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+ c urrent (I-Ca) by human recombinant interleukin-1 beta (IL-1) was exami ned in guinea pig ventricular myocytes using the whole cell voltage-cl amp technique. I-Ca was evoked in Cs+-loaded myocytes by depolarizing pulses from a holding potential of -40 mV. In the presence of an acidi c external solution (pH 5.8), the response of I-Ca to isoproterenol (I so; 0.01 and 1 mu M) was markedly decreased compared with control myoc ytes 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 signif icantly increased compared with untreated cells. Despite this effect o f IL-1, maximum I-Ca density with 0.01 and I mu M Iso was still 51 and 58%, respectively, less than that measured at pH 7.4. The enhanced be ta-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 prote in kinase C, phorbol 12-myristate 13-acetate, did not mimic the effect s 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 p rotein kinase C. These cellular mechanisms may play a role in altering ventricular function during cytokine-mediated inflammatory processes that are initiated by myocardial ischemia.