Potency and In Vitro Tolerance of Organic Nitrates: Partially Denitrated Metabolites Contribute to the Tolerance-Devoid Activity of Pentaerythrityl Tetranitrate

Abstract

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.

Characterization of New Organic Nitrate Hybrid Drugs Covalently Bound to Valsartan and Cilostazol

“…4b, table 1). On the other hand, the less potent organic nitrates ISDN and ISMN showed little change in their concentration-relaxation curve upon rechallenge (as reported previously by Koenig et al [25]), suggesting that the induction of clinical tolerance for these compounds may require more time to manifest, for example through some translational and/or transcriptional processes. As with SNP, all three of the cilostazol-based compounds showed a clear right shift of the concentration-relaxation curve upon rechallenge ( fig.…”

A new class of organic nitrates: investigations on bioactivation, tolerance and cross‐tolerance phenomena

“…The present study extends our previous results on organic nitrate bioactivation and tolerance mechanisms (Munzel et al., 2005a; Daiber et al., 2008). We have shown that a clear correlation between the number of nitrate (‐ONO 2 ) groups in the molecule and the vasodilator potency exists (Koenig et al., 2007a; Wenzel et al., 2007b). Moreover, we demonstrated that potency correlates with the induction of the formation of mitochondrial ROS (Daiber et al., 2004).…”

“…In previous studies, we have demonstrated that organic nitrate potency correlates with the number of nitrate groups and that high potency nitrates with pD 2 ‐values >6 [pentaerithrityl tetranitrate (PETN), GTN and pentaerithrityl trinitrate (PETriN)] are bioactivated by ALDH‐2 (Daiber et al. , 2004; Koenig et al. , 2007a; Wenzel et al.…”

Organic Nitrates and Nitrate Resistance in Diabetes: The Role of Vascular Dysfunction and Oxidative Stress with Emphasis on Antioxidant Properties of Pentaerithrityl Tetranitrate

“…A remarkable exception seems to be PETN [72]. Some of these effects are related to special pharmacokinetics of PETN [73, 74], but, upon chronic administration, PETN also induces antioxidant pathways at the genomic level and cardioprotective genes (e.g., Apex1 and NFAT5) [75]. Among these induced antioxidant genes are heme oxygenase-1 (HO-1) and ferritin [76], both possessing highly protective properties.…”