A comparative study of glyceryl trinitrate biotransformation and glyceryl trinitrate induced relaxation in bovine pulmonary artery and vein

1987 ◽  
Vol 65 (6) ◽  
pp. 1146-1150 ◽  
Author(s):  
J. H. Kawamoto ◽  
J. F. Brien ◽  
G. S. Marks ◽  
K. Nakatsu
Keyword(s):  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Glyceryl Trinitrate ◽  
Pulmonary Arteries ◽  
Organic Nitrate ◽  
Tissue Samples ◽  
Series Of Experiments ◽  
Layer Chromatography ◽  
Arteries And Veins

Recent evidence supports the hypothesis that the mechanism by which glyceryl trinitrate induces relaxation of vascular smooth muscle involves the biotransformation of glyceryl trinitrate. This study was conducted to determine if there was a direct correlation between the capacity of vascular smooth muscle preparations to biotransform glyceryl trinitrate and their sensitivity to the relaxant effect of this organic nitrate. Isolated bovine pulmonary arteries and veins were contracted subtnaxirnally and cumulative dose–response relationships to glyceryl trinitrate were obtained; the vein was approximately 10 times more sensitive than the artery to glyceryl trinitrate induced relaxation. In a separate series of experiments, these vascular tissues were contracted submaximally and incubated with 0.5 μM [14C]glyceryl trinitrate for 2 min, during which glyceryl trinitrate induced relaxation was monitored. At 2 min, tissue samples were taken for determination of glyceryl trinitrate and glyceryl-1,2- and 1,3-dinitrate content by thin-layer chromatography and liquid scintillation spectrometry. Biotransformation of glyceryl trinitrate to glyceryl dinitrate occurred concomitantly with relaxation of these blood vessels. The concentration of glyceryl dinitrate in the vein was significantly less than that in the artery (p ≤ 0.05), even though significantly greater relaxation of the vein than the artery was observed (p ≤ 0.05). From these data, a simple linear relationship between glyceryl trinitrate biotransformation and relaxation is not apparent.

YC-1 enhances the responsiveness of tolerant vascular smooth muscle to glyceryl trinitrate

2001 ◽  
Vol 79 (1) ◽  
pp. 43-48 ◽  
Author(s):  
Deirdre A O'Reilly ◽  
Brian E McLaughlin ◽  
Gerald S Marks ◽  
James F Brien ◽  
Kanji Nakatsu
Keyword(s):  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Glyceryl Trinitrate ◽  
Metabolic Activation ◽  
Nitric Oxide Donor ◽  
Organic Nitrate ◽  
Organic Nitrates ◽  
Cardiovascular Medicine ◽  
Left Shift ◽  
Concentration Response Curve

A major limitation of the use of organic nitrates in cardiovascular medicine is the development of tolerance, which has been attributed, in part, to a decrease in their metabolic activation in the vascular smooth muscle cell. Recently, 3-(5'-hydroxymethyl-2'-furyl)-1-benzylindazole (YC-1) was shown to potentiate vascular smooth muscle responsiveness to glyceryl trinitrate (GTN), sodium nitroprusside, and the nitric oxide donor NOC 18, in organic nitrate-naïve vascular smooth muscle. We used GTN-tolerant rabbit aortic rings (RARs) to test the hypothesis that a non-vasorelaxant concentration of YC-1 enhances the ability of the prototypical organic nitrate GTN to relax vascular smooth muscle and elevate intravascular cGMP under conditions of GTN tolerance. Treatment with YC-1 (3 µM) produced a left shift of the GTN concentration-response curve and decreased the EC50 value for GTN-induced relaxation in both GTN-tolerant and non-tolerant RARs (P < 0.05). Intravascular cGMP elevation induced by GTN was enhanced in the presence of YC-1 in GTN-tolerant and non-tolerant RARs (P < 0.05). These observations indicate that YC-1, or similarly acting drugs, may be useful in overcoming the tolerance that develops during sustained GTN therapy, and that its mechanism may involve enhanced cGMP formation.Key words: glyceryl trinitrate, 3-(5'-hydroxymethyl-2'-furyl)-1-benzylindazole (YC-1), organic nitrate tolerance, cGMP, vasorelaxation.

