Atrioventricular conduction following ligation of the anterior septal artery in the dog. An electrocardiographic, histopathologic and histochemical study.
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Animals↗
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Results for “PENTAERYTHRITOL”
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The gastrointestinal absorption of organic nitrates.
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Administration, Oral↗
Lactate studies of the dog in oligemic shock.
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Acid-Base Equilibrium↗
Vascular symptomatic relief during administration of ethylchlorophenoxyisobutyrate (clofibrate).
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Adult↗
Cross-polarisation method for improvement of 14N NQR signal detectability.
This is a study of the cross-polarization effects in the case of 14N quadrupolar spin-system with a long spin-lattice relaxation time. Two important benefits of the cross-polarization technique were demonstrated for PETN: (i) a polarization transfer resulting in increased NQR single shot signal response and (ii) a dynamic reduction in recovery time of the NQR system allowing scan repetition on a much shorter timescale. It was proved that this technique can reduce the optimal waiting time between pulse sequences up to 60 times through a significant reduction of the relaxation time of the quadrupolar spin-system. All experiments were carried out at room temperature using spin-locking multi-pulse sequences and small external magnetic field.
Algorithms↗
NO-donors, part X [1] : investigations on the stability of pentaerythrityl tetranitrate (PETN) by HPLC-chemoluminescence-N-detection (CLND) versus UV-detection in HPLC.
HPLC in combination with chemoluminescence-N-detection (CLND) is very useful for the analysis of pentaerythrityl tetranitrate (PETN) and its possible biological and chemical degradation products pentaerythrityl trinitrate (PETriN), pentaerythrityl dinitrate (PEDiN) and pentaerythrityl mononitrate (PEMonoN). Quantification is more convenient and sensitivity of this method is about four times higher compared to UV-detection. The present study demonstrates that PETN is a chemically more stable compound in vitro than expected. No degradation was observed in aqueous buffers (37 degrees C, pH 5.6, 7.4), human plasma, and simulated intestinal or gastric fluid. On the other hand, the addition of increasing amounts of thioles (cysteine, thioglycolic acid) induced an increasing degradation of PETN.
Chromatography, High Pressure Liquid↗
Identification of the nitrate esters of five alkyl alcohols by thin-layer chromatography.
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Acetone↗
Comparison of glyceryl trinitrate-induced with pentaerythrityl tetranitrate-induced in vivo formation of superoxide radicals: effect of vitamin C.
Glyceryl trinitrate (GTN) and pentaerythrityl tetranitrate (PETN) are among the most known organic nitrates that are used in cardiovascular therapy as vasodilators. However, anti-ischemic therapy with organic nitrates is complicated by the induction of nitrate tolerance. When nitrates are metabolized to release nitric oxide (NO), there is considerable coproduction of superoxide radicals in vessels leading to inactivation of NO. However, nitrate-induced increase of superoxide radical formation in vivo has not been reported. In this work, the authors studied the in vivo formation of superoxide radicals induced by treatment with PETN or GTN and determined the antioxidant effect of vitamin C. The formation of superoxide radicals was determined by the oxidation of 1-hydroxy-3-carboxy-pyrrolidine (CP-H) to paramagnetic 3-carboxy-proxyl (CP) using electron spin resonance spectroscopy. CP-H (9 mg/kg intravenous bolus and 0.225 mg/kg per minute continuous intravenous GTN or PETN 130 microg/kg) were infused into anesthetized rabbits. Every 5 min, blood samples were obtained from Arteria carotis to measure the CP formation. Both PETN and GTN showed similar vasodilator effects. Formation of CP in blood after infusions of GTN and PETN were 2.0+/-0.4 microM and 0.98+/-0.23 microM, respectively. Pretreatment with 30 mg/kg vitamin C led to a significant decrease in CP formation: 0.27+/-0.14 microM (vitamin C plus GTN) and 0.34+/-0.15 microM (vitamin C plus PETN). Pretreatment of animals with superoxide dismutase (15,000 units/kg) significantly inhibited nitrate-induced nitroxide formation. Therefore, in vivo infusion of GTN or PETN in rabbits increased the formation of superoxide radicals in the vasculature. PETN provoked a minimal stimulation of superoxide radical formation without simultaneous development of nitrate tolerance. The data suggest that the formation of superoxide radicals induced by organic nitrate correlates with the development of nitrate tolerance. The effect of vitamin C on CP formation leads to the conclusion that vitamin C can be used as an effective antioxidant for protection against nitrate-induced superoxide radical formation in vivo.
Animals↗
Beneficial effect of pentaerythrityl tetranitrate on functional and morphological changes in the rat thoracic aorta evoked by long-term nitric oxide synthase inhibition.
