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At least 19 recordsLinked to original sources
PubMed1987

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

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 submaximally 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 microM [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 less than or equal to 0.05), even though significantly greater relaxation of the vein than the artery was observed (p less than or equal to 0.05). From these data, a simple linear relationship between glyceryl trinitrate biotransformation and relaxation is not apparent.

Animals↗
PubMedDate not supplied

Pentaerythritol trinitrate and glyceryl trinitrate on intramyocardial oxygenation and perfusion in the dog. Krogh analysis of transmural metabolism.

1. The effect of intravenous pentaerythritol trinitrate and glyceryl trinitrate on left ventricular subepicardial (epi) and subendocardial (endo) PO2 and perfusion were compared in anaesthetized open-chest mongrel dogs. Tissue PO2 was determined simultaneously at a depth of 3 mm (epicardial) and 9 mm (endocardial) with small platinum electrodes by polarography. In a separate series of dogs tissue perfusion of those regions was measured by hydrogen (H2) clearance using similar electrodes. 2. Both nitrates increased endocardial PO2 while epicardial PO2 was not altered. Perfusion was determined at the point of the maximal rise in endocardial PO2 (4-7 min after injection of either nitrate). At that period average coronary artery inflow and epicardial perfusion were decreased but endocardial perfusion was not significantly altered. 3. Using the data on PO2, hydrogen clearance and intercapillary distance, the effect of the nitrates on transmural metabolism (oxygen consumption) was estimated by Krogh analysis. Basal endocardial metabolism was 20-30% higher than epicardial metabolism. The nitrates reduced metabolism in each region. The absolute decrease in oxygen consumption was greater in the endocardium. 4. The results show that both pentaerythritol trinitrate and glyceryl trinitrate improve endocardial oxygenation by producing a more favourable balance between perfusion and oxygen requirements in that region.

Animals↗
PubMed2000

Bioavailability and pharmacokinetic profile of glyceryl trinitrate and of glyceryl dinitrates during application of a new glyceryl trinitrate transdermal patch.

The pharmacokinetics and bioavailability of glyceryl trinitrate (GTN, CAS 55-63-0) and of its main metabolites, i.e. 1,2-glyceryl dinitrate (1,2-GDN, CAS 621-65-8) and 1,3-glyceryl dinitrate (1,3-GDN, CAS 623-87-0), were compared during a single 24-h application of a new GTN transdermal patch (Epinitril 10, hereinafter called EPI-10) or a reference patch (hereinafter called ND-10) releasing 10 mg GTN in 24 h. The study was an open, randomized balanced cross-over study on 24 healthy male volunteers to whom the patches were applied to the antero-lateral part of the thorax in two periods separated by a 3-day wash-out. Blood samples were collected before administration, during the 24-h patch application and at 0.5, 2 and 3 h after patch removal. Assayed in plasma were GTN, 1,2-GDN and 1,3-GDN using validated GC/MS methods with stable isotope-labeled internal standards (15N3-GTN, 15N2-1,2-GDN, and 15N2-1,3-GDN). The ratios of the AUCs of GTN, 1,2-GDN and 1,3-GDN measured during application of EPI-10 or of ND-10 were within the 0.85-1.25 limits required to assess equivalence of the extent of bioavailability. The ratios of the Cmax were within said limits for the signal metabolite 1,2-GDN and only slightly below (0.78-1.16) for the parent GTN. EPI-10 can therefore be considered equivalent to ND-10 also with regard to the rate of bioavailability. Under both patches GTN reached steady-state levels after 3-6 h of patch application and remained on sustained levels during the whole 24-h application. The plasma levels of 1,2-GDN were about 6 times higher than those of GTN. The plasma levels of 1,3-GDN were similar to those of GTN. Upon removal of the patches the concentrations of the three nitrates fell to negligible values within 3 h. Both patches were well tolerated at the application site. For its small size, thinness and transparency, EPI-10 is very patient friendly, a quality that improves compliance with the therapeutic regimen.

