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PubMed2004

The effect of nitric oxide on the resting tone and the contractile behaviour of the external urethral sphincter: a functional urodynamic study in healthy humans.

AIMS: This functional urodynamic study assessed the effect of the nitric oxide donor isosorbide dinitrate on the external urethral sphincter and hypothesised first that nitric oxide could lower the resting sphincter pressure, second that nitric oxide could influence the sphincter contractility during magnetic stimulation, and third that nitric oxide could induce a faster external urethral sphincter fatigue during continuous magnetic stimulation. METHODS: Eight healthy males gave their written informed consent and were included. A 2-channel microtip pressure transducer catheter was inserted into the urethra measuring the bladder and the external urethral sphincter pressure. Magnetic stimulation of the sacral roots was performed to evoke reproducible contractions of the external urethral sphincter. The baseline protocol included six single pulse stimulations and three stimulations 10sec in duration each for two frequencies 5Hz and 50Hz with intensities at the motor threshold of the pelvic floor. Then the subjects received 10 mg of isosorbide nitrate sublingually and the protocol was repeated 5min, 20min, 40min and 60min after drug administration. RESULTS: The sublingual administration of isosorbide dinitrate could significantly reduce the resting pressure of the external urethral sphincter for at least one hour. The maximal contractile strength measured as the maximal urethral pressure during single pulse and continuous magnetic stimulation of the sacral roots also decreased significantly. Nitric oxide did not induce a significantly faster fatigue of the external urethral sphincter during continuous magnetic stimulation of the sacral roots. CONCLUSIONS: This study shows a functionally relevant effect of nitric oxide on the resting tone and the contractile behaviour of the human external urethral sphincter in vivo while the fatigue properties did not changed significantly. Nitric oxide donors could offer a new pharmacological approach to treat urinary retention due to overactive or non-relaxing external urethral sphincter.

Adult↗
PubMed1999

Isosorbide aerosol: an option for the treatment of hypertensive crises.

In this study the authors assessed the effectiveness and safety of isosorbide dinitrate aerosol administered through the oral mucosa in 30 adult patients who presented with a hypertensive crisis (mean arterial pressure > 130 mm Hg and evidence of target organ damage). The patients were given a first dose of 1.25 mg of aerosol when they were admitted to the hospital; a second dose was administered 15 minutes later if the mean arterial pressure had not decreased by > 15%. An electrocardiogram (ECG) was obtained for every patient immediately prior to and 30 minutes after administration of the medication. Nine patients (30%) had a good response with one dose, whereas 21 patients (70%) required a second dose. All 30 patients had a significant reduction of the arterial blood pressure (187+/-13 / 121+/-6.6 to 153+/-15.3 / 92.3+/-7.6 mm Hg; p<0.005) as well as of the mean arterial pressure (136.6+/-8 to 109.5+/-7 mm Hg; p<0.005) in a period of 30 minutes. No adverse effects, rebound hypertension, or severe hypotension were observed. These figures remained under control for 6 hours. Two of the patients had angina pectoris at admission and their ECG showed subepicardial ischemia, both of which disappeared with the medication. A second ECG appeared normal. A reduction of 14% in heart rate was obtained (95+/-15 to 82+/-14 beats per minute; p<0.005). These observations suggest that isosorbide dinitrate aerosol is an effective and safe alternative for the treatment of patients with hypertensive crises.

Administration, Oral↗
PubMed2001

The effect of sildenafil on nitric oxide-mediated vasodilation in healthy men.

