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Eike Noack - One of the best experts on this subject based on the ideXlab platform.
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Nitrovasodilator induced relaxation and tolerance development in porcine vena cordis magna dependence on intact endothelium
British Journal of Pharmacology, 1994Co-Authors: Georg Kojda, Jan Klaus Beck, Wilfried Meyer, Eike NoackAbstract:1. Isolated segments of porcine vena cordis magna exhibited a reproducible contractile activity upon application of prostaglandin F2 alpha (PGF2 alpha) or KCl, that was independent of the presence of intact endothelium. Substance P (3 nM) elicited strictly endothelium-dependent relaxations amounting to 46.1 +/- 1.4% (n = 206) of contractions induced by 10 microM PGF2 alpha. 2. S-nitroso-N-acetyl-D,L-penicillamine (SNAP), a compound that spontaneously liberates nitric oxide, concentration-dependently relaxed PGF2 alpha-precontracted (50 microM) venous segments. Tolerance induction (incubation with 100 microM SNAP for 30 min) within the same segments resulted in a 3 fold attenuation of this effect, which was not further reduced after additional preincubation with glyceryl trinitrate (GTN). Removal of endothelium or the presence of N omega-nitro-L-arginine methylester (L-NAME) significantly improved the potency of SNAP before and after tolerance induction. 3. Concentration-dependent relaxations induced by GTN in non-tolerant veins were similar in the presence and absence of endothelium but much more reduced in tolerant endothelium-denuded (75 fold) compared to intact (20 fold) segments. In contrast, the presence of L-NAME significantly improved GTN-activity solely in non-tolerant veins, which, therefore, also resulted in a more pronounced attenuation of activity due to tolerance induction (100 fold). Preincubation of intact veins with SNAP also reduced GTN-activity but to a lesser extent (10 fold). 4. The more delayed but much longer, and compared to GTN somewhat weaker, acting new Nitrovasodilator N-(3-nitrato-pivaloyl)-1-cysteineethylester (SPM 3672) was more potent in denuded than intact non-tolerant venous segments. Induction of tolerance by GTN resulted in a 2 fold-attenuation of potency. This effect was increased to 15 fold in denuded veins but solely due to enhanced potency of SPM 3672 caused by removal of endothelium.5. These data demonstrate that intact endothelium of porcine vena cordis magna attenuates the relaxant potency of Nitrovasodilators but also probably participates in vascular bioactivation of GTN.We suggest that the reduced potency of Nitrovasodilators is due to endogenous production of nitricoxide, which may affect the soluble guanylate cyclase/cyclic GMP-system or inhibit nitrate bioactivation pathways.
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Nitrovasodilator‐induced relaxation and tolerance development in porcine vena cordis magna: dependence on intact endothelium
British journal of pharmacology, 1994Co-Authors: Georg Kojda, Jan Klaus Beck, Wilfried Meyer, Eike NoackAbstract:1. Isolated segments of porcine vena cordis magna exhibited a reproducible contractile activity upon application of prostaglandin F2 alpha (PGF2 alpha) or KCl, that was independent of the presence of intact endothelium. Substance P (3 nM) elicited strictly endothelium-dependent relaxations amounting to 46.1 +/- 1.4% (n = 206) of contractions induced by 10 microM PGF2 alpha. 2. S-nitroso-N-acetyl-D,L-penicillamine (SNAP), a compound that spontaneously liberates nitric oxide, concentration-dependently relaxed PGF2 alpha-precontracted (50 microM) venous segments. Tolerance induction (incubation with 100 microM SNAP for 30 min) within the same segments resulted in a 3 fold attenuation of this effect, which was not further reduced after additional preincubation with glyceryl trinitrate (GTN). Removal of endothelium or the presence of N omega-nitro-L-arginine methylester (L-NAME) significantly improved the potency of SNAP before and after tolerance induction. 