Endothelium-dependent increase in vascular sensitivity to phenylephrine in long-term streptozotocin diabetic rat...

1. The effect of short- and long-term streptozotocin (STZ)-induced diabetes (12 and 52 weeks) on the vascular response to phenylephrine was examined in the isolated thoracic aorta with and without intact endothelium from diabetic, age matched control rats and diabetic rats treated with insulin. 2. Twelve weeks after induction of diabetes, aortae with intact endothelium demonstrated no changes either in sensitivity (defined as pD2) or contractility (defined as the maximal developed tension per aortic tissue wet weight) to phenylephrine. 3. In contrast, 52 weeks after induction of diabetes, aortae with intact endothelium demonstrated an increased sensitivity to phenylephrine while contractility to phenylephrine was not changed. Insulin treatment partially corrected the increased sensitivity to phenylephrine observed in diabetic rat aorta. 4. Removal of endothelium abolished the difference in phenylephrine sensitivity between diabetic and control aortae at 52 weeks. 5. Pretreatment of intact aortae with methylene blue, an inhibitor of endothelium-derived relaxing factor (EDRF), abolished the difference in phenylephrine sensitivity between control and diabetic rat aortae at 52 weeks, while pretreatment with indomethacin, an inhibitor of cyclo-oxygenase, had no effect. These results suggest that decreases in production or release of EDRF might be responsible for the increased vascular sensitivity to phenylephrine observed in long-term STZ diabetic rats. 6. Acetylcholine-induced relaxation, which is EDRF-dependent, was less in diabetic rat aortae with intact endothelium at 52 weeks, but not at 12 weeks. These results further support the theory that decreases in capacity of the endothelium to synthesize or release EDRF may occur in long-term STZ diabetic rats.