Abnormal endothelin B receptor vasomotor responses in patients with Hirschsprung's disease.
BACKGROUND
Hirschsprung's disease is associated with defects in the endothelin-3 and endothelin B receptor genes.


OBJECTIVE
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).


CONCLUSIONS
In the majority of patients with Hirschsprung's disease, there is a functional defect of the vascular endothelin B receptor.
Newby
D E
DE
Clinical Pharmacology Unit and Research Centre, University of Edinburgh, Edinburgh, UK. d.e.newby@ed.ac.uk
Strachan
F E
FE
Webb
D J
DJ
D000328:Adult; D065128:Endothelin Receptor Antagonists; D005260:Female; D005542:Forearm / Q000098:blood supply; D006627:Hirschsprung Disease / Q000503:physiopathology*; D006801:Humans; D008297:Male; D009842:Oligopeptides; D010880:Piperidines; D044023:Receptor, Endothelin B; D017466:Receptors, Endothelin / Q000819:agonists / Q000502:physiology*; D012039:Regional Blood Flow / Q000187:drug effects; D014662:Vasoconstrictor Agents; D014666:Vasomotor System / Q000187:drug effects / Q000503:physiopathology*; D014757:Viper Venoms
D065128:Endothelin Receptor Antagonists; D009842:Oligopeptides; D010880:Piperidines; D044023:Receptor, Endothelin B; D017466:Receptors, Endothelin; D014662:Vasoconstrictor Agents; D014757:Viper Venoms; C057354:sarafotoxins s6; C086539:BQ 788