Isosorbide dinitrate and hydralazine in blacks with heart failure.
Explore the source record for details and available documents.
Black People↗
SEARCH · Search PubMed
Results for “Isosorbide Dinitrate”
Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.
Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.
Pentaerithrityl tetranitrate and its phase I metabolites are potent activators of cellular cyclic GMP accumulation.
Using pig kidney epithelial cells (LLC-PK1), the present study assesses the cyclic GMP stimulatory effect of pentaerithrityl tetranitrate and its metabolites in comparison to other therapeutically used nitric oxide donors. Pentaerithrityl tetranitrate was found to be the most potent activator of cyclic GMP synthesis compared to other clinically relevant organic nitrates (glyceryl trinitrate, isosorbide dinitrate, isosorbide-5-mononitrate). The phase I metabolite pentaerithrityl trinitrate was equipotent with its parent compound in stimulating cyclic GMP. The concentration-response curves of pentaerithrityl dinitrate and isosorbide dinitrate for cyclic GMP accumulation were virtually identical. In contrast, pentaerithrityl mononitrate and the phase II metabolite pentaerithrityl trinitrate glucuronide did not alter basal cyclic GMP levels. It is concluded that the long-term vasodilatory and antiischemic effects of pentaerithrityl tetranitrate are caused to a substantial extent by cyclic GMP-mediated actions of its pharmacologically active phase I metabolites.
Animals↗
Non-invasive evaluation of endothelial function in hypertensive elderly patients.
Impaired endothelium-dependent vasomotion is a diffuse disease process resulting in abnormal regulation of blood vessel tone and loss of several atheroprotective effects of the normal endothelium. The aim of the present study was to investigate the effects of aging and hypertension on endothelial function. Sixty-six geriatric subjects with ages over 60 (48 hypertensive and 18 healthy) and 40 middle-aged subjects (16 hypertensive and 24 healthy) were included in the study. Systemic vascular endothelial function was evaluated through measuring brachial arterial vasodilation, a physiologic answer to reactive hyperemia occured with increased blood flow in the vessel after transient ischemia (flow-mediated dilation, FMD%), and with carotid artery intima-media thickness (IMT) measurement, using high-resolution ultrasonography. Endothelial independent vasodilation was also measured after administration of sublingual isosorbide dinitrate (isosorbide dinitrate mediated dilation, IDNMD%). FMD% was significantly decreased in elderly and/or hypertensive (HT) patients (geriatric HT: 9.5 +/- 4.7%, geriatric non-HT: 12.7 +/- 5.5%, middle-aged HT: 12.9 +/- 4.3% and middle-aged non-HT: 18.9 +/- 8.1%) (geriatric HT versus geriatric non-HT (P = 0.02), geriatric HT versus middle-aged HT (P = 0.01), geriatric non-HT versus middle-aged non-HT (P = 0.008)). Both FMD% and IDNMD% were inversely correlated with age, baseline vessel diameter and carotid artery intima-media thickness. FMD% was also inversely correlated with diastolic blood pressure. No correlation was found between FMD% and systolic blood pressure, serum cholesterol and triglyceride levels. Endothelium dependent (EDD) and independent dilatation of large arteries decreased with aging even in the healthy elderly, and FMD further declined in HT elderly patients, indicating that age and hypertension independently impair endothelial function. Positive correlations with age and hypertension, and significant inverse correlation with FMD, makes carotid artery IMT a possible indicator of endothelial function.
Adult↗
Stimulation of coronary vascular PGI2 by organic nitrates.
