Pentaerythrityl tetranitrate improves the outcome of children born to mothers with compromised uterine perfusion-12-months follow-up and safety data of the double-blind randomized PETN trial.

BACKGROUND: This is a follow-up study to the pentaerythrityl tetranitrate randomized controlled multicenter trial that reports neonatal outcome data of newborns admitted to neonatal intensive care units and outcome data of the offspring at 12 months of age. OBJECTIVE: We present data on adverse events reported during the study to document the safety of pentaerythrityl tetranitrate treatment during pregnancy. To further evaluate the effects of pentaerythrityl tetranitrate on neonatal and long-term outcomes, we present follow up data from of 240 children at 12 months of age, including information on height, weight, head circumference, developmental milestones, and the presence of chronic disease and of 144 newborns admitted to the neonatal intensive care unit during the trial. STUDY DESIGN: The pentaerythrityl tetranitrate trial was a randomized, double-blind, placebo-controlled study designed to assess the efficacy and safety of the nitric oxide-donor pentaerythrityl tetranitrate in the prevention of fetal growth restriction and perinatal death in pregnancies complicated by abnormal placental perfusion. RESULTS: Results at 12 months demonstrated that significantly more children were age appropriately developed without impairments in the pentaerythrityl tetranitrate group (P=.018). In addition, the presence of chronic disease was lower in the pentaerythrityl tetranitrate group (P=.041). Outcome data of the 144 newborns admitted to the neonatal intensive care unit did not reveal differences between the treatment and placebo groups. There were no differences in the number or nature of reported adverse events between the study groups. CONCLUSION: The analysis shows that study children born in the pentaerythrityl tetranitrate cohort have a clear advantage compared with the placebo group at the age of 12 months, as evidenced by the increased incidence of normal development without the presence of chronic disease. Although safety has been proven, further follow-up studies are necessary to justify pentaerythrityl tetranitrate treatment during pregnancies complicated by impaired uterine perfusion.

(1-(4-(5-Phenyl-1,3,4-oxadiazol-2-yl)phenyl)-1H-1,2,3-triazol-4-yl)-methylenyls α,ω-Bisfunctionalized 3- and 4-PEG: Synthesis and Photophysical Studies.

Two new azaheterocycle-based bolas, such as (1-(4-(5-phenyl-1,3,4-oxadiazol-2-yl)phenyl)-1H-1,2,3-triazol-4-yl)-methylenyls α,ω-bisfunctionalized PEGs, were prepared via Cu-catalyzed click reaction between 2-(4-azidophenyl)-5-(aryl)-oxadiazole-1,3,4 and terminal ethynyls derived from PEG-3 and PEG-4. Due to the presence of two heteroaromatic cores and a PEG linker, these bola molecules are considered as promising fluorescent chemosensors for electron-deficient species. As a result of a well-pronounced "turn-off" fluorescence response towards common nitro-explosive components, such as 2,4-dinitrotoluene (DNT) and 2,4,6-trinitrotoluene (TNT), hard-to-detect pentaerythritol tetranitrate (PETN), as well as Hg2+ cation was observed.

Effect of pentaerythritol tetranitrate (PETN) on the development of fetal growth restriction in pregnancies with impaired uteroplacental perfusion at midgestation-a randomized trial.

