Free radicals mediate endothelial dysfunction of coronary arterioles in diabetes.
Previous studies have demonstrated that vascular responses to acetylcholine (ACh) are impaired in diabetes mellitus (DM).


OBJECTIVE
Since reactive oxygen species (ROS) generation is increased in various disease states including DM, and a direct reaction between nitric oxide (NO) and superoxide anion has been demonstrated, we tested the hypothesis that inhibition of ROS will restore coronary microvascular responses to ACh in a dog model of DM (alloxan 60 mg/kg, i.v., 1 week prior to study).


METHODS
Changes in coronary microvascular diameters in diabetic (blood glucose >200 mg%) and normal animals to ACh (1-100 microM, topically) in the presence and absence of superoxide dismutase and catalase were measured using intravital microscopy coupled to stroboscopic epi-illumination and jet ventilation.


RESULTS
In diabetic animals in the absence of ROS scavengers, ACh induced coronary microvascular dilation was impaired when compared to normal animals (ACh 100 microM: DM=25+/-5%; normal=64+/-13%, P<0.05). Topical application of SOD (250 U/ml) and catalase (250 U/ml) restored to normal ACh induced coronary microvascular responses in DM while having no affect in normal animals. Responses to adenosine and nitroprusside were not different between normal and diabetic groups.


CONCLUSIONS
These data provide direct evidence that oxygen-derived free radicals contribute to impaired endothelium-dependent coronary arteriolar dilation in diabetic dogs in vivo.
Ammar
R F
RF
VA Medical Center, Highway 6 West, Iowa City, IA 52246, USA.
Gutterman
D D
DD
Brooks
L A
LA
Dellsperger
K C
KC
D000109:Acetylcholine / Q000494:pharmacology; D000241:Adenosine / Q000494:pharmacology; D000496:Alloxan / Q000494:pharmacology; D000704:Analysis of Variance; D000818:Animals; D001160:Arterioles; D002374:Catalase / Q000494:pharmacology*; D003331:Coronary Vessels; D003921:Diabetes Mellitus, Experimental / Q000503:physiopathology*; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000187:drug effects / Q000503:physiopathology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D016166:Free Radical Scavengers / Q000494:pharmacology*; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D009599:Nitroprusside / Q000494:pharmacology; D013482:Superoxide Dismutase / Q000494:pharmacology*; D014665:Vasodilator Agents / Q000494:pharmacology
D004791:Enzyme Inhibitors; D016166:Free Radical Scavengers; D014665:Vasodilator Agents; D009599:Nitroprusside; D000496:Alloxan; D002374:Catalase; D019001:Nitric Oxide Synthase; D013482:Superoxide Dismutase; D000241:Adenosine; D000109:Acetylcholine