Adhesiveness↗
PubMedDate not supplied

Pentaerythritol trinitrate and glyceryl trinitrate on myocardial oxygen consumption and haemodynamics in the dog.

1. The effects of pentaerythritol trinitrate (pentrinitrol) and glyceryl trinitrate on myocardial oxygen consumption and myocardial and systemic haemodynamics were studied in anaesthetized open-chest dogs. An in vivo oximeter in the coronary sinus permitted continuous determination of arteriovenous oxygen difference and myocardial oxygen consumption. All parameters were determined simultaneously at various intervals after drug administration. 2. Myocardial oxygen consumption was diminished by both nitrates for more than 16 min. Changes in arteriovenous oxygen difference and coronary sinus oxygen content were variable between drugs. Following an initial transient increase, coronary blood flow was reduced by both nitrates. Aortic blood pressure, aortic blood flow, left ventricular end-diastolic pressure and left ventricular dP/dt were also reduced. Heart rate and contractile force were not appreciably altered by either nitrate. 3. The decrease in myocardial oxygen consumption appears to be associated with the haemodynamic profile of these drugs. Both nitrates produced comparable reductions in preload (left ventricular end-diastolic pressure) and afterload (aortic pressure) as well as dP/dt.

Animals↗
PubMed1995

Tolerance development and arterial and venous tissue-/plasma levels of glyceryl trinitrate and glyceryl dinitrate in patients treated with nitroglycerin infusion.

Venous vessels (vena saphena magna) and arteries (left internal mammary artery) from patients treated with long-term ( > 24 h) intravenous infusions of nitroglycerin (CAS 55-63-0, glyceryl trinitrate, GTN) prior to coronary by-pass surgery were studied. Tissue concentrations of GTN and its dinitrate metabolites were determined as well as plasma-concentrations of GTN and glyceryl dinitrates (GDN's) on both the arterial and the venous side. The relaxant effect of GTN on the isolated vein preparations was studied and compared with those from two other groups of patients, one not exposed to GTN and the other exposed to a short-term infusion of GTN. Wide variations were found both in plasma and in tissue concentrations of GTN and GDN's on the venous and the arterial side. However, no extraction across the arterial-venous bed could be observed. Correlations were found between the dose given and the concentrations of drug and metabolites in both venous and arterial plasma as well as between 1,2-GDN in venous plasma and venous tissue, between 1,2-GDN in arterial plasma and arterial tissue and the same applied to 1,3-GDN on the arterial side. No correlations were found between the tissue concentrations of drug or metabolites and the relaxation induced by GTN in vitro. Venous vessels from patients treated with long-term infusions of GTN showed a pronounced decrease in relaxation as compared to vessels from patients not treated with nitroglycerin infusions and a slight decrease as compared to veins from patients treated with a shortterm infusion.

Aged↗
PubMed1984

Biotransformation of glyceryl trinitrate to glyceryl dinitrate by human hemoglobin.

The elimination of glyceryl trinitrate (GTN) by man is rapid and its clearance exceeds cardiac output. It is therefore clear that a variety of tissues in addition to liver are involved in the biotransformation of GTN. Incubation of GTN with the 25 000 X g supernatant fraction of lysed human erythrocytes resulted in a 39.6% +/- 5.5 (SD) elimination of GTN after 40 min. After pretreatment of the lysate supernatant fraction with carbon monoxide, GTN elimination was only 26% +/- 4.5. These data indicated that hemoglobin might be involved in GTN elimination. When purified hemoglobin was incubated with GTN, a 77.1% +/- 6.4 elimination of GTN was observed, accompanied by glyceryl dinitrate formation. The biotransformation of GTN was inhibited by pretreatment with carbon monoxide. The results indicate that the biotransformation of GTN by human erythrocytes is due, at least in part, to interaction with hemoglobin.

Adult↗
PubMedDate not supplied

Tissue disposition of glyceryl trinitrate, 1,2-glyceryl dinitrate, and 1,3-glyceryl dinitrate in tolerant and nontolerant rats.