BACKGROUND: Sildenafil, a treatment for erectile dysfunction, is a specific phosphodiesterase type 5 (PDE 5) inhibitor that enhances nitric oxide (NO)-mediated vasodilation in the corpus cavernosum by inhibiting cyclic guanosine monophosphate breakdown. Since PDE 5 is widely expressed in the vasculature, we examined the hypothesis that sildenafil could enhance NO-mediated vasodilation in other vascular beds and improve endothelial function. METHODS: NO-mediated responses to acetylcholine (endothelium-dependent) and nitroglycerin (endothelium-independent) were measured in healthy men in the dorsal hand vein (n = 13), after the administration of either sildenafil 50 mg or placebo. Flow-mediated dilation of the brachial artery and forearm postischemic reactive hyperemia were measured before and after sildenafil 50 mg, isosorbide dinitrate 5 mg, and placebo in a double-blind, randomized, crossover study (n = 11). RESULTS: In the hand vein, sildenafil administration increased sensitivity to local nitroglycerin. The 50% effective dose decreased approximately 4-fold from 13.5 ng/min (range, 6.9-26.6 ng/min) to 2.7 ng/min (range, 1.1-6.4 ng/min) (P =.025). Sildenafil decreased the maximum venoconstriction induced by phenylephrine from 81% +/- 3% to 74% +/- 3% (P =.025). Sildenafil did not significantly affect the maximal venodilatory response to acetylcholine (35% +/- 7% after placebo versus 32% +/- 8% after sildenafil) (P =.7). In the arterial vasculature, flow-mediated dilation before (2.4% +/- 1%) and after (2.8% +/- 1.4%) sildenafil (P =.8) and postischemic reactive hyperemia area under the curve before (1807 +/- 393 mL. min. s/100 mL) and after (1467 +/- 257 mL. min. s/100 mL) sildenafil were not different (P =.8). Resting heart rate, blood pressure, and resting brachial artery diameter were unchanged after sildenafil administration. Isosorbide dinitrate, an endothelium-independent vasodilator, caused a significant increase in resting brachial artery diameter from 0.53 +/- 0.01 cm to 0.56 +/- 0.02 cm (P =.005), without altering flow-mediated dilation. CONCLUSIONS: In healthy men sildenafil increased sensitivity to nitroglycerin, an exogenous NO donor, approximately 4-fold but did not affect endothelium-dependent, NO-mediated responses in either the hand vein or forearm vasculature. Differential vascular responses to sildenafil may localize its enhancement of endogenous NO-mediated vasodilation to vascular beds such as the corpus cavernosum.

Acetylcholine↗
PubMed1983

Comparative hemodynamic study of IS-5-MN and ISDN in man--which are equieffective doses?

In a crossover study, the hemodynamic effects of 40 mg sustained release isosorbide dinitrate were compared with those of 40 mg isosorbide-5-mononitrate in 10 patients after myocardial infarction. No differences between both drugs were seen in the magnitude of their effects on cardiac preload. The onset of the effect, however, was faster after IS-5-MN and reached its nadir earlier than after sustained release ISDN. Thus, both drugs are hemodynamically equieffective in equal doses, but their effects show different time courses.

Adult↗
PubMed1986

Influence of beta-blocker coadministration on the kinetics of isosorbide mononitrate and dinitrate.

The influence of beta-blocker coadministration on the kinetics of oral isosorbide-5-mononitrate (ISMN) and isosorbide dinitrate (ISDN) was studied in healthy volunteers. In the first study, 12 subjects ingested 20 mg ISMN on three occasions: in the control state, during coadministration of metipranolol (20 mg 3 times daily), or during metoprolol (100 mg twice daily). There were no significant differences among the three phases in peak serum ISMN concentration (470 ng/ml), the time of peak (0.6 h after dose), elimination half-life (4.5 h), or oral clearance (142 ml/min). In the second study, 10 subjects received 20 mg ISDN in the control state and again during coadministration of propranolol (80 mg 3 times daily). There were no differences between the two phases in peak serum ISDN concentration (20 ng/ml) or the time of peak (0.6 h). Propranolol increased, although not significantly, ISDN clearance (16.5 vs 12.3 L/min, P less than 0.1), and had no effect on total area under the curve for ISMN, the major metabolite of ISDN. Thus, therapeutic doses of these beta-blockers have a minimal influence on the kinetics of single doses of ISMN or ISDN in healthy individuals.

Adrenergic beta-Antagonists↗
PubMed1997

Intravascular ultrasonic evidence by constant cross-sectional area of atherosclerotic plaques during coronary vasomotion in humans.

AIMS: This study aims to visualize ultrasonically deformation of atherosclerotic plaques in human coronary arteries during vasoconstriction and vasodilatation. METHODS AND RESULTS: Intravascular ultrasound detected occult atherosclerosis in angiographically normal coronary arteries of eight patients with chest pain at rest. During the acetylcholine provocative test, intravascular ultrasound monitored deformation of the atherosclerotic plaques. At the last step of the test, intracoronary injection of isosorbide dinitrate caused vasodilation. Under control, acetylcholine-treated, and isosorbide dinitrate-treated conditions, cross-sectional areas of sonolucent circle and vessel lumen were measured. Subtraction of the latter from the former gave the area of atherosclerotic plaque. In the process of vasoconstriction and vasodilation, the plaque area did not change significantly. CONCLUSION: The cross-sectional area of the atherosclerotic plaque appeared to be constant during vasomotion of human coronary arteries.

