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A study of the mode of action of isoidide dinitrate. Clark, Stewart Cecil

Abstract

Isoidide dinitrate (IIDN), a new nitrate ester, an isomer of isosorbide dinitrate (ISDN) and isomannide dinitrate (IMDN), has been studied on the isolated rabbit intestine and on the anesthetized rat blood pressure. Potency was observed as was tachyphylaxis and the effect of certain blocking agents. On the isolated rabbit intestine similar results were obtained when nitroglycerin was substituted for IIDN. In both preparations IIDN was more potent than ISDN or IMDN and ISDN more potent than IMDN. The potency dependence on configuration suggests a possible action on specific receptor sites. A type of tachyphylaxis to IIDN which was prominent in the isolated rabbit intestine was almost absent in the anesthetized rat blood pressure. This is probably due to metabolism of the drug in the intact animal and further suggests an action on receptors. In these preparations the nitrate action was not blocked by: the beta adrenergic blocking agents DCI or nethalide, the alpha adrenergic blocking agent dibenzyline, or a combination of an alpha and a beta blocking agent. Drugs that are selectively blocked by these agents were used as controls to indicate the presence of the desired blocking action. Neither the primary bretylium-like action nor the secondary reserpine-like action of guanethidine blocked the effect of IIDN on the isolated rabbit intestine. Depletion of catechol amines by pretreating the animals with reserpine did not alter the response of either preparation to the nitrate esters. The antihistamine diphenhydramine did not block the vasodepressor action of IIDN on the anesthetized rat blood pressure. It was concluded that although IIDN probably does not exert its effect through combination with adrenergic or histaminergic receptors, it possibly acts on receptors which are specific for the nitrite or nitrate group.

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