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 meta bolites in comparison to other therapeutically used nitric oxide donors. Pe ntaerithrityl tetranitrate was found to be the most potent activator of cyc lic GMP synthesis compared to other clinically relevant organic nitrates (g lyceryl trinitrate, isosorbide dinitrate, isosorbide-5-mononitrate). The ph ase I metabolite pentaerithrityl trinitrate was equipotent with its parent compound in stimulating cyclic GMP. The concentration-response curves of pe ntaerithrityl dinitrate and isosorbide dinitrate for cyclic GMP accumulatio n were virtually identical. In contrast, pentaerithrityl mononitrate and th e phase II metabolite pentaerithrityl trinitrate glucuronide did not alter basal cyclic GIMP levels. It is concluded that the long-term vasodilatory a nd antiischemic effects of pentaerithrityl tetranitrate are caused to a sub stantial extent by cyclic GMP-mediated actions of its pharmacologically act ive phase I metabolites. (C) 1998 Academic Press.