Nitrogen-bound diazen-1-ium-1,2-diolates (diazeniumdiolates, "NONOates", "solid NO") are generally prepared from secondary amines and nitric oxide and are compounds of first choice for the direct release of nitric oxide (NO). First, we report on the relationships between the structures of the amines and the formation rates of the corresponding NONOates, second on the structures of the NONOates and the rate of NO release and finally between the rates of NONOate formation and NO release from these species. A series of differently sized and substituted cyclic and aliphatic amines were used to quantify the reactivity of amines towards NO by monitoring the decrease in NO pressure with the NOtizer, an apparatus developed for this study. The release of NO was measured amperometrically with an NO-sensitive electrode and the half-lives of novel diazeniumdiolates were determined by UV spectroscopy. It was found that steric hindrance
Neither therapeutic dosage of nitrovasodilators nor the development of tolerance correlates with nitrate groups in these molecules. Clinically, low dosages of glyceryl trinitrate (GTN) develop tolerance, but 100-fold higher dosages of pentaerythrityl tetranitrate (PETN) do not. Vasorelaxation was studied on prostaglandian F2alpha (PGF2alpha)-precontracted porcine pulmonary arteries in organ bath procedure. In vitro tolerance was induced by incubating the arteries with different nitrate concentrations and thereafter concentration-response curves were repeated. Furthermore, 14 mg/kg PETN were daily administered to rats by gavage; PETN and metabolites were measured in feces and blood. In vitro, the vasodilator potencies increased from mononitrates to tetranitrates (pD2: 4.14 to 8.18); PETN was the most potent vasodilator. In vitro tolerance was found with PETN and trinitrates but not with dinitrates and mononitrates. Thus, in vitro tolerance correlated with the in vitro potency of nitrates but not with the vasodilator potency of NO donors in general, because S-nitroso-N-aectyl-D-penicillamine and N-phenylpiperazin-NONOate were more potent than GTN but did not induce tolerance. After feeding of rats with PETN, pentaerythrityl dinitrate (PEdiN) and mononitrate (PEmonoN) but neither PETN nor PEtriN (both detected in feces) were found in the blood. The missing systemic bioavailability of PETN and PEtriN may explain the discrepancy between in vitro and in vivo findings. We conclude that the partially denitrated metabolites PEdiN and PEmonoN contribute to the moderate and tolerance-devoid clinical activity of PETN.
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