Pentaerithrityl tetranitrate and its phase I metabolites are potent activators of cellular cyclic GMP accumulation

Using pig kidney epithelial cells (LLC-PK₁), the present study assesses the cyclic GMP stimulatory effect of pentaerithrityl tetranitrate and its metabolites in comparison to other therapeutically used nitric oxide donors. Pentaerithrityl tetranitrate was found to be the most potent activator of cyclic GMP synthesis compared to other clinically relevant organic nitrates (glyceryl trinitrate, isosorbide dinitrate, isosorbide-5-mononitrate). The phase I metabolite pentaerithrityl trinitrate was equipotent with its parent compound in stimulating cyclic GMP. The concentration-response curves of pentaerithrityl dinitrate and isosorbide dinitrate for cyclic GMP accumulation were virtually identical. In contrast, pentaerithrityl mononitrate and the phase II metabolite pentaerithrityl trinitrate glucuronide did not alter basal cyclic GMP levels. It is concluded that the long-term vasodilatory and anti-ischemic effects of pentaerithrityl tetranitrate are caused to a substantial extent by cyclic GMP-mediated actions of its pharmacologically active phase I metabolites.