Endothelial function in the isolated perfused mesentery and aortae of rats with streptozotocin-induced diabetes: effect of treatment with the aldose reductase inhibitor, ponalrestat.
1. Noradrenaline sensitivity and relaxation to acetylcholine were investigated in the isolated perfused mesentery and in aortic rings of control and streptozotocin (STZ)-induced (50 mg kg-1) diabetic Charles River rats. 2. In addition, noradrenaline sensitivity and acetylcholine relaxation were similarly assessed in streptozotocin-induced diabetic rats treated from the time of onset of diabetes with the aldose reductase inhibitor, ponalrestat (100 mg kg-1 day-1). 3. The untreated diabetic rats (2-10 weeks after injection of STZ) demonstrated enhanced vascular sensitivity to noradrenaline in the perfused mesenteric arterial tree, compared with age matched controls (pEC50 [-log concentration (M)]: diabetic 5.62 +/- 0.09, n = 18, versus control 5.23 +/- 0.07, n = 16, P < 0.01). 4. Acetylcholine-induced relaxation was significantly impaired in the perfused mesentery of the diabetic animals compared to controls (pED50 [-log dose (mol)]: diabetic 9.87 +/- 0.10, n = 20, versus controls, 10.29 +/- 0.09, n = 20, P < 0.05). 5. In contrast, the aortic ring preparations demonstrated no significant functional differences between the diabetic and control groups in response to either noradrenaline (pEC50: diabetic 7.66 +/- 0.08, n = 15, versus controls 7.55 +/- 0.06, n = 15, NS), or acetylcholine (pEC50: diabetics 7.30 +/- 0.06, n = 15, versus controls 7.40 +/- 0.09, n = 15, NS). 6. Treatment with the aldose reductase inhibitor, ponalrestat, did not affect the increased vascular reactivity to noradrenaline, or impaired relaxation to acetylcholine in the perfused mesentery.
Division of Physiology, United Medical School Smooth Muscle Group, London.
P D
PD
Taylor
A D
AD
Wickenden
D J
DJ
Mirrlees
L
L
Poston
D000109:Acetylcholine / Q000494:pharmacology; D000449:Aldehyde Reductase / Q000037:antagonists & inhibitors*; D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000503:physiopathology; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy / Q000503:physiopathology*; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000503:physiopathology; D005260:Female; D066298:In Vitro Techniques; 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; D009638:Norepinephrine / Q000494:pharmacology; D010793:Phthalazines / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D014655:Vascular Resistance / Q000187:drug effects
D010793:Phthalazines; C042829:ponalrestat; D000449:Aldehyde Reductase; D000109:Acetylcholine; D009638:Norepinephrine