Acetylcholine↗
PubMed2004

Pharmacokinetics of three organic nitrates in Chinese healthy male volunteers.

Eighteen Chinese male subjects completed a single-blind, randomized, three-treatment, three-period, cross-over study. In each treatment phase, subjects received a single dose of 20 mg isosorbide dinitrate (CAS 87-33-2, ISDN) intravenous infusion, 20 mg isosorbide 5-mononitrate (CAS 16051-77-7, 5-ISMN) tablet or 20 mg isosorbide 5-mononitrate intravenous infusion. Each consecutive dosing was separated by a washout period of 7 days. Following each dosing, venous blood samples were collected over a period of 16 h. Plasma concentrations of ISDN and its two active metabolites isosorbide 2-mononitrate (2-ISMN), 5-ISMN had been measured by a validated gas chromatographic method. Various pharmacokinetic parameters including AUC0-t, AUC0-infinity, Cmax, tmax, t1/2, Kelm and MRT were determined for the three formulations and found to be in good agreement with literature values. AUC0-t and AUC0-infinity of 5-ISMN tablet and intravenous infusion were 2694 +/- 496 ng x ml(-1) x h vs. 2548 +/- 556 ng x ml(-1) x h and 3266 +/- 624 ng x ml(-1) x h vs. 3178 +/- 769 ng x ml(-1) x h, respectively, and the relative bioavailability of 5-ISMN tablet was 105 +/- 20%. As compared with 5-ISMN intravenous infusion, ISDN can rapidly reach the plateau concentration and metabolize to its active metabolites 5-ISMN and 2-ISMN, which both have vasodilator effect. The results of this study suggest that as evaluated from the pharmacokinetic profiles of the three formulations, 5-ISMN tablet and ISDN intravenous infusion are ideal vasodilators and anti-angina drugs especially in acute conditions due to their rapid onset and long duration of action.

Administration, Oral↗
PubMed1987

Hemodynamic effects of oral isosorbide-5-mononitrate and dinitrate in ischemic heart failure.

Isosorbide-5-mononitrate (ISMN), the main metabolite of isosorbide dinitrate (ISDN) was recently introduced in clinical use. The hemodynamic effects of oral ISMN and ISDN, administered in equal doses, were studied in a randomized, crossover fashion in 20 patients with pump failure of ischemic etiology. Baseline hemodynamic criteria for admission into the study were: pulmonary capillary wedge pressure (PCW) of at least 20 mmHg and systolic arterial pressure (AP) above 90 mmHg. Hemodynamic parameters were serially measured and systemic vascular resistance was calculated up to 6 h postadministration of either ISMN or ISDN single dose (40 mg). Maximal effects obtained were statistically significantly different from baseline. While ISMN and ISDN appeared to be equipotent in reducing the filling pressure, with a maximum effect reached in 60-120 min, the mononitrate maintained its effects for a longer period.

Administration, Oral↗
PubMed1985

[4 different nitrate preparations with regard to the possible development of tolerance in long-term treatment].

Thirty-two hospitalized patients with angiographically-documented coronary artery disease and stable angina pectoris (NYHA class III) were randomly assigned to one of four treatment groups. After a one-week washout period, baseline examinations (systolic time intervals, blood pressure and exercise ECG) were performed. The patients were then treated with either 20 mg isosorbide dinitrate in sustained-release form (sustained-release ISDN), 20 mg isosorbide 5-mononitrate (IS 5-MN), 2.5 mg buccal nitroglycerin in sustained-release form (NTGB) or 6.5 mg oral nitroglycerin in sustained-release form (NTGO) and one hour thereafter, the heart rate, blood pressure and systolic time intervals were determined. Subsequently, the patients were treated with the respective nitrates four times daily for two weeks. On the seventh and 14th days, the heart rate, blood pressure and systolic time intervals were again determined before and after the first dose of the day. Additionally, after the first dose on the 14th day, an exercise ECG was performed. The effect of the nitrates on the venous capacitance system is reflected by the increase in the PEP/LVET ratio where NTGO and NTGB elicited marked actions and those of sustained-release ISDN and IS 5-MN were of a lesser extent. An effect on systolic and diastolic blood pressure at rest and during exercise could be documented only after administration of NTGB. The anti-ischemic effect of the nitrates was based on the reduction of ST-segment depression during exercise; after two weeks of treatment, sustained-release ISDN and IS 5-MN were associated with complete tolerance development while NTGO continued to exert a slight, and NTGB a clear reduction in ST-segment depression. Personal protocols documented that nitrate consumption and rate of anginal attacks during longterm treatment were unaffected by sustained-release ISDN, IS 5-MN and NTGO, but were reduced by 50% while on treatment with NTGB.