BACKGROUND: Fetal growth restriction is strongly associated with impaired placentation and abnormal uteroplacental blood flow. Nitric oxide donors such as pentaerythritol tetranitrate are strong vasodilators and protect the endothelium. Recently, we demonstrated in a randomized controlled pilot study a 38% relative risk reduction for the development of fetal growth restriction or perinatal death following administration of pentaerythritol tetranitrate to pregnant women at risk, identified by impaired uterine perfusion at midgestation. Results of this monocenter study prompted the hypothesis that pentaerythritol tetranitrate might have an effect in pregnancies with compromised placental function as a secondary prophylaxis. OBJECTIVE: This study aimed to test the hypothesis that the nitric oxide donor pentaerythritol tetranitrate reduces fetal growth restriction and perinatal death in pregnant women with impaired placental perfusion at midgestation in a multicenter trial. STUDY DESIGN: In this multicenter, randomized, double-blind, placebo-controlled trial, 2 parallel groups of pregnant women presenting with a mean uterine artery pulsatility index >95th percentile at 19+0 to 22+6 weeks of gestation were randomized to 50-mg Pentalong or placebo twice daily. Participants were assigned to high- or low-risk groups according to their medical history before randomization was performed block-wise with a fixed block length stratified by center and risk group. The primary efficacy endpoint was the composite outcome of perinatal death or development of fetal growth restriction. Secondary endpoints were neonatal and maternal outcome parameters. RESULTS: Between August 2017 and March 2020, 317 participants were included in the study and 307 were analyzed. The cumulative incidence of the primary outcome was 41.1% in the pentaerythritol tetranitrate group and 45.5% in the placebo group (unadjusted relative risk, 0.90; 95% confidence interval, 0.69-1.17; adjusted relative risk, 0.90; 95% confidence interval, 0.69-1.17; P=.43). Secondary outcomes such as preterm birth (unadjusted relative risk, 0.73; 95% confidence interval, 0.56-0.94; adjusted relative risk, 0.73; 95% confidence interval, 0.56-0.94; P=.01) and pregnancy-induced hypertension (unadjusted relative risk, 0.65; 95% confidence interval, 0.46-0.93; adjusted relative risk, 0.65; 95% confidence interval, 0.46-0.92; P=0.01) were reduced. CONCLUSION: Our study failed to show an impact of pentaerythritol tetranitrate on the development of fetal growth restriction and perinatal death in pregnant women with impaired uterine perfusion at midgestation. Pentaerythritol tetranitrate significantly reduced secondary outcome parameters such as the incidence of preterm birth and pregnancy-induced hypertension in these pregnancies.

Iron and Copper Doped Zinc Oxide Nanopowders as a Sensitizer of Industrial Energetic Materials to Visible Laser Radiation.

The development of methods ensuring reliable control over explosive chemical reactions is a critical task for the safe and efficient application of energetic materials. Triggering the explosion by laser radiation is one of the promising methods. In this work, we demonstrate a technique of applying the common industrial high explosive pentaerythritol tetranitrate (PETN) as a photosensitive energetic material by adding zinc oxide nanopowders doped with copper and iron. Nanopowders of ZnO:Fe and ZnO:Cu able to absorb visible light were synthesized. The addition of one mass percent nanopowders in PETN decreased the threshold energy density of its initiation through Nd:YAG laser second harmonic (2.33 eV) by more than five times. The obtained energetic composites can be reliably initiated by a CW blue laser diode with a wavelength of 450 nm and power of 21 W. The low threshold initiation energy and short irradiation exposure of the PETN-ZnO:Cu composite makes it applicable in laser initiation devices. PETN-ZnO:Cu also can be initiated by an infrared laser diode with a wavelength of 808 nm. The proposed photochemical mechanism of the laser-induced triggering of the explosion reaction in the studied energetic composites was formulated. The results demonstrate the high promise of using nanomaterials based on zinc oxide as a sensitizer of industrial energetic materials to visible laser radiation.

Vascular biotransformation of organic nitrates is independent of cytochrome P450 monooxygenases.

BACKGROUND AND PURPOSE: Organic nitrates such as nitroglycerin (NTG) or pentaerythritol tetranitrate (PETN) have been used for over a century in the treatment of angina or ischaemic heart disease. These compounds are prodrugs which release their nitrovasodilators upon enzymic bioactivation by aldehyde dehydrogenase (ALDH2) or cytochromes P450 (CYP). Whereas ALDH2 is known to directly activate organic nitrates in vessels, the contribution of vascular CYPs is unknown and was studied here. EXPERIMENTAL APPROACH: As all CYPs depend on cytochrome P450 reductase (POR) as electron donor, we generated a smooth muscle cell-specific, inducible knockout mouse of POR (smcPOR-/- ) to investigate the contribution of POR/CYP to vascular biotransformation of organic nitrates. KEY RESULTS: Microsomes containing recombinant CYPs expressed in human vascular tissues released nitrite from NTG and PETN with CYP2C9 and CYP2C8 being most efficient. SFK525, a CYP suicide inhibitor, blocked this effect. smcPOR-/- mice exhibited no obvious cardiovascular phenotype (normal cardiac weight and endothelium-dependent relaxation) and plasma and vascular nitrite production was similar to control (CTL) animals. NTG- and PETN-induced relaxation of isolated endothelium-intact or endothelium-denuded vessels were identical between CTL and smcPOR-/- . Likewise, nitrite release from organic nitrates in aortic rings was not affected by deletion of POR in smooth muscle cells (SMCs). In contrast, inhibition of ALDH2 by benomyl (10 µM) inhibited NTG-induced nitrite production and relaxation. Deletion of POR did not modulate this response. CONCLUSIONS AND IMPLICATIONS: Our data suggest that metabolism by vascular CYPs does not contribute to the pharmacological function of organic nitrates.

