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.

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.

scholarly journals Arteriolar vasodilation involves actin depolymerization

2018 ◽  
Vol 315 (2) ◽  
pp. H423-H428
Author(s):  
Philip S. Clifford ◽  
Brian S. Ferguson ◽  
Jeffrey L. Jasperse ◽  
Michael A. Hill
Keyword(s):  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Sodium Nitroprusside ◽  
Light Chain ◽  
Myosin Light Chain ◽  
Muscle Relaxation ◽  
Nitric Oxide Donor ◽  
Smooth Muscle Relaxation ◽  
Myosin Light Chain Phosphorylation ◽  
Actin Depolymerization

It is generally assumed that relaxation of arteriolar vascular smooth muscle occurs through hyperpolarization of the cell membrane, reduction in intracellular Ca2+ concentration, and activation of myosin light chain phosphatase/inactivation of myosin light chain kinase. We hypothesized that vasodilation is related to depolymerization of F-actin. Cremaster muscles were dissected in rats under pentobarbital sodium anesthesia (50 mg/kg). First-order arterioles were dissected, cannulated on glass micropipettes, pressurized, and warmed to 34°C. Internal diameter was monitored with an electronic video caliper. The concentration of G-actin was determined in flash-frozen intact segments of arterioles by ultracentrifugation and Western blot analyses. Arterioles dilated by ~40% of initial diameter in response to pinacidil (1 × 10−6 mM) and sodium nitroprusside (5 × 10−5 mM). The G-actin-to-smooth muscle 22α ratio was 0.67 ± 0.09 in arterioles with myogenic tone and increased significantly to 1.32 ± 0.34 ( P < 0.01) when arterioles were dilated with pinacidil and 1.14 ± 0.18 ( P < 0.01) with sodium nitroprusside, indicating actin depolymerization. Compared with control vessels (49 ± 5%), the percentage of phosphorylated myosin light chain was significantly reduced by pinacidil (24 ± 2%, P < 0.01) but not sodium nitroprusside (42 ± 4%). These findings suggest that actin depolymerization is an important mechanism for vasodilation of resistance arterioles to external agonists. Furthermore, pinacidil produces smooth muscle relaxation via both decreases in myosin light chain phosphorylation and actin depolymerization, whereas sodium nitroprusside produces smooth muscle relaxation primarily via actin depolymerization. NEW & NOTEWORTHY This article adds to the accumulating evidence on the contribution of the actin cytoskeleton to the regulation of vascular smooth muscle tone in resistance arterioles. Actin depolymerization appears to be an important mechanism for vasodilation of resistance arterioles to pharmacological agonists. Dilation to the K+ channel opener pinacidil is produced by decreases in myosin light chain phosphorylation and actin depolymerization, whereas dilation to the nitric oxide donor sodium nitroprusside occurs primarily via actin depolymerization. Listen to this article’s corresponding podcast at https://ajpheart.podbean.com/e/vascular-smooth-muscle-actin-depolymerization/ .

Cytochrome P-450 mediated biotransformation of organic nitrates

1990 ◽  
Vol 68 (12) ◽  
pp. 1552-1557 ◽  
Author(s):  
Bernard J. McDonald ◽  
Brian M. Bennett
Keyword(s):  
Glyceryl Trinitrate ◽  
Microsomal Fraction ◽  
Direct Interaction ◽  
Organic Nitrate ◽  
Organic Nitrates ◽  
Aerobic Conditions ◽  
First Order ◽  
Preferential Formation ◽  
First Order Kinetics ◽  
Cytochrome P 450

The vascular biotransformation of organic nitrates appears to be a prerequisite for their action as vasodilators. In the current study, we assessed the involvement of cytochrome P-450 in the denitration of glyceryl trinitrate and the enantiomers of isoidide dinitrate. Denitration of organic nitrates by the microsomal fraction of rat liver was NADPH dependent and followed apparent first-order kinetics. Under aerobic conditions, the t1/2 of D-isoidide dinitrate was significantly shorter than that of L-isoidide dinitrate (11.9 vs. 14.1 min, p ≤ 0.05), which is consistent with the greater potency of the D-enantiomer for vasodilation. Under anaerobic conditions, the denitration of glyceryl trinitrate was very rapid (t1/2 approximately 30 s). Organic nitrate biotransformation was inhibited by carbon monoxide, SKF 525A, and dioxygen. This suggests that the biotransformation of organic nitrates can occur through the direct interaction with the heme moiety of cytochrome P-450. The biotransformation of glyceryl trinitrate was catalyzed preferentially by those isoenzymes induced by phenobarbital. The biotransformation of glyceryl trinitrate was regioselective for 1,3-glyceryl dinitrate formation except in phenobarbital-induced microsomes under aerobic conditions, in which preferential formation of 1,2-glyceryl dinitrate occurred. These data suggest that cytochrome P-450 is involved in the biotransformation of organic nitrates and raises the possibility that vascular cytochrome P-450 may play a role in the mechanism-based biotransformation of organic nitrates, the result of which is vascular smooth muscle relaxation.Key words: cytochrome P-450, glyceryl trinitrate, isoidide dinitrate, biotransformation, liver.