3. Concentration-dependent relaxations induced by GTN in non-tolerant veins were similar in the presence and absence of endothelium but much more reduced in tolerant endothelium-denuded (75 fold) compared to intact (20 fold) segments. In contrast, the presence of L-NAME significantly improved GTN-activity solely in non-tolerant veins, which, therefore, also resulted in a more pronounced attenuation of activity due to tolerance induction (100 fold). Preincubation of intact veins with SNAP also reduced GTN-activity but to a lesser extent (10 fold). 4. The more delayed but much longer, and compared to GTN somewhat weaker, acting new Nitrovasodilator N-(3-nitrato-pivaloyl)-1-cysteineethylester (SPM 3672) was more potent in denuded than intact non-tolerant venous segments. Induction of tolerance by GTN resulted in a 2 fold-attenuation of potency. This effect was increased to 15 fold in denuded veins but solely due to enhanced potency of SPM 3672 caused by removal of endothelium.5. These data demonstrate that intact endothelium of porcine vena cordis magna attenuates the relaxant potency of Nitrovasodilators but also probably participates in vascular bioactivation of GTN.We suggest that the reduced potency of Nitrovasodilators is due to endogenous production of nitricoxide, which may affect the soluble guanylate cyclase/cyclic GMP-system or inhibit nitrate bioactivation pathways.
Rudi Busse - One of the best experts on this subject based on the ideXlab platform.
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Increased Nitrovasodilator Sensitivity in Endothelial Nitric Oxide Synthase Knockout Mice: Role of Soluble Guanylyl Cyclase
Hypertension, 2000Co-Authors: Ralf P. Brandes, Do-yei Kim, Friedrich-hubertus Schmitz-winnenthal, Mojgan Amidi, Axel Gödecke, Alexander Mülsch, Rudi BusseAbstract:Abstract —Endogenously produced nitric oxide (NO) modulates Nitrovasodilator-induced relaxation. We investigated the underlying mechanism in wild-type (WT) mice and endothelial NO synthase knockout (eNOS −/− ) mice to determine whether a chronic lack of endothelial NO alters the soluble guanylyl cyclase (sGC) pathway. In aortic segments from eNOS −/− mice, the vasodilator sensitivity to sodium nitroprusside (SNP) was significantly greater than that in WT mice. There was no difference in sensitivity to the G-kinase I activator 8-para-chlorophenylthio-cGMP or to cromakalim. N ω -Nitro-l-arginine had no effect on the SNP-induced relaxation in eNOS −/− but increased the sensitivity in WT mice so it was no longer different than that of eNOS −/− . Basal cGMP levels in aortic rings were significantly lower in eNOS −/− mice than in WT mice. SNP (300 nmol/L) induced a significantly greater cGMP accumulation in eNOS −/− mice than in WT mice. The maximal SNP-induced (10 μmol/L) increase in cGMP was similar in both strains. SNP-stimulated sGC activity was significantly greater in eNOS −/− mice than in WT mice. Incubation of aortic segments from WT mice with N ω -nitro-l-arginine increased sGC activity, an effect prevented by coincubation with SNP (10 μmol/L). The aortic expressions of the sGC α1 and β1 subunits in WT and eNOS −/− mice were identical as determined with Western blot analysis. These data suggest that chronic exposure to endothelium-derived NO, as well as acute exposure to Nitrovasodilator-derived NO, desensitizes sGC to activation by NO but does not alter sGC expression. Both the acute cessation of endothelial NO formation in WT mice and the chronic deficiency of NO in eNOS −/− mice restore the NO sensitivity of sGC and enhance vascular smooth muscle relaxation in response to Nitrovasodilator agents.
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Elevated guanosine 3':5'-cyclic monophosphate mediates the depression of Nitrovasodilator reactivity in endothelium-intact blood vessels.
