Effects of combined inhibition of ATP-sensitive potassium channels, nitric oxide, and prostaglandins on hyperemia during moderate exercise

Abstract

ATP-sensitive potassium (KATP) channels have been suggested to contribute to coronary and skeletal muscle vasodilation during exercise, either alone or interacting in a parallel or redundant process with nitric oxide (NO), prostaglandins (PGs), and adenosine. We tested the hypothesis that KATP channels, alone or in combination with NO and PGs, regulate exercise hyperemia in forearm muscle. Eighteen healthy young adults performed 20 min of moderate dynamic forearm exercise, with forearm blood flow (FBF) measured via Doppler ultrasound. After steady-state FBF was achieved for 5 min (saline control), the KATP inhibitor glibenclamide (Glib) was infused into the brachial artery for 5 min (10 μg·dl−1·min−1), followed by saline infusion during the final 10 min of exercise ( n = 9). Exercise increased FBF from 71 ± 11 to 239 ± 24 ml/min, and FBF was not altered by 5 min of Glib. Systemic plasma Glib levels were above the therapeutic range, and Glib increased insulin levels by ∼50%, whereas blood glucose was unchanged (88 ± 2 vs. 90 ± 2 mg/dl). In nine additional subjects, Glib was followed by combined infusion of NG-nitro-l-arginine methyl ester (l-NAME) plus ketorolac (to inhibit NO and PGs, respectively). As above, Glib had no effect on FBF but addition of l-NAME + ketorolac (i.e., triple blockade) reduced FBF by ∼15% below steady-state exercise levels in seven of nine subjects. Interestingly, triple blockade in two subjects caused FBF to transiently and dramatically decrease. This was followed by an acute recovery of flow above steady-state exercise values. We conclude 1) opening of KATP channels is not obligatory for forearm exercise hyperemia, and 2) triple blockade of NO, PGs, and KATP channels does not reduce hyperemia more than the inhibition of NO and PGs in most subjects. However, some subjects are sensitive to triple blockade, but they are able to restore FBF acutely during exercise. Future studies are required to determine the nature of these compensatory mechanisms in the affected individuals.