The tissue distribution of glyceryl trinitrate (GTN) and its two dinitrate metabolites 1,2-glyceryl dinitrate (1,2-GDN) and 1,3-glyceryl trinitrate (1,3-GDN), was studied in GTN-tolerant and nontolerant male Sprague-Dawley rats. The concentrations of GTN, 1,2-GDN, and 1,3-GDN were measured in plasma, heart, brain, liver, aortic tissue, and adipose tissue at various time points after a subcutaneous dose of GTN (50 mg/kg). At the first time point (5 hr), concentrations of GTN, 1,2-GDN, and 1,3-GDN in plasma were equal for tolerant and nontolerant rats, but the elimination rate was altered for the tolerant rats as compared with nontolerant rats. In adipose tissue, the concentration of GTN was significantly higher as compared with concentrations of the dinitrate metabolites. In contrast, the other tissues studied showed significantly higher concentrations of the GDNs when compared with GTN. The 1,3-GDN/1,2-GDN ratio decreased with time for both tolerant and nontolerant rats. This study indicates that long-term GTN administration results not only in tolerance development, but also in altered pharmacokinetics of GTN, 1,2-GDN, and 1,3-GDN. The results also show that the 1,3-GDN/1,2-GDN ratio is dependent on the GTN concentration.

Animals↗
PubMed2003

Botulinum toxin as second-line therapy for chronic anal fissure failing 0.2 percent glyceryl trinitrate.

PURPOSE: Glyceryl trinitrate paste is used by many as first-line therapy for chronic anal fissure but heals only approximately 50 to 60 percent of fissures. We use botulinum toxin as second-line therapy after failed glyceryl trinitrate and aimed to evaluate efficacy, side effects, and patient preference. METHODS: A prospective, nonrandomized, open-label study of patients with chronic anal fissure failing a course of glyceryl trinitrate treated with 20 units of botulinum toxin A injected into the internal sphincter was conducted. Symptomatic relief, visual healing of fissures, side effects, and patient preference were assessed at 8-week follow-up. RESULTS: Forty patients underwent botulinum toxin treatment. Twenty-nine patients (73 percent) overall were improved symptomatically and avoided surgery. Seventeen fissures (43 percent) were healed, whereas 23 fissures (57 percent) remained unhealed. Of the unhealed fissures, 5 (12 percent) were asymptomatic, 7 (18 percent) were symptomatically much improved, and 11 (27 percent) were no better symptomatically and came to surgery. Discomfort associated with injection was minimal. Of 34 patients undergoing botulinum toxin injection in the clinic, 24 (71 percent) preferred botulinum toxin, 7 glyceryl trinitrate (20 percent; difference = 51 percent; 95 percent confidence interval = 31-71 percent), and 9 percent were undecided. Transient minor incontinence symptoms were noted in 7 patients (18 percent). CONCLUSIONS: Second-line botulinum toxin injection improves symptoms in approximately three-quarters of patients after failed primary glyceryl trinitrate therapy and at least in the short term avoids surgical sphincterotomy. Botulinum toxin heals approximately one-half of these fissures. Discomfort and side effects were minimal. A policy of first-line glyceryl trinitrate/second-line botulinum toxin will avoid sphincterotomy in 85 to 90 percent. Higher rates of healing may be achieved by giving botulinum toxin as first-line therapy, or addressing the chronic fibrotic nature of the fissure.

Adult↗
PubMed1985

Exposure to glyceryl trinitrate during gun powder production: plasma glyceryl trinitrate concentration, elimination kinetics, and discomfort among production workers.

