Abstract

The present study compared five standard (isoidide dinitrate, isosorbide dinitrate, erythritol tetranitrate, mannitol hexanitrate, pentaerythritol tetranitrate) and 22 novel organic nitrates with nitroglycerin pharmacologically (specific vasodilator activity) and biochemically (inhibition of terminal electron transport). Pharmacologically, standard nitrates were less effective than nitroglycerin at specific vasodilation, and of the other nitrates (tested at 200 µg/kg), only pentaerythritol trinitrate (40 µg/kg) resembled nitroglycerin (20 µg/kg). The reduced nicotinamide adenine dinucleotide (NADH) oxidase activity of Keilin-Hartree preparations was effectively inhibited (64% at 1 mM) by nitroglycerin; standard nitrates were less potent. Of the other nitrates, two (galactitol and mannitol pentanitrate) were several times as potent as nitroglycerin, and pentaerythritol trinitrate was nearly equipotent for NADH oxidase inhibition. In studies with rat heart mitochondria, nitroglycerin (up to 4 mM) had only slight effects on oxidative phosphorylation, principally decreasing respiratory control ratios by inhibition of state 3 respiration. Aerobic energy-linked reversed electron transport was the bioenergetic function most sensitive to nitroglycerin, with an unusual pattern of inhibition. We conclude that the biochemical test (NADH oxidase inhibition) does not correlate with the pharmacologic test of specific vasodilation, since the two compounds most active biochemically were either inert or weakly active pharmacologically; only pentaerythritol trinitrate was similar to nitroglycerin in both tests.