Enhanced endothelin-1 response and receptor expression in small mesenteric arteries of insulin-resistant rats

Abstract

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 ETBantagonist 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 ( E max) 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 E max to ET-1 was enhanced in both groups. Pretreatment with A-192621 enhanced the E max 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.