Fenfluramine potentiates canine pulmonary vasoreactivity to endothelin-1

The appetite suppressant fenfluramine, a serotonin uptake inhibitor, has been implicated in the development of primary pulmonary hypertension (PPH). The effect of fenfluramine on the pressor response to endothelin-1 (ET-1) in the canine pulmonary circulation was determined using the isolated perfused dog lung. Pulmonary vascular resistance was measured using vascular occlusion techniques. Group 1 (n = 4) consisted of isolated lung lobes treated with 10^-8 M ET-1 alone. For group 2 (n = 4) and group 3 (n = 4), dogs were given 15 mg fenfluramine daily for 14 days prior to sacrifice for isolated lung perfusion. In group 2, lobes were treated with 10^-7 M fenfluramine after lung isolation. In group 3, the isolated lobes were treated with 10^-8 M ET-1 similar to group 1. Acute treatment of the isolated lobes in group 2 with 10-7 M fenfluramine increased pulmonary arterial pressure. In group 3, administration of 10^-8 M ET-1 potentiated the effect of ET-1 on post-capillary resistance relative to group 1, and elicited an increase in precapillary resistance, an effect not present in group 1. These results indicate that chronic fenfluramine exposure potentiates the pulmonary vasoconstrictor response to ET-1, and suggests that elevated levels of serotonin may 'prime' the pulmonary circulation to become hyperreactive to other vasoactive substances possibly leading to the development of disease states such as primary pulmonary hypertension.