Richard Bouley, a postdoctoral student in Brown's lab, proposed bypassing the V2R which is activated through a signaling molecule called cyclic-AMP. Bouley thought the same effect might be achieved by increasing another signaling molecule, cyclic-GMP (cGMP) which would accumulate aquaporins on the cell membrane, thus stimulating water permeability.

Viagra's non-blood pressure effect successfully 'mimics' vasopressin action

In vitro tests showed that cGMP elevation in these cells "could be achieved by inhibition of cGMP phosphodiesterases (PDE), specifically PDE5" a PDE isoform that is expressed in renal collecting ducts. The search then began for a PDE5 inhibitor that had been clinically tested. It didn't take long: Viagra (sildenafil citrate marketed by Pfizer Inc.) is a cGMP phosphodiesterase inhibitor with annual U.S. sales estimated at about $1 billion in the erectile dysfunction market.

Administering Viagra to kidney cells showed a rapid rise in cGMP levels, not because more was being produced, but because less was being broken down. When tested in Brattleboro rats, which don't produce vasopressin, Viagra "mimicked the effect of vasopressin," Brown said, "producing the cascade of events leading to aquaporin accumulation on the cell surface."

"This study provides proof-of-principle data that pharmacologically mediated PDE5 inhibition can potentially be used to bypass the V2R signaling cascade, leading to AQP2 appearance on the plasma membrane of epithelial cells," the paper said. Brown added later that there "are many diseases where there are problems in trafficking of proteins that don't get to the right place, and it's unlikely that this mechanism is restricted to the w
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29-Jun-2005