Nitric oxide formation from glyceryl trinitrate in the developing guinea-pig hippocampus

2000 ◽  
Vol 12 (6) ◽  
pp. 245 ◽  
Author(s):  
Adrian C. Crowe ◽  
Malcolm E. Chang ◽  
Brian E. McLaughlin ◽  
James F. Brien
Keyword(s):  
Nitric Oxide ◽  
Guinea Pig ◽  
Glyceryl Trinitrate ◽  
Life Time ◽  
Organic Nitrate ◽  
Postnatal Life ◽  
No Donor ◽  
Aerobic Conditions ◽  
No Formation ◽  
Pharmacologic Effect

Glyceryl trinitrate (GTN) is classified as an organic nitrate vasodilator drug. GTN is considered to be a prodrug because it undergoes biotransformation at its site of action to form nitric oxide (NO) or a NO adduct, which produces its pharmacologic effect. The objectives of this study were to determine whether the hippocampus can biotransform GTN to NO using aerobic conditions, and whether biotransformation of GTN to NO is age-dependent during postnatal life. Time-dependent formation of NO occurred during the incubation of 100 µM GTN with 2.5% (w/v) homogenate of guinea-pig hippocampus at 37°C using aerobic conditions. GTN-derived NO formation was similar in magnitude for the three selected postnatal ages that were studied, that is, postnatal days 10, 20 and > 60. The data demonstrate that the capacity of the hippocampus for NO formation from GTN is fully developed in the guinea-pig in early postnatal life. In view of these findings, it is conceivable that a NO donor drug, selectively metabolized to NO in the hippocampus, could be a useful therapeutic intervention to mitigate structural and/or functional defects in this brain region resulting from decreased NO formation or availability.

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.

5-HT activates nitric oxide-generating neurons to stimulate chloride secretion in guinea pig distal colon

1998 ◽  
Vol 275 (4) ◽  
pp. G829-G834 ◽  
Author(s):  
Atsukazu Kuwahara ◽  
Hirofumi Kuramoto ◽  
Makoto Kadowaki
Keyword(s):  
Nitric Oxide ◽  
Guinea Pig ◽  
Short Circuit ◽  
Short Circuit Current ◽  
Distal Colon ◽  
Chloride Secretion ◽  
Evoked Response ◽  
Evoked Responses ◽  
No Donor ◽  
Simultaneous Application

The participation of nitric oxide (NO) in serotonin (5-hydroxytryptamine; 5-HT)-evoked chloride secretion in guinea pig distal colon was examined. Submucosal/mucosal segments were mounted in Ussing flux chambers, and an increase in short-circuit current ( I sc) was used as an index of secretion. Addition of 5-HT to the serosal side produced a concentration-dependent (10−7–10−5M) increase in I sc caused by chloride secretion. N G-nitro-l-arginine (l-NNA) significantly reduced the 5-HT-evoked early (P-1) and late (P-2) responses to 61.1 and 70.6% of control, respectively. Neurally evoked response was also inhibited by l-NNA. The NO donor sodium nitroprusside (SNP, 10−4 M) increased basal I sc mainly because of chloride secretion. The SNP-evoked response was significantly reduced by tetrodotoxin but was unchanged by atropine or indomethacin. These results suggest that the 5-HT-evoked increase in I sc is associated with an NO-generating mechanism. Atropine significantly reduced the 5-HT (10−5 M)-evoked P-1 and P-2 responses to 71.8 and 19.7% of control, respectively. Simultaneous application of atropine andl-NNA further decreased the 5-HT-evoked responses more than either drug alone; application ofl-NNA and atropine decreased the 5-HT-evoked P-1 and P-2 responses to 68.5 and 39.2% of atropine-treated tissues, respectively. These results suggest that noncholinergic components of P-1 and P-2 responses are 71.8 and 19.7% of control, respectively, and that NO components of P-1 and P-2 responses are 32 and 61%, respectively, of the noncholinergic component of the 5-HT-evoked responses. The results provide evidence that NO may participate as a noncholinergic mediator of 5-HT-evoked chloride secretion in guinea pig distal colon.

