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Interleukin-1 enhances beta-responsiveness of cardiac L-type calcium current suppressed by acidosis
1Department of Physiology, University of Nebraska College of Medicine, Omaha 68189-4575.
Insights
Interleukin-1 beta (IL-1) partially restores beta-adrenergic control of cardiac calcium channels under acidic conditions. This effect involves enhanced sodium-hydrogen exchange via protein kinase C, impacting ventricular function during inflammation.
Area of Science:
- Cardiology
- Molecular Biology
- Cell Physiology
Background:
- Acidosis impairs beta-adrenergic control of cardiac L-type Ca2+ current (ICa).
- Interleukin-1 beta (IL-1) is a cytokine involved in inflammatory processes.
Purpose of the Study:
- To investigate the effect of IL-1 on the beta-adrenergic modulation of cardiac ICa under acidic conditions.
- To elucidate the cellular mechanisms underlying IL-1's action.
Main Methods:
- Whole-cell voltage-clamp technique in guinea pig ventricular myocytes.
- Application of acidic external solution (pH 5.8) and isoproterenol (Iso).
- Treatment with IL-1, amiloride, protein kinase C inhibitors, and a PKC activator.
Main Results:
- Acidosis significantly reduced isoproterenol-stimulated ICa.
- IL-1 pretreatment partially restored beta-adrenergic responsiveness in acidic conditions.
- IL-1's effect was abolished by amiloride and protein kinase C inhibitors, but not mimicked by a PKC activator.
Conclusions:
- IL-1 partially restores beta-adrenergic control of cardiac Ca2+ channels suppressed by acidosis.
- IL-1 likely enhances Na+/H+ exchange via a protein kinase C-dependent pathway.
- These mechanisms may influence ventricular function during inflammatory conditions like myocardial ischemia.
Abstract:
Modulation of the beta-adrenergic control of the cardiac L-type Ca2+ current (ICa) by human recombinant interleukin-1 beta (IL-1) was examined in guinea pig ventricular myocytes using the whole cell voltage-clamp technique. ICa was evoked in Cs(+)-loaded myocytes by depolarizing pulses from a holding potential of -40 mV. In the presence of an acidic external solution (pH 5.8), the response of ICa to isoproterenol (Iso; 0.01 and 1 microM) was markedly decreased compared with control myocytes studied at pH 7.4. However, when cells were pretreated with 1 ng/ml IL-1 and then exposed to acid media, beta-responsiveness was significantly increased compared with untreated cells. Despite this effect of IL-1, maximum ICa density with 0.01 and 1 microM Iso was still 51 and 58%, respectively, less than that measured at pH 7.4. The enhanced beta-responsiveness produced by IL-1 was eliminated by adding amiloride to block Na+/H+ exchange or protein kinase C inhibitors staurosporine (10 nM) and calphostin C (50 nM). However, a direct activator of protein kinase C, phorbol 12-myristate 13-acetate, did not mimic the effects of the cytokine. These data demonstrate that IL-1 partially restores the beta-adrenergic control of cardiac Ca2+ channels suppressed under acidic conditions. Moreover, they suggest that IL-1 acts by enhancing Na+/H+ exchange through a second messenger pathway that may involve protein kinase C. These cellular mechanisms may play a role in altering ventricular function during cytokine-mediated inflammatory processes that are initiated by myocardial ischemia.