GLUCOCORTICOIDS REGULATE NA-MUSCLE THROUGH THE GLUCOCORTICOID RECEPTOR-MEDIATED MECHANISM( TRANSPORT IN VASCULAR SMOOTH)

The incidence of hypertension in conditions of chronic glucocorticoid (GC) excess is very high, though the mechanism whereby GC elevate bloo d pressure is far from being understood. We have recently found that G C markedly increase influx of Na+ in vascular smooth muscle (VSM) cell s. We and other investigators have previously described receptors for GC in arterial tissues, and we have now examined whether the effect of GC on Na+ transport in VSM is mediated through these receptors. Vascu lar smooth muscle cells were cultured from rabbit aortas. The cells we re treated for 48 h with 10(-7) mol/L dexamethasone (DEX), in the pres ence or absence of RU 486, a competitive inhibitor of DEX binding to i ts receptor, or progesterone, an allosteric accelerator of DEX dissoci ation from the receptor. Unidirectional influx of Na+ was measured wit h Na-22 as tracer. Dexamethasone more than doubled the influx rate of Na+, RU 486 completely prevented this increase, and progesterone reduc ed the DEX-induced increase by approximately 80%. The time of the cell exposure to DEX necessary for the DEX effect to occur was 4 to 6 h, w ith a maximal effect at 48 h, suggesting a genomic effect. Addition of protein synthesis inhibitors, actinomycin D or cycloheximide, to VSM cells cultured in the presence of DEX prevented the increase of Na+ in flux by DEX. Addition of amiloride (1.5 mumol/L, to block Na+ channels ) or bumetanide (a specific blocker of Na+, K+, 2Cl--cotransporter) to cell media, 15 min before Na-22 influx measurement, inhibited DEX-inc reased Na+ transport by 75% and 28%, respectively; these effects were additive, whereas inhibition of Na+/H+ antiporter and Na+/Ca2+ exchang er was without effect. We conclude that: 1) at physiologic concentrati ons, GC enhance sodium influx into VSM cells; 2) this effect is mediat ed through arterial GC receptors; and 3) two distinct transmembrane tr ansport systems for Na+ in VSM cells are activated by GC.