The present study examined whether pentaerythrityl tetranitrate (PETN), a tolerance-devoid exogenous donor of nitric oxide (NO), could attenuate functional and morphological changes in the rat thoracic aorta evoked by 6-week NO synthase inhibition by NG-nitro-L-arginine methyl ester (L-NAME). Systolic blood pressure in L-NAME + PETN-treated rats (163 +/- 1 mm Hg) was significantly lower than in L-NAME-treated rats (172 +/- 2 mm Hg) but was still higher than in age-matched controls (126 +/- 2 mm Hg). Six weeks of treatment of rats with L-NAME significantly inhibited endothelium-dependent relaxation of the isolated thoracic aorta induced by acetylcholine. The inhibitory effect of L-NAME was entirely reversed by the simultaneous treatment with PETN. The enhancing effect of L-NAME on noradrenaline-induced contraction was antagonised by long-term treatment with PETN. Wall thickness, cross-sectional area and wall/diameter ratio of the thoracic aorta in L-NAME-treated rats were markedly increased. In the L-NAME + PETN-treated rats, the increment of these parameters was significantly lower. The results suggest that PETN administered to rats during development of NO-deficient hypertension prevented functional impairment and at the same time reduced structural changes in the thoracic aorta induced by long-term inhibition of NO synthase.
Animals↗
Determination of vasodilators and their metabolites in plasma by liquid chromatography with a nitrosyl-specific detector.
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Chromatography, High Pressure Liquid↗
Flash ignition and initiation of explosives-nanotubes mixture.
Optical ignition and initiation of energetic materials could thus far be only accomplished through lasers, with specific characteristics of high power, pulse length, wavelength, and a small target area that greatly inhibit their applications. Here, we report that an ignition and an initiation process, further leading to actual detonation, does occur for energetic materials in lax contact with carbon nanotubes that are prone to opto-thermal activity via a conventional flashbulb. Our results show that, for the first time, optical initiation of energetic materials is possible on a large surface area and using ordinary light intensity of several W/cm2. The implication is that energetic materials mixed with optically active nanotubes could be new ideal candidates for safety apparatus, such as the firing of bolts on space shuttle rockets and aircraft exit doors.
Nanotubes, Carbon↗
Pentaerythrityl tetranitrate attenuates structural changes in conduit arteries evoked by long-term NO-synthase inhibition.
The aim of the study was to determine whether the pentaerythrityl tetranitrate (PETN), a tolerance devoid exogenous NO donor could prevent morphological changes in the cardiovascular system evoked by long-term NO-synthase inhibition. Three groups of 10-week-old Wistar rats were used: (1) controls, (2) treated by L-N(G)-nitroarginine methyl ester (L-NAME) in water (50 mg kg(-1)), and (3) treated by L-NAME (50 mg kg(-1) in water)+PETN (2x50 mg kg(-1), using gavage). Blood pressure (BP) was measured by the tail plethysmographic method. After sacrificing the animals were perfused (120 mmHg) by glutaraldehyde fixative and processed according to standard electron microscopy procedure. Wall thickness (WT), cross sectional area (CSA), inner diameter (ID) of thoracic aorta (TA), carotid (CA) and septal branch of the left descending coronary artery (RS) were measured in light microscopy. After 6 weeks, the BP was increased to 172+/-1.7 mmHg (P<0.01) in the L-NAME group, compared to 127+/-1.4 mmHg in controls. In L-NAME+PETN-treated rats, BP was 163+/-0.9 mmHg (P<0.01), and significantly lower (P<0.01) in comparison to L-NAME-treated rats. Heart weight and heart/body weight ratio was not significantly changed. In L-NAME-treated rats, both WT and CSA were increased in all three arteries (P<0.01). ID was increased only in TA (P<0.01). Wall/diameter ratio (WD) was increased in TA (P<0. 01) and CA (P<0.01). In L-NAME+PETN treated rats, WT was found to be increased only in TA (P<0.01). In comparison to the L-NAME treated group, WT was decreased in TA (P<0.01), in CA (P<0.01), in RS (P<0. 05). CSA was increased only in TA (P<0.01), yet in comparison to the L-NAME group it was decreased in CA (P<0.01). ID was increased in comparison to both control and L-NAME treated rats only in TA (P<0. 01). WD did not differ from the control value. In comparison to L-NAME-treated rats, it was decreased in both TA and CA (P<0.01). These data suggest that the changes in the cardiovascular system evoked by long-term NO-synthase inhibition were attenuated by simultaneous administration of the exogenous donor of nitric oxide - PETN.
Animals↗
Number of nitrate groups determines reactivity and potency of organic nitrates: a proof of concept study in ALDH-2-/- mice.
