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NEUROHUMORAL CONTROL OF CARDIOVASCULAR FUNCTION

Increased release of serotonin from rat ileum due to dexfenfluramine

Departments of ¹Medicine and ³Surgery, Veterans Administration Medical Center and University of Minnesota, Minneapolis, Minnesota 55417; and ²Department of Cardiology, University of Vienna, Vienna A-1090, Austria

Submitted 23 March 2004 ; accepted in final form 2 July 2004

Plasma levels of serotonin are elevated in primary pulmonary hypertension even after bilateral lung transplantation, suggesting a possible etiologic role. Serotonin is released primarily from the small intestine. Anorectic agents, such as dexfenfluramine, which can cause pulmonary hypertension, are known to inhibit potassium channels in vascular smooth muscle cells. We examined the hypothesis that dexfenfluramine may stimulate release of serotonin from the ileum by inhibition of K⁺ channels. In an isolated loop of rat ileum perfused with a physiological salt solution, the administration of dexfenfluramine, its major metabolite D-norfenfluramine, the potassium channel blocker 4-aminopyridine (5 mM), and caffeine (30 mM) increased serotonin levels in the venous effluent. Potassium chloride (60 mM) tended to increase serotonin levels. In genetically susceptible individuals, dexfenfluramine may induce pulmonary hypertension by increasing cytosolic calcium in enterochromaffin cells of the small intestine, thus releasing serotonin and causing vasoconstriction. This work indicates that dexfenfluramine and its major metabolite D-norfenfluramine can increase serotonin release from the small intestine.

enterochromaffin; potassium channel; hypertension

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