Administration, Oral↗
PubMed1995

Oral nitrate preparations: an update.

Oral nitrates are used in the treatment of angina and congestive heart failure. In 1993, more than 12 million prescriptions for chronic administration of oral nitrates were written in the United States. Three nitrate compounds are currently available on the U.S. market: nitroglycerin, isosorbide dinitrate and the most recent, isosorbide mononitrate. Oral nitrates are available in sublingual, translingual (spray), transmucosal, chewable or sustained-release forms. Despite the complexity of choices, therapy can be simplified and remain efficacious, provided that attention is given to circumventing tolerance, a challenging problem with nitrate therapy. Tolerance can be avoided by ensuring that there is a daily nitrate-free interval using eccentric (i.e., 8 A.M. and 2 P.M.), twice-daily dosing of standard or sustained-release forms, or frequent intermittent low dosages.

Administration, Oral↗
PubMed1987

Mononitrates as monotherapy in the prophylactic treatment of angina pectoris.

This article reviews the results of double-blind comparative studies on the therapeutic use of isosorbide 5-mononitrate as monotherapy in the prophylaxis of angina pectoris. Isosorbide 5-mononitrate appears at least as effective as the same dosage of isosorbide dinitrate and is probably superior to the calcium antagonists. Recent data have shown that isosorbide 5-mononitrate in a controlled-release formulation given once daily has a significantly better antianginal effect than placebo without inducing the development of tolerance.

Angina Pectoris↗
PubMed2003

Effect of different intensities of exercise on endothelium-dependent vasodilation in humans: role of endothelium-dependent nitric oxide and oxidative stress.

BACKGROUND: Aerobic exercise enhances endothelium-dependent vasodilation in hypertensive patients, patients with chronic heart failure, and healthy individuals. However, it is unclear how the intensity of exercise affects endothelial function in humans. The purpose of the present study was to determine the effects of different intensities of exercise on endothelium-dependent vasodilation in humans. METHODS AND RESULTS: We evaluated the forearm blood flow responses to acetylcholine, an endothelium-dependent vasodilator, and isosorbide dinitrate, an endothelium-independent vasodilator, before and after different intensities of exercise (mild, 25% VO2max; moderate, 50% VO2max; and high, 75% VO2max; bicycle ergometers, 30 minutes, 5 to 7 times per week for 12 weeks) in 26 healthy young men. Forearm blood flow was measured using a mercury-filled Silastic strain-gauge plethysmograph. Twelve weeks of moderate-intensity exercise, but not mild- or high-intensity exercise, significantly augmented acetylcholine-induced vasodilation (7.5+/-2.4 to 11.4+/-5.8 mL/min per 100 mL tissue; P<0.05). No intensity of aerobic exercise altered isosorbide dinitrate-induced vasodilation. The administration of NG-monomethyl-L-arginine, a nitric oxide synthase inhibitor, abolished the moderate-intensity exercise-induced augmentation of the forearm blood flow response to acetylcholine. High-intensity exercise increases plasma concentrations of 8-hydroxy-2'-deoxyguanosine (from 6.7+/-1.1 to 9.2+/-2.3 ng/mL; P<0.05) and serum concentrations of malondialdehyde-modified low-density lipoprotein (from 69.0+/-19.5 to 82.4+/-21.5 U/L; P<0.05), whereas moderate exercise tended to decrease both indices of oxidative stress. CONCLUSIONS: These findings suggest that moderate-intensity aerobic exercise augments endothelium-dependent vasodilation in humans through the increased production of nitric oxide and that high-intensity exercise possibly increases oxidative stress.

Acetylcholine↗
PubMed1985

Anti-anginal and anti-ischemic efficacy of conventional and slow release formulations of isosorbide-5-mononitrate in angina pectoris.

