Evaluation of the Antianginal Effect of Isosorbide-5-Mononitrate in Patients with Chronic Stable Angina Pectoris

Yasky, J; Ontanilla, Eduardo; Koch, Julio E.

doi:10.1159/000174921

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“…Several clinical studies report that chronic ISMN treatment does not result in drug tolerance. 6,7,18) These studies suggest that ISMN is an effective antianginal agent for patients chronically treated with nitrates. However, there are few papers that have confirmed experimentally whether GTN is effective in relieving an anginal attack in patients chronically treated with ISMN.…”

Section: Discussionmentioning

confidence: 91%

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Tolerance to Nitroglycerin Induced by Isosorbide-5-Mononitrate Infusion in Vivo.

Manabe

Yamamoto

Satoh

et al. 2001

Biological & Pharmaceutical Bulletin

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Nitrates are still important drugs for clinical therapy of the patient with ischemic heart disease and for relief of anginal attack. Treatments with nitrates, however, develop vascular tolerance associated with attenuation of hemodynamic and antianginal effects.2,3) When a therapeutic plasma level of nitrates is maintained over 24 h, it may cause a tolerance to nitrates.2,3) Isosorbide-5-mononitrate (ISMN) is one of the active metabolites of isosorbide dinitrate and has been clinically used. 4,5) Because this agent is hard to metabolize further by the hepatic metabolic system, its therapeutic plasma level can be sustained for a longer period. 4,5) ISMN is clinically used for treatment of patients with hypertension or angina pectoris.6-8) Sublingual dosing of nitroglycerin (glyceryl trinitrate; GTN) is used for relief of the anginal pain of patients treated chronically with ISMN. Many clinical reports show lack of development of tolerance to ISMN. 7,9) However, we failed to find a report on whether the tolerance to GTN occurs when there has been chronical treatment with ISMN. In the present study, we compared tolerance to GTN in the rat infused continuously with ISMN to the rat infused continuously with GTN. MATERIALS AND METHODSThe investigation conformed to the Guiding Principles for the Care and Use of Experimental Animals in Hokkaido College of Pharmacy (published in 2001).Materials ISMN and GTN were supplied by Toa Eiyo Ltd., Fukushima, Japan. Osmotic pumps (Alzet Animal Preparation Male Sprague Dawley rats weighing 250-300 g were anesthetized with sodium pentobarbital (60 mg/kg, i.p.). Under artificial respiration, the left common carotid artery and the right external jugular vein were dissected free, and cannulated. A cannula introduced into the carotid artery was filled with saline solution containing heparin (100 units/ml), and connected to a pressure transducer. Heart rate was monitored from the ECG limb lead II. Mean arterial blood pressure and heart rate were recorded on a polygraph via a blood pressure amplifier (San-Ei 2238) and a bioelectric amplifier (San-Ei 1253A), respectively. ISMN and GTN dissolved in 99% ethanol were diluted with 5% glucose to prepare the solution at the concentration of 0.25-250 mg/kg and 0.25 mg/kg-2.5 mg/kg, respectively. Therefore, the final concentrations of ethanol and glucose were 5% and 5%, respectively. ISMN (0.25-250 mg/kg) or GTN (0.25 mg/kg-2.5 mg/kg) was injected through the right external jugular vein. Some rats were chronically infused with ISMN or GTN using an osmotic pump (ALZET ® Model 2001 and 2ML1) embedded subcutaneously in their back. The osmotic pump was filled with either 99% ethanol as vehicle, 250 mg/ml ISMN, 13 mg/ml GTN, or 20 mg/ml GTN, dissolved in 99% ethanol, and the solution was pumped out at 10 ml/h. ISMN was infused at the dose of 2.5 mg/h/rat for 3 or 7 d, whereas GTN was infused at 1.3 mg/h/rat for 7 d or 0.2 mg/h/rat for 3 d.Statistics The results are expressed as meansϮS.E.M. The significance of differences between groups was evaluated b...

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Section: Discussionmentioning

confidence: 91%

“…4,5) ISMN is clinically used for treatment of patients with hypertension or angina pectoris. [6][7][8] Sublingual dosing of nitroglycerin (glyceryl trinitrate; GTN) is used for relief of the anginal pain of patients treated chronically with ISMN. Many clinical reports show lack of development of tolerance to ISMN.…”

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confidence: 99%