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Chronic and Selective Endothelin Receptor Antagonism on Microvascular Function in Type 2 Diabetes
Author(s) -
Sachidanandam Kamakshi,
Harris Alex,
Elgebaly Mostafa,
Hutchinson Jim,
Muller Erin,
Ergul Adviye
Publication year - 2007
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.21.6.lb90-d
Subject(s) - medicine , endocrinology , myograph , endothelin receptor , diabetes mellitus , type 2 diabetes , nitric oxide , antagonist , endothelial dysfunction , receptor , endothelin 1 , blockade
Vascular dysfunction caused by hyperreactivity and/or impaired relaxation in diabetes causes increased cardiovascular morbidity and mortality. Endothelin‐1 (ET‐1) is chronically elevated in diabetes and affects vascular function. The current study sought to examine the relative roles of the two ET receptors governing microvascular function in Goto‐Kakizaki (GK) rats, a normotensive, non‐obese model of Type 2 diabetes. GK and control Wistar rats received either an ETA (Atrasentan, 5 mg/kg/day) or ETB (A‐192621, 15 or 30 mg/kg/day) receptor antagonist for four weeks. At week 18, vascular function was assessed on a wire‐myograph. Maximum response to ET‐1 was increased in diabetes, and attenuated by ETA blockade and ETB antagonism at 30 mg/kg. Relaxation to acetylcholine was similar across groups. Blockade of the nitric oxide (NO) pathway impaired relaxation in diabetes indicating a compensatory upregulation of this pathway in diabetes. This effect was reversed by ETA blockade. However, 30 mg/kg ETB antagonism almost completely blocked vasorelaxation in GK rats. Thus, both ETA and ETB receptors contribute to the regulation of vascular function in diabetes in an NO‐dependant manner.