Plasma glyceryl trinitrate (GTN) concentration was studied in 12 volunteers producing gun powder. Serial blood samples were obtained from the cubital vein before and during work at two sites of production; high concentrations of GTN were detected in the plasma. Control specimens from a femoral vein contained much less GTN, indicating that blood in the cubital vein was enriched by dermally absorbed GTN. In the roll mill area concentrations of GTN in the cubital vein were higher than in the press area, but individual factors were also important since some workers consistently had higher concentration of GTN than others. Differences in absorption were more important than differences in the metabolism of GTN since only a small variation in disappearance rate was found after a sublingual test dose of GTN. Moderate changes in pulse rate and blood pressure were noted during the day. The major discomfort experienced was a headache that increased during working hours, but this was not significantly related to GTN concentrations in the air or in the blood from the cubital vein. The observations imply that major efforts should be made to reduce dermal contact with GTN during production work.

Adult↗
PubMed1992

Comparative in vitro study of a series of organic nitroesters: unique biphasic concentration-effect curves for glyceryl trinitrate in isolated bovine arterial smooth muscle and lack of stereoselectivity for some glyceryl trinitrate analogues.

Four different organic nitroesters, constituting a homologous series based on unbranched polyalcohols, were compared with regard to in vitro relaxation of isolated bovine mesenteric arteries contracted with 2.5 microM phenylephrine. The organic nitroesters included ethylene glycol dinitrate (EGDN), dinitratopropane (DPN), glyceryl trinitrate (GTN), and tetranitratobutane. Glyceryl trinitrate exhibited a biphasic concentration-effect relationship, with pD2 values of 11.5 +/- 0.5 and 7.2 +/- 0.2 for the high-pD2 and low-pD2 component of the relaxation curve, respectively. The high-pD2 and low-pD2 component contributed 28 and 72% of the maximal response, respectively. EGDN, DPN, and tetranitratobutane induced monophasic concentration-effect curves with pD2 values of 7.4 +/- 0.1, 7.8 +/- 0.2, and 6.9 +/- 0.6, respectively. Stereoisomeric forms of DPN and tetranitratobutane showed no difference with regard to relaxing potency in bovine mesenteric artery. GTN has a partly unique mechanism for vascular smooth muscle relaxation that distinguishes this compound from other related organic nitroesters.

Animals↗
PubMed2000

Plasma levels of glyceryl trinitrate and dinitrates during application of three strengths of a new glyceryl trinitrate transdermal patch.

The pharmacokinetic characteristics and the bioavailability of glyceryl trinitrate (GTN, CAS 55-63-0) and of its main metabolities 1,2-glyceryl dinitrate (1,2-GDN, CAS 621-65-8) and 1,3-glyceryl dinitrate (1,3-GDN, CAS 623-87-0) during a single 24-h application of three strengths of a newly developed GTN transdermal patch (Epinitril) were investigated. The three strengths coded in this paper EPI-5, EPI-10 and EPI-15 have a nominal release rate of GTN of 5, 10 and 15 mg, respectively, in 24 h. The study was an open, randomized balanced cross-over study on 18 healthy male volunteers, to whom the patches were applied for 24 h to the antero-lateral part of the thorax in three periods, separated by an at least 3-day wash-out. Blood samples were collected before administration, during the 24-h patch application and 1, 3 and 6 h after patch removal. Assayed in plasma were GTN, 1,2-GDN and 1,3-GDN using validated GC/MS methods with stable isotope labeled internal standards (15N3-GTN, 15N2-1,2-GDN, and 15N2-1,3-GDN). GTN and its two metabolites reached the plateau already 3 h after application of the patches and remained on extended and fairly constant levels during the whole 24-h application. The plasma levels of the three nitrates were proportional to the strengths of the patches. The plasma levels of 1,2-GDN were about 6 times higher than those of GTN. The plasma levels of 1,3-GDN were similar to those of GTN. Upon removal of the patches the concentrations of the three nitrates fell to negligible values within 3 h, an important property when an intermittent GTN therapy is needed in order to avoid tolerance to the drug. The patches were well tolerated at the application site. For their good tolerability, small size and transparency, the new GTN patches are very patient friendly, a quality that improves compliance with the therapeutic regimen.

Adhesiveness↗
PubMed1994

The effects of hypothermic and normothermic cardiopulmonary bypass on glyceryl trinitrate activity.

