What is the mechanism in which spironolactone and progesterone increase blood pressure
Geller syndrome is an autosomal-dominant form of hypertension resembling Liddle syndrome, associated with hypokalemia, metabolic alkalosis, and suppressed renin and aldosterone level. Affected individuals develop hypokalemia and early-onset hypertension, which, in females, is exacerbated by pregnancy, often requiring premature delivery in the absence of preeclampsia. Candidate gene sequencing followed by structural protein analysis revealed that a mutated MR (S810L) allowed for activation by steroids lacking a 21-hydroxyl group, such as progesterone, which under normal conditions is not possible. At baseline, the mutated MR is constitutively active, explaining its features of increase distal sodium reabsorption via downstream activation of ENaC.
In this disorder, a novel leucine residue (instead of serine) at position amino acid 810 lies within the MR ligand-binding domain, allowing activation of the receptor by spironolactone instead of inhibition. Amiloride and triamterene are used for treatment of this rare condition.
