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1 University of Georgia College of Pharmacy, Augusta 30912-3910; 2 Vascular Biology Center, Departments of Pharmacology and Toxicology, Surgery, Physiology, and Endocrinology, School of Medicine, Medical College of Georgia, Augusta 30912-3910; and 3 Augusta Veterans Affairs Medical Center, Augusta, Georgia 30904-6285
Hyperinsulinemia, a primary feature of insulin resistance, is
associated with increased endothelin-1 (ET-1) activity. This study
determined the vascular response to ET-1 and receptor binding characteristics in small mesenteric arteries of insulin-resistant (IR)
rats. Rats were randomized to control (C) (n = 32) or IR (n = 32) groups. The response to ET-1 was assessed (in
vitro) in arteries with (Endo+) and without (Endo
) endothelium. In
addition, arteries (Endo+) were pretreated with the ETB
antagonist A-192621 or the ETA antagonist A-127722.
Finally, binding characteristics of [125I]ET-1 were
determined. Results showed that in Endo+ arteries the maximal
relaxation (Emax) to ET-1 was similar between C
and IR groups; however, the concentration at 50% of maximum relaxation (EC50) was decreased in IR arteries. In Endo arteries,
the Emax to ET-1 was enhanced in both groups.
Pretreatment with A-192621 enhanced the Emax and
EC50 to ET-1 in both groups. In contrast, A-127722
inhibited the ET-1 response in all arteries in a
concentration-dependent manner; however, a greater ET-1 response was
seen at each concentration in IR arteries. Maximal binding of
[125I]ET-1 was increased in IR versus C arteries although
the dissociation constant values were similar. In conclusion, we found
the vasoconstrictor response to ET-1 is enhanced in IR arteries due to
an enhanced expression of ET receptors and underlying endothelial dysfunction.
hyperinsulinemia; ETA; ETB
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