Structure-Activity Relationships for Blood Pressure Effects of Prednisolone in Sheep

Abstract

This study investigated the effect of 5 day infusions of 6α and 9α-fluoro and 16α, 17α-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. 9α-fluoro substitution greatly enhanced both the pressor and MC activity of prednisolone. The effect of 9α-fluoro substitution on pressor activity was not affected by β-methylation at C-16 (betamethasone), but was attenuated by either α-hydroxylation or α-methylation at C-16 (triamcinolone and dexamethasone, respectively). The effect of 9α-fluoro substitution on MC activity as determined by urinary Na excretion was not altered by a methyl group at C-16 in either α or β configuration but the MC activity was attenuated by an α-hydroxyl group at C-16. In contrast, 6α-fluoro substitution had little influence on pressor, MC and GC activities. 16α, 17α-acetonide and 16α, 17α-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 a ‘hypertensinogenic’ class of steroid activity which can be distinguished from their MC and GC activity.

Key Words:

• Prednisolone
• synthetic glucocorticoids
• hypertension
• structure-activity relationships