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PubMed1995

GSH-independent denitration of organic nitrate esters in rabbit hepatic and vascular cytosol.

The denitration of organic nitrate esters in rabbit hepatic cytosol was characterized. Sephadex G-200 chromatography of ammonium sulfate precipitate (40-80%) from hepatic cytosol demonstrated the presence of two distinct activities (peak I and peak II) responsible for the denitration of nitroglycerin (NTG) and isosorbide dinitrate (ISDN). The denitration of peak I required dithiothreitol (DTT), but not glutathione (GSH), and was not inhibited by S-alkyl GSH, an inhibitor of glutathione S-transferase (GST). Whereas, the denitration activity of peak II was potentiated by GSH, and was inhibited by S-alkyl GSH. These results strongly suggest that the denitration of organic nitrate esters, such as NTG and ISDN, can be catalyzed by at least two enzymes, GSH-independent denitration (peak I) and the GSH-dependent denitration (peak II, GST), in rabbit hepatic cytosol. The denitration activity of peak I was inhibited by SH-modified reagent, indicating that free thiol(s) is (are) critical for expression of the denitration activity. Also, in rabbit vascular cytosol, the cofactor requirement for denitration and response to S-hexyl GSH suggest the participation of GSH-independent enzyme which is responsible for the denitration of organic nitrate esters.

Animals↗
PubMed1991

Coronary hemodynamics and coronary flow reserve after intracoronary diltiazem in humans.

To analyze the effect of the calcium antagonist diltiazem on coronary hemodynamics, epicardial coronary artery diameter, coronary blood flow and coronary blood flow velocity were assessed at baseline and after a 0.5 mg intracoronary bolus of diltiazem in nonstenotic coronary arteries of awake humans. Patients (n = 20) were first randomized to pretreatment with either placebo (n = 10) or isosorbide dinitrate (0.5 microgram/kg/min infusion; n = 10), and coronary flow reserve was measured before and after administration of diltiazem. There were significant increases in epicardial coronary artery diameter (10%; p = 0.0001) and coronary blood flow (30%; p = 0.0001) in all patients after administration of diltiazem. Whereas basal coronary blood flow velocity increased only slightly (7%; p = not significant), there was a significant decrease in coronary flow reserve (10%; p = 0.004). Increases in coronary diameter and blood flow after diltiazem were comparable in patients pretreated with placebo or nitrates. However, the decrease in coronary flow reserve was significant only in patients pretreated with placebo (19%; p = 0.0008). This reduction in coronary flow reserve could be due to "raising the floor" (increased baseline coronary blood flow) or "lowering the ceiling" (reduction of maximal coronary blood flow).

Adult↗
PubMed1982

Effect of nitrate on determinants of myocardial oxygen consumption during exercise.

We evaluated the effects of isosorbide dinitrate on some of the major determinants of myocardial oxygen demand during upright exercise in ten normal subjects. In addition to heart rate and systolic blood pressure, we assessed left ventricular size and performance by echocardiography. Compared to the control study, heart rate was significantly faster after the nitrate administration at rest (67 +/- 14 versus 83 +/- 21 beats/minute), but there was no difference in heart rate at any stage during exercise. Systolic blood pressure also was significantly lower at rest after nitrate (104 +/- 8 versus 92 +/- 2 mm Hg) but was similar to control after 6 minutes of exercise. Echocardiographic end-diastolic dimension was decreased at rest post-nitrate (45.3 +/- 4.7 versus 40.2 +/- 4.2 mm) and remained significantly reduced during exercise by an analysis of variance. We conclude that a major beneficial effect of nitrates on myocardial oxygen demand during upright exercise is a decrease in left ventricular size which reduces wall tension.

Adult↗
PubMed1981

The linearity of the end-systolic pressure-volume relationship in man and its sensitivity for assessment of left ventricular function.