Engineering the Microstructure and Morphology of Explosive Films via Control of Interfacial Energy.

Physical vapor deposition of organic explosives enables growth of polycrystalline films with a unique microstructure and morphology compared to the bulk material. This study demonstrates the ability to control crystal orientation and porosity in pentaerythritol tetranitrate films by varying the interfacial energy between the substrate and the vapor-deposited explosive. Variation in density, porosity, surface roughness, and optical properties is achieved in the explosive film, with significant implications for initiation sensitivity and detonation performance of the explosive material. Various surface science techniques, including angle-resolved X-ray photoelectron spectroscopy and multiliquid contact angle analysis, are utilized to characterize interfacial characteristics between the substrate and explosive film. Optical microscopy and scanning electron microscopy of pentaerythritol tetranitrate surfaces and fracture cross sections illustrate the difference in morphology evolution and the microstructure achieved through surface energy modification. X-ray diffraction studies with the Tilt-A-Whirl three-dimensional pole figure rendering and texture analysis software suite reveal that high surface energy substrates result in a preferred (110) out-of-plane orientation of pentaerythritol tetranitrate crystallites and denser films. Low surface energy substrates create more randomly textured pentaerythritol tetranitrate and lead to nanoscale porosity and lower density films. This work furthers the scientific basis for interfacial engineering of polycrystalline organic explosive films through control of surface energy, enabling future study of dynamic and reactive detonative phenomena at the microscale. Results of this study also have potential applications to active pharmaceutical ingredients, stimuli-responsive polymer films, organic thin film transistors, and other areas.

Fetal programming effects of pentaerythritol tetranitrate in a rat model of superimposed preeclampsia.

Preeclampsia is a common medical condition during pregnancy and a major cause of maternal and prenatal mortality. The present study was conducted to investigate the effects of maternal treatment with pentaerythritol tetranitrate (PETN) in Dahl salt-sensitive rats (DSSR), a model of superimposed preeclampsia. F0 parental DSSR were treated with PETN (50 mg/kg) from the time point of mating to the end of lactation. Maternal PETN treatment improved fetal growth and had no effect on blood pressure in DSSR offspring fed with normal chow or high-salt diet. Upon high-fat diet (HFD) feeding, offspring from PETN-treated mother showed improved glucose tolerance despite similar weight gain. Unexpectedly, maternal PETN treatment significantly potentiated the HFD-induced blood pressure elevation in male DSSR offspring. Endothelium-derived hyperpolarization factor (EDHF)-mediated vasodilation was similar between NCD-fed and HFD-fed control offspring but was markedly reduced in HFD-fed PETN offspring. EDHF genes were downregulated in the vasculature of HFD-fed PETN offspring, which was associated with epigenetic changes in histone modifications. In conclusion, maternal PETN treatment in DSSR shows both beneficial and unfavorable effects. It improves fetal growth and ameliorates glucose tolerance in the offspring. Although maternal PETN treatment has no effect on blood pressure in offspring fed with normal chow or high-salt diet, the offspring is at higher risk to develop HFD-induced hypertension. PETN may potentiate the blood pressure response to HFD by epigenetic modifications of EDHF genes. KEY MESSAGES: The core findings of this article suggest that maternal PETN treatment of DSSR, a rat model of a spontaneous superimposed preeclampsia, leads to • Improvement of fetal growth; • No changes of maternal blood pressure or markers of preeclampsia; • Amelioration of HFD-induced glucose intolerance in adult offspring; • No changes in blood pressure development of the offspring on normal chow or high salt-diet; • Potentiation of blood pressure elevation of the offspring on HFD.

Renal Effects of Fetal Reprogramming With Pentaerythritol Tetranitrate in Spontaneously Hypertensive Rats.