Biotransformation of glyceryl trinitrate and isosorbide dinitrate in vascular smooth muscle made tolerant to organic nitrates

1989 ◽  
Vol 67 (11) ◽  
pp. 1381-1385 ◽  
Author(s):  
Christopher J. Slack ◽  
Brian E. McLaughlin ◽  
James F. Brien ◽  
Gerald S. Marks ◽  
Kanji Nakatsu
Keyword(s):  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Glyceryl Trinitrate ◽  
Isosorbide Dinitrate ◽  
Isosorbide Mononitrate ◽  
Organic Nitrate ◽  
Organic Nitrates ◽  
Nitrate Anion ◽  
Pharmacologically Active

It has been proposed that organic nitrates are prodrugs and biotransformation to a pharmacologically active metabolite (i.e., nitric oxide) must occur before the onset of vasodilation. If this postulated mechanism is correct, tolerance to organic nitrate-induced vasodilation might involve decreased biotransformation of organic nitrates by vascular smooth muscle. In this study, biotransformation of isosorbide dinitrate (ISDN) and glyceryl trinitrate (GTN) was estimated by measuring isosorbide mononitrate (ISMN) and glyceryl dinitrate (GDN), respectively, rather than the nitrate anion, because of a more sensitive method for measurement of ISMN and GDN. To test this hypothesis, isolated rabbit aortic strips (RAS) were made tolerant in vitro by incubation with 500 μM GTN or ISDN for 1 h. After a washout period and submaximal contraction with phenylephrine, the tissues were incubated with either 2.0 μM [14C]ISDN or 0.5 μM [14C]GTN for 2 min. ISDN- or GTN-induced relaxation of RAS was monitored and tissue parent drug and metabolite contents were determined by thin-layer chromatography and liquid scintillation spectrometry. ISDN- and GTN-induced relaxation of RAS and the metabolite concentrations were significantly less for both GTN- and ISDN-tolerant tissue compared with nontolerant tissue. These results are consistent with the hypothesis that organic nitrate biotransformation is required for organic nitrate-induced vasodilation.Key words: organic nitrates, glyceryl trinitrate, isosorbide dinitrate, biotransformation, prodrug, tolerance.

Biotransformation of glyceryl trinitrate by blood platelets as compared to vascular smooth muscle cells

1996 ◽  
Vol 309 (2) ◽  
pp. 209-213 ◽  
Author(s):  
Artur-Aron Weber ◽  
Thomas Neuhaus ◽  
Claudia Seul ◽  
Rainer Düsing ◽  
Karsten Schrör ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Glyceryl Trinitrate ◽  
Vascular Smooth Muscle Cells ◽  
Blood Platelets ◽  
Muscle Cells

scholarly journals Effects of dexmedetomidine on porcine pulmonary artery vascular smooth muscle

2019 ◽  
Author(s):  
Mami Chikuda ◽  
Kenichi Sato
Keyword(s):  
Smooth Muscle ◽  
Pulmonary Artery ◽  
Vascular Smooth Muscle ◽  
Local Anesthetics ◽  
Pulmonary Arteries ◽  
Dependent Manner ◽  
Concentration Dependent Manner ◽  
Duration Of Action ◽  
Porcine Pulmonary Artery ◽  
Ca2 Channels