Glyceryl trinitrate (GTN) is used to control arterial blood pressure during cardiopulmonary bypass (CPB) procedures, but its effects are often decreased during the period of extracorporeal support. The plasma and urine concentrations of GTN and glyceryl-1,2-dinitrate (1,2-GDN) and glyceryl-1,3-dinitrate (1,3-GDN) for male and female patients who received GTN during hypothermic CPB, and male and female patients who were given GTN during normothermic CPB, were measured by gas-liquid chromatography. During hypothermic CPB, the male and female subjects experienced significant decreases in GTN clearance (P < 0.05), 66% and 52%, respectively. Neither the males nor the females who underwent normothermic CPB experienced any significant change in GTN clearance. These results suggest that the lower core temperature during hypothermic CPB may decrease the biotransformation of GTN to GDNs and nitric oxide, thereby resulting in less dilation of blood vessels. Furthermore, the males in the hypothermic CPB group had significantly greater urinary concentrations of 1,3-GDN and 1,2-GDN than the females (P < 0.05), and the normothermic CPB males had a significantly greater urinary concentration of 1,2-GDN than the females in that group. The normothermic CPB males also had significantly higher plasma concentration of GTN at two time points, and 1,3-GDN at one time point, than the females. These data suggest that there may be a gender difference in GTN biotransformation.

Aged↗
PubMed1994

Plasma concentrations of glyceryl trinitrate and its dinitrate metabolites after sublingual administration to volunteers. Simultaneous determination of glyceryl trinitrate and its dinitrate metabolites.

The plasma profiles of nitroglycerin (glyceryl trinitrate, GTN, CAS 55-63-0) and its dinitrate metabolites (1,2-GDN and 1,3-GDN) were estimated after sublingual administration of GTN tablets 0.5 mg (Nitromex) given in single doses to 20 volunteers. Blood samples (totally 20) were collected to 2 h after administration, and the plasma concentrations of GTN, 1,2-GDN, and 1,3-GDN were measured simultaneously by gas chromatography. The pharmacokinetic parameters, Cmax, tmax, t1/2, and the dinitrate ratio (AUC1,2-GDN/AUC1,3-GDN) were determined for each subject. The plasma concentrations of GTN reached a maximum of 1.38 ng/ml (mean) (range: 0.32-3.18 ng/ml) after 4.9 min (mean) (range: 3-8 min). The plasma concentrations of 1,2-GDN and 1,3-GDN reached a maximum of 3.11 ng/ml (mean) (range: 1.14-5.44 ng/ml) and 0.70 ng/ml (mean) (range: 0.33-1.19 ng/ml) after 13.7 min (mean) (range: 8-40 min) and 17.6 min (mean) (range: 8-40 min). The t1/2 values (mean) were 3.3, 35.5, and 38.1 min for GTN, 1,2-GDN, and 1,3-GDN, respectively. The dinitrate ratio was estimated to be 4.1 (mean).

Administration, Sublingual↗
PubMed1994

Effect of dexamethasone treatment on the biotransformation of glyceryl trinitrate: cytochrome P450 3A1 mediated activation of rat aortic guanylyl cyclase by glyceryl trinitrate.