AIMS: Current antihypertensive therapies cannot cure hypertension and a life-long medication is necessary. Maternal treatment may represent a promising strategy for hypertension treatment. We have previously shown that maternal treatment of spontaneously hypertensive rats (SHR) with pentaerythritol tetranitrate (PETN) leads to a persistent blood pressure reduction in the female offspring. The underlying mechanisms include improved endothelial function resulting from long-lasting epigenetic changes. In the present study, we address the renal effects of maternal PETN treatment. METHODS AND RESULTS: F0 parental SHR were fed with either normal chow or PETN-containing (1 g/kg) chow ad libitum from the time point of mating to the end of lactation period. The F1 offspring received normal chow without PETN from the time point of weaning (at the age of 3 weeks). At the age of 16 weeks, female PETN offspring showed lower blood pressure than the control. No difference was observed in male offspring. All following experiments were performed with kidneys from 16-week-old female offspring. Maternal PETN treatment reduced the mRNA and protein expression of angiotensin-converting enzyme (ACE) and basic fibroblast growth factor (FGF2), resulting from epigenetic modifications found at the proximal promoter regions. The expression levels of mineralocorticoid receptor (MR) and factors in the MR signalling pathway (Rac1 and Sgk1) were also reduced by PETN. Major profibrotic cytokines, including Wnt4, TNF-alpha, TGF-beta, and MMP9, were downregulated by PETN, which was associated with reduced collagen deposition and glomerulus sclerosis in the kidney of PETN offspring. In addition, PETN treatment also decreased the markers of inflammation and immune cell infiltration in the kidneys. CONCLUSIONS: PETN maternal treatment leads to epigenetic changes in the kidney of female SHR offspring. The reduced renal inflammation, alleviated kidney fibrosis, and decreased MR signalling are potential mechanisms contributing to the observed blood pressure-lowering effect.

Selective colorimetric detection of pentaerythritol tetranitrate (PETN) using arginine-mediated aggregation of gold nanoparticles.

Detection of pentaerythritol tetranitrate (PETN) as an explosive has been of great interest because of public safety and military concerns. Here, we have presented a simple, selective and sensitive colorimetric method for direct detection of PETN. The gold nanoparticles (AuNPs) were first exposed to arginine which has primary amines in its structure. Electron deficient -NH2 groups from arginine could strongly interact with -NO2 groups of PETN as electron donors. Hydrogen bonding happens between the -NO2 group of PETN and -NH2 group of arginine molecules. Therefore, selective aggregation of AuNPs happened because of the donor-acceptor and hydrogen bonding interactions. Due to the aggregation, the color of reddish AuNPs turned to blue or purple depend on PETN concentration. A good linear relationship was achieved between the aggregation signal (absorbance ratio of A650/A520) of the probe and the concentration of PETN with a limit of detection of 0.169 µmol L-1. Furthermore, we have found that the developed probe can detect PETN in complex matrices of groundwater and soil samples.

Molecular dynamics research on effect of doping defects on properties of PETN.

To investigate the effect of doping defects on properties of pentaerythritol tetranitrate (PETN), the "perfect" and doping defective crystal models of PETN containing pentaerythritol (PE), pentaerythritol mononitrate (PEMonoN), pentaerythritol dinitrate (PEDiN), and pentaerythritol trinitrate (PETRIN) were established, respectively. Molecular dynamics (MD) method was applied to perform simulations, and sensitivity, detonation performance, and mechanical properties were calculated and compared. The results indicate that compared with PETN (1 1 0) supercell model, the interaction energy of trigger bond and cohesive energy density of the doped defect models decreased by 2.21~12.43 kJ mol-1 and 0.0219~0.0421 kJ cm-3, respectively, indicating that the sensitivity of defective models increases and the safety decreases. The density, detonation velocity, and detonation pressure of the doped defect model decreased by 0.018~0.061 g cm-3, 77.833~272.809 m s-1, and 0.746~2.544 GPa, respectively, and the oxygen balance is declined, indicating that the energy density of PETN decreased and the power decreased. Doped defects also cause the elastic modulus, bulk modulus, and shear modulus of PETN to decrease by 0.75~2.16 GPa, 0.44~0.89 GPa, and 0.30~0.89 GPa, respectively. The ratio of bulk modulus to shear modulus and Cauchy pressure increased by 0.05~0.28 GPa and 0.09~1.13 GPa, respectively, indicating that the deformation resistance, fracture strength, and hardness of the doped defect model decrease, stiffness decreases, and flexibility and ductility increase.

Air blast TNT equivalence factors of high explosive material PETN for bare charges.

