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Frantisek Kristek - One of the best experts on this subject based on the ideXlab platform.

  • The effect of an NO donor, Pentaerythrityl Tetranitrate, on biochemical, functional, and morphological attributes of cardiovascular system of spontaneously hypertensive rats.
    General physiology and biophysics, 2009
    Co-Authors: Ima Dovinova, S. Cacanyiova, Fáberová, Frantisek Kristek
    Abstract:

    The status of nitric oxide (NO) in spontaneously hypertensive rats (SHR) is unclear and its bioavailability may be affected by imbalance with reactive oxygen species. We studied cardiovascular effects of an NO donor, Pentaerythrityl Tetranitrate (PETN) in SHR. We used Wistar rats, SHR and SHR treated with PETN (200 mg/kg/day). After six weeks, myocardium and aorta from each group were taken for biochemical and iliac artery for functional and morphological study. Long-term administration of PETN to SHR increased cGMP level in platelets and did not affect blood pressure. In myocardium, the therapy resulted in a decrease in cardiac hypertrophy and MDA level, and the increased antioxidant enzyme activity of superoxide dismutase (SOD) and glutathione peroxidase (GPx). In aorta, PETN decreased the NO-synthase activity and had no affect on the enzyme activities of SOD and GPx or on MDA level. In the iliac artery, the endothelium-dependent relaxation to acetylcholine was slightly improved and the maximum vasoconstriction to noradrenaline was decreased. Wall thickness, cross-sectional area, inner diameter, and wall thickness/ inner diameter measured after perfusion fixation (120 mmHg) were not affected. The small effect of PETN on cardiovascular system suggests that NO deficiency is probably not the main cause of pathological alterations in SHR.

  • Long-term effects of early administered sildenafil and NO donor on the cardiovascular system of SHR.
    Journal of physiology and pharmacology : an official journal of the Polish Physiological Society, 2007
    Co-Authors: Frantisek Kristek, Koprdová R, Martina Cebova
    Abstract:

    We evaluated the long-term effect of NO-donor, Pentaerythrityl Tetranitrate (Petn), and sildenafil citrate (sildenafil) on the cardiovascular system of the spontaneously hypertensive rat (SHR). Petn (100 mg/kg/day) and sildenafil (10 mg/kg/day) were administered to SHR individually or together from week 4 (pre-hypertensive period) to week 9 of age. Blood pressure (BP) was measured using a plethysmographic method. The animals were perfused with a glutaraldehyde fixative (120 mmHg). Carotid (AC) and coronary artery (RS) were processed according to electron microscopy procedure. Geometry of the arteries was measured on semi-thin sections using light microscopy. Administration of Petn and sildenafil to SHR individually or together did not prevent an increase of BP, but evoked a decrease of cardiac hypertrophy. Petn and sildenafil affected the geometry of RS and AC differently. In the RS, an increase of inner diameter (ID) without an increase of wall thickness (WT) resulted in increased WT/ID and circumferential stress. In the AC, changes in ID were accompanied by changes in WT and, thereby, WT/ID and circumferential stress remained unchanged. The arterial wall mass of both arteries was increased. The data suggest that administration of the NO donor, Petn, and/or sildenafil does not result in a beneficial effect on the myocardium or on the geometry of the carotid and coronary arteries.

  • Beneficial effect of Pentaerythrityl Tetranitrate on functional and morphological changes in the rat thoracic aorta evoked by long-term nitric oxide synthase inhibition.
    Vascular pharmacology, 2002
    Co-Authors: Jozef Török, Frantisek Kristek
    Abstract:

    Abstract 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.