The linearity and sensitivity of the end-systolic pressure-volume (P-Ves) relation to the inotropic state of the left ventricle were investigated in 11 patients with coronary heart disease and one patient with congestive cardiomyopathy. To minimize autonomic reflex responses, propranolol, 0.15 mg/kg, and atropine, 1 mg, were administered i.v. at the beginning of the study. Three ventriculograms were performed: at rest, after oral isosorbide dinitrate, 10 mg (systolic pressure decrease greater than or equal to 15 mm Hg), and during infusion of methoxamine, 2 mg/min (systolic pressure increase greater than or equal to 10 mm Hg). The three points of the Pv-Ves relation showed linearity (r greater than or equal to 0.96). The relation between the slope k of the P-Ves relation and the left ventricular ejection fraction at rest was best described by an exponential function (r = 0.94). The use of peak systolic pressure instead of end-systolic pressure showed equally good results. The intercept of the P-Ves line on the abscissa, which represents the theoretical end-systolic volume at zero pressure, was not related to the ejection fraction under control conditions. The P-Ves relation in postextrasystolic beats was displaced toward the left (smaller end-systolic volumes) and became steeper.

Atropine↗
PubMedDate not supplied

Measurement of plasma concentrations of vasodilators and metabolites by the TEA Analyzer.

The determination of therapeutic levels of glyceryl trinitrate (GTN), isosorbide dinitrate (ISDN), pentaerythritol tetranitrate (PETN), and their metabolites in human plasma was conducted using the TEA Analyzer interfaced to a high-performance liquid chromatograph (HPLC-TEA). Chromatographic separation of these compounds was accomplished under isocratic HPLC conditions. The sensitivity of the instrument was established to be 0.1 ng for each of the three nitrate esters. At the 5 ng ml-1 plasma fortification level, the precision of the method gives mean relative standard deviations (RSD) of +/- 10.2 per cent, +/- 6.5 per cent, and +/- 5.9 per cent for GTN, ISDN, and PETN, respectively. The recoveries for the nitrate esters and their metabolites from human plasma over the range 1-50 ng ml-1 are presented. The specific and sensitive HPLC-TEA method developed in this study provides a reliable and rapid assay for the routine analysis for metabolism or bioavailability studies of nitrate esters and their metabolites in plasma of blood, with a detection limit as low as 1 ng ml-1.

Chromatography, High Pressure Liquid↗
PubMed1991

The effect of isosorbide-mononitrate eye drops on the human intraocular pressure and aqueous humor dynamics.

In a randomized, double-masked, single drop study the effect of topical isosorbid-mononitrate (ISMO) 0.5% eye drops, the main metabolite of isosorbid-dinitrate, widely used in the treatment of coronary heart diseases, was studied in patients suffering from open angle glaucoma or ocular hypertension. There was no statistically significant IOP change within 8 hours posttreatment after topical administration of ISMO 0.5%. There were no side effects after application of the ophthalmic solution of ISMO 0.5%. There were no significant changes in blood pressure and pulse rate either. A 2% ophthalmic solution of ISMO was investigated with respect to a response on the aqueous humor dynamics in 10 healthy volunteers. Anterior chamber fluorophotometry revealed a mean increase in aqueous flow of 39% within 3 hours after topical application (P less than 0.01). However, in comparison to the placebo treated fellow eyes there were no statistical significant difference in aqueous humor flow during the time of investigation. There was a statistical significant reduction of IOP during the same time period (p less than 0.03) in all treated eyes.

Aqueous Humor↗
PubMed1989

Nitrate therapy for left ventricular failure complicating acute myocardial infarction: a haemodynamic comparison of intravenous, buccal, and transdermal delivery systems.

The haemodynamic effects of three different methods of nitrate administration [intravenous (i.v.) isosorbide dinitrate (ISDN) and buccal and transdermal nitroglycerin (NTG)] were evaluated in 36 patients with acute left ventricular failure due to a recent myocardial infarction. Similar reductions in pulmonary artery occluded pressure (p less than 0.01) followed all three regimens without change in heart rate and cardiac and stroke volume indices. Significant reductions in systemic arterial pressure and vascular resistance followed both ISDN and buccal NTG but not transdermal NTG. A disadvantage of the buccal NTG delivery was an abrupt and, on occasion, inappropriate reduction in blood pressure. The more gradual and controlled reduction of systemic blood pressure with substantial falls in pulmonary artery occluded pressure following ISDN infusion suggest that in the context of myocardial infarction this method of nitrate delivery may have safety advantages; however, when invasive haemodynamic monitoring facilities are not available, transdermal delivery may offer a practical alternative.