Biotransformation of glyceryl trinitrate by rat brain homogenate

1992 ◽  
Vol 70 (6) ◽  
pp. 935-937 ◽  
Author(s):  
Gerald S. Marks ◽  
Brian E. McLaughlin ◽  
Kanji Nakatsu ◽  
James F. Brien
Keyword(s):  
Nitric Oxide ◽  
Glyceryl Trinitrate ◽  
Rat Brain ◽  
Brain Homogenate ◽  
Organic Nitrate ◽  
Oxide Formation ◽  
Anaerobic Conditions ◽  
Nitric Oxide Formation ◽  
Selective Formation ◽  
Vasodilator Drug

Incubation of glyceryl trinitrate (GTN) with 5% (w/v) rat brain homogenate (RBH) resulted in biotransformation of the organic nitrate vasodilator drug to a mixture of glyceryl-1,2-dinitrate (1,2-GDN) and glyceryl-1,3-dinitrate (1,3-GDN). Heating of the RBH at 100 °C for 5 min and (or) pretreatment with 5 mM N-ethylmaleimide at 37 °C for 10 min demonstrated that about two-thirds of the GTN biotransformation activity was due to a sulfhydryl-dependent enzymatic process resulting in the predominant formation of 1,2-GDN, and that the remaining biotransformation activity was due to a sulfhydryl-dependent nonenzymatic process resulting in the selective formation of 1,3-GDN. In a preliminary experiment, nitric oxide formation was observed during the incubation of GTN with RBH under anaerobic conditions. These data support the idea that some of the therapeutic and adverse effects of GTN are mediated through its action in the central nervous system.Key words: glyceryl trinitrate, biotransformation, rat brain homogenate, sulfhydryl-dependent enzyme, nitric oxide formation.

Nitric Oxide Synthase Inhibition: A New Principle in the Treatment of Migraine Attacks

Cephalalgia ◽  
1998 ◽  
Vol 18 (1) ◽  
pp. 27-32 ◽  
Author(s):  
LH Lassen ◽  
M Ashina ◽  
I Christiansen ◽  
V Ulrich ◽  
R Grover ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Statistical Evaluation ◽  
Double Blind Study ◽  
Double Blind ◽  
No Donor ◽  
Pain Mechanisms ◽  
No Formation ◽  
Subsequent Phase ◽  
Synthase Inhibitor ◽  
Oxide Synthase

Glyceryl trinitrate, an exogenous nitric oxide (NO) donor, and histamine, which causes NO formation in vascular endothelium, have been shown to trigger migraine attacks. However, it remains uncertain whether NO is involved in the subsequent phase of migraine attacks. To answer this question we studied the effect of L-NGmethylarginine hydrochloride (546C88), a NO-synthase inhibitor, on spontaneous migraine attacks. In a double-blind study design, 18 patients with migraine without aura randomly 546C88 (6 mg/ kg) or placebo (5% dextrose) iv given over 15 min for a single migraine attack (546C88: placebo, 15:3). Furthermore, 11 placebo-treated patients from previous double-blind trials with almost identical design were added to the placebo group in the statistical evaluation. Two hours after the infusion, 10 of 15 L-NGmethylarginine hydrochloride-treated patients experienced headache relief compared to 2 of 14 placebotreated patients ( p=0.01). Symptoms such as phono- and photophobia were also significantly improved. A similar trend for nausea was not significant. We conclude that NO may be involved in the pain mechanisms throughout the course of spontaneous migraine attacks.

Effect of in vivo nitrate tolerance on hypersensitivity to NO donors after NO-synthase blockade

2002 ◽  
Vol 80 (11) ◽  
pp. 1106-1118 ◽  
Author(s):  
Jodan D Ratz ◽  
Michael A Adams ◽  
Brian M Bennett
Keyword(s):  
Nitric Oxide ◽  
Glyceryl Trinitrate ◽  
Nitrate Tolerance ◽  
Metabolite Formation ◽  
No Donor ◽  
No Donors ◽  
Nos Inhibitors ◽  
Pressure Lowering ◽  
Oxide Synthase