The present study summarizes recent investigations in our laboratory, demonstrating that a number of organic nitrates, including glyceryltrinitrate, isosorbide dinitrate, isosorbide-2-mononitrate and the novel nitrate teopranitol stimulate the release of a prostacyclin (PGI2)-like antiplatelet activity from isolated bovine coronary arteries and veins. In bioassay experiments this increase amounted to 50 to 200% of control. Evidence for nitrate induced PGI2 stimulation is presented by inhibition of its formation by indomethacin and dexamethasone, the demonstration of inhibition of thrombin induced thromboxane generation of washed platelet suspensions by nitrate stimulated vessel incubates and an enhanced accumulation of the hydrolysis product of PGI2, 6-oxo-PGF1 alpha, in incubates of teopranitol stimulated vessels. This action is obtained at nanomolar, i.e. therapeutic concentrations of the compounds and requires the presence of free nitro group(s) at [exo] position of the isohexide molecule. There was no correlation between PGI2 release and the relaxing action of the nitrates on isolated vessel strips. The inhibitor of cyclic GMP accumulation, methylene-blue, also blocked the generation of the antiplatelet activity by glyceryltrinitrate and teopranitol. Recent evidence suggests that cGMP accumulation via intermediate nitrogen oxide (NO) production mediates the vascular effects of organic nitrates. Since NO is also a potent antiplatelet agent, it is concluded that a nitrate stimulated PGI2 release associated with or mediated by NO formation might explain the antiplatelet actions of organic nitrates in vitro and ex vivo.
Animals↗
Pharmacokinetics of various preparations of organic nitrates.
The pharmacokinetics of different formulations of glyceryl trinitrate, isosorbide dinitrate, isosorbide 5-mononitrate and isosorbide 2-mononitrate are reviewed.
Delayed-Action Preparations↗
Oxidative stress and mitochondrial aldehyde dehydrogenase activity: a comparison of pentaerythritol tetranitrate with other organic nitrates.
Mitochondrial aldehyde dehydrogenase (ALDH-2) was recently identified to be essential for the bioactivation of glyceryl trinitrate (GTN). Here we assessed whether other organic nitrates are bioactivated by a similar mechanism. The ALDH-2 inhibitor benomyl reduced the vasodilator potency, but not the efficacy, of GTN, pentaerythritol tetranitrate (PETN), and pentaerythritol trinitrate in phenylephrine-constricted rat aorta, whereas vasodilator responses to isosorbide dinitrate, isosorbide-5-mononitrate, pentaerythritol dinitrate, pentaerythritol mononitrate, and the endothelium-dependent vasodilator acetylcholine were not affected. Likewise, benomyl decreased GTN- and PETN-elicited phosphorylation of the cGMP-activated protein kinase substrate vasodilator-stimulated phosphoprotein (VASP) but not that elicited by other nitrates. The vasodilator potency of organic nitrates correlated with their potency to inhibit ALDH-2 dehydrogenase activity in mitochondria from rat heart and increase mitochondrial superoxide formation, as detected by chemiluminescence. In contrast, mitochondrial ALDH-2 esterase activity was not affected by PETN and its metabolites, whereas it was inhibited by benomyl, GTN applied in vitro and in vivo, and some sulfhydryl oxidants. The bioactivation-related metabolism of GTN to glyceryl-1,2-dinitrate by isolated RAW macrophages was reduced by the ALDH-2 inhibitors benomyl and daidzin, as well as by GTN at concentrations >1 microM. We conclude that mitochondrial ALDH-2, specifically its esterase activity, is required for the bioactivation of the organic nitrates with high vasodilator potency, such as GTN and PETN, but not for the less potent nitrates. It is interesting that ALDH-2 esterase activity was inhibited by GTN only, not by the other nitrates tested. This difference might explain why GTN elicits mitochondrial superoxide formation and nitrate tolerance with the highest potency.
Aldehyde Dehydrogenase↗
Direct inhibition of platelet function by organic nitrates via nitric oxide formation.