BACKGROUND AND PURPOSE: Mitochondrial aldehyde dehydrogenase (ALDH-2) has been shown to provide a pathway for bioactivation of organic nitrates and to be prone to desensitization in response to highly potent, but not to less potent, nitrates. We therefore sought to support the hypothesis that bioactivation by ALDH-2 critically depends on the number of nitrate groups within the nitrovasodilator. EXPERIMENTAL APPROACH: Nitrates with one (PEMN), two (PEDN; GDN), three (PETriN; glyceryl trinitrate, GTN) and four (pentaerithrityl tetranitrate, PETN) nitrate groups were investigated. Vasodilatory potency was measured in isometric tension studies using isolated aortic segments of wild type (WT) and ALDH-2-/- mice. Activity of the cGMP-dependent kinase-I (reflected by levels of phosphorylated VAsodilator Stimulated Phosphoprotein, P-VASP) was quantified by Western blot analysis, mitochondrial dehydrogenase activity by HPLC. Following incubation of isolated mitochondria with PETN, PETriN-chromophore and PEDN, metabolites were quantified using chemiluminescence nitrogen detection and mass spectrometry. KEY RESULTS: Compared to WT, vasorelaxation in response to PETN, PETriN and GTN was attenuated about 10fold in ALDH-2-/- mice, identical to WT vessels preincubated with inhibitors of ALDH-2. Reduced vasodilator potency correlated with reduced P-VASP formation and diminished biotransformation of the tetranitrate- and trinitrate-compounds. None of these findings were observed for PEDN, GDN and PEMN. CONCLUSIONS AND IMPLICATIONS: Our results support the crucial role of ALDH-2 in bioactivating highly reactive nitrates like GTN, PETN and PETriN. ALDH-2-mediated relaxation by organic nitrates therefore depends mainly on the number of nitrate groups. Less potent nitrates like PEDN, GDN and PEMN are apparently biotransformed by other pathways.
Aldehyde Dehydrogenase↗
[The effect of five different long-acting nitroglycerine derivatives on angina pectoris].
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Administration, Oral↗
[Quantitative gas chromatography-mass spectrometry determination of pentaerythrityl tetranitrate metabolites pentaerythrityl trinitrate, pentaerythrityl dinitrate and pentaerythrityl in human plasma].
Assay methods based on gas chromatography/mass spectroscopy (GC-MS) may be used to measure PE1N (pentaerithrityl mononitrate, CAS 1607-00-7), PE2N (pentaerithrityl dinitrate, CAS 1607-01-8) and intermediate pentaerithrityltrinitrate (PE3N, CAS 1607-17-6) in human plasma. Based on this method a simplified method to quantify the metabolites of PETN (pentaerithrityl tetranitrate, CAS 78-11-5, Pentalong) is described. In the present study a consistent method to extract the metabolites of human plasma and following derivatisation is described. Since PE1N can be quantified up to 150 ng/ml, PE2N and PE3N up to 30 ng/ml in human plasma, a dilution of the plasma samples can be avoided. The mean recovery rate is not so high as in other described methods, and inaccuracy is about 10%. Therefore a calibration range between 0.2-30 ng/ml of PE2N and 1-150 ng/ml of PE1N has to be considered. The described method offers an alternative and applicable option to quantify the PETN-metabolites and elucidate their part as NO-donors.
Biotransformation↗
In vivo effects of pentaerythrityl-tetranitrate and isosorbide-5-mononitrate on the development of atherosclerosis and endothelial dysfunction in cholesterol-fed rabbits.
We wished to determine whether long-term treatment with organic nitrovasodilators has pharmacological effects on the development of atherosclerotic lesions and endothelial dysfunction in cholesterol-fed rabbits. For 15 weeks, six groups of 9 New Zealand White rabbits received a standard diet, which contained no admixture, pentaerythrityl-tetranitrate (PETN 6 mg/kg body weight/day), or isosorbide-5-mononitrate (ISMN 2 mg/kg body weight/day). In the other three groups, the same diets were further enriched with cholesterol (0,75%). Four rings of thoracic aorta were used for tension studies; these rings and the aortas from the aortic arch to bifurcation were then fixed in formol and stained with Sudan IV to determine the area of luminal atherosclerotic lesions by a computerized laser-scanning approach. The cholesterol diet increased plasma levels of cholesterol from 69.8 +/- 10.4 to 907.1 +/- 85.5 mg/dl. A similar result was obtained in the group receiving PETN/cholesterol, but the group fed ISMN/cholesterol showed a significantly higher plasma level of cholesterol (1,165 +/- 81.4 mg/dl). Plasma levels of PETN metabolites were still detectable by gas chromatography/mass spectrometry after a 24-h in vivo washout period. The cholesterol diet induced a pronounced degree of atherosclerotic lesions in the aortic arch and the thoracic and abdominal aorta: 73.3 +/- 1.9, 46.3 +/- 2.5, and 49.6 +/- 3.6%, respectively. Additional treatment with PETN resulted in a reduction of this atherosclerotic area to 58.6 +/- 2.05% (p < 0.0001), 34.7 +/- 1.98% (p < 0.01), and 39.3 +/- 3.06% (p < 0.05). In contrast, ISMN had no significant effect on this parameter. The cholesterol diet also induced an endothelial dysfunction as indicated by the diminished vasorelaxation induced by acetylcholine (ACh). Treatment with PETN completely inhibited the development of endothelial dysfunction, whereas ISMN had no effect. In the three groups receiving a cholesterol diet, an increased extent of aortic lesions significantly correlated with increased endothelial dysfunction measured in the same preparations. The long-term treatment with PETN did not affect the vasorelaxing potency of PETN in aortic rings, and similar results were obtained in the case of ISMN. We conclude that long-term treatment with doses of PETN, which do not promote the development of in vitro vascular nitrate tolerance, may protect against atherosclerosis and endothelial dysfunction. This novel, yet unknown pharmacodynamic quality of nitrovasodilators like PETN may contribute to their long-term efficacy in coronary artery disease but may also imply new therapeutic indications in the future.
