The coronary circulation in diabetes: influence of reactive oxygen species on K+ channel-mediated vasodilation

Enhanced oxidative stress, particularly an excess production of superoxide, has been implicated in the altered vasomotor responsiveness observed in diabetes mellitus (DM). Recent evidence suggests that an altered regulation of K+ channel activity by enhanced oxidative stress may participate in the abnormal vascular responses. This review examines the mechanism of hyperglycemia-induced superoxide production and describes the consequences on hyperpolarization-mediated vasodilation. Several pathways have been proposed as mechanisms for hyperglycemia-induced superoxide overproduction, including increased flux through the polyol pathway, depletion of nicotinamide adenine dinucleotide phosphate (NADPH), altered endogenous antioxidant enzymes, and reduced availability of tetrahydrobiopterin, an essential cofactor for nitric oxide synthase (NOS). The resulting excess production of superoxide has been implicated in the impaired dilator responses to ATP-sensitive K+ (KATP) channel openers in aorta and in mesenteric and cerebral arteries of streptozotocin-induced diabetic rats. This may have important implications for ischemia-mediated vasodilation. Potential alterations in voltage-sensitive K+ (KV) channel regulation also have been implicated in the vascular pathogenesis of DM. For example, incubation of small rat coronary arteries in high glucose for 24 h greatly reduces KV channel activity and functional responses, both of which can be partially restored by antioxidant treatment. However, not all K+ channels are adversely affected by reactive oxygen species (ROS). For example, high-conductance Ca(2+)-activated K+ (BKCa) channels may compensate for the loss of other vasodilator mechanisms in disease states such as atherosclerosis where ROS generation is increased. Therefore, BKCa channels may be refractory to superoxide, providing a compensatory mechanism for partially reversing the reduced dilator responses attributed to the dysfunction of other K+ channel types. In summary, determining the effect of ROS on K+ channel-mediated dilation will be important for understanding the pathophysiology of diabetic vascular dysfunction and for developing therapies to improve tissue perfusion in this disease.