Reduced coronary NO production in conscious dogs after the development of alloxan-induced diabetes

The role of nitric oxide (NO) in the control of coronary blood flow (CBF) d uring the development of diabetes is unknown. To study this, mongrel dogs w ere chronically instrumented using sterile techniques for measurements of s ystemic hemodynamics and CBF. With heart rate controlled (150 beats/min), v eratrine (1-10 mu g/kg) caused dose-dependent increases in CBF; e.g., 5 mu g/kg of veratrine increased CBF by 57 +/- 7% from 41 +/- 1.3 ml/min (P < 0. 05). The dogs developed diabetes 4-5 wk after injection of alloxan (40-60 m g/kg iv, blood glucose levels were 384 +/- 18 mg/dl). After diabetes the sa me doses of veratrine caused smaller increases in CBF; i.e., 5 mu g/kg of v eratrine increased CBF by 32 +/- 2% (P < 0.05 compared with control) from 2 8 +/- 4 ml/min. ACh- and adenosine-induced coronary vasodilation were reduc ed after diabetes as well. In anesthetized dogs after diabetes, vagal stimu lation caused smaller increases in CBF. ACh and bradykinin caused smaller i ncreases in NO, production in coronary microvessels from diabetic dogs. Fur thermore, despite the fact that mRNA for endothelial cell NO synthase from the aorta was increased twofold with the use of Northern blotting, the prot ein for aortic endothelial constitutive NO synthase was reduced by 66% afte r diabetes, as determined by Western blotting. Our results indicate that th e NO-dependent coronary vasodilation by the Bezold-Jarisch reflex is impair ed in conscious dogs after diabetes. The mechanism responsible for the impa ired endothelium-dependent coronary vasodilation is most likely the decreas ed release of NO from the endothelium.