IL-1 INHIBITS BETA-ADRENERGIC CONTROL OF CARDIAC CALCIUM CURRENT - ROLE OF L-ARGININE NITRIC-OXIDE PATHWAY

Modulation of the beta-adrenergic control of cardiac L-type Ca2+ curre nt (I-Ca) by human recombinant interleukin-1 beta (IL-1) was examined in adult guinea pig ventricular myocytes using the whole cell voltage- clamp technique. I-Ca was elicited in Cs+-loaded myocytes by depolariz ing pulses from a holding potential of -40 mV. Isoproterenol (0.01 and 1 mu M) exposed to myocytes pretreated with 1 ng/ml IL-1 evoked a sig nificantly smaller increase in I-Ca density compared with control cell s. This IL-1-mediated decrease in beta-responsiveness was usually obse rved with pretreatment periods of >1 h and varied as a function of the L-arginine concentration of the pretreatment medium. In addition, it was prevented by 1) IL-1 receptor antagonist, 2) substituting D-argini ne for L-arginine, or 3) incubating cells with the nitric oxide syntha se inhibitor N-G-monomethyl-L-arginine. Thus the present data illustra te that IL-1 significantly alters the beta-adrenergic control of cardi ac Ca2+ channels by cellular mechanisms that involve the activation of nitric oxide synthase. These mechanisms may play a role in altering v entricular function during cytokine-mediated inflammatory processes af fecting the heart.