Structure-activity relationships for blood pressure effects of prednisolone in sheep.

Abstract

This study investigated the effect of 5 day infusions of 6 alpha and 9 alpha-fluoro and 16 alpha, 17 alpha-acetal analogues of prednisolone on blood pressure in conscious sheep. In vivo mineralocorticoid (MC) and glucocorticoid (GC) activities of these steroids were also measured. Prednisolone (100 mg/d) produced a small increase in mean arterial pressure associated with increased fasting plasma [glucose] and polyuria, but had no MC activity. 9 alpha-fluoro substitution greatly enhanced both the pressor and MC activity of prednisolone. The effect of 9 alpha-fluoro substitution on pressor activity was not affected by beta-methylation at C-16 (betamethasone), but was attenuated by either alpha-hydroxylation or alpha-methylation at C-16 (triamcinolone and dexamethasone, respectively). The effect of 9 alpha-fluoro substitution on MC activity as determined by urinary Na excretion was not altered by a methyl group at C-16 in either alpha or beta configuration but the MC activity was attenuated by an alpha-hydroxyl group at C-16. In contrast, 6 alpha-fluoro substitution had little influence on pressor, MC and GC activities. 16 alpha, 17 alpha-acetonide and 16 alpha, 17 alpha-butylidenedioxy substitution increased the pressor activity of parent compounds, but had no influence on either GC or MC activity. This study demonstrates a dissociation between the pressor effects and the MC and GC activities associated with steroid administration and provides further evidence to support the concept of 'hypertensinogenic' class of steroid activity which can be distinguished from their MC and GC activity.