Naunyn-Schmiedeberg's archives of pharmacology, 1991Co-Authors: William F. Jackson, Rudi BusseAbstract:The influence of endothelium-derived nitric oxide (EDNO) on relaxation induced by the Nitrovasodilators, sodium nitroprusside and sodium nitrite was assessed in phenylephrine-stimulated hamster thoracic aortas, a preparation that displays significant basal release of EDNO. Removal of the endothelium or treatment with the NO synthase inhibitors, NG-nitro-l-arginine (L-NAG, 10–30 µM) or NG-methyl-l-arginine (L-NMMA; 100 µM) increased the potency and, except for sodium nitroprusside in endothelium-denuded segments, also increased the efficacy of the Nitrovasodilators. Removal of the endothelium had no effect on relaxations induced by isoproterenol, an indication that these effects were specific for the Nitrovasodilators. Removal of the endothelium, treatment of endothelium-intact preparations with L-NAG or L-NMMA, or exposure of these vessels to the guanylate cyclase inhibitor, methylene blue (10 µM) increased reactivity of the aortas to the guanosine 3′:5′-cyclic monophosphate (cGMP) analogue, 8-Br cGMP. Measurement of cGMP revealed that endothelium-intact segments had a 6.5 fold higher level of cGMP than endothelium-denuded preparations and that sodium nitroprusside increased cGMP in both preparations by similar amounts in a concentration-dependent fashion. Exposure of endothelium-denuded or L-NAG-treated segments to sodium nitroprusside, to mimic the effects of basally released EDNO, depressed sodium nitrite and 8-Br cGMP reactivity in a manner similar to endothelium-intact segments. These data indicate that EDNO increases cGMP levels in vascular smooth muscle and that the elevated cGMP levels depress Nitrovasodilator and 8-Br cGMP reactivities.
Georg Kojda - One of the best experts on this subject based on the ideXlab platform.
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Nitrovasodilator induced relaxation and tolerance development in porcine vena cordis magna dependence on intact endothelium
British Journal of Pharmacology, 1994Co-Authors: Georg Kojda, Jan Klaus Beck, Wilfried Meyer, Eike NoackAbstract:1. Isolated segments of porcine vena cordis magna exhibited a reproducible contractile activity upon application of prostaglandin F2 alpha (PGF2 alpha) or KCl, that was independent of the presence of intact endothelium. Substance P (3 nM) elicited strictly endothelium-dependent relaxations amounting to 46.1 +/- 1.4% (n = 206) of contractions induced by 10 microM PGF2 alpha. 2. S-nitroso-N-acetyl-D,L-penicillamine (SNAP), a compound that spontaneously liberates nitric oxide, concentration-dependently relaxed PGF2 alpha-precontracted (50 microM) venous segments. Tolerance induction (incubation with 100 microM SNAP for 30 min) within the same segments resulted in a 3 fold attenuation of this effect, which was not further reduced after additional preincubation with glyceryl trinitrate (GTN). Removal of endothelium or the presence of N omega-nitro-L-arginine methylester (L-NAME) significantly improved the potency of SNAP before and after tolerance induction. 3. Concentration-dependent relaxations induced by GTN in non-tolerant veins were similar in the presence and absence of endothelium but much more reduced in tolerant endothelium-denuded (75 fold) compared to intact (20 fold) segments. In contrast, the presence of L-NAME significantly improved GTN-activity solely in non-tolerant veins, which, therefore, also resulted in a more pronounced attenuation of activity due to tolerance induction (100 fold). Preincubation of intact veins with SNAP also reduced GTN-activity but to a lesser extent (10 fold). 4. The more delayed but much longer, and compared to GTN somewhat weaker, acting new Nitrovasodilator N-(3-nitrato-pivaloyl)-1-cysteineethylester (SPM 3672) was more potent in denuded than intact non-tolerant venous segments. Induction of tolerance by GTN resulted in a 2 fold-attenuation of potency. This effect was increased to 15 fold in denuded veins but solely due to enhanced potency of SPM 3672 caused by removal of endothelium.5. These data demonstrate that intact endothelium of porcine vena cordis magna attenuates the relaxant potency of Nitrovasodilators but also probably participates in vascular bioactivation of GTN.We suggest that the reduced potency of Nitrovasodilators is due to endogenous production of nitricoxide, which may affect the soluble guanylate cyclase/cyclic GMP-system or inhibit nitrate bioactivation pathways.