Acetylcholine↗
Unexpected, tolerance-devoid vasomotor and platelet actions of pentaerythrityl tetranitrate.
Efficacy of nitrate therapy is limited by tolerance. A surprising upregulation of ex vivo platelet activity, a decrease in platelet thiol levels, and an enhanced release of vasoconstrictors from platelets is associated with enhanced superoxide-mediated oxidant stress leading to vascular tolerance to nitrates. We tested the NO-donor pentaerythrityl tetranitrate (PETN), which to date had not been precisely tested either with regard to the induction of tolerance or to a potential development of changes in platelet activity in comparison with glycerol trinitrate (GTN). Long-term instrumented dogs nonintermittently received: 1.5 microg/kg/min GTN, i.v., with or without vitamin C (55 microg/kg/min, i.v.) or PETN 4 x 60 mg/day orally for 5 days. Tested daily were (a) the dilation of the epicardial arteries, (b) thrombin-induced (0.5 U/ml) increases of the intracellular Ca2+ concentration and aggregability of platelets, (c) concentrations of reduced low-molecular-weight thiols (LMTs) in plasma and platelets, and (d) formation of reactive oxygen species (ROSs). During nonintermittent PETN and during GTN with additional vitamin C, a 9.8 +/- 0.4% coronary artery dilation was observed in contrast to that with GTN alone, which resulted in complete tolerance at day 4. This vascular tolerance was associated with enhanced platelet activity and formation of ROSs (incubated platelets) and a 38 +/- 3% reduction in LMT. These unfavorable changes were absent in the presence of PETN or with additional vitamin C as an antioxidant. Vascular tolerance associated with platelet upregulation is avoided either by nonintermittent nitroglycerin (5 days) when vitamin C is coadministered or by pentaerythrityl tetranitrate without the coadministration of vitamin C.
Animals↗
Association between vascular tolerance and platelet upregulation: comparison of nonintermittent administration of pentaerithrityltetranitrate and glyceryltrinitrate.
Enhanced formation of oxygen-derived radicals O plays a dominant role in the development of nitrate tolerance. In 18 healthy subjects, this study tested the effect of additional vitamin C (Vit-C) administration (1 g three times daily) on glyceryltrinitrate (GTN)-induced hemodynamic changes during 3 days of nonintermittent transdermal administration of GTN (0.4 mg/h) in comparison with administration of pentaerithrityltetranitrate (PETN, 40 mg three times daily, orally). GTN caused an immediate significant rise in arterial conductivity (a/b ratio of dicrotic pulse pressure, from 2.33 +/- 0.06 to 2.52 +/- 0.06). Within 2 days of GTN administration, the a/b ratio progressively decreased and reached pre-GTN control levels, documenting tolerance. However, the administration of GTN along with Vit-C or with PETN alone induced changes in the a/b ratio and in the orthostatic reaction, which were fully maintained for the period of treatment. This vascular tolerance seen after GTN treatment was paralleled by an upregulation of ex vivo platelet activity, which was evident from a rise in aggregation from 29.2 +/- 2.8% at control day to 85.4 +/- 8.5% at day 3, and additionally from thrombin-induced increases of intracellular Ca concentration from 494 +/- 60 nM at control day to 741 +/- 37 nM at day 3. This upregulation was not observed during PETN or GTN; with additional Vit-C administration. Administration of PETN or GTN, the latter supplemented by Vit-C, induced neither vascular tolerance nor the upregulation of washed platelet activity during nonintermittent administration, in contrast to GTN without Vit-C. This is explained by a diminished formation of reactive oxygen species when PETN or when GTN along with Vit-C is used.
Adult↗