This study investigates the mechanisms of platelet inhibition by the nitrate esters isosorbide dinitrate, isoidide dinitrate, isomannide dinitrate, isosorbide 2-mononitrate and isosorbide 5-mononitrate as compared to the spontaneous nitric oxide (NO)-donor linsidomine, the active metabolite of molsidomine. Nitrates and linsidomine dose-dependently inhibited aggregation, ATP secretion and thromboxane formation of washed human platelets at a rank order of potency, identical with that for stimulation of cyclic GMP in cultured rat lung fibroblasts. While linsidomine (0.1 mM) caused a 3-fold platelet cGMP elevation, there was a weak (< or = 30%) but significant cGMP stimulation by organic nitroesters, which was tightly correlated with inhibition of platelet aggregation (r = 0.926, P = 0.008). Zaprinast (2 microM) potentiated, while methylene blue (1 microM) and oxyhemoglobin (10 microM) reversed the antiaggregatory effects. Linsidomine (0.5 microM-0.1 mM) dose-dependently released NO in a cell-free system. No spontaneous NO release was detected with organic nitroesters (0.1 mM). These data suggest that, to some extent, bioactivation of organic nitroesters occurs in platelets, resulting in platelet inhibition via the NO/cGMP system.
Adenosine Triphosphate↗
Periods of cluster headache induced by nitrate therapy and spontaneous remission of angina pectoris during active clusters.
Glyceryl trinitrate (GTN) is known to induce single extra attacks of cluster headache (CH) during active cluster periods, most probably via actions of nitric oxide (NO). Induction of whole periods of CH by organic nitrates has, however, attracted little attention in the literature. We report on eight patients with episodic CH and coexistent effort-induced angina pectoris. Cases 1-6 had been free of their headaches for many years but got recurrence of CH within a few weeks after the administration of long-acting organic nitrates (isosorbide-dinitrate, isosorbide-5-mononitrate or slow-release GTN) aimed at treating their chest pains. These nitrate-induced headache periods were more severe and had a longer duration than the previous spontaneous ones. Furthermore, one of the subjects and two additional cases experienced a marked reduction of their anginal attacks during successive CH periods. Exercise time to effort-induced angina was increased in all three patients and one of them revealed a markedly elevated threshold for eliciting ischaemic cardiac symptoms by standardized physical exercise on a cycle ergometer. We hypothesize whether extra CH periods elicited by sustained nitrate therapy and remission of angina pectoris during active clusters are caused by central mechanisms involving inhibition of sympathetic tone and effects on both cranial vessels and cardiac functions.
Adolescent↗
Clinical pharmacokinetics of organic nitrates.
Plasma concentrations of glyceryl trinitrate (nitroglycerin), isosorbide dinitrate and isosorbide 2- and 5-mononitrates in man have been measured after administration via different routes. Appropriate precautions have to be taken in the administration of these agents (to avoid loss during intravenous infusion), and in their sampling and assay. Pharmacokinetic calculations based on plasma concentrations should be viewed with caution, as the data on which these calculations are based are often very limited, and the very rapid disappearance of for example glyceryl trinitrate from plasma makes the choice of an appropriate kinetic model and exact calculations difficult. Glyceryl trinitrate disappears from plasma within a few minutes, and a high apparent volume of distribution and a very high systemic clearance are found. After oral administration, plasma concentrations are very low; with sublingual or cutaneous administration, higher plasma concentrations can be obtained, suggesting a high first-pass extraction after oral administration, but quantitative data on bioavailability are lacking. For isosorbide dinitrate the systemic clearance, although high, is lower than for glyceryl trinitrate; disappearance from the plasma is slower and plasma concentrations after different routes of administration are much higher. Here too, quantitative data on bioavailability are lacking. High plasma concentrations of isosorbide 2-mononitrate and isosorbide 5-mononitrate are found in plasma after administration of isosorbide dinitrate. These metabolites have a good bioavailability, and half-lives of around 2.5 hours for isosorbide 2-mononitrate and 5 hours for isosorbide 5-mononitrate. Only very limited data are available about the influence of disease states and interactions with food and other drugs on the kinetics of the organic nitrates. It is very difficult to correlate the effects of the nitrates to their plasma concentrations; counter-regulation, development of tolerance, and the presence of metabolites could disturb the interpretation of such a relationship. It is at present impossible to predict the pharmacological effects or the efficacy of organic nitrates on the basis of their plasma concentrations.
