THE PACEMAKER CURRENT I-F IN SINGLE HUMAN ATRIAL MYOCYTES AND THE EFFECT OF BETA-ADRENOCEPTOR AND A(1)-ADENOSINE RECEPTOR STIMULATION

1 We used single human atrial myocytes to study I-f occurrence, proper ties and pharmacological modulation. Cells were obtained by chunk enzy matic digestion from samples of right atrial appendages of patients un dergoing corrective cardiac surgery. 2 Patch-clamped cells in the whol e-cell configuration were superfused with a modified Tyrode solution t o reduce contamination by interfering currents and to amplify I-f. The average cell membrane capacitance was 85.06 +/- 2.41 pF (n = 531). Da ta were consistent with the geometrical dimensions of the cells (lengt h 94.2 +/- 1.89 mu m, width 17.9 +/- 0.42 mu m, n=126). 3 When hyperpo larizing to -120 mV from a holding potential of -40 mV, 252 of 306 tes ted cells (82%) expressed a hyperpolarization-activated inward current (I-f density =3.77+0.25 pA pF(-1)); the current was considered to be present in a given cell if its density at -120 mV was larger than 0.5 pA pF(-1). 4 Current activation was sigmoidal and fitted a Boltzmann m odel; the average activation curve (n=25) showed a maximum current amp litude of 205.97 +/- 19.94 pA, corresponding to 3.87 +/- 0.63 pA pF(-1 ), voltage of half-maximal activation (V-1/2,) at -86.68 +/- 2.19 mV a nd a slope of -11.39 +/- 0.69 mV. The reversal potential of I-f measur ed by tail-current analysis was -13.07 +/- 1.92 mV (n=6). The addition of CsCl (5 mM) fully and reversibly blocked the current. 5 In the pre sence of the beta-adrenoceptor agonist isoprenaline (Iso, 1 mu M), V-1 /2 was significantly shifted toward less negative potentials by 6.06 /- 1.96 mV (n=16, P=0.0039). The selective A(1)-adenosine receptor ago nist cyclopentyladenosine (CPA, 1 mu M) caused a statistically signifi cant shift of V-1/2 toward more negative potentials with respect to th e control curve, both in the absence (-7.37 +/- 1.83 mV, P=0.0005, n=1 1) and in the presence of 1 mu M Iso (-4.97 +/- 1.78, P=0.031, n=6). 6 These results demonstrate that a current with the properties of I-f d escribed in cardiac primary and secondary pacemakers occurs in the maj ority of human atrial cells. While the pathophysiological relevance of I-f in human atrial tissue remains to be defined, our data clearly sh ow that it is modulated through stimulation of beta-adrenoceptors and A(1)-adenosine receptors.