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Nitrovasodilator‐induced relaxation and tolerance development in porcine vena cordis magna: dependence on intact endothelium
British journal of pharmacology, 1994Co-Authors: Georg Kojda, Jan Klaus Beck, Wilfried Meyer, Eike NoackAbstract:1. Isolated segments of porcine vena cordis magna exhibited a reproducible contractile activity upon application of prostaglandin F2 alpha (PGF2 alpha) or KCl, that was independent of the presence of intact endothelium. Substance P (3 nM) elicited strictly endothelium-dependent relaxations amounting to 46.1 +/- 1.4% (n = 206) of contractions induced by 10 microM PGF2 alpha. 2. S-nitroso-N-acetyl-D,L-penicillamine (SNAP), a compound that spontaneously liberates nitric oxide, concentration-dependently relaxed PGF2 alpha-precontracted (50 microM) venous segments. Tolerance induction (incubation with 100 microM SNAP for 30 min) within the same segments resulted in a 3 fold attenuation of this effect, which was not further reduced after additional preincubation with glyceryl trinitrate (GTN). Removal of endothelium or the presence of N omega-nitro-L-arginine methylester (L-NAME) significantly improved the potency of SNAP before and after tolerance induction. 3. Concentration-dependent relaxations induced by GTN in non-tolerant veins were similar in the presence and absence of endothelium but much more reduced in tolerant endothelium-denuded (75 fold) compared to intact (20 fold) segments. In contrast, the presence of L-NAME significantly improved GTN-activity solely in non-tolerant veins, which, therefore, also resulted in a more pronounced attenuation of activity due to tolerance induction (100 fold). Preincubation of intact veins with SNAP also reduced GTN-activity but to a lesser extent (10 fold). 4. The more delayed but much longer, and compared to GTN somewhat weaker, acting new Nitrovasodilator N-(3-nitrato-pivaloyl)-1-cysteineethylester (SPM 3672) was more potent in denuded than intact non-tolerant venous segments. Induction of tolerance by GTN resulted in a 2 fold-attenuation of potency. This effect was increased to 15 fold in denuded veins but solely due to enhanced potency of SPM 3672 caused by removal of endothelium.5. These data demonstrate that intact endothelium of porcine vena cordis magna attenuates the relaxant potency of Nitrovasodilators but also probably participates in vascular bioactivation of GTN.We suggest that the reduced potency of Nitrovasodilators is due to endogenous production of nitricoxide, which may affect the soluble guanylate cyclase/cyclic GMP-system or inhibit nitrate bioactivation pathways.
Johan Van De Voorde - One of the best experts on this subject based on the ideXlab platform.
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Basic Mechanisms of Action of Nitrovasodilators and Development of Tolerance to Organic Nitrates
Textbook of Angiology, 2000Co-Authors: Johan Van De Voorde, Marcus BogaertAbstract:Nitrovasodilators are among the oldest but still most widely used drugs in cardiovascular medicine.1 As early as 1867, Brunton noted that inhalation of amyl nitrite relieved anginal pain within seconds,13 and in 1879, Murrell established the use of nitroglycerin for prophylaxis and relief of acute anginal attacks.64 Even though the beneficial effects of nitrates were recognized more than 100 years ago, their impact on the organism and their cellular mechanism of action were elucidated only in the 1970s and 1980s. Nitrovasodilators were then found to be a peculiar kind of prodrug; they undergo biotransformation to their active form, nitric oxide (NO), at their site of action, mainly the vascular smooth muscle. NO synthesized by vascular endothelial cells has an important role in physiological regulation of vascular smooth muscle tone (see Chapter 2 in this book). Recognition of the physiological role of NO renewed interest in the Nitrovasodilators, because they were then seen as a substitute for failing endogenous NO in patients with endothelial dysfunction (e.g., in angina and myocardial infarction).