Administration, Oral↗
Electrocardiographic analysis of the effects of isosorbide-5-mononitrate on regional myocardial ischemia in conscious dogs.
Whereas the clinical efficacy of isosorbide-5-mononitrate (IS-5-MN) in angina pectoris has been demonstrated unequivocally, the action of the substance on acute myocardial ischemia in animal models has not been investigated yet. Therefore, IS-5-MN and, for comparison in some experiments, isosorbide dinitrate and isosorbide-2-mononitrate were studied on a model of a brief intermittent myocardial ischemia in dogs. Ischemia was produced by occlusion of a coronary artery. Simultaneously, the dogs were loaded by treadmill exercise (model I) or injection of isoprenaline (model II). Local S-T segment changes were derived with epicardial electrodes. The action of orally administered IS-5-MN, isosorbide-2-mononitrate and isosorbide dinitrate of S-T segment elevations was studied with model I. A dose of 20 mg/dog produced a significant lowering of the S-T elevations (17, 13 and 15%). With 40 mg of IS-5-MN and isosorbide dinitrate per dog, similar effects were obtained (18 and 21%, with no statistical significant differences in comparison with 20 mg/dog). The time course of the action of IS-5-MN and the dose-response curve after i.v. injection were evaluated with model II. Even 5 hr after 20 mg of IS-5-MN per dog, a significant reduction of S-T elevations could be demonstrated. Significant effects on the epicardially derived S-T elevations have already been observed at doses of IS-5-MN that do not yet lead to a lowering of the systolic blood pressure in conscious dogs. Higher doses that lower the systolic blood pressure do not lead to any further lowering of the observed S-T elevations.
Administration, Oral↗
Nitrate therapy in patients with coronary artery disease--preparations and doses with and without development of tolerance.
Rapid tolerance development with respect to hemodynamic, anti-anginal and anti-ischemic effects is a relevant clinical problem associated with any longterm treatment with nitroglycerin, isosorbide dinitrate or isosorbide 5-mononitrate. Tolerance occurs with any dosing regimen that results in nitrate accumulation in the plasma or nearly-constant plasma concentrations, as is the case with multiple daily doses of oral nitrates or continuous application of transdermal patch systems. Nitrate tolerance can be prevented by the interval treatment. This encompasses incorporation of an application-free interval which prevents meaningful nitrate accumulation such that, from a low baseline level, renewed drug administration leads to an increase in the nitrate plasma concentration greater than 2.5-fold. From controlled studies, dosing regimens for interval treatment proven to be effective have been designated for isosorbide dinitrate and isosorbide 5-mononitrate, as well as for transdermal nitroglycerin patch systems. The early attenuation of nitroglycerin, seen within the first 12 h of its use, according to the results of a recently completed study, can be counteracted through continuously increasing plasma concentrations during this period. Interval treatment does not enable 24-h therapeutic protection. Studies with ST-Holter monitoring, however, have shown that adequate coverage can be provided for the period during which the vast majority of ischemic episodes occur. Clinically-relevant rebound phenomena do not occur during interval treatment. Pharmacological approaches to prevent nitrate tolerance, on the basis of the limited and, in part, conflicting data available, do not provide an alternative to interval treatment.
Administration, Cutaneous↗
Nitric oxide and castor oil-induced diarrhea.
