Hypertrophy Decreases Cardiac KATPChannel Responsiveness to Exogenous and Locally Generated (Glycolytic) ATP

This study tests the hypothesis that glycolytic regulation of KATPchannel activity is altered in myocardial hypertrophy. Left ventricular (LV) subendocardial myocytes were isolated from cats with normal or left ventricular hypertrophied hearts (LVH). Saponin-permeabilized open cell-attached patch configurations of normal and LVH cells were exposed to an exogenous ATP consuming system containing hexokinase and 2-deoxyglucose. Phosphoenol pyruvate (PEP, substrate for the last ATP producing step in glycolysis) was applied extracellularly; ADP was present. In both cell types, KATPchannels were activated in the absence of PEP, inhibited when PEP was added and activated again when PEP was removed, indicating the cells retained metabolic integrity and generated ATP in the proximity of their KATPchannels. Single channel conductance in the absence of PEP was similar (70 pS, normal; 66 pS, LVH). However, LVH KATPchannels showed enhanced activity (P0=0.50±0.03); normal (0.41±0.03) in PEP absence (P<0.05). PEP responsiveness was reduced in LVH, with IC50, PEP increased to 23μ ; (11μ normal). Lactate failed to activate KATPchannels in both cell types. The concentration-P0response curves obtained during exposure of open cells to exogenous ATP also revealed reduced responsiveness to ATP of LVH KATPchannels (IC50,ATP=283μ LVH; 93μ normal). Our data indicate myocardial hypertrophy increases the maximal activity of KATPchannels in the absence of ATP and reduces their responsiveness to ATP, including locally generated glycolytic ATP. These alterations in metabolic regulation of myocardial electrophysiology may contribute to diversity of action potential shortening in hypertrophied hearts during acute ischemia.