Modulation of the hyperpolarization-activated inward current (I-f) by antiarrhythmic agents in isolated human atrial myocytes

The hyperpolarization-activated inward current (I-f) has been discussed to contribute to arrhythmias in human atrial myocardium. I-f was found to be i ncreased by beta-adrenergic stimulation. In the present study, we evaluate the modulation of I-f by carbachol, adenosine and by class Ic, III and IV a ntiarrhythmic drugs in isolated human atrial myocytes. The whole-cell patch-clamp technique was used to record If in isolated myoc ytes from 18 human right atrial appendages. A typical time- and voltage-dep endent hyperpolarization-activated inward current could be recorded in all cells investigated (n=56). Mean current density recorded at -130 mV was -2. 8+/-1.2 pApF(-1). Both adenosine and carbachol were found to directly inhib it I-f in human atrial myocytes by shifting the activation curves to more n egative potentials. Adenosine 10(-5) mol/l shifted the potential of half-ma ximal activation by -5.9+/-0.4 mV from -99.4+/-0.6 mV to -105.3+/-0.4 mV (n =8; P<0.05), and carbachol 10-5 mol/l by -5.7+/-0.5 mV from -99.2+/-0.5 mV to -104.9+/-0.6 mV (n=6; P<0.05). The concentration-response curve of adeno sine calculated by a Hill function yielded a half-maximal effect of adenosi ne (EC50) at a concentration of 3.6+/-0.5 mu mol/l, a maximal shift of -6.5 +/-0.3 mV, and a Hill coefficient (h) of 2.40. We did not observe any effec t of flecainide (10(-5) mol/l; n=8), sotalol (10(-5) mol/l; n=6), amiodaron e (10(-5) mol/l; n=6) or verapamil (10(-5) mol/l; n=5) on I-f in human atri al myocytes. However, propafenone (10(-5) mol/l) was found to reversibly re duce I-f current size (9/13 cells) by shifting the activation curve by -5.2 +/-0.4 mV (P<0.05). In human atria adenosine- and muscarinic receptor stimu lation might function as endogenous protective mechanisms inhibiting the in itiation of ectopic tachycardia by reducing I-f current size. Propafenone m ay be more effective in some patients with atrial tachycardias that do not respond to other class Ic, III and IV antiarrhythmic drugs. However, it has yet to be defined whether these agents suppress atrial tachycardias via an inhibition of I-f in vivo.