tetrodotoxin and Hypertrophy--Left-Ventricular

Left ventricular hypertrophy (LVH) is frequently associated with clinical atrial arrhythmias, but little is known about how it causes those arrhythmias. Our previous studies have shown that LVH increases the late sodium current (I(Na-L)) that plays an important role in the genesis of ventricular arrhythmias. We hypothesize that LVH may also induce an upregulation of the I(Na-L) in atrial myocytes, leading to atrial electrical abnormalities. The renovascular hypertension model was used to induce LVH in rabbits. Action potential and membrane current recordings were performed in single myocytes. At a pacing cycle length of 2,000 ms, spontaneous phase-2 early afterdepolarizations (EADs) could be recorded from the left atrial myocytes in 10 of 12 LVH rabbits, whereas no EADs could be elicited in right atrial myocytes of LVH rabbits or atrial myocytes from any of the 12 control rabbits. Spontaneous automaticity (SA) from left atrial myocytes was observed in 9 out of 12 LVH rabbits, but none in right atrial myocytes of LVH rabbits or control rabbits, at a pacing rate of 8,000 ms. The left atrial myocytes of LVH rabbits had a significantly higher density of the I(Na-L) compared with those of control rabbits (0.90 +/- 0.12 in LVH vs. 0.50 +/- 0.08 pA/pF in control, n = 8, P < 0.01). Tetrodotoxin, an I(Na-L) blocker, abolished all atrial EADs and SA at 10 microM. Our results demonstrate that LVH induction results in a significant increase of I(Na-L) in the left atrial myocytes that may render these cells susceptible to the genesis of EADs and SA. The I(Na-L) may serve as a potentially useful ionic target for antiarrhythmic drugs for the treatment of atrial arrhythmias in the setting of LVH.

Topics: Action Potentials; Animals; Arrhythmias, Cardiac; Calcium Channel Blockers; Cell Separation; Electrophysiology; Heart Atria; Hypertrophy, Left Ventricular; In Vitro Techniques; Male; Membrane Potentials; Myocytes, Cardiac; Organ Size; Rabbits; Ryanodine; Sodium Channel Blockers; Sodium Channels; Tetrodotoxin

We investigated the effects of pressure overload hypertrophy on inward sodium (I Na) and calcium currents (I Ca) in single left ventricular myocytes to determine whether changes in these current systems could account for the observed prolongation of the action potential. Hypertrophy was induced by pressure overload caused by banding of the abdominal aorta. Whole-cell patch clamp experiments were used to measure tetrodotoxin (TTX)-sensitive inward currents. The main findings were that I Ca density was unchanged whereas I Na density after stepping from -80 to -30 mV was decreased by 30% (-9.0 +/- 1.16 pA pF(-1) in control and -6.31 +/- 0.67 pA pF(-1) in hypertrophy, p < 0.05, n = 6). Steady-state activation/inactivation variables of I Na, determined by using double-pulse protocols, were similar in control and hypertrophied myocytes, whereas the time course of fast inactivation of I Na was slowed (p < 0.05) in hypertrophied myocytes. In addition, action potential clamp experiments were carried out in the absence and presence of TTX under conditions where only Ca2+ was likely to enter the cell via TTX-sensitive channels. We show for the first time that a TTX-sensitive inward current was present during the plateau phase of the action potential in hypertrophied but not control myocytes. The observed decrease in I Na density is likely to abbreviate rather than prolong the action potential. Delayed fast inactivation of Na+ channels was not sustained throughout the voltage pulse and may therefore merely counteract the effect of decreased I Na density so that net Na+ influx remains unaltered. Changes in the fast I Na do not therefore appear to contribute to lengthening of the action potential in this model of hypertrophy. However, the presence of a TTX-sensitive current during the plateau could potentially contribute to the prolongation of the action potential in hypertrophied cardiac muscle.

Topics: Action Potentials; Animals; Calcium Channels; Guinea Pigs; Heart Ventricles; Hypertrophy, Left Ventricular; In Vitro Techniques; Myocytes, Cardiac; Sodium Channels; Tetrodotoxin

The objective was to test the hypothesis that the effects of the sodium channel blockers lignocaine and tetrodotoxin are modified in the presence of hypertension-induced hypertrophy. We describe the effects of lignocaine and tetrodotoxin on the action potentials and contractions of left ventricles isolated from 6-month-old Wistar Kyoto (WKY) rats and spontaneously hypertensive rats (SHRs). The upstroke velocity, amplitude, and overshoot of the action potential were reduced; action potentials were prolonged; and the contractions were reduced on the hypertrophied left ventricles of the SHRs. Lignocaine and tetrodotoxin reduced the upstroke velocity, amplitude, and overshoot and prolonged the left ventricular action potentials. These effects of lignocaine and tetrodotoxin on the SHR were less than those on the WKY left ventricle, possibly because the action potential was already modified by hypertrophy. Lignocaine also reduced the left ventricular contractions and the concentrations producing this reduction were lower for the hypertrophied than those for the normal left ventricle. Tetrodotoxin at 3 x 10(-6)-10(-5) M caused similar attenuation of the WKY and SHR left ventricle contractions. Our study shows that the effects of lignocaine on contraction are enhanced in the hypertrophied left ventricle of the SHR, which suggests that the binding is increased or the access of lignocaine to the receptor is enhanced in hypertrophy. In contrast, the effects of tetrodotoxin on contractions are similar, and thus the binding or access of tetrodotoxin to the receptor is not altered in the hypertrophied left ventricle of the SHR.

Topics: Action Potentials; Animals; Anti-Arrhythmia Agents; Hypertension; Hypertrophy, Left Ventricular; Lidocaine; Myocardial Contraction; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Sodium Channels; Tetrodotoxin; Ventricular Function, Left

In this study we examined the existence of T-type Ca(2+) current in ventricular myocytes isolated from rats with pressure-overload hypertrophy. The whole-cell clamp technique was used to record Ca(2+) currents in enzymatically dissociated ventricular cells. T- and L-type Ca(2+) currents were separated by applying voltage steps to different test potentials from a holding potential of -80 mV and -50 mV. T-type Ca(2+) current was defined as the difference between the currents from the two holding potentials. Ventricular myocytes from sham-operated rats showed only L-type Ca(2+) current (maximal density -13.9+/-1.3 pA/pF n=17), whereas ventricular myocytes isolated from rats with aortic stenosis showed both L- and T-type Ca(2+) currents. The average values of T- and L-type Ca(2+) current density were -4.8+/-0.4 pA/pF and -12.4+/-0.9 pA/pF (n=32), respectively. T-type Ca(2+) current was distinguished from L-type Ca(2+) current by its voltage dependence, its kinetics and by its strong blockade by nickel 50 microM. In conclusion, we have demonstrated that hypertrophied ventricular rat cells express T-type Ca(2+) channels and this finding strongly supports a role for this channel in regulating growth processes in cardiac tissue.

Topics: Animals; Aortic Valve Stenosis; Calcium Channels; Calcium Channels, L-Type; Calcium Channels, T-Type; Cells, Cultured; Heart; Heart Ventricles; Hypertrophy, Left Ventricular; Male; Membrane Potentials; Myocardium; Nickel; Patch-Clamp Techniques; Rats; Rats, Sprague-Dawley; Tetrodotoxin