Dual endothelin receptor antagonism prevents remodeling of resistance arteries in diabetes.

Canadian Journal of Physiology and Pharmacology
Kamakshi SachidanandamAdviye Ergul

Abstract

Vascular remodeling, characterized by extracellular matrix deposition and increased media-to-lumen (M/L) ratio, contributes to the development of microvascular complications in diabetes. We have previously shown in type 2 diabetic Goto-Kakizaki (GK) rats that selective ETA receptor blockade prevents medial thickening of mesenteric arteries via regulation of matrix metalloproteases (MMP), whereas selective ETB receptor blockade augments this thickening. The goal of this study was to determine the effect of combined ETA and ETB receptor blockade on resistance vessel remodeling. Vessel structure, MMP activity, and extracellular matrix proteins were assessed in control Wistar and diabetic GK rats treated with vehicle or bosentan (100 mg/kg per day) for 4 weeks (n = 7-9 per group). Bosentan completely prevented the increase in M/L ratio and MMP-2 activity in diabetes but paradoxically increased M/L ratio and MMP activation in control animals. Collagenase (MMP-13) activity and protein levels were significantly decreased in diabetes. Accordingly, collagen deposition was augmented in GK rats. Dual ET receptor antagonism improved enzyme activity and normalized MMP-13 levels in diabetic animals but blunted MMP-13 activity in control anim...Continue Reading

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Oct 22, 2005·American Journal of Physiology. Regulatory, Integrative and Comparative Physiology·Vera Portik-DobosAdviye Ergul
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Apr 22, 2008·American Journal of Physiology. Heart and Circulatory Physiology·Kamakshi SachidanandamAdviye Ergul

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Citations

Sep 17, 2010·Science Translational Medicine·Rohit N Kulkarni
Aug 18, 2012·Cardiology Research and Practice·Kento KitadaYasuo Matsumura

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