Administration, Buccal↗
PubMed1997

Comparison of hemodynamic effects of nitric oxide (NO) donors with different NO-releasing properties in rats.

The aim of this study was to compare the hemodynamic effects of three nitric oxide (NO) donors [i.e., (+/-)-(E)-ethyl-2-[(E)-hydroxyimino]-5-nitro-3-hexenamide (FK409), (+/-)-N-[(E)-4-ethyl-3-[(Z)-hydroxyimino]-6-methyl-5-nitro-3-he ptenyl]-3-pyridinecarboxamide (FR 146801) and isosorbide dinitrate (ISDN)] in rats. In in vitro experiments, FK409 had a higher spontaneous NO-releasing rate in solution and more potent vasorelaxant activity in isolated rat aorta than other drugs. FR146801 and ISDN showed almost the same vasorelaxant activity. In in vivo experiments, FK409 significantly decreased hematocrit at 1.0 mg/kg p.o., whereas FR146801 and ISDN significantly decreased it at 10 mg/kg p.o., suggesting that these NO-donating agents cause significant plasma volume expansion. However, only FK409 showed significant hypotensive effects immediately after oral administration even at 0.32 mg/kg; FR146801 and ISDN did not cause any significant hypotension at 10 mg/kg, suggesting that FK409 induces much more potent arterial vasodilation than other drugs. These findings suggest that NO donors induce significant plasma volume expansion and that the differences in the selectivities between these effects and their hypotensive effects is probably produced by their different NO-releasing activities.

Animals↗
PubMed1976

[Influence of nitrates on regional myocardial blood flow and left ventricular wall motion].

Regional myocardial blood flow was measured by means of a computerized gamma-camera system in 30 patients with coronary artery disease (CAD) and in 14 healthy control subjects. Ventricular wall motion was quantitatively analyzed in 65 CAD-patients. Global and semiregional blood flow measurements yielded only limited information. In contrast, measurements of regional blood flow permitted detection of hypoperfused myocardium and the effects of pharmacologic intervention. The administration of 15 mg isosorbide dinitrate (ISDN) resulted in an increase in blood flow in post-stenotic hypoperfused myocardial regions of 20p.c. and a decrease in flow through normal myocardium of 14 p.c. These observations represent the adaption of flow to a newly-established level of metabolic demand. This increase in blood flow coupled with a reduction in afterload leads to improved ventricular wall motion in 65-75 p.c. of areas of hypokinetic myocardium and, to a markedly lesser degree, in only 20-25 p.c. of akinetic regions. Dyskinetic regions show no improvement. As compared with the 13ml/loog/min increase in blood flow seen after intracoronary administration of 0.45 mg ISDN in normal coronary vessels, the compromised dilatory capacity of diseased coronary vessels results in a relatively small increase in flow of 6 ml/100 g/min. The reduction of the extravascular component of coronary resistance, thus, appears to be the mechanism primarily responsible for the therapeutic effect of nitrates.

Coronary Circulation↗
PubMed1996

Effects of nitric oxide-related agents on opioid regulation of rat testicular steroidogenesis.

These studies examined whether nitric oxide (NO) mediates opioid suppression of testicular steroidogenesis. Adult male rats were treated with various combinations of a NO synthase (NOS) inhibitor (NG-nitro-L-arginine methyl ester; NAME), a NO donor (isosorbide dinitrate; ISDN), an opioid agonist (morphine, and an opioid antagonist (naltrexone). Serum LH and testosterone and testicular interstitial fluid (TIF) testosterone concentrations were then measured. Inhibition of NO production by NAME reversed morphine-suppressed testosterone secretion; treatment with the NO donor, ISDN, reversed naltrexone-stimulated testosterone secretion. NAME did not alter morphine's effects on LH secretion and attenuated morphine's suppression of hCG-stimulated testosterone secretion, indicating that these effects occur directly in the testes and are not dependent on LH secretion. Even though these effects suggested possible interactions between NO and opioid systems, no additive or synergistic effects were found with suppressive combinations of morphine and ISDN, or with stimulatory combinations of naltrexone and NAME at does that had little effect on testosterone secretion when given alone. These results indicate that opioid and NO exert independent effects on testicular steroidogenesis through separate pathways or mechanisms and that NO does not mediate opioid-induced testicular suppression.

