Impaired dilation of coronary arterioles during increases in myocardial O(2) consumption with hyperglycemia.

Previous studies showed that nitric oxide (NO) plays an important role in coronary arteriolar dilation to increases in myocardial oxygen consumption (MVO(2)). We sought to evaluate coronary microvascular responses to endothelium-dependent and to endothelium-independent vasodilators in an in vivo model. Microvascular diameters were measured using intravital microscopy in 10 normal (N) and 9 hyperglycemic (HG; 1 wk alloxan, 60 mg/kg iv) dogs during suffusion of acetylcholine (1, 10, and 100 microM) or nitroprusside (1, 10, and 100 microM) to test the effects on endothelium-dependent and -independent dilation. During administration of acetylcholine, coronary arteriolar dilation was impaired in HG, but was normal during administration of nitroprusside. To examine a physiologically important vasomotor response, 10 N and 7 HG control, 5 HG and 5 N during superoxide dismutase (SOD), and 5 HG and 4 N after SQ29,548 (SQ; thromboxane A(2)/prostaglandin H(2) receptor antagonist) dogs were studied at three levels of MVO(2): at rest, during dobutamine (DOB; 10 microg. kg(-1). min(-1) iv), and during DOB with rapid atrial pacing (RAP; 280 +/- 10 beats/min). During dobutamine, coronary arterioles dilated similarly in all groups, and the increase in MVO(2) was similar among the groups. However, during the greater metabolic stimulus (DOB+RAP), coronary arterioles in N dilated (36 +/- 4% change from diameter at rest) significantly more than HG (16 +/- 3%, P < 0.05). In HG+SQ and in HG+SOD, coronary arterioles dilated similarly to N, and greater than HG (P < 0.05). MVO(2) during DOB+RAP was similar among groups. Normal dogs treated with SOD and SQ29,548 were not different from untreated N dogs. Thus, in HG dogs, dilation of coronary arterioles is selectively impaired in response to administration of the endothelium-dependent vasodilator acetylcholine and during increases in MVO(2).

Free radicals mediate endothelial dysfunction of coronary arterioles in diabetes.

UNLABELLED: 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.