The concept of TNT equivalence is often invoked to predict the blast parameters generated from explosions, in which high explosives other than Trinitrotoluene (TNT) are used. This paper discusses the TNT equivalence concept for bare charges using Pentaerythritol tetranitrate (PETN). At first, a review of different methods to derive TNT equivalence factors is given. After that, numerical simulations are conducted in order to obtain overpressure and impulse data, which is fitted by using the curve-fitting method. Meanwhile, the equations representing the fitted curves of peak overpressures and maximum impulses are employed to calculate the TNT equivalence factors for overpressure and impulse, respectively. Fitting these data, formulae are developed to calculate the TNT equivalence factors of PETN for overpressure and impulse. It is found that a single value, i.e. 1.258 for overpressure and 1.272 for impulse, can be used to convert the charge mass of PETN to TNT in the far field. This statement is confirmed by a series of free field air blast measurements. However, the TNT equivalence factors of PETN vary significantly in the near field. The value can be as large as 2.6 times the one in the far field.

Part per quadrillion quantitation of pentaerythritol tetranitrate vapor using online sampling gas chromatography-mass spectrometry.

The development of an online sampling method using programmable temperature vaporization gas chromatography with a mass spectrometer detector (PTV-GC/MS) for the analysis of trace pentaerythritol tetranitrate (PETN) vapor is presented. PETN degradation was minimized by optimizing the temperature and flow rates of the vapor sampling infrastructure. Validation of the online method was done using a previously published technique, vapor sampling with Tenax-TA thermal desorption tubes followed by analysis with a thermal desorption system coupled to a programmable temperature vaporization gas chromatograph with a micro-electron capture detector (TDS-PTV-GC/µECD). Trace PETN vapor was generated using state-of-the-art instrumentation known as the TESTbed, located at the US Naval Research Laboratory. For PETN vapor concentrations in the parts per trillionvolume (pptv) range, quantitative results from the TDS-PTV-GC/µECD consistently showed concentrations approximately double that measured by the online PTV-GC/MS method, indicating that sample loss due to additional exposure to the vapor sampling infrastructure occurs when using online sampling. Further utilization of the online PTV-GC/MS system allowed for the quantitation/semi-quantitation of PETN vapor concentrations as low as 260 parts per quadrillionvolume (ppqv) with only 10 min of sampling time.

Deep Ultraviolet Standoff Photoacoustic Spectroscopy of Trace Explosives.

We demonstrate deep ultraviolet (UV) photoacoustic spectroscopy (PAS) of trace explosives using a sensitive microphone at meter standoff distances. We directly detect 10 µg/cm2 of pentaerythritol tetranitrate (PETN), 2,4,6-trinitrotoluene (TNT), and ammonium nitrate (AN) with 1 s accumulations from a 3 m standoff distance. Large PAS signals for standoff detection are achieved by exciting into the absorption bands of the explosives with a 213 nm laser. We also investigate the impact of the deep UV photochemistry of AN on the PAS signal strength and stability. We find that production of gaseous species during photolysis of AN enhances the PAS signal strength. This deep UV photochemistry can, however, limit the PAS signal lifetimes when detecting trace quantities.

1H, 15N and 13C backbone resonance assignments of pentaerythritol tetranitrate reductase from Enterobacter cloacae PB2.

Pentaerythritol tetranitrate reductase (PETNR) is a flavoenzyme possessing a broad substrate specificity and is a member of the Old Yellow Enzyme family of oxidoreductases. As well as having high potential as an industrial biocatalyst, PETNR is an excellent model system for studying hydrogen transfer reactions. Mechanistic studies performed with PETNR using stopped-flow methods have shown that tunneling contributes towards hydride transfer from the NAD(P)H coenzyme to the flavin mononucleotide (FMN) cofactor and fast protein dynamics have been inferred to facilitate this catalytic step. Herein, we report the near-complete 1H, 15N and 13C backbone resonance assignments of PETNR in a stoichiometric complex with the FMN cofactor in its native oxidized form, which were obtained using heteronuclear multidimensional NMR spectroscopy. A total of 97% of all backbone resonances were assigned, with 333 out of a possible 344 residues assigned in the 1H-15N TROSY spectrum. This is the first report of an NMR structural study of a flavoenzyme from the Old Yellow Enzyme family and it lays the foundation for future investigations of functional dynamics in hydride transfer catalytic mechanism.

Indirect Determination of Pentaerythritol Tetranitrate (PETN) with a gold nanoparticles-based colorimetric sensor.