Isosorbide-5-mononitrate is an active metabolite of isosorbide dinitrate and is nearly 100% bioavailable after oral administration. Following administration of single oral doses of 10 to 50 mg, isosorbide-5-mononitrate exerts beneficial hemodynamic, anti-ischemic and anti-anginal effects within 30 to 45 minutes and the effects persist for several hours. During sustained therapy with conventional formulation, persistent anti-ischemic and anti-anginal effects have been reported when the drug is given in a dose of 20 mg two or three times a day. However, tolerance to anti-anginal and anti-ischemic effects develops rapidly if used in higher doses of 50 mg three times a day. Tolerance to anti-anginal effects within 20 hours of administration of a single oral dose of 100 mg, slow release isosorbide-5-mononitrate has been reported. Further, no improvement in exercise tolerance or ST segment depression could be documented at 4, 20 or 24 hours after therapy for one week with either 50 or 100 mg slow release isosorbide-5-mononitrate once a day. From the available reports, the most effective way to prescribe isosorbide-5-mononitrate for angina pectoris appears to be the conventional formulation in a dose of 20 mg two or three times a day.

Angina Pectoris↗
PubMed1992

[Nycthemeral changes in plasma concentrations of active nitrate derivatives. Comparison of a single dose of LP 60mg isosobide dinitrate and LP 20mg isosobide dinitrate administered 3 times daily].

The daily plasma level fluctuation is critical in the prevention of tolerance during long-term nitrate therapy. Two dosage regimens of sustained-release isosorbide dinitrate (ISDN) (60 mg tablet once daily vs 20 mg three times daily) were compared at steady state. Comparative bioavailability data of the two forms after single administration in 12 healthy subjects enabled calculation of the steady state blood levels of ISDN, IS-2MN and IS-5MN by simultation of the two regimens. Both achieved the required trough concentration to restore sensitivity to nitrates (100 micrograms/l for IS-5MN), but greater plasma level increases were observed (greater than 200 micrograms/l for IS-5MN), with 60 mg once daily. A parallel, randomised, double-blind, double placebo study involved 126 patients with stable angina, concomitantly receiving beta-blockers and/or calcium inhibitors. Ergometric parameters 4 hours after drug administration and clinical symptoms were compared at inclusion under 20 mg three times daily, and after a 4 week treatment with either dosage. Compared with 20 mg three times daily, the once daily regimen: improved equally the symptoms and ergometric parameters of stable angina in combination therapy; had a similar side-effect profile; enhanced the sensitivity to nitrate 4 hours after administration with regard to the hypotensive effect; the latter may clinically reflect the pharmacokinetic differences between the two regimens. Sixty milligrammes sustained release ISDN once daily may thus avoid nitrate tolerance and improve patient compliance.

Circadian Rhythm↗
PubMed1995

Human endothelial cells bioactivate organic nitrates to nitric oxide: implications for the reinforcement of endothelial defence mechanisms.

Although in therapeutic use for more than a century, the mode of cellular action of organic nitrates remains incompletely understood. Despite ample experimental evidence from animal studies to show that nitrates are metabolized to NO in the vascular smooth muscle, direct demonstration of such an activity in human vascular cells is still lacking. Moreover, the role of the endothelium in modulating the pharmacodynamic action of nitrates is far from clear. We therefore aimed to investigate whether or not human endothelial cells are capable of bioactivating these drugs to NO and whether the amounts generated are sufficient to elicit any biological effects. Using cultured human umbilical vein endothelial cells (HUVECs) as an established model system a combination of three different methods was used to address this issue: (1) quantification of NO formation upon endothelial nitrate metabolism using the oxyhaemoglobin technique; (2) evaluation of the second messenger response using radioimmunoassay for cGMP; and (3) assessment of mechanism and extent of potentiation of the anti-aggregatory effect of nitrates in the presence of endothelial cells as a relevant bioassay. We now show that superfusion of cultured human endothelial cells on microcarrier beads with either glyceryl trinitrate (GTN) or isosorbide dinitrate (ISDN; both at 0.1-100 mumol L-1) results in a concentration-dependent formation of NO. NO generation from isosorbide 5-mononitrate (IS-5-N) was below the detection limit. The amounts of NO produced (maximally 2.97 +/- 0.98 pmoles NO min-1 x mg protein with 100 mumol L-1 GTN; n = 8) were similar to those elicited upon challenge of the cells with 100 nM bradykinin. NO formation from either organic nitrate was accompanied, in a concentration-dependent and methylene blue-inhibitable manner, by stimulation of endothelial soluble guanylyl cyclase with consequent increases in the intracellular level of cGMP (maximally 32-fold over basal levels with ISDN), a significant portion of which was released into the extracellular space. Upon continuous 30 min superfusion or repeated application of high concentrations of GTN (100 mumol L-1) nitrate bioactivation to NO was subject to partial tachyphylaxis. Co-incubation of washed human platelets with HUVECs potentiated the anti-aggregatory action of nitrates in a cell number dependent and oxyhaemoglobin-sensitive manner and this effect, too, was accompanied by increases in intraplatelet cGMP levels. The potentiating effect was largely inhibited after blockade of sulfhydryl groups by pre-incubation of HUVECs with N-ethylmaleimide and completely abrogated after pretreatment of cells with the tissue fixative glutaraldehyde. These results demonstrate that human endothelial cells are capable of bioactivating organic nitrates to NO by an enzymatic, apparently thiol-sensitive pathway, in quantities sufficient to influence endothelial and platelet function. Besides the well known vasorelaxant action of organic nitrates, which is mainly due to their metabolism in the smooth muscle compartment, these drugs may therefore be endowed with a hitherto underestimated potential to directly influence endothelial functions via the NO/cGMP pathway. Through specific bioactivation in the endothelium itself organic nitrates can thus mimic and reinforce protective functions normally served by a functional endothelium such as the modulation of blood cell/vessel wall interactions and inhibition of cell proliferation.