Abstract Background Dexmedetomidine is added to local anesthetics to increase their potency and extend their duration of action, thus providing postoperative analgesia with a single administration. However, the effects and mechanism of action of dexmedetomidine on pulmonary arteries have not been determined. The aim of this study was to investigate the effect of dexmedetomidine on pulmonary artery vascular smooth muscle, evaluating changes in contraction tension. Methods Endothelium-denuded porcine pulmonary arteries were sliced into 2- to 3-mm rings. Changes in isometric contraction tension were measured with the addition of various substances at various concentrations, under different conditions of baseline stimulation (with KCl, Adrenaline, caffeine, or histamine) and different conditions of Ca2+ depletion with intracellular reservoirs or extracellular stores depleted. Results Dexmedetomidine increased the contraction tension induced by high-KCl depolarization in a concentration-dependent manner. Dexmedetomidine inhibited receptor-activated Ca2+ channels (RACCs) and phosphatidylinositol-1,4,5-triphosphate-induced Ca2+ release (IICR), but not Ca2+-induced Ca2+ release (CICR). Conclusions Dex increased the contraction tension resulting from depolarization stimulation by high KCl in a concentration-dependent manner in porcine pulmonary artery vascular smooth muscle. The enhancement of high KCl-induced contraction with Dex addition was mediated by α2 receptors. Dex suppressed increases in contraction tension induced by receptor stimulation with adrenaline, also in a concentration-dependent manner. Dex inhibited RACC and IICR, but not CICR. Elucidating the effects and mechanisms of action of Dex in the central arteries is likely to be useful as basic data for creating Dex-containing local anesthetics.

scholarly journals Severe asthma is associated with a remodeling of the pulmonary arteries in horses

2020 ◽  
Author(s):  
Serena Ceriotti ◽  
Michela Bullone ◽  
Mathilde Leclere ◽  
Francesco Ferrucci ◽  
Jean-Pierre Lavoie
Keyword(s):  
Pulmonary Hypertension ◽  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Muscle Mass ◽  
Pulmonary Arteries ◽  
Chronic Obstructive ◽  
Corticosteroid Administration ◽  
Wall Area ◽  
Hypoxic Vasoconstriction ◽  
Equine Asthma

AbstractPulmonary hypertension and cor pulmonale are complications of severe equine asthma, as a consequence of pulmonary hypoxic vasoconstriction. However, as pulmonary hypertension is only partially reversible by oxygen administration, other etiological factors are likely involved. In human chronic obstructive pulmonary disease, pulmonary artery remodeling contributes to the development of pulmonary hypertension. In rodent models, pulmonary vascular remodeling is present as a consequence of allergic airway inflammation. The present study investigated the presence of remodeling of the pulmonary arteries in severe equine asthma, its distribution throughout the lungs, and its reversibility following long-term antigen avoidance strategies and inhaled corticosteroid administration. Using histomorphometry, the total wall area of pulmonary arteries from different regions of the lung of asthmatic horses and controls was measured. The smooth muscle mass of pulmonary arteries was also estimated on lung sections stained for α-smooth muscle actin. Reversibility of vascular changes in asthmatic horses was assessed after 1 year of antigen avoidance alone or treatment with inhaled fluticasone. Pulmonary arteries showed increased wall area in apical and caudodorsal lung regions of asthmatic horses in both exacerbation and remission. The pulmonary arteries smooth muscle mass was similarly increased. Both treatments reversed the increase in wall area. However, normalization of the vascular smooth muscle mass was observed only after treatment with antigen avoidance, but not with fluticasone. In conclusion, severe equine asthma is associated with remodeling of the pulmonary arteries consisting in an increased smooth muscle mass. The resulting narrowing of the artery lumen could enhance hypoxic vasoconstriction, contributing to pulmonary hypertension. Vascular smooth muscle mass normalization is better achieved by antigen avoidance than with inhaled corticosteroids.

scholarly journals Nogo-B Receptor Directs Mitochondria-Associated Membranes to Regulate Vascular Smooth Muscle Cell Proliferation

2019 ◽  
Vol 20 (9) ◽  
pp. 2319
Author(s):  
Yi-Dong Yang ◽  
Man-Man Li ◽  
Gang Xu ◽  
Lan Feng ◽  
Er-Long Zhang ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Nuclear Localization ◽  
Epithelial Mesenchymal Transition ◽  
Pulmonary Arteries ◽  
Underlying Mechanism ◽  
Mesenchymal Transition ◽  
Vsmc Proliferation ◽  
Vsmcs Proliferation

