in blood pressure reflect the in vitro changes in myogenic tone. Accordingly, in salt-dependent hypertension, EOLC probably increases vascular resistance and blood pressure by reducing α2 Na + pump activity and promoting Ca 2+ entry via NCX in myocytes.

Ionic fluxes are thought to be involved in mediating the proliferation of peripheral blood lymphocytes (PBLs) in response to mitogenic substances. Among the earliest events occurring after the addition of mitogen to cultured lymphocytes are changes in rates of cation transport. We were interested, therefore, in the possible role of ion channels in mediating the lymphocyte proliferative response. The development of patch clamp techniques by Neher and colleagues has made it possible to study membrane conductances in a variety of small cell types. We have developed a method which uses monoclonal antibodies to make cells adhere to solid surfaces for two major reasons: (1) it is much easier to patch clamp stationary cells, and (2) the method can be used to selectively adhere a particular cell type from a heterogeneous population. We have used these techniques here to identify whole-cell potassium currents, in lymphocytes recognized by OKT11 monoclonal antibody, which are increased 1.9-fold by mitogenic stimulation.

The calcium currents of GH3 cells have been studied using the whole cell variant of the patch-clamp technique . Under conditions that eliminate sodium and potassium currents, we observed inward currents that activated within a few milliseconds, and deactivated with two time constants,^-150 us and is almost the same in amplitude from 10 to 100 ms . The components thus seem quite independent of each other, and must arise from two independent sets of channels. (c) The FD channels activate more rapidly than SD at 20 mV, by a factor of -2 as is shown in several ways . (d) In 10 Ca or 10 Ba, the activation curve for SD channels is^-20 mV more negative than for FD or Na channels . (e) FD channels conduct barium ions more effectively than calcium by a ratio of^-2 . (f) FD channels "wash out" within minutes after the patch electrode breaks into a cell, whereas SD channel current remains relatively stable. It is argued that SD channels, because of their negative activation threshold, are involved in electrical events near threshold, and that FD channels are best suited for calcium injection once a spike has been initiated .

There is a limited amount of information available on the mechanical and functional response of the nervous system to loading. While deformation of cerebral, spinal, or peripheral nerve tissue can have particularly severe consequences, most research in this area has concentrated on either demonstrating in-vivo functional changes and disclosing the effected anatomical pathways, or describing material deformations of the composite structure. Although such studies have successfully produced repeatable traumas, they have not addressed the mechanisms of these mechanically induced injuries. Therefore, a single cell model is required in order to gain further understanding of this complex phenomena. An isolated squid giant axon was subjected to controlled uniaxial loading and its mechanical and physiological responses were monitored with an instrument specifically designed for these experiments. These results determined that the mechanical properties of the isolated axon are similar to those of other soft tissues, and include features such as a nonlinear load-deflection curve and a hysteresis loop upon unloading. The mechanical response was modeled with the quasi-linear viscoelastic theory (Fung, 1972). The physiological response of the axon to quasi-static loading was a small reversible hyperpolarization; however, as the rate of loading was increased, the axon depolarized and the magnitude and the time needed to recover to the original resting potential increased in a nonlinear fashion. At elongations greater than twenty percent an irreversible injury occurs and the membrane potential does not completely recover to baseline.