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 mM 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 (pEC50: 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 125 mM 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 (pEC50: 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 (pEC50: 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).
Division of Physiology, United Medical School Smooth Muscle Group, London.
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Taylor
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Oon
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Thomas
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Poston
D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives / Q000494:pharmacology; D003692:Delayed-Action Preparations / Q000008:administration & dosage / Q000494:pharmacology; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy / Q000503:physiopathology*; D004343:Drug Implants; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000503:physiopathology; D005260:Female; D007328:Insulin / Q000494:pharmacology* / Q000627:therapeutic use; D008638:Mesenteric Arteries / Q000187:drug effects* / Q000503:physiopathology; D009119:Muscle Contraction / Q000187:drug effects; D009126:Muscle Relaxation / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000503:physiopathology; D019331:NG-Nitroarginine Methyl Ester; D009569:Nitric Oxide / Q000037:antagonists & inhibitors; D009599:Nitroprusside / Q000494:pharmacology; D009638:Norepinephrine / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D014655:Vascular Resistance / Q000187:drug effects*
D003692:Delayed-Action Preparations; D004343:Drug Implants; D007328:Insulin; D009599:Nitroprusside; D009569:Nitric Oxide; D001120:Arginine; D000109:Acetylcholine; D019331:NG-Nitroarginine Methyl Ester; D009638:Norepinephrine