Animals treated with nitric oxide synthase (NOS) inhibitors exhibit marked hypersensitivity to the blood pressure lowering effects of exogenous nitric oxide (NO) donors. We used this model as a sensitive index to evaluate the relative importance of reduced biotransformation of glyceryl trinitrate (GTN) to NO in the development of nitrate tolerance. NOS-blockade hypertension using NG-nitro-L-arginine methyl ester (L-NAME) caused a marked enhancement of the mean arterial pressure (MAP) decrease mediated by GTN in nontolerant rats. However, even large doses of GTN were unable to change the MAP in GTN-tolerant, NOS-blockade hypertensive animals. In contrast, the MAP responses to the spontaneous NO donor sodium nitroprusside (SNP) were completely unaltered in either tolerant rats or tolerant NOS-blockade hypertensive animals, indicating that NO-dependent vasodilatory mechanisms remain intact despite the development of GTN tolerance. The MAP-lowering effects of GTN in NOS-blockade hypertensive animals were restored 48 h after cessation of chronic GTN exposure. These alterations in the pharmacodynamic response to GTN during tolerance development and reversal were associated with parallel changes in the pattern of GTN metabolite formation, suggesting that the activity of one or more enzymes involved in nitrate metabolism was altered as a consequence of chronic GTN exposure. These findings suggest that the vasodilation resulting from the vascular biotransformation of GTN to NO (or a closely related species) is severely compromised in nitrate-tolerant animals, and that although other mechanisms may contribute to the vascular changes observed following the development of GTN tolerance, decreased GTN bioactivation is likely the most important.Key words: biotransformation, glyceryl trinitrate, hypertension, nitric oxide, tolerance.

Effect of a Nitric Oxide Donor (Glyceryl Trinitrate) on Nociceptive Thresholds in Man

Cephalalgia ◽  
1996 ◽  
Vol 16 (3) ◽  
pp. 169-174 ◽  
Author(s):  
LL Thomsen ◽  
J Brennum ◽  
HK Iverson ◽  
J Olesen
Keyword(s):  
Nitric Oxide ◽  
Glyceryl Trinitrate ◽  
Animal Studies ◽  
Crossover Design ◽  
Nitric Oxide Donor ◽  
Temporal Region ◽  
Double Blind ◽  
No Donor ◽  
Pain Detection ◽  
Nociceptive Input

Several animal studies suggest that nitric oxide (NO) plays a role in central and peripheral modulation of nociception. Glyceryl trinitrate GTN) exerts its physiological actions via donation of NO. The purpose of the present study was to examine the effect of this NO donor on nociceptive thresholds in man. On two different study days separated by at least, week 12 healthy subjects received a staircase infusion of GTN (0.015, 0.25. 1.0, 2.0 mg/kg/min. 20 min each dose) or placebo in a randomized double-blind crossover design. Before the infusion and after 15 min of infusion on each dose, pressure pain detection and tolerance thresholds were determined by pressure a gometry (Somomedic AB, Sweden) in three different anatomic regions (finger, a temporal region with interposed myofascial tissue and a temporal region without interposed myofascial tissue. Relative to placebo, the three higher GTN doses induced a decrease in both detection and tolerance thresholds in the temporal region with interposed myofascial tissue ( p=0.003 detection and p=0.002 tolerance threshold: Friedman). No such changes were observed in the other two stimulated regions. These results could reflect central facilitation of nociception by NO. However, we regard convergence, of nociceptive input from pericranial myofascial tissue and from cephalic blood vessels dilated by NO as a more likely, explanation of our findings.

Expression, localization, and regulation of NOS in human mast cell lines: effects on leukotriene production

Blood ◽  
2004 ◽  
Vol 104 (2) ◽  
pp. 462-469 ◽  
Author(s):  
Mark Gilchrist ◽  
Scott D. McCauley ◽  
A. Dean Befus
Keyword(s):  
Nitric Oxide ◽  
Protein Localization ◽  
Human Mast Cell ◽  
No Production ◽  
Ionophore A23187 ◽  
Dependent Manner ◽  
No Donor ◽  
No Formation ◽  
Health And Disease ◽  
Oxide Synthase

Abstract Nitric oxide (NO) is a potent radical produced by nitric oxide synthase (NOS) and has pleiotrophic activities in health and disease. As mast cells (MCs) play a central role in both homeostasis and pathology, we investigated NOS expression and NO production in human MC populations. Endothelial NOS (eNOS) was ubiquitously expressed in both human MC lines and skin-derived MCs, while neuronal NOS (nNOS) was variably expressed in the MC populations studied. The inducible (iNOS) isoform was not detected in human MCs. Both growth factor-independent (HMC-1) and -dependent (LAD 2) MC lines showed predominant nuclear eNOS protein localization, with weaker cytoplasmic expression. nNOS showed exclusive cytoplasmic localization in HMC-1. Activation with Ca2+ ionophore (A23187) or IgE-anti-IgE induced eNOS phosphorylation and translocation to the nucleus and nuclear and cytoplasmic NO formation. eNOS colocalizes with the leukotriene (LT)-initiating enzyme 5-lipoxygenase (5-LO) in the MC nucleus. The NO donor, S-nitrosoglutathione (SNOG), inhibited, whereas the NOS inhibitor, NG-nitro-l-arginine methyl ester (L-NAME), potentiated LT release in a dose-dependent manner. Thus, human MC lines produce NO in both cytoplasmic and nuclear compartments, and endogenously produced NO can regulate LT production by MCs. (Blood. 2004;104: 462-469)