Animals↗
PubMed1991

Flow-induced vasomotor response to tachycardia of the human internal mammary artery and saphenous vein grafts late following bypass surgery.

Increasing blood flow results in endothelium-dependent vasodilation of angiographically normal epicardial coronary arteries in humans. To compare the ability of internal mammary artery (IMA) and saphenous vein (SV) used as coronary artery bypass grafts to adapt their vasomotor tone to an increase in myocardial blood flow demand induced by tachycardia, 10 IMA and seven SV grafts were studied by quantitative angiography more than 6 months (range, 6-82 months) after surgery in 17 patients. All grafts were angiographically smooth and implanted to large nonakinetic perfusion zones. Angiograms were obtained in basal sinus rhythm (71 +/- 10 beats/min), during atrial pacing (129 +/- 9 beats/min), and after intragraft infusion of 1 mg isosorbide dinitrate (ISDN). In basal sinus rhythm, the cross-sectional area of SV was superior to that of IMA (10.7 +/- 3.6 versus 5.4 +/- 1.7 mm2; p less than 0.01). All IMA dilated during pacing (+14.8 +/- 11.5%; p less than 0.005) and a further increase in IMA cross-sectional area occurred after ISDN (+27.4 +/- 20.1% versus basal; p less than 0.005). In contrast, SV failed to dilate during pacing (+0.3 +/- 5.4%; p = NS) and after ISDN (+0.7 +/- 6.0% versus basal; p = NS). Thus, an increase in myocardial blood flow demand induced by tachycardia results in dilation of IMA but not of SV grafted on coronary vessels. The ability of the endothelium to modulate the vasomotor tone of IMA grafts in response to changes in blood flow could contribute to their excellent long-term functional results after coronary artery bypass surgery.

Adaptation, Physiological↗
PubMed1995

Effect of nitrovasodilators on the rhythmic contractions of guinea-pig isolated sphincter of Oddi.

The effects of amyl nitrite (CAS 8017-89-8) isosorbide dinitrate (CAS 87-33-2) and sodium nitroprusside (CAS 14402-89-2), on the acetylcholine-induced tachyrhythmia (greater than 9 waves/min) were investigated in the isolated guinea-pig sphincter of Oddi. Acetylcholine (10(-3) mol/l) produced an initial rapid rise in tension, the peak being followed by a gradual decrease associated with the initiation of the peristaltic waves. Nitrovasodilators significantly decreased the initial response to acetylcholine. Methylene blue (5 x 10(-5) mol/l), a soluble guanylate cyclase inhibitor, increased the tonic response to acetylcholine and reversed the inhibition caused by nitrovasodilators. The frequency and amplitude of peristaltic waves were decreased by nitrovasodilators. Methylene blue significantly increased both the frequency and amplitude of peristaltic waves, however, it did not reverse the inhibition caused by nitrovasodilators tested. Results suggest that nitrates decrease the acetylcholine-induced contraction and peristaltism of isolated guinea-pig sphincter of Oddi and NO released by acetylcholine may partially suppress its own tonic contractile response.

Acetylcholine↗
PubMed1984

Estimation of left ventricular myocardial function by the ejection fraction in isolated, chronic, pure aortic regurgitation.