The effect of NG-nitro-L-arginine methyl ester (L-NAME) on castor oil-induced diarrhea was studied in control rats and those treated with isosorbide dinitrate or isosorbide-5-mononitrate. Castor oil (2 ml) produced diarrhea that lasted at least 8 h. Pretreatment of the rats with L-NAME (1-25 mg/kg i.p.) 15 min before castor oil did not block the castor oil-induced diarrhea beyond 3 h after challenge but delayed its appearance (P < .05-.001). However, diarrhea was inhibited (P < .01-.001) during the entire 8 h if rats were treated twice with L-NAME (25 mg/kg) (15 min before and 3 h after castor oil). These findings suggest that L-NAME, once administered, loses its activity 3 h after its administration. The nitric oxide synthase substrate, L-arginine (150-600 mg/kg), reversed (P < .05-.01) the inhibitory effect of L-NAME on diarrhea induced by castor oil. This effect is enantiomer-specific because D-arginine (900 mg/kg) was without an effect. These results suggest that castor oil-induced diarrhea in rats involves the L-arginine nitric oxide pathway. This is further supported by the effect of isosorbide dinitrate (0.6-120 mg/kg) and isosorbide-5-mononitrate (0.6-120 mg/kg). When administered to castor oil-treated rats, these two nitric oxide-generating agents prevented in a dose-dependent fashion (P < .01-.001) the inhibitory effect of L-NAME (25 mg/kg).
Animals↗
Relationship of pharmacokinetic and pharmacodynamic properties of the organic nitrates.
Glyceryl trinitrate (nitroglycerin), isosorbide dinitrate and isosorbide mononitrate are, in various formulations, available for clinical use. The pharmacokinetics of glyceryl trinitrate are complex and only 1% of the drug administered orally can be detected in the plasma due to a pronounced arteriovenous concentration gradient, hydrolysis in the blood, and rapid denitration in the liver. There is a poor and usually transient correlation between plasma concentrations and therapeutic effects, due in part to the complex pharmacokinetics of glyceryl trinitrate, but primarily due to development of tolerance during continuous administration, either via the intravenous or cutaneous route. Isosorbide dinitrate kinetics are complicated by its extensive metabolism into 2- and 5-mononitrates, which are pharmacologically active, and which also accumulate more than the parent drug during long term treatment. These facts, combined with development of tolerance during long term therapy, preclude the establishment of a concentration-response relationship. Isosorbide-5-mononitrate has ideal and dose-linear kinetics and is nearly 100% bioavailable after oral administration. However, tolerance develops during long term therapy, and therefore a relationship between plasma concentrations and clinical effects cannot be established. On the basis of available data, plasma concentrations of various nitrates do not reliably predict clinical effects.
Angina Pectoris↗
Nitrate tolerance. How to prevent it or minimize its effect.
Continuous therapy with nitrates rapidly produces tolerance along with loss or diminution of circulatory, antianginal, and anti-ischemic effects. Development of tolerance can be avoided by various approaches. In patients with stable angina, intermittent use of nitrates with long nitrate-free intervals, use of transdermal nitroglycerin during the day or oral isosorbide dinitrate or isosorbide-5-mononitrate twice daily in the morning and early afternoon, and intermittent use of nitrates in combination with another class of antianginal agent are appropriate. In patients with unstable angina, continuous therapy with intravenous nitroglycerin is recommended during the acute phase of angina. Despite development of partial tolerance, oral isosorbide dinitrate, 30 to 60 mg four times a day, plus hydralazine may be useful for patients with congestive heart failure who cannot tolerate angiotensin-converting enzyme inhibitors. Concomitant use of sulfhydryl donors or angiotensin-converting enzyme inhibitors, agents that might theoretically prevent nitrate tolerance, is not recommended. Data on these agents are conflicting, and added costs and adverse effects are likely to preclude their use in the future.
Angina Pectoris↗
Pharmacokinetics of nitroglycerin and long-acting nitrate esters.
The current literature on the human pharmacokinetics of nitroglycerin, isosorbide dinitrate, and isosorbide mononitrates is briefly reviewed and evaluated. The pharmacokinetics of nitroglycerin are unusual in that its systemic clearance is extremely large and that there is a distinct arterial-venous gradient in plasma concentration. These features had created substantial difficulties in the documentation and interpretation of nitroglycerin plasma concentrations and pharmacokinetics. Studies with isosorbide dinitrate showed that this nitrate is absorbed as intact drug at about 20 percent of a comparable intravenous dose, firmly disproving a previous belief that orally administered nitrate is completely degraded by presystemic metabolism. The current data suggest that plasma nitrate concentration may relate to some of its pharmacologic effects after short-term dosing, but the concentration-response relationship is complex after long-term dosing. Studies of nitrate pharmacokinetics in their presumed sites of action, namely, the vasculature, appear to be useful for the further understanding of the mechanism of action for these vasodilators.
