Modulation of cardiac Na+ current by gadolinium, a blocker of stretch-induced arrhythmias

Department of Physiology, Medical College of Virginia, Virginia Commonwealth University, Richmond, Virginia 23298-0551 Gd 3+ blocks stretch-activated channels and suppresses stretch-induced arrhythmias. We used whole cell voltage clamp to examine whether effects on Na + channels might contribute to the antiarrhythmic efficacy of Gd 3+ . Gd 3+ inhibited Na + current ( I Na ) in rabbit ventricle (IC 50 = 48 µM at 35 mV, holding potential 120 mV), and block increased at more negative test potentials. Gd 3+ made the threshold for I Na more positive and reduced the maximum conductance. Gd 3+ (50 µM) shifted the midpoints for activation and inactivation of I Na 7.9 and 5.7 mV positive but did not alter the slope factor for either relationship. Activation and inactivation kinetics were slowed in a manner that could not be explained solely by altered surface potential. Paradoxically, Gd 3+ increased I Na under certain conditions. With membrane potential held at 75 mV, Gd 3+ still shifted threshold for activation positive, but I Na increased positive to 40 mV, causing the current-voltage curves to cross over. When availability initially was low, increased availability induced by Gd 3+ dominated the response at test potentials positive to 40 mV. The results indicate that Gd 3+ has complex effects on cardiac Na + channels. Independent of holding potential, Gd 3+ is a potent I Na blocker near threshold potential, and inhibition of I Na by Gd 3+ is likely to contribute to suppression of stretch-induced arrhythmias. lanthanides; mechanoelectrical feedback; mechanosensitive channels