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Coronary arteries from animals on normal diets (ND) exhibit well-maintained responses to dilators under ischemic conditions. The reported altered metabolic requirements and K+-currents in blood vessels from hypercholesterolemic animals fed high-fat diets (HF) led us to hypothesize that under metabolically depressed conditions (N2/2-deoxyglucose) coronary arteries from pigs would exhibit significantly decreased responses to adenosine (ADO) as compared with pigs given ND. Diet had no major effect on responses of coronary rings to ET-1, nor on the sensitivity to ADO or 2-chloroadenosine (2-CAD) relaxation under metabolically supported conditions. During metabolic inhibition the response curves for both ADO and 2-CAD were shifted to the right (P < 0.05), with the HF group shifted about 4-fold more than ND (P < 0.05). To determine the involvement of K+-channels, ADO responses were measured in the presence of 4-aminopyridine (4-AP, 1 mM) or glybenclamide (GLYB, 10 μM). The larger shift in the HF group during metabolic inhibition was not affected by GLYB, but disappeared in the presence of 4-AP with ND now behaving similarly to HF. These results indicate that HF diet may have a 4-AP–like effect on voltage-dependent K+-channels (KV). Patch-clamp measures of whole cell K+- currents showed the HF cells to have reduced 4-AP sensitive currents (P < 0.02). The 4-AP insensitive currents were similar in both groups. Thus, reduced KV channel activity may play a role in the depressed ADO relaxation associated with metabolic inhibition of HF coronary arteries. These factors may place the coronary circulation of HF at increased risk during an ischemic episode.