Nongenomic steroid action: Inhibiting effects on cell-to-cell communication between rat ventricular myocytes

Numerous steroids are now believed to possess rapid membrane effects independent of the classical gene activation pathways and are potent modulators of membrane proteins, including voltage-and ligand-operated channels. The effects of steroids on the functional state of the intercellular channels clustered in gap junctions were compared by estimation of either the permeability for a fluorescent dye or the electrical conductance in cardiac myocytes of newborn rat. At 25 muM, the esters of 17beta-estradiol, testosterone and two other androgen hormones rapidly abolished cell-to-cell communication, whereas none of the longer chain steroids, belonging to pregnane (17alpha-hydroxypregnenolone, hydrocortisone), sterol (cholesterol, 25-hydroxycholesterol), bile acid (cholic and lithocholic acids) and vitamin (D3) families, lowered the junctional permeability. Altogether, no correlation with the presence or position of double bonds nor with the trans- or cis-fusion of the A and B rings was recognized. Esterification was a prerequisite for the activity of extracellularly applied steroids but the number, nature and position of ester chain(s) had no influence. 17beta-estradiol or testosterone effects were not prevented when cells were prein-cubated with blockers of the estrogen or androgen nuclear receptors (tamoxifen and cyproterone acetate, respectively). This, together with the rapid time course of the steroid effect (complete within a few minutes), in a rather high active concentration range, suggests a nongenomic mechanism of action. The reversible uncoupling effect of steroids appears to be independent of the shape of the molecules and more probably related to their size and lipo-solubility, which condition their insertion into the lipid bilayer and their subsequent disturbing effects.