It is generally accepted that organic nitrates act via vascular biotransformation to an activator of guanylyl cyclase (presumably NO), resulting in increased cyclic GMP accumulation and vascular smooth muscle relaxation. Previously, we have shown that cytochrome P450 can mediate the biotransformation of glyceryl trinitrate (GTN) and that at least a portion of this biotransformation results in the formation of an activator of guanylyl cyclase. To assess the role of the cytochrome P450 3A subfamily in this phenomenon, we treated male and female rats with dexamethasone (DEX) (150 mg/kg, i.p., daily for 3 days). Under anerobic conditions, hepatic microsomal biotransformation of GTN was increased three-fold in DEX-treated male rats compared with all other treatment groups. Incubation of aortic 100,000 x g supernatant fraction from untreated rats (as a source of guanylyl cyclase) with GTN and hepatic microsomes from all groups resulted in concentration-dependent increases in guanylyl cyclase activation. Microsomes from DEX-treated male and female rats demonstrated a significantly greater activation of guanylyl cyclase compared with microsomes from untreated males and females. Furthermore, GTN-induced guanylyl cyclase activation mediated by microsomes from DEX-treated male and female rats was markedly inhibited by a polyclonal antibody raised to rat CYP3A1. Since CYP3A2 is absent or very low in hepatic microsomes from DEX-treated adult female rats, this identifies CYP3A1 as an isoform capable of biotransforming GTN to an activator of guanylyl cyclase. Similarly, CYP2C11 was identified as an isoform capable of biotransforming GTN to an activator of guanylyl cyclase, since monoclonal antibody to CYP2C11 inhibited GTN-induced activation of guanylyl cyclase mediated by microsomes from control male rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1983

Reduction of infarct size in patients with inferior infarction with intravenous glyceryl trinitrate. A randomised study.

Glyceryl trinitrate was previously said to be contraindicated in patients with acute myocardial infarction. Its intravenous administration during acute infarction, however, was associated with a beneficial effect as determined by ST segment mapping. Most recently in a selected group of patients with acute infarction and abnormal haemodynamics, intravenous glyceryl trinitrate was shown to reduce infarct size estimated by enzymes. The present study was performed to verify the safety of intravenous glyceryl trinitrate in patients with infarction under conventional clinical conditions without invasive monitoring and to determine its effect on infarct size in a prospective randomised trial involving 85 patients with infarction (43 treated and 42 control). Treated patients received glyceryl trinitrate within 10 hours of the onset of symptoms (mean 6.0 hours), and the dose was titrated to preset limits for changes in heart rate and blood pressure. In patients with inferior infarction, infarct size estimated by enzymes in the treated was only 12.2 +/- 1.8 versus 19.1 +/- 3.6 CK gram equivalents per metre squared in the placebo group. A similar but statistically insignificant trend was observed for subendocardial infarction but no difference was observed for anterior infarction. Ventricular arrhythmias determined from 24 hour tapes were more frequent in treated patients though this was not statistically significant. Lignocaine requirements in treated and control (1692 +/- 250 vs 1512 +/- 232 mg/24 h) were similar, as were the requirements for morphine (11.4 +/- 1.8 vs 12.2 +/- 2.2 mg/24 h). Results indicate that intravenous glyceryl trinitrate can be administered safely during evolving infarction without invasive monitoring and reduces infarct size in patients with inferior infarction.

Adult↗
PubMed1990

Biotransformation of glyceryl trinitrate and elevation of cyclic GMP precede glyceryl trinitrate-induced vasodilation.

In this study, we examined glyceryl trinitrate (GTN) biotransformation and cyclic GMP elevation in vascular smooth muscle before onset of GTN-induced relaxation. Isolated rabbit aortic strips (RAS) and strips of bovine pulmonary artery (BPA) and bovine pulmonary vein (BPV) were contracted submaximally and incubated with [3H]GTN. Before onset of GTN-induced vasodilation, the tissues were freeze-clamped and then analyzed for GTN, glyceryl-1,2-dinitrate (1,2-GDN), and glyceryl-1,3-dinitrate (1,3-GDN) and for cyclic GMP. Before onset of relaxation of RAS, BPA, and BPV, there was significant biotransformation of GTN to GDN and significant elevation of cyclic GMP. There was significantly greater biotransformation of GTN and elevation of cyclic GMP by BPV than by BPA incubated with the same concentration of GTN, which was temporally related with the more rapid onset of relaxation induced in BPV than in BPA. These results are consistent with the hypothesis that the magnitude of GTN biotransformation before vasodilation is the important determinant of subsequent tissue relaxation. In GTN biotransformation before vasodilation, there was preferential formation of 1,2-GDN. These data indicate that the mechanism of GTN biotransformation to 1,2-GDN is related to elevation of cyclic GMP and subsequent vasodilation.

Animals↗