Does recombinant human interleukin-11 exert direct electrophysiologic effects on single human atrial myocytes?
Recombinant human interleukin-11 (rhIL-11) treatment given to alleviate side effects of cancer therapy is associated with an increased susceptibility to atrial arrhythmias in elderly patients. To elucidate the mechanism underlying this action, we investigated the direct electrophysiologic effect of rhIL-11 on single human atrial myocytes (HuAM) using the patch-clamp technique. Action potentials (AP) at different driving rates were recorded in the perforated-patch configuration, and L-type calcium current (I(Ca,L)), outward potassium currents (I(to) and I(K)), and the hyperpolarization-activated pacemaker current If were measured in the disrupted whole-cell configuration. At therapeutic concentrations (i.e., 10-100 ng/ml), rhIL-11 did not modify AP parameters and cycle-length dependence of AP duration. I(Ca,L) (measured at 0 mV) was 370 +/- 45 pA in control and 379 +/- 48 pA and 368 +/- 42 pA in the presence of 10 and 50 ng/ml rhIL-11, respectively (p = NS). The amplitude and activation of I(to) were not modified by rhIL-11 (i.e., I(to) was at +60 mV: 2.1 +/- 0.2 nA in control vs. 1.9 +/- 0.2 nA and 2.1 +/- 0.2 nA in the presence of 10 and 50 ng/ml rhIL-11, respectively, p = NS). Similarly, late currents measured at the end of the pulse were unchanged in the presence of 10 or 50 ng/ml of rhIL-11. If activation was not modified by rhIL-11: maximal current was 173 +/- 34 pA in control and 159 +/- 35 pA and 117 +/- 14 pA in the presence of 10 and 50 ng/ml of rhIL-11, respectively; midpoint activation was -99 +/- 3 mV in control and -98 +/- 4 mV and -94 +/- 2 mV in the presence of 10 and 50 ng/ml of rhIL-11, respectively (p = NS). Thus, it is unlikely that direct alterations of membrane potential and currents of HuAM caused by rhIL-11 are the basis for the genesis of atrial arrhythmias observed in patients treated with this agent.
Sartiani
Laura
L
Center of Molecular Medicine (CIMMBA) and Department of Preclinical and Clinical Pharmacology, University of Firenze, Italy.
De Paoli
Petra
P
Lonardo
Giuseppe
G
Pino
Roberto
R
Conti
Andrea A
AA
Cerbai
Elisabetta
E
Pelleg
Amir
A
Belardinelli
Luiz
L
Mugelli
Alessandro
A
D000200:Action Potentials / Q000187:drug effects; D000368:Aged; D001145:Arrhythmias, Cardiac / Q000139:chemically induced* / Q000378:metabolism / Q000503:physiopathology; D020517:Atrial Appendage / Q000378:metabolism; D002478:Cells, Cultured; D005260:Female; D006801:Humans; D017370:Interleukin-11 / Q000009:adverse effects* / Q000494:pharmacology; D007473:Ion Channels / Q000187:drug effects / Q000378:metabolism; D008297:Male; D009206:Myocardium / Q000166:cytology / Q000378:metabolism; D018408:Patch-Clamp Techniques; D011994:Recombinant Proteins / Q000009:adverse effects / Q000494:pharmacology
D017370:Interleukin-11; D007473:Ion Channels; D011994:Recombinant Proteins