Mitochondria-associated membranes (MAM) are a well-recognized contact link between the mitochondria and endoplasmic reticulum that affects mitochondrial biology and vascular smooth muscle cells (VSMCs) proliferation via the regulation of mitochondrial Ca2+(Ca2+m) influx. Nogo-B receptor (NgBR) plays a vital role in proliferation, epithelial-mesenchymal transition, and chemoresistance of some tumors. Recent studies have revealed that downregulation of NgBR, which stimulates the proliferation of VSMCs, but the underlying mechanism remains unclear. Here, we investigated the role of NgBR in MAM and VSMC proliferation. We analyzed the expression of NgBR in pulmonary arteries using a rat model of hypoxic pulmonary hypertension (HPH), in which rats were subjected to normoxic recovery after hypoxia. VSMCs exposed to hypoxia and renormoxia were used to assess the alterations in NgBR expression in vitro. The effect of NgBR downregulation and overexpression on VSMC proliferation was explored. The results revealed that NgBR expression was negatively related with VSMCs proliferation. Then, MAM formation and the phosphorylation of inositol 1,4,5-trisphosphate receptor type 3 (IP3R3) was detected. We found that knockdown of NgBR resulted in MAM disruption and augmented the phosphorylation of IP3R3 through pAkt, accompanied by mitochondrial dysfunction including decreased Ca2+m, respiration and mitochondrial superoxide, increased mitochondrial membrane potential and HIF-1α nuclear localization, which were determined by confocal microscopy and Seahorse XF-96 analyzer. By contrast, NgBR overexpression attenuated IP3R3 phosphorylation and HIF-1α nuclear localization under hypoxia. These results reveal that dysregulation of NgBR promotes VSMC proliferation via MAM disruption and increased IP3R3 phosphorylation, which contribute to the decrease of Ca2+m and mitochondrial impairment.

Effect of changes in pH on wall tension in isolated rat pulmonary artery: role of the RhoA/Rho-kinase pathway

2004 ◽  
Vol 287 (4) ◽  
pp. L673-L684 ◽  
Author(s):  
Jean-Marc Hyvelin ◽  
Clare O’Connor ◽  
Paul McLoughlin
Keyword(s):  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Kinase Inhibitor ◽  
Pulmonary Arteries ◽  
Rho Kinase ◽  
Systemic Circulation ◽  
Pulmonary Vasculature ◽  
Tension Development ◽  
Kinase Pathway

Pulmonary arteries (PA) are resistant to the vasodilator effects of extracellular acidosis in systemic vessels; the mechanism underlying this difference between systemic and pulmonary circulations has not been elucidated. We hypothesized that RhoA/Rho-kinase-mediated Ca2+ sensitization pathway played a greater role in tension development in pulmonary than in systemic vascular smooth muscle and that this pathway was insensitive to acidosis. In arterial rings contracted with the α1-agonist phenylephrine (PE), the Rho-kinase inhibitor Y-27632 (≤3 μM) induced greater relaxation in precontracted PA rings than in aortic rings. In PA rings stimulated by PE, the activation of RhoA was greater than in aorta. Normocapnic acidosis (NA) induced a smaller relaxation in precontracted PA than in aorta. However, in the presence of nifedipine and thapsigargin, when PE-induced contraction was predominantly mediated by Rho-kinase, the relaxant effect of NA was reduced and similar in both vessel types. Furthermore, in the presence of Y-27632, NA induced a greater relaxation in both PA and aorta, which was similar in both vessels. Finally, in α-toxin-permeabilized smooth muscle, PE-induced contraction at constant Ca2+ activity was inhibited by Y-27632 and unaffected by acidosis. These results indicate that Ca2+ sensitization induced by the RhoA/Rho-kinase pathway played a greater role in agonist-induced vascular smooth muscle contraction in PA than in aorta and that tension mediated by this pathway was insensitive to acidosis. The predominant role of the RhoA/Rho-kinase pathway in the pulmonary vasculature may account for the resistance of this circulation to the vasodilator effect of acidosis observed in the systemic circulation.

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