Chronic bosentan treatment improves renal artery vascular function in diabetes.
OBJECTIVE
Endothelin-1 (ET-1) has been suggested to play an important role in the pathogenesis of diabetes-induced vascular complications. The primary purpose of the present study was to examine the potential beneficial effects of chronic ET receptor blockade (with bosentan) on vascular function in renal arteries from streptozotocin (STZ)-induced diabetic rats.


METHODS
Wistar rats were divided into four groups: control (C), control bosentan-treated (CB), diabetic (D) and diabetic bosentan-treated (DB). Following 10 weeks of bosentan treatment, vascular responses to norepinephrine (NE), ET-1, acetylcholine (ACh) were determined in vascular segments of renal arteries, both with and without the endothelium denuded, according to the following protocol: (1) a cumulative dose-response curve (DRC) to NE in the absence and presence of the nitric oxide synthase (NOS) inhibitor L-NAME (2) cumulative DRC to ET-1 and (3) cumulative DRC to ACh in precontracted arteries. In addition, plasma ET-1 was assayed and ET-1-like immunoreactivity was determined in vascular tissues by immunohistochemistry.


RESULTS
The maximum contractile responses to NE and ET-1 were markedly exaggerated in endothelium-intact renal arteries from untreated D rats while ACh responses were preserved. Arteries denuded of endothelium did not exhibit exaggerated responses to NE or ET-1. L-NAME treatment did not affect responses to NE in arteries with or without endothelium. Strikingly, responses to NE and ET-1 (in arteries with endothelium) were completely normalized following long-term bosentan treatment. In addition, plasma ET-1 levels did not differ between C and D groups. However, renal arteries isolated from the D group exhibited increased ET-1-like immunoreactivity (local ET-1 content).


CONCLUSIONS
These data uncover, for the first time, beneficial effects of mixed ETA/ETB receptor blockade on renal artery vascular function in diabetes. Alterations in the production and/or action of ET-1 may have important implications in the development of vascular dysfunction in experimental diabetes.
Arikawa
E
E
Division of Pharmacology and Toxicology, Faculty of Pharmaceutical Sciences, The University of British Columbia, Vancouver, Canada.
Verma
S
S
Dumont
A S
AS
McNeill
J H
JH
D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D000077300:Bosentan; D003921:Diabetes Mellitus, Experimental / Q000503:physiopathology*; D004305:Dose-Response Relationship, Drug; D019332:Endothelin-1 / Q000097:blood / Q000378:metabolism; D004730:Endothelium, Vascular / Q000503:physiopathology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009638:Norepinephrine / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D012077:Renal Artery / Q000187:drug effects* / Q000503:physiopathology*; D013449:Sulfonamides / Q000494:pharmacology*; D013997:Time Factors; D014661:Vasoconstriction; D014662:Vasoconstrictor Agents / Q000494:pharmacology
D000959:Antihypertensive Agents; D019332:Endothelin-1; D004791:Enzyme Inhibitors; D013449:Sulfonamides; D014662:Vasoconstrictor Agents; D000109:Acetylcholine; D000077300:Bosentan; D019331:NG-Nitroarginine Methyl Ester; D009638:Norepinephrine