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Mechanisms involved in the development of tolerance to Nitrovasodilator
Journal of Cardiovascular Pharmacology, 1991Co-Authors: Johan Van De VoordeAbstract:The identification of endothelium-derived relaxing factor (EDRF) as nitric oxide (NO) has highlighted the clinical importance of NO-containing drugs (Nitrovasodilators and molsidomine). The development of tolerance and cross-tolerance is a well-known problem with the classic Nitrovasodilators. Although counterregulatory reflex mechanisms might be involved, desensitization of the vascular smooth muscle cells is the best documented mechanism of tolerance. Impaired metabolization of organic nitrates due to deficiency of reduced thiol groups seems to be the major mechanism responsible for this vascular desensitization. Tolerance preventing strategies (nitrate-free periods, administration of N-acetylcysteine, and use of drugs that do not require thiolgroups for activation of guanylate cyclase) are based on this mechanism.
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Mechanisms involved in the development of tolerance to Nitrovasodilators
Journal of Cardiovascular Pharmacology, 1991Co-Authors: Johan Van De VoordeAbstract:The identification of endothelium-derived relaxing factor (EDRF) as nitric oxide (NO)-containing drugs (nitrovasoldilators and molsidomine). The development of tolerance and cross-tolerance is a well-known problem with the classic Nitrovasodilators. Although counterregulatory reflex mechanisms might be involved, desensitization of the vascular smooth muscle cells is the best documented mechanism of tolerance. Impaired metabolization of organic nitrates due to deficiency of reduced thiol groups seems to be the major mechanism responsible for this vascular desensitization
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Parallelisms and differences in the effects of endothelium-derived relaxing factor, Nitrovasodilators, and SIN-1 on rat aorta
Journal of Cardiovascular Pharmacology, 1991Co-Authors: Johan Van De Voorde, Marnix Claeys, Willy Eechaute, I. LeusenAbstract:The endothelium-derived relaxiong factor (EDRF), classic Nitrovasodilators (nitroglycerin, isosorbide dinitrate, etc.), and molsidomine are generally believed to relax vascular smooth muscle through a similar mechanism, namely a nitric oxide (NO)-mediated stimulation of guanylate cyclase, leading to increased cyclic GMP levels, inducing relaxation. Using precontracted rat aortic rings, we investigated the influence of different agents, known to interact with NO, on the relaxation effects elicited by EDRF (released by acetylcholine), NO (generated from acidified nitrite), nitroglycerin, and SIN-1 (the active metabolite of molsidomine).
Jan Klaus Beck - One of the best experts on this subject based on the ideXlab platform.