In patients with aortic regurgitation (AR), the left ventricular (LV) ejection fraction (EF) may not adequately reflect depressions of myocardial contractility due to decreased aortic impedance. The sensitivity of end-systolic pressure-volume relations and stress-volume relations in detecting myocardial depression in patients with AR was studied. In 12 patients with normal valvular function but with varying LV function (due to coronary heart disease in 9 patients and dilated cardiomyopathy in 3 patients) (group 1), and in 8 patients with AR (group 2), LV angiography was performed before and after sublingual application of isosorbide dinitrate. Heart rate was kept constant by right atrial pacing. In group 1, the slope k of the end-systolic pressure-volume relation was to EF at rest: k = 0.091.e0.051 EF; r = 0.88. In AR, this relation was shifted significantly to the right: k = 0.019.e0.066 EF; r = 0.92. This shift persisted when the end-systolic stress-volume relation instead of the end-systolic pressure-volume relation was calculated. Thus, in patients with AR the end-systolic pressure-volume relation is flatter than that in patients with intact valvular function at a given EF. The same is true for the end-systolic stress-volume relation. The data indicate that EF overestimates myocardial contractility in AR compared with end-systolic pressure-volume or stress-volume relations. This overestimation is probably a result of decreased aortic impedance in AR.

Adult↗
PubMed1999

[The treatment of chronic fissure in ano with nitrate ointment].

A chronic anal fissure may be regarded as an ischaemic ulcer. Until recently, its treatment necessitated surgical intervention to lower the tension of the internal sphincter (lateral internal sphincterotomy), or manual dilatation of the anus. A disadvantage of both methods is the risk of permanent sphincter injury resulting in reduced continence. Local application of ointment containing nitroglycerin (glyceryltrinitrate) or isosorbide dinitrate reduces the pressure at rest in the anal canal and increases the anodermal blood circulation. Both ointments in most patients lead to healing of the chronic anal fissure. Nitroglycerin ointment in a prospective, randomized trial brought about better healing than placebo treatment. The advantage of the ointment treatment, the needlessness of sphincterotomy, is particularly important in cases of existing sphincter abnormalities. It has the disadvantage that it takes longer for the fissure pain to abate. The principal side effect is headache. In over 50% of the patients the treatment has to be continued for longer than 6 weeks. Little is known as yet about the risk of recurrence. Before surgical interventions as the treatment of first choice can be definitely replaced by treatment with nitrate ointment the good results of the ointment treatment have to be confirmed. Also, more has to be found out about the risk of recurrence, the optimal duration of the treatment and the choice of the type of nitrate ointment.

Administration, Topical↗
PubMed1994

Effects of nitric oxide-related agents on rat testicular function.

The effects of nitric oxide (NO)-related agents on testicular function were examined in male rats with measurements of serum luteinizing hormone, serum testosterone, testicular interstitial fluid (TIF) testosterone, and TIF volumes. Serum and TIF testosterone levels and luteinizing hormone secretion were significantly decreased by the NO donor, isosorbide dinitrate (ISDN), and the NO synthase (NOS) substrate, L-arginine methyl ester, a source for the endogenous production of NO. The effects of ISDN on TIF volumes were inconsistent, but L-arginine methyl ester decreased TIF formation in a dose-dependent manner. In addition, ISDN dose dependently suppressed testosterone secretion stimulated by human chorionic gonadotropin treatment, suggesting that the effects on testosterone secretion were independent of changes in secretion of the endogenous gonadotropin luteinizing hormone. ISDN, L-arginine methyl ester, and the endogenous NOS substrate L-arginine completely blocked testosterone secretion stimulated by the NOS inhibitor NG-nitro-L-arginine methyl ester (NAME), whereas the relatively inactive NOS substrate, D-arginine, only partially blocked NAME-stimulated testosterone secretion. Hydralazine and nicardipine, two vasodilators that do not exhibit prominent NO-related effects, also blocked basal testosterone secretion and testosterone secretion stimulated by the vasoconstrictor NAME.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acid Oxidoreductases↗
PubMed1994

Lack of pharmacologic tolerance and rebound angina pectoris during twice-daily therapy with isosorbide-5-mononitrate.