  • Pentaerythrityl Tetranitrate attenuates structural changes in conduit arteries evoked by long term no synthase inhibition
    British Journal of Pharmacology, 2000
    Co-Authors: Frantisek Kristek
    Abstract:

    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-NG-nitroarginine methyl ester (L-NAME) in water (50 mg kg−1), and (3) treated by L-NAME (50 mg kg−1 in water)+PETN (2×50 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. British Journal of Pharmacology (2000) 130, 450–456; doi:10.1038/sj.bjp.0703307

  • Pentaerythrityl Tetranitrate attenuates structural changes in conduit arteries evoked by long-term NO-synthase inhibition
    British journal of pharmacology, 2000
    Co-Authors: Frantisek Kristek
    Abstract:

    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-NG-nitroarginine methyl ester (L-NAME) in water (50 mg kg−1), and (3) treated by L-NAME (50 mg kg−1 in water)+PETN (2×50 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

Dimitrios Tsikas - One of the best experts on this subject based on the ideXlab platform.

  • Results, meta-analysis and a first evaluation of U_NOxR, the urinary nitrate-to-nitrite molar ratio, as a measure of nitrite reabsorption in experimental and clinical settings
    Amino Acids, 2018
    Co-Authors: Dimitrios Tsikas, Erik Hanff, Alexander Bollenbach, Ruan Kruger, Vu Vi Pham, Kristine Chobanyan-jürgens, Dirk Wedekind, Tanja Arndt, Anne Jörns, Jimmy F. P. Berbée
    Abstract:

    We recently found that renal carbonic anhydrase (CA) is involved in the reabsorption of inorganic nitrite (NO_2^−), an abundant reservoir of nitric oxide (NO) in tissues and cells. Impaired NO synthesis in the endothelium and decreased NO bioavailability in the circulation are considered major contributors to the development and progression of renal and cardiovascular diseases in different conditions including diabetes. Isolated human and bovine erythrocytic CAII and CAIV can convert nitrite to nitrous acid (HONO) and its anhydride N_2O_3 which, in the presence of thiols (RSH), are further converted to S -nitrosothiols (RSNO) and NO. Thus, CA may be responsible both for the homeostasis of nitrite and for its bioactivation to RSNO/NO. We hypothesized that enhanced excretion of nitrite in the urine may contribute to NO-related dysfunctions in the renal and cardiovascular systems, and proposed the urinary nitrate-to-nitrite molar ratio, i.e., U_NOxR, as a measure of renal CA-dependent excretion of nitrite. Based on results from clinical and experimental animal studies, here, we report on a first evaluation of U_NOxR. We determined U_NOxR values in preterm neonates, healthy children, and adults, in children suffering from type 1 diabetes mellitus (T1DM) or Duchenne muscular dystrophy (DMD), in elderly subjects suffering from chronic rheumatic diseases, type 2 diabetes mellitus (T2DM), coronary artery disease (CAD), or peripheral arterial occlusive disease (PAOD). We also determined U_NOxR values in healthy young men who ingested isosorbide dinitrate (ISDN), Pentaerythrityl Tetranitrate (PETN), or inorganic nitrate. In addition, we tested the utility of U_NOxR in two animal models, i.e., the LEW.1AR1- iddm rat, an animal model of human T1DM, and the APOE*3 - Leiden.CETP mice, a model of human dyslipidemia. Mean U_NOxR values were lower in adult patients with rheumatic diseases (187) and in T2DM patients of the DALI study (74) as compared to healthy elderly adults (660) and healthy young men (1500). The intra- and inter-variabilities of U_NOxR were of the order of 50% in young and elderly healthy subjects. U_NOxR values were lower in black compared to white boys (314 vs. 483, P  = 0.007), which is in line with reported lower NO bioavailability in black ethnicity. Mean U_NOxR values were lower in DMD (424) compared to healthy (730) children, but they were higher in T1DM children (1192). ISDN (3 × 30 mg) decreased stronger U_NOxR compared to PETN (3 × 80 mg) after 1 day ( P  = 0.046) and after 5 days ( P  = 0.0016) of oral administration of therapeutically equivalent doses. In healthy young men who ingested NaNO_3 (0.1 mmol/kg/d), U_NOxR was higher than in those who ingested the same dose of NaCl (1709 vs. 369). In LEW.1AR1- iddm rats, mean U_NOxR values were lower than in healthy rats (198 vs. 308) and comparable to those in APOE*3 - Leiden.CETP mice (151).