Absorption↗
Pharmacokinetics and pharmacodynamics of organic nitrates.
The pharmacokinetic and pharmacodynamic aspects of organic nitrates are discussed, with particular emphasis on the 3 major organic nitrates currently in use, nitroglycerin (NTG), isosorbide dinitrate and isosorbide-5-mononitrate. After intravenous administration, both NTG and isosorbide dinitrate exhibit large systemic clearances and both nitrates appear to be extensively distributed in vascular and other peripheral tissues. Two pharmacokinetic features appear particularly notable for NTG: there is a significant arteriovenous extraction of the drug, and its systemic clearance is related to cardiac output. Both of these features, plus other evidence, suggest that organic nitrates may be substantially removed from the systemic circulation by the vasculature itself. During nitrate tolerance, plasma drug concentrations remain elevated, but vascular activity is diminished. This apparent paradox might be explainable by a unifying hypothesis of reduced nitrate metabolism during vascular tolerance; thus, in the tolerant state, reduced systemic clearance of the intact drug brought about elevated plasma concentrations, whereas reduced cellular metabolism at the smooth muscle brought about a decrease in vascular activity. The complex relations among plasma kinetics, vascular metabolism and pharmacologic action of organic nitrates are still poorly understood.
Animals↗
Use of nitrates in acute and chronic congestive heart failure.
The literature available on the use of nitrates (glyceryl trinitrate, isosorbide dinitrate and isosorbide 5-mononitrate) as various formulations (oral, buccal, sublingual, transdermal and intravenous) in the treatment of acute and chronic congestive heart failure is reviewed. There are adequate data on the acute haemodynamic effects of these preparations, but little information is available on the long term use of nitrates in chronic congestive heart failure. The exception is isosorbide dinitrate, which, in combination with hydralazine, has been shown to reduce mortality.
Acute Disease↗
Effect of 5-isosorbide mononitrate on isosorbide dinitrate-induced relaxation of rabbit aortic rings.
The ability of isosorbide dinitrate (ISDN) and its two metabolites, 5-isosorbide mononitrate (5-ISMN) and 2-isosorbide mononitrate (2-ISMN), to relax phenylephrine-contracted rabbit aortic rings was compared. The three organic nitrates demonstrated similar efficacy. ISDN was found to be the most potent (median effective dose (ED50); 1.5 X 10(-7) +/- 1.1 X 10(-7) M), followed by 2-ISMN (ED50, 1.8 X 10(-6) +/- 9 X 10(-7) M) and 5-ISMN (ED50, 8.2 X 10(-6) +/- 3.6 X 10(-6) M). The log dose-response curve of ISDN in rabbit aortic rings was constructed in the absence and presence of three fixed concentrations of 5-ISMN (5 X 10(-6), 10(-5), and 3 X 10(-5) M). No shift in the ISDN dose-response curve at high ISDN concentrations was noted in the presence of 5-ISMN. Using the isobolographic method with fixed ISDN/5-ISMN ratio mixtures, no evidence for an antagonistic effect of 5-ISMN on ISDN-induced vasodilation was obtained. Analysis of the fixed ISDN/5-ISMN ratio mixture responses by the median-effect plot showed no antagonistic effect. It is concluded that in rabbit aortic rings 5-ISMN, the major metabolite of ISDN, is not an antagonist of ISDN at a "nitrate receptor," and no support is provided for the hypothesis that the accumulation in plasma of metabolites (e.g., 5-ISMN) with longer half-lives than the parent drug explains tolerance to organic nitrates.
Animals↗