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Overview

This program is based on the hypothesis that salt-dependent hypertension involves the following sequence of events (see Figure 1): Salt retention, as a result of excessive intake or reduced renal excretion, leads to secretion of endogenous ouabain (EO) and elevation of plasma levels in many patients with essential hypertension (EH).

In rodents, prolonged treatment with ouabain leads to hypertension; thus the ouabain-hypertensive (OH) rat appears to be a good model for EH. EO, an adrenocortical hormone, or ouabain, selectively inhibits Na+ pumps with a2 or a3 subunits in neurons, artery myocytes and endothelial cells. Consequently, local intracellular Na+ concentrations rise at plasma membrane-sarco/endo-plasmic reticulum (PM-S/ER) junctions or PLasmERosomes (see Figure 2 below) where these Na+ pumps are located. Then, via Na/Ca exchange (NCX), local Ca2+ signaling and Ca2+ storage are augmented; in the chronic state, however, endothelium-dependent vasodilation may be suppressed. The net result is an increase in vasoconstriction, peripheral vascular resistance (PVR) and blood pressure.

This hypothesis is being tested on isolated small arteries and myocytes from rats and mice. The studies are designed to elucidate the detailed mechanism of action of acute and chronic low dose ouabain treatment. The OH rat model, several transgenic mouse lines with altered plasma membrane (PM) ion transporters and transmitter receptors and novel anti-ouabain agents and NCX blockers are used for these studies.

Figure 2

PlasmE model
Model of the PLasmERosome showing key transport proteins involved in local control of jS/ER Ca2+ stores and modulation of Ca2+ signaling. The PM region shows vasoconstrictor (agonist) receptors and a nearby PM microdomain containing: store operated channels (SOCs), a2/a3 Na+ pumps, the sodium/calcium exchanger (NCX), adjacent jS/ER with sarcoplasmic reticulum Ca-ATPase (SERCA), inositol tris phosphate receptors (IP3R), ryanodine receptors (RYR), and the intervening “diffusion-restricted” cytosolic space (“J”). [Na+]J rises in the restricted (aqua colored) space following inhibition of a2/a3 Na+ pumps by low-dose ouabain. ECF = extracellular fluid. The a1 Na+ pumps and PM Ca2+ pumps (PMCA) are widely distributed in the PM, but excluded from the PLasmERosomes.
 

There are four projects and three cores.

  • Project 1 (M.P. Blaustein, Project Leader) is characterizing the physiology and pharmacology of several key steps in smooth muscle within intact arteries, in the pathway from ouabain to increased PVR.
  • Project 2 (V.A. Golovina, Project Leader) is focused on store-operated Ca2+ entry and storage mechanisms in freshly isolated myocytes, and the effects of acute and chronic ouabain treatment on these mechanisms which appear to be altered in OH rats.
  • Project 3 (W.G. Wier, Project Leader) employs novel measurements of quantal content and Ca2+ signaling to characterize details of sympathetic neuromuscular transmission in small arteries, and is determining how acute and chronic ouabain treatment influences these parameters.
  • Project 4 (T.L. Pallone, Project Leader) is elucidating the effects of acute and chronic ouabain treatment on Ca2+ signaling in endothelial cell and/or pericyte function in renal descending vasa recta and, based on preliminary data, is exploring the apparent dysfunction of these signaling mechanisms in OH rats.

The projects are supported by administrative, animal model/analytic chemistry/biochemistry and imaging/electrophysiology/relational database cores. The results are elucidating the mechanism(s) by which ouabain alters Ca2+ homeostasis, augments sympathetic neuromuscular transmission, influences endothelial feedback and induces hypertension. This is providing insight into novel targets for anti-hypertensive therapy.