PREVENTION BY INSULIN-TREATMENT OF ENDOTHELIAL DYSFUNCTION BUT NOT ENHANCED NORADRENALINE-INDUCED CONTRACTILITY IN MESENTERIC RESISTANCE ARTERIES FROM STREPTOZOTOCIN-INDUCED DIABETIC RATS

1 Streptozotocin-induced diabetic rats (Wistar) were implanted with sustained release insulin pellets (release rate = 4 u day(-1)) or with placebo pellets (palmitic acid) from the onset of glycosuria. 2 Noradrenaline sensitivity, endothelium-dependent relaxation to acetylcholine and endothelium-independent relaxation to sodium nitroprusside were assessed in mesenteric resistance arteries from the insulin-treated (IT) diabetic animals and compared to placebo-implanted (PI) diabetics and age-matched controls. 3 Arteries from PI-diabetic rats (8-10 weeks) demonstrated an enhanced maximal response to noradrenaline compared to controls, which was not prevented by insulin treatment (control 2.65+/-0.17 mN mm(-1), n = 18 arteries versus PI-diabetic 3.73+/-0.40 mN mm(-1), n = 5, P<0.05; control versus IT-diabetic 4.02+/-0.19 mN mm(-1), n = 22, P<0.001). Sensitivity to noradrenaline was similar between the three groups. 4 In the presence of the nitric oxide synthase inhibitor NG-nitro-L-arginine methyl ester (L-NAME), IT and PI arteries were more sensitive to noradrenaline than control arteries (pEC(50): control 5.75+/-0.08, n = 17, versus PI-diabetic 6.14 +/- 0.09, n = 8, P<0.05; control versus IT-diabetic 6.38+/-0.08, n = 20, P<0.001). 5 The maximum contractile response to depolarizing 125mM K+ was significantly enhanced in IT-diabetic arteries but not PI-diabetic when compared to control arteries (maximum response: control 3.74+/-0.15 mN mm(-1) n = 18, versus PI-diabetic 3.61+/-0.19 mN mm(-1), n = 11, NS; control versus IT-diabetic 4.66+/-0.18 mN mm(-1), n = 22, P<0.001). 6 Endothelium-dependent relaxation to acetylcholine was profoundly impaired in the PI-diabetic arteries, but in the IT-diabetic arteries was not significantly different from controls (pEC(50): control 7.64+/-0.19, n=17, versus PI-diabetic 6.07+/-0.12, n=8, P<0.001; control versus IT-diabetic 7.36+/-0.09, n = 22, NS). 7 Endothelium-independent relaxation to sodium nitroprusside was slightly but significantly impaired in the PI-diabetic arteries, but was not significantly different in the IT-diabetic arteries compared to controls. (pEC(50): control 7.78+/-0.10, n = 13, versus PI-diabetic 7.31+/-0.13, n = 13, P<0.05; control, versus IT-diabetic 7.64+/-0.09, n = 16, NS).