Metabolic Inhibition Activates a Non-selective Current Through Connexin Hemichannels in Isolated Ventricular Myocytes

Intracellular Na+accumulation and K+loss play important roles in the pathogenesis of arrhythmias and injury in the ischemic heart. We investigated the role of metabolically sensitive connexin hemichannels as a potential route for Na+influx and K+efflux during ischemia, using dye uptake and electrophysiological measurements to assay hemichannel activity in isolated rabbit ventricular myocytes. Consistent with the known size selectivity of connexin hemichannels, 50% of myocytes exposed to either low extracellular Ca2+(an established method for opening connexin hemichannels) or to metabolic inhibitors (a recently described method for opening hemichannels) accumulated fluorescent dyes with <1000 MW (propidium iodide and calcein), but excluded a larger dye with 1500–3000 MW (dextran–rhodamine). Using the whole cell patch clamp technique, we found that metabolic inhibitors activated a non-selective current permeant to both small and large cations, and blocked by La3+, similar to the properties of connexin 43 when overexpressed in human embryonic kidney (HEK) cells. These findings indicate that isolated cardiac myocytes endogenously express metabolically-sensitive connexin hemichannels. If activated during ischemia, these hemichannels could contribute significantly to altered ionic fluxes promoting arrhythmias and myocardial injury.