D E Newby1, F E Strachan, D J Webb. 1. Clinical Pharmacology Unit and Research Centre, University of Edinburgh, Edinburgh, UK. d.e.newby@ed.ac.uk
Abstract
BACKGROUND: Hirschsprung's disease is associated with defects in the endothelin-3 and endothelin B receptor genes. AIM: To assess the in vivo vasomotor responses to endothelin B receptor stimulation in patients with Hirschsprung's disease. METHODS: Forearm blood flow was measured using venous occlusion plethysmography in 10 patients with Hirschsprung's disease and 10 matched healthy controls during intra-brachial infusion of the highly selective endothelin B receptor agonist, sarafotoxin S6c. To simulate endothelin B receptor dysfunction, sarafotoxin S6c was co-infused with the highly selective endothelin B receptor antagonist, BQ-788, in six of the healthy controls. RESULTS: Sarafotoxin S6c caused a brief initial vasodilatation followed by a slow-onset, sustained vasoconstriction (p<0.001). Compared to control subjects, patients with Hirschsprung's disease had a substantial impairment of the initial vasodilatation whilst producing a more pronounced subsequent vasoconstriction (p<0.001). In healthy controls, co-infusion of BQ-788 and sarafotoxin S6c caused a similar pattern of responses to those obtained in patients with Hirschsprung's disease: abolition of the initial vasodilatation and augmentation of subsequent vasoconstriction (p<0.001). DISCUSSION: In the majority of patients with Hirschsprung's disease, there is a functional defect of the vascular endothelin B receptor.
BACKGROUND:Hirschsprung's disease is associated with defects in the endothelin-3 and endothelin B receptor genes. AIM: To assess the in vivo vasomotor responses to endothelin B receptor stimulation in patients with Hirschsprung's disease. METHODS: Forearm blood flow was measured using venous occlusion plethysmography in 10 patients with Hirschsprung's disease and 10 matched healthy controls during intra-brachial infusion of the highly selective endothelin B receptor agonist, sarafotoxin S6c. To simulate endothelin B receptor dysfunction, sarafotoxin S6c was co-infused with the highly selective endothelin B receptor antagonist, BQ-788, in six of the healthy controls. RESULTS: Sarafotoxin S6c caused a brief initial vasodilatation followed by a slow-onset, sustained vasoconstriction (p<0.001). Compared to control subjects, patients with Hirschsprung's disease had a substantial impairment of the initial vasodilatation whilst producing a more pronounced subsequent vasoconstriction (p<0.001). In healthy controls, co-infusion of BQ-788 and sarafotoxin S6c caused a similar pattern of responses to those obtained in patients with Hirschsprung's disease: abolition of the initial vasodilatation and augmentation of subsequent vasoconstriction (p<0.001). DISCUSSION: In the majority of patients with Hirschsprung's disease, there is a functional defect of the vascular endothelin B receptor.
Authors: Anthony P Davenport; Kelly A Hyndman; Neeraj Dhaun; Christopher Southan; Donald E Kohan; Jennifer S Pollock; David M Pollock; David J Webb; Janet J Maguire Journal: Pharmacol Rev Date: 2016-04 Impact factor: 25.468