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

Hyperinsulinemia, a primary feature of insulin resistance, is associated wi th increased endothelin-1 (ET-1) activity. This study determined the vascul ar response to ET-1 and receptor binding characteristics in small mesenteri c 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 v itro) 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 [I-125] ET-1 w ere determined. Results showed that in Endo+ arteries the maximal relaxatio n (E-max) to ET-1 was similar between C and IR groups; however, the concent ration 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 contra st, 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 concen tration in IR arteries. Maximal binding of [I-125] 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 e ndothelial dysfunction.