Biotransformation↗
PubMed1983

An open, long-term, multi-centre study of the anti-anginal efficacy and safety of isosorbide 5-mononitrate at low doses in patients with coronary heart disease.

A total of 250 patients with coronary heart disease diagnosed clinically, by ECG and in some cases by coronary angiography, was treated with isosorbide 5-mononitrate, 221 of the patients being treated for up to 6 months. In 181 patients previously treated with isosorbide dinitrate (ISDN)-retard, the mean daily dosage of nitrate was reduced from 77 mg (200 mg maximum) ISDN to 45 mg (120 mg maximum) isosorbide 5-mononitrate in long-term treatment. During previous treatment with ISDN-retard (with high doses in some cases: 80 to 200 mg daily in 48.6% of patients and 40 mg or less daily in only 33.1%), 4.5% of the patients were totally free of angina pectoris attacks. In the same patients, this proportion was 53.6% after administration of isosorbide 5-mononitrate for 6 months (dosage 40 mg daily or less in 67.4% of patients, 80 mg or more in 8.8% of patients). A substantial increase in subjective exercise tolerance and the reduction in incidence of angina pectoris was associated with a marked reduction in nitrate consumption for acute attacks. Isosorbide 5-mononitrate lowered slightly the blood pressure and heart rate. Treatment with isosorbide 5-mononitrate was withdrawn in 22 (8.8%) patients due to nitrate intolerance (headache in 7.6%) and in a further 7 (2.8%) patients for other reasons. Of patients completing 6-months' treatment, 9.9% reported one or more reversible undesirable reactions typical of nitrates at the start of the trial (compared with 6.8% in the pre-trial period). The incidence of such effects decreased to 1.4% after 6 months. The incidence of tolerable headache was 7.7% during the first week on isosorbide 5-mononitrate, decreasing to 0.9% after 24 weeks (5.9% in the pre-trial period). The laboratory parameters and subjective tolerability data confirmed the therapeutic safety of isosorbide 5-mononitrate.

Adult↗
PubMed1987

Determination of nitrates in plasma.

Because of the high efficacy of existing nitrates, alternative dosage formulations have been developed rather than new compounds. These new formulations challenge the analyst to develop analytical methods with lower sensitivity and higher precision. Isosorbide dinitrate is analysed in the presence of its major metabolites isosorbide 2-mononitrate and isosorbide 5-mononitrate. The present method is an improvement over previously published methods. It is not possible to analyse glyceryl trinitrate and its major metabolites 1,2-glyceryl dinitrate and 1,3-glyceryl dinitrate with the necessary sensitivity in one chromatogram. A 2-step procedure is therefore applied. The extraction procedures, the gas chromatographic conditions, imprecision and inaccuracy of the methods, the lower limits of quantitation, sample chromatograms and applications of all methods are described in detail. Thus, the possibilities of modern analytical methods in the determination of nitrates in the lower picogram region are demonstrated.

Biotransformation↗