  • Results, meta-analysis and a first evaluation of UNOxR, the urinary nitrate-to-nitrite molar ratio, as a measure of nitrite reabsorption in experimental and clinical settings
    Amino acids, 2018
    Co-Authors: Dimitrios Tsikas, Erik Hanff, Alexander Bollenbach, Ruan Kruger, Vu Vi Pham, Kristine Chobanyan-jürgens, Dirk Wedekind, Tanja Arndt, Anne Jörns, Jimmy F. P. Berbée
    Abstract:

    We recently found that renal carbonic anhydrase (CA) is involved in the reabsorption of inorganic nitrite (NO2−), an abundant reservoir of nitric oxide (NO) in tissues and cells. Impaired NO synthesis in the endothelium and decreased NO bioavailability in the circulation are considered major contributors to the development and progression of renal and cardiovascular diseases in different conditions including diabetes. Isolated human and bovine erythrocytic CAII and CAIV can convert nitrite to nitrous acid (HONO) and its anhydride N2O3 which, in the presence of thiols (RSH), are further converted to S-nitrosothiols (RSNO) and NO. Thus, CA may be responsible both for the homeostasis of nitrite and for its bioactivation to RSNO/NO. We hypothesized that enhanced excretion of nitrite in the urine may contribute to NO-related dysfunctions in the renal and cardiovascular systems, and proposed the urinary nitrate-to-nitrite molar ratio, i.e., UNOxR, as a measure of renal CA-dependent excretion of nitrite. Based on results from clinical and experimental animal studies, here, we report on a first evaluation of UNOxR. We determined UNOxR values in preterm neonates, healthy children, and adults, in children suffering from type 1 diabetes mellitus (T1DM) or Duchenne muscular dystrophy (DMD), in elderly subjects suffering from chronic rheumatic diseases, type 2 diabetes mellitus (T2DM), coronary artery disease (CAD), or peripheral arterial occlusive disease (PAOD). We also determined UNOxR values in healthy young men who ingested isosorbide dinitrate (ISDN), Pentaerythrityl Tetranitrate (PETN), or inorganic nitrate. In addition, we tested the utility of UNOxR in two animal models, i.e., the LEW.1AR1-iddm rat, an animal model of human T1DM, and the APOE*3-Leiden.CETP mice, a model of human dyslipidemia. Mean UNOxR values were lower in adult patients with rheumatic diseases (187) and in T2DM patients of the DALI study (74) as compared to healthy elderly adults (660) and healthy young men (1500). The intra- and inter-variabilities of UNOxR were of the order of 50% in young and elderly healthy subjects. UNOxR values were lower in black compared to white boys (314 vs. 483, P = 0.007), which is in line with reported lower NO bioavailability in black ethnicity. Mean UNOxR values were lower in DMD (424) compared to healthy (730) children, but they were higher in T1DM children (1192). ISDN (3 × 30 mg) decreased stronger UNOxR compared to PETN (3 × 80 mg) after 1 day (P = 0.046) and after 5 days (P = 0.0016) of oral administration of therapeutically equivalent doses. In healthy young men who ingested NaNO3 (0.1 mmol/kg/d), UNOxR was higher than in those who ingested the same dose of NaCl (1709 vs. 369). In LEW.1AR1-iddm rats, mean UNOxR values were lower than in healthy rats (198 vs. 308) and comparable to those in APOE*3-Leiden.CETP mice (151).

