Deficit in the sulfonylurea receptor KATP channel complex compromises the metabolic benefit of exercise training resulting in cardiac deficits

The sulfonylurea‐receptor protein that forms the stress‐responsive ATP‐sensitive potassium (KATP) channel, is the identified binding site for sulfonylurea medications used widely in the treatment of type 2 diabetes mellitus. Clinical studies have indicated a compromised exertional capacity in diabetic patients treated with sulfonylureas yet the mechanism for this drug‐induced impairment is unknown. Here the response following genetic ablation of KATP channel function (KO) was compared to wild‐type controls following a 28‐day endurance swimming protocol. While chronic aquatic training resulted in a lighter, leaner and fitter wild‐type cohort, the KO manifested less augmentation in exercise capacity and lacked metabolic improvement in body fat composition and glycemic handling. Skeletal muscle analysis demonstrated myocellular defects compatible with repetitive injury/regeneration. Moreover, the continuous stress of swimming unmasked a survival disadvantage in the KO, associated with pathologic calcium‐dependent structural damage in the heart, abnormal hypertrophic development and impaired cardiac function. Thus, intact function of the sulfonylurea‐receptor KATP channel complex is mandatory for the attainment of the optimal physiologic benefits of exercise training while preventing injury. This work provides a mechanism for sulfonylurea‐cardiovascular exercise intolerance and has wide‐ranging implications for diabetic patients treated with KATP channel antagonists. Clinical Pharmacology & Therapeutics (2005) 77 , P54–P54; doi: 10.1016/j.clpt.2004.12.097