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

Abstract

Gd3+ blocks stretch-activated channels and suppresses stretch-induced arrhythmias. We used whole cell voltage clamp to examine whether effects on Na+ channel might contribute to the antiarrhythmic efficacy of Gd3+ Gd3+ inhibited Na′ current (INa) in rabbit ventricle (IC50 = 48 μM at -35 mV, holding potential -120 mV), and block increased at more negative test potentials. Gd3+ made the threshold for INa more positive and reduced the maximum con tuctance. Gd3+ (50 μM) shifted the midpoints for activation and inactivation of INa 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, Gd3+ increased INa under certain conditions. With membrane potential held at -75 mV, Gd3+ still shifted threshold for activation positive, but INa increased positive to -40 mV, causing the current-voltage curves to cross over. When availability initially was low, increased availability induced by Gd3+ dominated the response at test potentials positive to -40 mV. The results indicate that Gd3+ has complex effects on cardiac Na+ channels. Independent of holding potential, Gd3+ is a potent INa blocker near threshold potential, and inhibition of INa by Gd3+ is likely to contribute to suppression of stretch-induced arrhythmias.