Pentaerythritol tetranitrate (PETN) is the nitrate ester of pentaerythritol, used as an energetic and filling material for military and civilian purposes and rarely for terrorist actions. As there is no reliable nano-colorimetric method for PETN assay, we developed an indirect method based on the determination of nitrite, obtained by reduction of nitrate derived from the alkaline hydrolysis of PETN with H2O2. We colorimetrically determined the final product, nitrite, by both conventional Griess reaction and a recently developed gold nanoparticle-4-aminothiophenol-N-(1-naphthyl)-ethylenediamine (AuNP-4-ATP+NED) method. Nitramines (RDX and HMX), if present, could be degraded by alkaline hydrolysis, without affecting PETN. The analytical performance characteristics of the developed assays as molar absorptivity (ε), limits of detection (LOD) and quantification (LOQ) were: ɛ=1.06×105 L mol-1 cm-1, LOD=0.03mgL-1 and LOQ=0.11mgL-1 for indirect Griess method; ɛ=1.9×104Lmol-1 cm-1; LOD=0.12mgL-1 and LOQ=0.4mgL-1 for AuNP-4-ATP+NED method. Both methods were applied to a 1:1 (w/w) mixture of PETN and TNT (corresponding to the composition of military explosive 'Pentolite'). In order to eliminate the interference from TNT, the Meisenheimer anion of TNT formed in alkaline medium was retained on a strongly basic anion exchange resin column. As PETN had a very low solubility in water, common soil ions could be eliminated by prewashing the sample with water, or in acetone-water mixtures, Ca2+, K+, Cl-, SO42-, and NO3- could be tolerated at equal (1:1) mass ratios. Soil nitrates and nitrites, at a mass ratio of 50:1, could be separated from PETN with the aid of their insolubilities in acetone and of their retention affinity toward a strongly basic anion-exchange resin. The developed method was statistically validated against a reference GC-MS method.

Ultraviolet Raman Wide-Field Hyperspectral Imaging Spectrometer for Standoff Trace Explosive Detection.

We constructed the first deep ultraviolet (UV) Raman standoff wide-field imaging spectrometer. Our novel deep UV imaging spectrometer utilizes a photonic crystal to select Raman spectral regions for detection. The photonic crystal is composed of highly charged, monodisperse 35.5 ± 2.9 nm silica nanoparticles that self-assemble in solution to produce a face centered cubic crystalline colloidal array that Bragg diffracts a narrow ∼1.0 nm full width at half-maximum (FWHM) UV spectral region. We utilize this photonic crystal to select and image two different spectral regions containing resonance Raman bands of pentaerythritol tetranitrate (PETN) and NH4NO3 (AN). These two deep UV Raman spectral regions diffracted were selected by angle tuning the photonic crystal. We utilized this imaging spectrometer to measure 229 nm excited UV Raman images containing ∼10-1000 µg/cm2 samples of solid PETN and AN on aluminum surfaces at 2.3 m standoff distances. We estimate detection limits of ∼1 µg/cm2 for PETN and AN films under these experimental conditions.

Pentaerythritol Tetranitrate Targeting Myocardial Reactive Oxygen Species Production Improves Left Ventricular Remodeling and Function in Rats With Ischemic Heart Failure.

Reduced nitric oxide bioavailability contributes to progression of cardiac dysfunction and remodeling in ischemic heart failure. Clinical use of organic nitrates as nitric oxide donors is limited by development of nitrate tolerance and reactive oxygen species formation. We investigated the effects of long-term therapy with pentaerythritol tetranitrate (PETN), an organic nitrate devoid of tolerance, in rats with congestive heart failure after extensive myocardial infarction. Seven days after coronary artery ligation, rats were randomly allocated to treatment with PETN (80 mg/kg BID) or placebo for 9 weeks. Long-term PETN therapy prevented the progressive left ventricular dilatation and improved left ventricular contractile function and relaxation in rats with congestive heart failure. Mitochondrial superoxide anion production was markedly increased in the failing left ventricular myocardium and nearly normalized by PETN treatment. Gene set enrichment analysis revealed that PETN beneficially modulated the dysregulation of mitochondrial genes involved in energy metabolism, paralleled by prevention of uncoupling protein-3, thioredoxin-2, and superoxide dismutase-2 downregulation. Moreover, PETN provided a remarkable protective effect against reactive fibrosis in chronically failing hearts. Mechanistically, induction of heme oxygenase-1 by PETN prevented mitochondrial superoxide generation, NOX4 upregulation, and ensuing formation of extracellular matrix proteins in fibroblasts from failing hearts. In summary, PETN targeting reactive oxygen species generation prevented the changes of mitochondrial antioxidant enzymes and progressive fibrotic remodeling, leading to amelioration of cardiac functional performance. Therefore, PETN might be a promising therapeutic option in the treatment of ischemic heart diseases involving oxidative stress and impairment in nitric oxide bioactivity.

