Aspects of the biogenic amine-depleting activity of ethyl 3-acetamido-4H-pyrrolo-[3,4-c]isoxazole-5(6H)-carboxylate in the rat.

Agents have been found which cause marked lowering of the catecholamine and/or 5-hydroxytryptamine concentrations in tissues and some (for example, a-methyldihydroxyphenylalanine, guanethidine and reserpine) are useful in the treatment of hypertension (Hafkenschiel & Sellers, 1954; Richardson & Wyso, 1959; Hollander, 1961; Page, Hurley & Dustan, 1961; Gillespie, Oates, Crout & Sjoerdsma, 1962; Cannon, Whitlock, Morris, Angers & Laragh, 1962). Ethyl 3-acetamido-4H-pyrrolo[3,4-c]isoxazole-5(6H)-carboxylate (CL-62375) has been reported to decrease both the catecholamine and 5-hydroxytryptamine concentrations in tissues of the rat (Lippmann & Wishnick, 1967). After a single administration of CL-62375 there is an appreciable lowering of the catecholamine concentration in the heart and brain and a slight fall in brain 5-hydroxytryptamine. After repeated administration of CL-62375 the heart shows the largest decrease in the catecholamine concentration followed by the brain and the adrenals; the brain 5-hydroxytryptamine decreases appreciably. CL-62375 causes a lowering of blood pressure in the rat (Cummings & Welter, 1967, personal communication). Studies on the mechanism of the biogenic amine-depleting activity of CL-62375 were carried out and the results are presented in the present paper.