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Nitrovasodilator induced relaxation and tolerance development in porcine vena cordis magna dependence on intact endothelium
British Journal of Pharmacology, 1994Co-Authors: Georg Kojda, Jan Klaus Beck, Wilfried Meyer, Eike NoackAbstract:1. Isolated segments of porcine vena cordis magna exhibited a reproducible contractile activity upon application of prostaglandin F2 alpha (PGF2 alpha) or KCl, that was independent of the presence of intact endothelium. Substance P (3 nM) elicited strictly endothelium-dependent relaxations amounting to 46.1 +/- 1.4% (n = 206) of contractions induced by 10 microM PGF2 alpha. 2. S-nitroso-N-acetyl-D,L-penicillamine (SNAP), a compound that spontaneously liberates nitric oxide, concentration-dependently relaxed PGF2 alpha-precontracted (50 microM) venous segments. Tolerance induction (incubation with 100 microM SNAP for 30 min) within the same segments resulted in a 3 fold attenuation of this effect, which was not further reduced after additional preincubation with glyceryl trinitrate (GTN). Removal of endothelium or the presence of N omega-nitro-L-arginine methylester (L-NAME) significantly improved the potency of SNAP before and after tolerance induction. 3. Concentration-dependent relaxations induced by GTN in non-tolerant veins were similar in the presence and absence of endothelium but much more reduced in tolerant endothelium-denuded (75 fold) compared to intact (20 fold) segments. In contrast, the presence of L-NAME significantly improved GTN-activity solely in non-tolerant veins, which, therefore, also resulted in a more pronounced attenuation of activity due to tolerance induction (100 fold). Preincubation of intact veins with SNAP also reduced GTN-activity but to a lesser extent (10 fold). 4. The more delayed but much longer, and compared to GTN somewhat weaker, acting new Nitrovasodilator N-(3-nitrato-pivaloyl)-1-cysteineethylester (SPM 3672) was more potent in denuded than intact non-tolerant venous segments. Induction of tolerance by GTN resulted in a 2 fold-attenuation of potency. This effect was increased to 15 fold in denuded veins but solely due to enhanced potency of SPM 3672 caused by removal of endothelium.5. These data demonstrate that intact endothelium of porcine vena cordis magna attenuates the relaxant potency of Nitrovasodilators but also probably participates in vascular bioactivation of GTN.We suggest that the reduced potency of Nitrovasodilators is due to endogenous production of nitricoxide, which may affect the soluble guanylate cyclase/cyclic GMP-system or inhibit nitrate bioactivation pathways.
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Nitrovasodilator‐induced relaxation and tolerance development in porcine vena cordis magna: dependence on intact endothelium
British journal of pharmacology, 1994Co-Authors: Georg Kojda, Jan Klaus Beck, Wilfried Meyer, Eike NoackAbstract:1. Isolated segments of porcine vena cordis magna exhibited a reproducible contractile activity upon application of prostaglandin F2 alpha (PGF2 alpha) or KCl, that was independent of the presence of intact endothelium. Substance P (3 nM) elicited strictly endothelium-dependent relaxations amounting to 46.1 +/- 1.4% (n = 206) of contractions induced by 10 microM PGF2 alpha. 2. S-nitroso-N-acetyl-D,L-penicillamine (SNAP), a compound that spontaneously liberates nitric oxide, concentration-dependently relaxed PGF2 alpha-precontracted (50 microM) venous segments. Tolerance induction (incubation with 100 microM SNAP for 30 min) within the same segments resulted in a 3 fold attenuation of this effect, which was not further reduced after additional preincubation with glyceryl trinitrate (GTN). Removal of endothelium or the presence of N omega-nitro-L-arginine methylester (L-NAME) significantly improved the potency of SNAP before and after tolerance induction. 3. Concentration-dependent relaxations induced by GTN in non-tolerant veins were similar in the presence and absence of endothelium but much more reduced in tolerant endothelium-denuded (75 fold) compared to intact (20 fold) segments. In contrast, the presence of L-NAME significantly improved GTN-activity solely in non-tolerant veins, which, therefore, also resulted in a more pronounced attenuation of activity due to tolerance induction (100 fold). Preincubation of intact veins with SNAP also reduced GTN-activity but to a lesser extent (10 fold). 4. The more delayed but much longer, and compared to GTN somewhat weaker, acting new Nitrovasodilator N-(3-nitrato-pivaloyl)-1-cysteineethylester (SPM 3672) was more potent in denuded than intact non-tolerant venous segments. Induction of tolerance by GTN resulted in a 2 fold-attenuation of potency. This effect was increased to 15 fold in denuded veins but solely due to enhanced potency of SPM 3672 caused by removal of endothelium.5. These data demonstrate that intact endothelium of porcine vena cordis magna attenuates the relaxant potency of Nitrovasodilators but also probably participates in vascular bioactivation of GTN.We suggest that the reduced potency of Nitrovasodilators is due to endogenous production of nitricoxide, which may affect the soluble guanylate cyclase/cyclic GMP-system or inhibit nitrate bioactivation pathways.