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+ channels might contribute to the antiarrhythmic efficacy of Gd3+. Gd3+ inhibited Na+ current ( I Na) 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 I Na more positive and reduced the maximum conductance. Gd3+ (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, Gd3+ increased I Naunder certain conditions. With membrane potential held at −75 mV, Gd3+ 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 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 I Na blocker near threshold potential, and inhibition of I Na by Gd3+ is likely to contribute to suppression of stretch-induced arrhythmias.