Biotransformation of organic nitrates and vascular smooth muscle cell function

1994 ◽  
Vol 15 (7) ◽  
pp. 245-249 ◽  
Author(s):  
Brian M. Bennett ◽  
Bernard J. McDonald ◽  
Rita Nigam ◽  
W. Craig Simon
Keyword(s):  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Smooth Muscle Cell ◽  
Muscle Cell ◽  
Vascular Smooth Muscle Cell ◽  
Cell Function ◽  
Organic Nitrates

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

Metabolic activation of AMP kinase in vascular smooth muscle

2005 ◽  
Vol 98 (1) ◽  
pp. 296-306 ◽  
Author(s):  
L. J. Rubin ◽  
L. Magliola ◽  
X. Feng ◽  
A. W. Jones ◽  
C. C. Hale
Keyword(s):  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Metabolic Stress ◽  
Metabolic Activation ◽  
Physiological Saline ◽  
Immunoblot Analysis ◽  
Smooth Muscle Contraction ◽  
Striated Muscles ◽  
Ampk Activity ◽  
Pronounced Reduction

AMP-activated kinase (AMPK) is a highly conserved heterotrimeric kinase that functions as a metabolic master switch to coordinate cellular enzymes involved in carbohydrate and fat metabolism that regulate ATP conservation and synthesis. AMPK is activated by conditions that increase AMP-to-ATP ratio, such as exercise and metabolic stress. In the present study, we probed whether AMPK was expressed in vascular smooth muscle and would be activated by metabolic stress. Endothelium-denuded porcine carotid artery segments were metabolically challenged with 2-deoxyglucose (10 mM) plus N2 (N2-2DG). These vessels exhibited a rapid increase in AMPK activity by 1 min that was near maximal by 20 min. AMPK inactivation on return to normal physiological saline was ∼50% in 1 min and fully recovered by 5 min. Immunoprecipitation of the α1- and α2-catalytic subunit followed by immunoblot analysis for [P]Thr172-AMPK indicates that α1-AMPK accounts for all activity. Little if any α2-AMPK was detected in carotid smooth muscle. AMPK activity was not increased by contractile agonist (endothelin-1) or by the reported AMPK activators 5-aminoimidazole-4-carboxamide ribofuranoside (2 mM), metformin (2 mM), or phenformin (0.2 mM). AMPK activation by N2-2DG was associated with a rapid and pronounced reduction in endothelin-induced force and reduced phosphorylation of Akt and Erk 1/2. These data demonstrate that AMPK expression differs in vascular smooth muscle compared with striated muscles and that activation and inactivation after metabolic stress occur rapidly and are associated with signaling pathways that may regulate smooth-muscle contraction

Peroxynitrite inhibits the expression of Giα protein and adenylyl cyclase signaling in vascular smooth muscle cells

2008 ◽  
Vol 294 (2) ◽  
pp. H775-H784 ◽  
Author(s):  
Marcel Bassil ◽  
Yuan Li ◽  
Madhu B. Anand-Srivastava
Keyword(s):  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Map Kinase ◽  
Adenylyl Cyclase ◽  
Vascular Smooth Muscle Cells ◽  
Muscle Cells ◽  
P38 Map Kinase ◽  
Nitric Oxide Donor ◽  
Dependent Manner

We previously showed that S-nitroso- N-acetylpenicillamine, a nitric oxide donor, decreased the levels and functions of Giα proteins by formation of peroxynitrite (ONOO−) in vascular smooth muscle cells (VSMC). The present studies were undertaken to investigate whether ONOO− can modulate the expression of Giα protein and associated adenylyl cyclase signaling in VSMC. Treatment of A-10 and aortic VSMC with ONOO− for 24 h decreased the expression of Giα-2 and Giα-3, but not Gsα, protein in a concentration-dependent manner; expression was restored toward control levels by 111Mn-tetralis(benzoic acid porphyrin) and uric acid, but not by 1 H[1,2,4]oxadiazole[4,3-a]quinoxaline-1-one (ODQ) and KT-5823. cGMP levels were increased by ∼50% and 150% by 0.1 and 0.5 mM ONOO−, respectively, and attenuated toward control levels by ODQ. In addition, 0.5 mM ONOO− attenuated the inhibition of adenylyl cyclase by ANG II and C-type atrial natriuretic peptide (C-ANP4–23), as well as the inhibition of forskolin-stimulated adenylyl cyclase activity by GTPγS, whereas, the Gs-mediated stimulations were augmented. In addition, 0.5 mM ONOO− decreased phosphorylation of ERK1/2 and p38 MAP kinase and enhanced JNK phosphorylation but did not affect AKT1/3 phosphorylation. These results suggest that ONOO− decreased the expression of Gi proteins and associated functions in VSMC through a cGMP-independent mechanism and may involve the MAP kinase signaling pathway.

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