Time-course changes in plasma endothelin-1 and its effects on the mesenteric arterial bed in streptozotocin-induced...

To examine the mechanisms underlying the elevated plasma endothelin-1 (ET-1) in diabetes and its vascular effects.

Relationships between the plasma ET-1 level and the levels of other plasma constituents (glucose, cholesterol, and triglyceride) were found in 10-week streptozotocin (STZ)-induced diabetic rats. In contrast, at 1 week after the STZ injection only plasma ET-1 and glucose levels were elevated, suggesting that the hyperglycaemia might trigger the excess production of ET-1. Incubation with high glucose promoted the release of ET-1 from the isolated mesenteric arterial bed. In STZ-induced diabetic rats, the maximum contractile response of the mesenteric arterial bed to ET-1 was significantly reduced, and the vasoconstriction and vasodilation induced by the ET(B)-receptor agonist IRL-1620 in this bed were significantly impaired. The vascular responses induced by these ET receptor agonists were restored to normal by chronic treatment of diabetic rats with insulin for 7 or 4 weeks.

These results suggest: (1) that the marked increase in plasma glucose in STZ-induced diabetic rats elevates the plasma ET-1; and (2) that the decreased contractile and vasodilator responses of the mesenteric arterial bed to ET-1 receptor agonists may be due to desensitization of not only ET(A), but also ET(B) receptors, an effect secondary to the elevation of plasma ET-1.