scholarly journals Effect of Treatment Delay, Stroke Type, and Thrombolysis on the Effect of Glyceryl Trinitrate, a Nitric Oxide Donor, on Outcome after Acute Stroke: A Systematic Review and Meta-Analysis of Individual Patient from Randomised Trials

2016 ◽  
Vol 2016 ◽  
pp. 1-12 ◽  
Author(s):  
Philip M. Bath ◽  
Lisa Woodhouse ◽  
Kailash Krishnan ◽  
Craig Anderson ◽  
Eivind Berge ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Glyceryl Trinitrate ◽  
Acute Stroke ◽  
Meta Analysis ◽  
Haemorrhagic Stroke ◽  
Stroke Onset ◽  
Nitric Oxide Donor ◽  
No Donor ◽  
No Donors ◽  
Subacute Stroke

Background.Nitric oxide (NO) donors are a candidate treatment for acute stroke and two trials have suggested that they might improve outcome if administered within 4–6 hours of stroke onset. We assessed the safety and efficacy of NO donors using individual patient data (IPD) from completed trials.Methods.Randomised controlled trials of NO donors in patients with acute or subacute stroke were identified and IPD sought from the trialists. The effect of NO donor versus control on functional outcome was assessed using the modified Rankin scale (mRS) and death, by time to randomisation. Secondary outcomes included measures of disability, mood, and quality of life.Results.Five trials (4,197 participants) were identified, all involving glyceryl trinitrate (GTN). Compared with control, GTN lowered blood pressure by 7.4/3.3 mmHg. At day 90, GTN did not alter any clinical measures. However, in 312 patients randomised within 6 hours of stroke onset, GTN was associated with beneficial shifts in the mRS (odds ratio (OR) 0.52, 95% confidence interval (CI) 0.34–0.78) and reduced death (OR 0.32, 95% CI 0.14–0.78).Conclusions.NO donors do not alter outcome in patients with recent stroke. However, when administered within 6 hours, NO donors might improve outcomes in both ischaemic and haemorrhagic stroke.

Nitric oxide-induced vasodilation of organic nitrate-tolerant rabbit aorta

1988 ◽  
Vol 66 (10) ◽  
pp. 1344-1346 ◽  
Author(s):  
Christopher J. Slack ◽  
Brian E. McLaughlin ◽  
Kanji Nakatsu ◽  
Gerald S. Marks ◽  
James F. Brien
Keyword(s):  
Nitric Oxide ◽  
Glyceryl Trinitrate ◽  
Isosorbide Dinitrate ◽  
Vascular Tissue ◽  
Rabbit Aorta ◽  
Nitrate Tolerance ◽  
Organic Nitrate ◽  
Vasodilator Agents ◽  
Vasodilator Drugs ◽  
Before And After

It is postulated that the organic nitrate vasodilator agents, including glyceryl trinitrate (GTN) and isosorbide dinitrate (ISDN), are prodrugs, such that biotransformation to the active inorganic metabolite, nitric oxide (NO), occurs prior to the onset of vasodilation. Furthermore, it is proposed that organic nitrate tolerance in vascular tissue involves decreased formation of NO. To test this latter hypothesis, we examined vasodilation induced by NO, GTN, and ISDN in non-tolerant, GTN-tolerant, and ISDN-tolerant rabbit aortic rings (RARs). Isolated RARs were contracted submaximally with phenylephrine; the time of onset of relaxation and percent relaxation of tissue were determined in response to NO (0.3 μM), GTN (0.03 μM), and ISDN (0.12 μM) before and after a 1-h treatment with 500 μM GTN, 500 μM ISDN, or buffer only. The data demonstrated that the response to NO was not changed in GTN-tolerant and ISDN-tolerant tissues, in which there was virtually no GTN-induced or ISDN-induced relaxation. These results are consistent with the postulate that organic nitrate vasodilator drugs must undergo biotransformation to NO before vasodilation can occur and that the mechanism of organic nitrate tolerance involves decreased formation of NO.

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