  • Lack of oxidative stress during sustained therapy with isosorbide dinitrate and Pentaerythrityl Tetranitrate in healthy humans: a randomized, double-blind crossover study.
    Journal of cardiovascular pharmacology, 2003
    Co-Authors: Roland Keimer, Friederike K. Stutzer, Dimitrios Tsikas, Raphael Troost, Frank-mathias Gutzki, Jürgen C. Frölich
    Abstract:

    Summary:The mechanisms by which tolerance to organic nitrates develops are still poorly understood. Enhanced oxidative stress, i.e., increased free radical production following organic nitrate administration, has been recently suggested as a possible mechanism. A randomized, double-blind, crossover

Andreas Daiber - One of the best experts on this subject based on the ideXlab platform.

  • Pharmacology of Nitrovasodilators
    Nitrite and Nitrate in Human Health and Disease, 2017
    Co-Authors: Thomas Münzel, Andreas Daiber
    Abstract:

    Organic nitrates such as nitroglycerin, isosorbide mono- and dinitrate, and Pentaerythrityl Tetranitrate, are potent vasodilators that improve clinical symptoms in patients with acute and chronic congestive heart failure, coronary artery disease, or arterial hypertension. The mechanisms underlying vasodilation include the release of nitric oxide or a related compound in response to intracellular bioactivation (for GTN, the mitochondrial aldehyde dehydrogenase), the activation of the enzyme soluble guanylyl cyclase, and the activation of the cGMP-dependent kinase. Side effects of organic nitrates include nitrate tolerance development and the induction of endothelial dysfunction, phenomena, which are likely being linked to increased production of reactive oxygen and nitrogen species.

  • Organic nitrates: update on mechanisms underlying vasodilation, tolerance and endothelial dysfunction.
    Vascular pharmacology, 2014
    Co-Authors: Thomas Münzel, Sebastian Steven, Andreas Daiber
    Abstract:

    Given acutely, organic nitrates, such as nitroglycerin (GTN), isosorbide mono- and dinitrates (ISMN, ISDN), and Pentaerythrityl Tetranitrate (PETN), have potent vasodilator and anti-ischemic effects in patients with acute coronary syndromes, acute and chronic congestive heart failure and arterial hypertension. During long-term treatment, however, side effects such as nitrate tolerance and endothelial dysfunction occur, and therapeutic efficacy of these drugs rapidly vanishes. Recent experimental and clinical studies have revealed that organic nitrates per se are not just nitric oxide (NO) donors, but rather a quite heterogeneous group of drugs considerably differing for mechanisms underlying vasodilation and the development of endothelial dysfunction and tolerance. Based on this, we propose that the term nitrate tolerance should be avoided and more specifically the terms of GTN, ISMN and ISDN tolerance should be used. The present review summarizes preclinical and clinical data concerning organic nitrates. Here we also emphasize the consequences of chronic nitrate therapy on the supersensitivity of the vasculature to vasoconstriction and on the increased autocrine expression of endothelin. We believe that these so far rather neglected and underestimated side effects of chronic therapy with at least GTN and ISMN are clinically important.

  • Chronic protection against ischemia and reperfusion-induced endothelial dysfunction during therapy with different organic nitrates
    Clinical Research in Cardiology, 2012
    Co-Authors: Monica Lisi, Saverio Dragoni, Dirk Stalleicken, Thomas Münzel, Matthias Oelze, Andrew Liuni, Sebastian Steven, Mary-clare Luca, Franco Laghi-pasini, Andreas Daiber
    Abstract:

    Introduction Ischemic and pharmacologic preconditioning have great clinical potential, but it remains unclear whether their effects can be maintained over time during repeated exposure.We have previously demonstrated that the acute protective effect of nitroglycerin (GTN) is attenuated during repeated daily administration. Pentaerythrityl Tetranitrate (PETN) is an organic nitrate with different hemodynamic and biochemical properties. The purpose of the current experiment was to study the preconditioning-like effects of PETN and GTN during repeated daily exposure. Methods and results In a randomized, investigator-blind parallel trial, 30 healthy (age 25–32) volunteers were randomized to receive (1) transdermal GTN (0.6 mg/h) administered for 2 h a day for 6 days; (2) oral PETN (80 mg) once a day for 6 days; or (3) no therapy. One week later, endothelium-dependent flow-mediated dilation was assessed before and after exposure to ischemia and reperfusion (IR). IR caused a significant blunting of the endothelium-dependent relaxation in the control group (FMD before IR: 5.8 ± 2.1%; after IR 1.0 ± 2.1%; P  

