Beta-Adrenergic and ATP Sensitive Potassium Channel Effects on Ventricular Action Potential Duration: Alterations with Exercise Training

Abstract

Regular exercise-training is known to reduce the incidences and severity of ischemic heart disease, but the mechanistic nature is unknown. Recently, we showed that regular exercise prolongs the left ventricular action potential duration (APD) at resting heart rate (HR) while shortening it at high HR. These adaptations enhance cardiac contractility at rest while preventing Ca2+ overload and/or inadequate filling during exercise. Here we test the hypothesis that exercise-training induced changes in the APD are due to a reduced responsiveness to β-adrenergic regulation, and increased ATP sensitive potassium channel (KATP) function. Female and male Sprague-Dawley rats were randomly assigned to voluntary wheel running or control groups. After 6-8 weeks training, cardiac myocytes were isolated from the apex and base regions of the left ventricle with collagenase–protease dispersion technique. APD were measured with glass micro-electrode at 1 or 10 Hz stimulation. At 1 Hz, the non-selective β agonist Isoproterenol shortened the APD an effect largely reversed by selective β1-AR blocker Atenolol (0.1 μM), but not selective β2-AR antagonist ICI 118,551 (0.1 μM). Wheel running shifted the Isoproterenol dose-response curve (0.01-100 nM) rightward compared to controls, with LogIC50 decreased by exercise-training in both male and female rats by ∼ one log unit. The addition of KATP inhibitor glibenclamide (2 µM) prolonged APD at 10 Hz, with a greater prolongation observed in myocytes from exercise-trained rats. In conclusion, the exercise program down regulated the β1-AR to isoproterenol an adaptation that would contribute to prolonged action potential in non-stressed hearts where the activation of the sympathetic nervous system is low, while the exercise-training induced decline in the APD under energy demanding conditions (e.g. high HR) seems caused at least in part by increased KATP repolarizing current.