Use of nitrates in ischemic heart disease.

Short-acting nitrates are beneficial in acute myocardial ischemia. However, many unresolved questions remain about the use of long-acting nitrates in stable ischemic heart disease. The use of long-acting nitrates is weakened by the development of endothelial dysfunction and tolerance. Also, we currently ignore whether lower doses of transdermal nitroglycerin would be better than those presently used. Multivariate analysis data from large nonrandomized studies suggested that long-acting nitrates increase the incidence of acute coronary syndromes, while data from another multivariate study indicate that they have positive effects. Because of methodological differences and open questions, the two studies cannot be compared. A study in Japanese patients with vasospastic angina has shown that, when compared with calcium antagonists, long-acting nitrates do not improve long-term prognosis and that the risk for cardiac adverse events increases with the combined therapy. We have many unanswered questions.

Maternal treatment of spontaneously hypertensive rats with pentaerythritol tetranitrate reduces blood pressure in female offspring.

Pentaerythritol tetranitrate is devoid of nitrate tolerance and shows no reproductive or developmental toxicity in animal studies. Recently, pentaerythritol tetranitrate has been demonstrated to reduce the risk of intrauterine growth restriction and the risk of preterm birth in women with abnormal placental perfusion. This study was conducted to test the perinatal programming effect of pentaerythritol tetranitrate in spontaneously hypertensive rats, a rat model of genetic hypertension. Parental spontaneously hypertensive rats were treated with pentaerythritol tetranitrate (50 mg/kg per day) during pregnancy and lactation periods; the offspring received standard chow without pentaerythritol tetranitrate after weaning. Maternal treatment with pentaerythritol tetranitrate had no effect on blood pressure in male offspring. In the female offspring, however, a persistent reduction in blood pressure was observed at 6 and 8 months. This long-lasting effect was accompanied by an upregulation of endothelial nitric oxide synthase, mitochondrial superoxide dismutase, glutathione peroxidase 1, and heme oxygenase 1 in the aorta of 8-month-old female offspring, which was likely to result from epigenetic changes (enhanced histone 3 lysine 27 acetylation and histone 3 lysine 4 trimethylation) and transcriptional activation (enhanced binding of DNA-directed RNA polymerase II to the transcription start site of the genes). In organ chamber experiments, the endothelium-dependent, nitric oxide-mediated vasodilation to acetylcholine was enhanced in aorta from female offspring of the pentaerythritol tetranitrate-treated parental spontaneously hypertensive rats. In conclusion, maternal pentaerythritol tetranitrate treatment leads to epigenetic modifications, gene expression changes, an improvement of endothelial function and a persistent blood pressure reduction in the female offspring.

Accurate quantitation of pentaerythritol tetranitrate and its degradation products using liquid chromatography-atmospheric pressure chemical ionization-mass spectrometry.

After an explosion of pentaerythritol tetranitrate (PETN), its degradation products pentaerythritol trinitrate (PETriN), dinitrate (PEDiN) and mononitrate (PEMN) were detected using liquid chromatography-atmospheric-pressure chemical-ionization-mass spectrometry (LC-APCI-MS). Discrimination between post-explosion and naturally degraded PETN could be achieved based on the relative amounts of the degradation products. This information can be used as evidence when investigating a possible relationship between a suspect and a post-explosion crime scene. The present work focuses on accurate quantitation of PETN and its degradation products, using PETriN, PEDiN and PEMN standards specifically synthesized for this purpose. With the use of these standards, the ionization behavior of these compounds was studied, and a quantitative method was developed. Quantitation of PETN and trace levels of its degradation products was shown to be possible with accuracy between 85.7% and 103.7% and a precision ranging from 1.3% to 11.5%. The custom-made standards resulted in a more robust and reliable method to discriminate between post-explosion and naturally-degraded PETN.