Vascular effects of the dinitrate and mononitrate esters of isosorbide, isomannide and isoidide

Bogaert, M. G.; Rosseel, M. T.

doi:10.1007/bf00500061

Cited by 65 publications

(10 citation statements)

References 5 publications

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“…Despite the differences in potency, the three organic nitrates were equally efficacious as indicated by the maximal responses of the aortic rings obtained with the three compounds, which were not significantly different. The order of potency of ISDN, 2-ISMN, 5-ISMN in rabbit aortic rings was similar to that reporped for canine systemic and coronary vascular beds (Wendt 1972) and the perfused hindlimb of the dog (Bogaert and Rosseel 1972). Since Barge interindividual differences in the vasodilator response to organic nitrates have been observed (Wendt 1972;Parker et al 1975;MacKenzie and Parratt 1977), the appreciable interanimal variation in the response to ISDN, 2-ISMN, …”

Section: Response Qf' Rabbit Aortic Rings To Isdn 2-ism' and 5-ismmmentioning

confidence: 65%

Effect of 5-isosorbide mononitrate on isosorbide dinitrate-induced relaxation of rabbit aortic rings

Bennett¹,

Tam²,

Alstyne³

et al. 1984

Can. J. Physiol. Pharmacol.

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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.

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Section: Response Qf' Rabbit Aortic Rings To Isdn 2-ism' and 5-ismmmentioning

confidence: 65%

Effect of 5-isosorbide mononitrate on isosorbide dinitrate-induced relaxation of rabbit aortic rings

Bennett¹,

Tam²,

Alstyne³

et al. 1984

Can. J. Physiol. Pharmacol.

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“…These workers concluded that since ISDN disappears quickly from the blood the prolonged action of ISDN may be attributed in part to the mononitrate derivatives. Although it has been shown that the metabolites of ISDN are weak vasodepressors compared to the parent drug (Bogaert & Rosseel, 1972;Wendt, 1972), it is conceivable that the high concentrations achieved in our patients may partially contribute to the pharmacologic activity of the drug. These levels were found to be approximately 2-5 times higher for 2-ISDN, and 12-24 times higher for 5-ISMN than those of the parent drug.…”

Section: Methodsmentioning

confidence: 75%

Plasma concentrations of isosorbide dinitrate and its metabolites after chronic high oral dosage in man.

Shane¹,

Iazzetta²,

Chisholm³

et al. 1978

Brit J Clinical Pharma

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I We have previously reported that vasodilator headache due to isosorbide dinitrate (ISDN) can be circumvented by using small 'priming' doses for an induction period of 1-2 weeks, after which it is possible to increase to dose rapidly to 360-720 mg, daily without recurrence of headache and without toxicity. The present study corroborates this earlier finding. 2. Chronic oral administration of doses of ISDN of this order of magnitude results in prolonged high plasma concentrations of the parent compound, as well as higher levels of the metabolites 2-ISMN and 5-ISMN. 3. It is our thesis that chronic high oral dosage of ISDN saturates the intrahepatic biotransformation process, and allows high concentrations of ISDN and its metabolites to enter the systemic circulation.

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“…Further chemical research has followed two directions: First, the research into metabolites of ISDN found an active principle in isosorbide mononitrate (ISMN) (8,29,45,52). The bioavailability after oral administration is high with almost no first-pass effect.…”

Section: Introductionmentioning

confidence: 99%

SP/W‐5186: A Novel Sulfhydryl‐Containing NO Donor

Bonn

Scharfenecker

Friehe

et al. 1998

Cardiovascular Drug Reviews

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Vascular effects of the dinitrate and mononitrate esters of isosorbide, isomannide and isoidide

Cited by 65 publications

References 5 publications

Effect of 5-isosorbide mononitrate on isosorbide dinitrate-induced relaxation of rabbit aortic rings

Effect of 5-isosorbide mononitrate on isosorbide dinitrate-induced relaxation of rabbit aortic rings

Plasma concentrations of isosorbide dinitrate and its metabolites after chronic high oral dosage in man.

SP/W‐5186: A Novel Sulfhydryl‐Containing NO Donor

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