IMPAIRMENT OF CORONARY BLOOD-FLOW REGULATION BY ENDOTHELIUM-DERIVED NITRIC-OXIDE IN DOGS WITH ALLOXAN-INDUCED DIABETES

Diabetes mellitus is a major cause of ischemic coronary artery disease . Endothelial dysfunction is implicated in the pathogenesis of diabeti c vascular disease. To examine coronary blood flow (CBF) regulation wi th endothelium-derived nitric oxide (EDNO) in the diabetic state, we c ompared the effects of both acetylcholine (ACh) and adenosine (Ado) on left circumflex coronary artery (LCX) blood flow in 12 vehicle-treate d and 21 dogs made diabetic with alloxan anesthetized with pentobarbit al. All dogs were pretreated with aspirin to inhibit endogenous prosta glandins. None of the hemodynamic parameters were significantly differ ent in the two groups. The percent change in coronary vascular resista nce (CVR) after ACh (100 ng/kg) infusion was significantly attenuated in diabetic dogs (-56.5 +/- 1.4%) as compared with vehicle-treated dog s (-64.5 +/- 1.2%) (p < 0.01) whereas the effect of Ado (1 mu g/kg) wa s not different between the two groups (-71.1 +/- 1.5% in vehicle, -67 .0 +/- 1.3% in diabetes). After infusion of incremental doses of N-G-n itro-L-arginine methyl ester (L-NAME) 10-(5)-10(-3)M, the effect of AC h was progressively inhibited in both groups and was different no long er between the two groups after the maximal dose. L-Arginine (r-ARG), but not D-ARG, significantly restored the effect of ACh in diabetic do gs but did not affect vehicle-treated dogs, The effect of Ado did not change after L- and D-ARG administration. Cu, Zn-superoxide dismutase (Cu, Zn-SOD) had no effect on any of the effects of ACh and Ado in dia betic dogs, Regulation of CBF with EDNO is impaired in dogs with allox an-induced diabetes, and this impairment is partially restored by L-AR G.