Effect of advanced glycation end products on dilation of rat skeletal muscle arterioles

Abstract

Post translational protein modification, including the formation and accumulation of advanced glycation endproducts (AGE), may contribute to vascular dysfunction in diabetes. This study investigated the effect of AGE on dilation of arterioles possessing myogenic tone. AGE were manufactured by incubating 250 mM glucose‐6‐phosphate with 10 mg/ml BSA in PBS for 60 days. The effects of the modified protein were studied on isolated, pressurized (70 mmHg) first‐order arterioles from rat cremaster muscle. The AGE preparation inhibited dilation of the arterioles caused by both acetylcholine (ACh; endothelium‐dependent) and sodium nitroprusside (SNP), but had no effect on adenosine‐induced vasodilation. Iberiotoxin (0.1 μM), an antagonist of large‐conductance, Ca2+‐activated K+ channels (BKCa), inhibited ACh‐induced dilation. The combination of iberiotoxin and AGE did not cause a greater inhibition of ACh‐induced vasodilation than the application of iberiotoxin or AGE alone. The inhibitory effect of AGE on ACh‐ and SNP‐induced vasodilation was abolished by pre‐incubation of the arterioles individually with the NOS inhibitor L‐NAME (100 μM), the anti‐oxidant lipoic acid (2 μM) or the NADPH oxidase inhibitor apocynin (500 μM). Taken together, these observations suggest that AGE inhibit ACh‐ and SNP‐induced dilation of the arterioles by inhibiting BKCa, through generation of reactive oxygen species.