Interleukin-1 enhances beta-responsiveness of cardiac L-type calcium current suppressed by acidosis.

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.