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Abnormal endothelin B receptor vasomotor responses in patients with Hirschsprung's disease
D E Newby1, F E Strachan, D J Webb
1Clinical Pharmacology Unit and Research Centre, University of Edinburgh, Edinburgh, UK. d.e.newby@ed.ac.uk
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.