The pacemaker current I_f in single human atrial myocytes and the effect of β‐adrenoceptor and A₁‐adenosine receptor stimulation

Abstract

1 We used single human atrial myocytes to study I f occurrence, properties and pharmacological modulation. Cells were obtained by chunk enzymatic digestion from samples of right atrial appendages of patients undergoing corrective cardiac surgery. 2 Patch-clamped cells in the whole-cell con®guration were superfused with a modi®ed Tyrode solution to reduce contamination by interfering currents and to amplify I f . The average cell membrane capacitance was 85.06+2.41 pF (n=531). Data were consistent with the geometrical dimensions of the cells (length 94.2+1.89 mm, width 17.9+0.42 mm, n=126). 3 When hyperpolarizing to 7120 mV from a holding potential of 740 mV, 252 of 306 tested cells (82%) expressed a hyperpolarization-activated inward current (I f density =3.77+0.25 pA pF 71 ); the current was considered to be present in a given cell if its density at 7120 mV was larger than 0.5 pA pF 71 . 4 Current activation was sigmoidal and ®tted a Boltzmann model; the average activation curve (n=25) showed a maximum current amplitude of 205.97+19.94 pA, corresponding to 3.87+0.63 pA pF 71 , voltage of half-maximal activation (V 1/2 ) at 786.68+2.19 mV and a slope of 711.39+0.69 mV. The reversal potential of I f measured by tail-current analysis was 713.07+1.92 mV (n=6). The addition of CsCl (5 mM) fully and reversibly blocked the current. 5 In the presence of the b-adrenoceptor agonist isoprenaline (Iso, 1 mM), V 1/2 was signi®cantly shifted toward less negative potentials by 6.06+1.96 mV (n=16, P=0.0039). The selective A 1 -adenosine receptor agonist cyclopentyladenosine (CPA, 1 mM) caused a statistically signi®cant shift of V 1/2 toward more negative potentials with respect to the control curve, both in the absence (77.37+1.83 mV, P=0.0005, n=11) and in the presence of 1 mM Iso (74.97+1.78, P=0.031, n=6). 6 These results demonstrate that a current with the properties of I f described in cardiac primary and secondary pacemakers occurs in the majority of human atrial cells. While the pathophysiological relevance of I f in human atrial tissue remains to be de®ned, our data clearly show that it is modulated through stimulation of b-adrenoceptors and A 1 -adenosine receptors.

Transverse tubules are a common feature in large mammalian atrial myocytes including human

“…These cells are extremely small compared with cell diameters for sheep, horse, cow, and human cells in the present study. Other studies (36,37) have measured dimensions of human atrial myocytes from the right atrial appendage reporting values of 94.2 or 81 m length and 17.9 or 17 m width, which are in good agreement with a diameter of 17.3 Ϯ 1.2 m measured in the current study. The small cells in the study by Legato (27), obtained from an unspecified atrial region, may form part of the specialized sinoatrial node, and since we have shown a correlation between cell width and the presence of t tubules, perhaps in these small cells t tubules may not be needed.…”

Single-Channel Properties Support a Potential Contribution of Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels and I f to Cardiac Arrhythmias

“…This indicated that native I f activates well within the diastolic voltage range of human atrial myocardium, which has been controversial on the basis of whole-cell measurements in recent years. 8,26 Thus, I f indeed might contribute to arrhythmogenesis in working myocardium.…”

HCN2 Overexpression in Newborn and Adult Ventricular Myocytes

“…However, I f is present in both automatic 1 and nonautomatic [2][3][4][5][6] regions of the heart, and the threshold voltage varies widely among cardiac regions, being least negative in sinus node (Ϫ40 mV in rabbit 7 ) and most negative in ventricle (Ϫ108 mV or more negative 5,8,9 ). Interestingly, I f activates at less negative voltages in newborn ventricle (Ϫ70 mV in rat 8,10 ).…”