Table 1.

Key differences between inorganic and organic nitrate

	Organic nitrates	Inorganic nitrate
Chemical Structure	Esters of nitric acid (RONO2), where R-represents an organic residue. They are thus small non-polar hydrocarbon chains attached to a nitrooxy-radical (–ONO2).	Salts of nitric acid (nitrate anion bonded to metal cation, such as Na or K).
NO release	Tonic	Released preferentially during hypoxia and acidosis (“when” and “where” it is needed)
Tolerance	Yes	No
Headaches	Yes, often pronounced	No
Currently used by clinicians	Yes, variably	No
Oral bioavailability	Variable, due to hepatic first-pass metabolism	High oral bioavailability. Do not undergo first-pass metabolism
Metabolism and Elimination	Cytochrome P450 system, ALDH-2	Via the nitrate-nitrite pathway: Enterosalivary circulation (reductase activity of bacteria on tongue generates nitrite) Nitrite is metabolized to NO via deoxyhemoglobin, deoxymyoglobin, xanthine oxidase and other enzymes Ultimately excreted by the kidneys
Published or ongoing trials in HFpEF	Nitrate’s effect on activity tolerance in HFPEF (NEAT HFpEF): phase IIb cross-over trial of isosorbide mononitrate in HFpEF154 NCT01516346: phase IIa parallel-arm trial testing the effect of prolonged therapy (24 weeks) with isosorbide dinitrate± hydralazine on late systolic LV load (primary endpoint), LV mass, fibrosis and diastolic function	Published: phase IIa single-dose inorganic nitrate trial, demonstrating improvements in aerobic capacity, exercise vasodilatory and cardiac output reserve, late systolic load. Possible improvement in mitochondrial oxidative function.56 Ongoing, single dose: Phase IIa trials with single-dose inhaled and IV nitrite (NCT02262078, NCT01932606) Ongoing, sustained administration: Phase IIa dose-finding pharmacokinetics/ pharmacodynamics study with KNO3 (NCT02256345) KNO3CK OUT HFPEF: Phase IIb cross-over RCT with KNO3 for 6 weeks.