  • Chronic protection against ischemia and reperfusion-induced endothelial dysfunction during therapy with different organic nitrates.
    Clinical research in cardiology : official journal of the German Cardiac Society, 2012
    Co-Authors: Monica Lisi, Saverio Dragoni, Dirk Stalleicken, Thomas Münzel, Matthias Oelze, Andrew Liuni, Sebastian Steven, Mary-clare Luca, Franco Laghi-pasini, Andreas Daiber
    Abstract:

    Introduction Ischemic and pharmacologic preconditioning have great clinical potential, but it remains unclear whether their effects can be maintained over time during repeated exposure.We have previously demonstrated that the acute protective effect of nitroglycerin (GTN) is attenuated during repeated daily administration. Pentaerythrityl Tetranitrate (PETN) is an organic nitrate with different hemodynamic and biochemical properties. The purpose of the current experiment was to study the preconditioning-like effects of PETN and GTN during repeated daily exposure.

  • Potency and in vitro tolerance of organic nitrates: partially denitrated metabolites contribute to the tolerance-devoid activity of Pentaerythrityl Tetranitrate.
    Journal of cardiovascular pharmacology, 2007
    Co-Authors: Andreas Koenig, Kathrin Lange, Joerg Konter, Andreas Daiber, Dirk Stalleicken, Erika Glusa, Jochen Lehmann
    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.

Jochen Lehmann - One of the best experts on this subject based on the ideXlab platform.

  • A Novel Key Player in the Development of Tolerance in Response to Organic Nitrates
    2011
    Co-Authors: Philip Wenzel, Andreas Seeling, Dirk Stalleicken, Matthias Oelze, Meike Coldewey, Marcus Hortmann, Ulrich Hink, Hanke Mollnau, Henry Weiner, Jochen Lehmann
    Abstract:

    Objective—Nitrate tolerance is likely attributable to an increased production of reactive oxygen species (ROS) leading to an inhibition of the mitochondrial aldehyde dehydrogenase (ALDH-2), representing the nitroglycerin (GTN) and Pentaerythrityl Tetranitrate (PETN) bioactivating enzyme, and to impaired nitric oxide bioactivity and signaling. We tested whether differences in their capacity to induce heme oxygenase-1 (HO-1) might explain why PETN and not GTN therapy is devoid of nitrate and cross-tolerance. Methods and Results—Wistar rats were treated with PETN or GTN (10.5 or 6.6 g/kg/min for 4 days). In contrast to GTN, PETN did not induce nitrate tolerance or cross-tolerance as assessed by isometric tension recordings in isolated aortic rings. Vascular protein and mRNA expression of HO-1 and ferritin were increased in response to PETN but not GTN. In contrast to GTN therapy, NO signaling, ROS formation, and the activity of ALDH-2 (as assessed by an high-performance liquid chromatography–based method) were not significantly influenced by PETN. Inhibition of HO-1 expression by apigenin induced “tolerance” to PETN whereas HO-1 gene induction by hemin prevented tolerance in GTN treated rats. Conclusions—HO-1 expression and activity appear to play a key role in the development of nitrate tolerance and might represent an intrinsic antioxidative mechanism of therapeutic interest. (Arterioscler Thromb Vasc Biol. 2007;27:0-0.)