OBJECTIVE: To determine whether isosorbide-5-mononitrate (IS-5-MN), an active metabolite of isosorbide dinitrate, when given twice daily (in the morning and 7 hours later), prevents development of tolerance and reduction in exercise performance or is associated with a rebound increase in anginal attacks in patients with stable angina pectoris. DESIGN: Multicenter, placebo-controlled, parallel-group, double-blind, randomized study. SETTING: Four university teaching hospitals and five private cardiology outpatient clinics. PATIENTS: 116 patients with stable exertional angina who stopped treadmill exercise because of angina pectoris. INTERVENTION: After stopping all antianginal drugs with the exception of beta-blockers, patients received single-blind placebo for 1 week followed by either 20 mg of IS-5-MN (n = 60 patients) or placebo (n = 62 patients) twice daily at 0800 hours and 1500 hours for 2 weeks. MEASUREMENTS: Serial symptom-limited exercise tests and patients' diaries recording activity and date, time, and severity of anginal attacks. RESULTS: Compared with placebo recipients, patients receiving IS-5-MN walked significantly longer at 2, 5, and 7 hours after the 0800-hour dose (P < 0.01) and at 2 and 5 hours after the 1500-hour dose (P < 0.01). Before the morning (0800-hour) dose, exercise duration increased by 0.53 minutes in placebo recipients and by 0.85 minutes in those receiving IS-5-MN therapy (P = 0.10). Neither nocturnal nor early-morning anginal attacks increased during IS-5-MN therapy compared with placebo. Headaches occurred in 19 (32%) patients in the IS-5-MN group and in 9 (15%) patients in the placebo group but necessitated discontinuation of treatment in only 2 (3%) patients in the IS-5-MN group. CONCLUSION: Isosorbide-5-mononitrate, 20 mg twice daily given 7 hours apart, was well tolerated and improved exercise performance for 7 hours after the morning dose and for 5 hours after the afternoon dose without evidence of development of pharmacologic tolerance. No rebound increase in anginal attacks was found.

Adult↗
PubMed2004

[Experimental research on the apoptosis of Hep-A cells induced by hyperthermia combined with ISDN].

To investigate the apoptosis of Hep-A cells induced by hyperthermia combined with Nitric Oxide donor (Isosorbide dinitrate, ISDN) and its mechanism. The inhibitory effect on the growth of Hep-A cells was measured by MTT assay. Apoptosis of Hep-A cells was observed by electron microscopy and flow cytometry. The levels of Bcl-2 were detected with Western blot assay. It showed stronger antiproliferative ability in three experimental groups than that in control, and hyperthermia combined with ISDN group had better inhibitory effect than other groups (p < 0.05). With electron microscopy, marked changes of cell apoptosis were observed, including microvilli disappearance or reduction, cell shrinkage, chromatin condensation or margination and the presence of "apoptosis bodies". The apoptotic ratio induced by hyperthermia and ISDN group was higher than other groups, furthermore, the levels of Bcl-2 were decreased in three experimental groups. The present study indicated that hyperthermia combined with ISDN could induce apoptosis of Hep-A cells and be more effective than either hyperthermia or ISDN, which may be related to expression decreased Bcl-2.

Animals↗
PubMed1994

Antiplatelet activities of FK409, a new spontaneous NO releaser.

1. We reported that (+/-)-(E)-ethyl-2-[(E)-hydroxyimino]-5-nitro-3-hexeneamide (FK409) released nitric oxide (NO) spontaneously with a chemiluminescence analyzer. The aim of this study was to compare antiplatelet activities of FK409, a new NO releaser, with those of isosorbide dinitrate (ISDN) in vivo and in vitro. In order to elucidate the differences in antiplatelet activities between FK409 and ISDN, we compared their modes of action. 2. In in vitro experiments, FK409 had a more potent inhibitory effect on rat platelet aggregation induced by adenosine 5'-diphosphate (2.0 microM) than ISDN (IC50 = 4.32 +/- 0.95 microM and > 100 microM respectively). 3. In the rat extracorporeal shunt model (in vivo experiments), FK409 suppressed thrombus formation dose-dependently from 0.32 mg kg-1, p.o. and showed the maximum inhibition (52% inhibition vs. vehicle treatment) at 10 mg kg-1, p.o., while ISDN showed no inhibition at 10 mg kg-1 and only 17% inhibition at 32 mg kg-1, p.o. 4. FK409 could generate nitrite, which is an oxidative product of NO, much faster than ISDN in phosphate buffer solution and rat plasma during 60-min incubation at 37 degrees C. 5. These data show that FK409 has more potent antiplatelet effects than ISDN, by acting through spontaneously released NO.

Animals↗