Long-term endothelin receptor blockade improves cardiovascular function in diabetes.
To evaluate the potential contribution of endothelin-1 (ET-1) toward the cardiovascular complications of diabetes, the present study examined the effects of chronic ET receptor blockade with bosentan on heart function and vascular reactivity in streptozotocin (STZ)-induced diabetic rats. Wistar rats were divided into four groups: control, control bosentan-treated, diabetic, and diabetic bosentan-treated. After chronic bosentan treatment, cardiac function and vascular reactivity were assessed. Exvivo working heart function was determined in terms of rate of contraction (+dP/dt), rate of relaxation (-dP/dt), and left ventricular developed pressure (LVDP). Contractile responses to ET-1 were determined in isolated superior mesenteric arteries. In addition, ET-1-like immunoreactivity was determined in ventricular and vascular tissues by immunohistochemistry. Cardiac function was depressed in the untreated-diabetic group. Bosentan treatment improved working heart function; hearts from the diabetic bosentan-treated group exhibited improved LVDP and -dP/dt. The contractile responses of mesenteric arteries to ET-1 were exaggerated in the untreated-diabetic group. Long-term bosentan treatment normalized these responses. Immunohistochemical analyses revealed increased ET-1-like immunoreactivity in ventricular and vascular tissues from untreated diabetic rats. These data show the beneficial effects of ET(A/B) receptor blockade on cardiovascular function in STZ-diabetic rats. An altered ET-1 system may contribute toward the pathogenesis of cardiovascular dysfunction in diabetes.
Verma
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Division of Pharmacology and Toxicology, Faculty of Pharmaceutical Sciences, The University of British Columbia, Vancouver, Canada.
Arikawa
E
E
McNeill
J H
JH
D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D016279:Atrial Function, Left / Q000187:drug effects; D000077300:Bosentan; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy*; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000032:analysis / Q000097:blood; D008297:Male; D008638:Mesenteric Arteries / Q000502:physiology; D009200:Myocardial Contraction / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D013449:Sulfonamides / Q000494:pharmacology*; D014661:Vasoconstriction / Q000187:drug effects
D000959:Antihypertensive Agents; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D013449:Sulfonamides; D000077300:Bosentan