  • NO donors. Part 18: Bioactive metabolites of GTN and PETN--synthesis and vasorelaxant properties.
    Bioorganic & medicinal chemistry letters, 2008
    Co-Authors: Kathrin Lange, Andreas Seeling, Andreas Koenig, Carolin Roegler, Jochen Lehmann
    Abstract:

    The vasodilators glyceryl trinitrate (GTN) and Pentaerythrityl Tetranitrate (PETN) are supposed to be degraded in vivo to the lower nitrates PETriN, PEDN, PEMN, 1,2-GDN, 1,3-GDN, 1-GMN, and 2-GMN. We synthesized these bioactive metabolites as reference compounds for pharmacokinetic studies. The use of HPLC-methods for monitoring the stepwise reduction of PETN to lower nitrates and the syntheses of the glyceryl dinitrates proved advantageous. Furthermore, we measured the vasorelaxant properties of all metabolites by performing organ bath experiments with porcine pulmonary arteries. In general, the vasodilator potency increases with the number of nitrate moieties in the compound.

  • Heme Oxygenase-1: A Novel Key Player in the Development of Tolerance in Response to Organic Nitrates
    Arteriosclerosis thrombosis and vascular biology, 2007
    Co-Authors: Philip Wenzel, Andreas Seeling, Dirk Stalleicken, Matthias Oelze, Meike Coldewey, Marcus Hortmann, Ulrich Hink, Hanke Mollnau, Henry Weiner, Jochen Lehmann
    Abstract:

    Objective— Nitrate tolerance is likely attributable to an increased production of reactive oxygen species (ROS) leading to an inhibition of the mitochondrial aldehyde dehydrogenase (ALDH-2), representing the nitroglycerin (GTN) and Pentaerythrityl Tetranitrate (PETN) bioactivating enzyme, and to impaired nitric oxide bioactivity and signaling. We tested whether differences in their capacity to induce heme oxygenase-1 (HO-1) might explain why PETN and not GTN therapy is devoid of nitrate and cross-tolerance. Methods and Results— Wistar rats were treated with PETN or GTN (10.5 or 6.6 μg/kg/min for 4 days). In contrast to GTN, PETN did not induce nitrate tolerance or cross-tolerance as assessed by isometric tension recordings in isolated aortic rings. Vascular protein and mRNA expression of HO-1 and ferritin were increased in response to PETN but not GTN. In contrast to GTN therapy, NO signaling, ROS formation, and the activity of ALDH-2 (as assessed by an high-performance liquid chromatography–based method) were not significantly influenced by PETN. Inhibition of HO-1 expression by apigenin induced “tolerance” to PETN whereas HO-1 gene induction by hemin prevented tolerance in GTN treated rats. Conclusions— HO-1 expression and activity appear to play a key role in the development of nitrate tolerance and might represent an intrinsic antioxidative mechanism of therapeutic interest.

  • Potency and in vitro tolerance of organic nitrates: partially denitrated metabolites contribute to the tolerance-devoid activity of Pentaerythrityl Tetranitrate.
    Journal of cardiovascular pharmacology, 2007
    Co-Authors: Andreas Koenig, Kathrin Lange, Joerg Konter, Andreas Daiber, Dirk Stalleicken, Erika Glusa, Jochen Lehmann
    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.

  • Heme oxygenase-1: a novel key player in the development of tolerance in response to organic nitrates
    2007
    Co-Authors: Philip Wenzel, Andreas Seeling, Dirk Stalleicken, Matthias Oelze, Meike Coldewey, Marcus Hortmann, Ulrich Hink, Hanke Mollnau, Henry Weiner, Jochen Lehmann
    Abstract:

    Objective—Nitrate tolerance is likely attributable to an increased production of reactive oxygen species (ROS) leading to an inhibition of the mitochondrial aldehyde dehydrogenase (ALDH-2), representing the nitroglycerin (GTN) and Pentaerythrityl Tetranitrate (PETN) bioactivating enzyme, and to impaired nitric oxide bioactivity and signaling. We tested whether differences in their capacity to induce heme oxygenase-1 (HO-1) might explain why PETN and not GTN therapy is devoid of nitrate and cross-tolerance. Methods and Results—Wistar rats were treated with PETN or GTN (10.5 or 6.6 g/kg/min for 4 days). In contrast to GTN, PETN did not induce nitrate tolerance or cross-tolerance as assessed by isometric tension recordings in isolated aortic rings. Vascular protein and mRNA expression of HO-1 and ferritin were increased in response to PETN but not GTN. In contrast to GTN therapy, NO signaling, ROS formation, and the activity of ALDH-2 (as assessed by an high-performance liquid chromatography–based method) were not significantly influenced by PETN. Inhibition of HO-1 expression by apigenin induced “tolerance ” to PETN whereas HO-1 gene induction by hemin prevented tolerance in GTN treated rats. Conclusions—HO-1 expression and activity appear to play a key role in the development of nitrate tolerance and might represent an intrinsic antioxidative mechanism of therapeutic interest. (Arterioscler Thromb Vasc Biol. 2007;27:1729-1735.) Key Words: organic nitrates nitrate tolerance heme oxygenase-1 reactive oxygen species When given acutely, organic nitrates such as nitroglyc-erin (glyceryl trinitrate, GTN) have potent antiische-mic effects.1 Their clinical usefulness during long-term treat-ment, however, is limited because of the development of tolerance and cross-tolerance to endothelium-dependent and independent vasodilators.2 The phenomenon of nitrate toler-ance was observed first in response to treatment with GTN,3 but seems also to be shared by other organic nitrates such as isosorbide dinitrate (ISDN)4 and mononitrate (ISMN), but interestingly not by pentaerithrityl Tetranitrate (PETN).5,

Georg Kojda - One of the best experts on this subject based on the ideXlab platform.

  • Effect of oral organic nitrates on expression and activity of vascular soluble guanylyl cyclase
    British journal of pharmacology, 2008
    Co-Authors: Marc Oppermann, T Suvorava, Vt-v Dao, M Bas, Georg Kojda
    Abstract:

    Background and purpose: The regulation of vascular soluble guanylyl cyclase (sGC) expression by nitric oxide (NO) is still under discussion. In vitro, NO has been shown to downregulate the expression of sGC but it is unclear if this mechanism is operative in vivo and occurs during nitrate treatment. Experimental approach: We investigated whether high dose isosorbide mononitrate (ISMN) or Pentaerythrityl Tetranitrate (PETN) treatment changes vascular sGC expression and activity in vivo. New Zealand White rabbits received a standard diet, 2 or 200 mg ISMN kg−1 d−1 for 16 weeks, and C57BL/6 mice received a standard diet, 6, 60 or 300 mg PETN kg−1 d−1 for four weeks. Absorption was checked by measuring the plasma levels of the drug/metabolite. Key results: Western blots of rabbit aortic rings showed similar protein levels of sGC α1- (P=0.2790) and β1-subunits (P=0.6900) in all groups. Likewise, ANOVA showed that there was no difference in the expression of sGC in lungs of PETN-treated mice (P=0.0961 for α1 and P=0.3709 for β1). The activities of isolated sGC in response to SNAP (1 μM–1 mM) were identical in aortae of ISMN-treated rabbits (P=0.0775) and lungs of PETN-treated mice (P=0.6348). The aortic relaxation response to SNAP slightly decreased at high ISMN but not at high PETN. Conclusions and implications: These data refute the hypothesis that therapeutic treatment with long acting NO donors has a significant impact on the regulation of vascular sGC expression and activity in vivo. British Journal of Pharmacology (2008) 155, 335–342; doi:10.1038/bjp.2008.269; published online 30 June 2008

  • In vivo effects of Pentaerythrityl-Tetranitrate and isosorbide-5-mononitrate on the development of atherosclerosis and endothelial dysfunction in cholesterol-fed rabbits.
    Journal of cardiovascular pharmacology, 1995
    Co-Authors: Georg Kojda, Dorothea Stein, Eva Kottenberg, Ebbo Michael Schnaith, Eike Noack
    Abstract:

    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.