Interleukin-1 beta and tumor necrosis factor alpha inhibit the release of [H-3]-noradrenaline from isolated human atrial appendages

In the present study, we have investigated the ability of human recombinant interleukin-1 beta (hIL-1 beta) and human recombinant tumor necrosis factor-alpha (hTNF-alpha) to modulate the stimulation-induced (S-I) outflow of [H-3]-noradrenaline ([H-3]-NA) from isolated superfused human atria. Pieces of human right atrial appendages were excised during routine cardiac surgery. Tissues were incubated with [H-3]-NA (0.2 mu mol/l) for 30 min at 37 degrees C, then inserted in a Brandel suprafusion system where the radio-activity was washed for 75 min with a Krebs-Henseleit solution at a rate of 0.4 ml/min. Thereafter, the effluent was collected for the remainder of the protocol during which two trains of electrical stimulation (50 mA intensity, 5 Hz frequency, 60 s duration, 2 ms pulses) were delivered at 10 min and 45 min (short protocol) or 85 min (long protocol). The effect of drugs on the S-I outflow of [H-3]-NA was determined by adding drugs 20 min (short protocol) or 60 min (long protocol) before the second stimulation. Experiments were carried out in the continuous presence of desipramine (1 mu mol/l) to prevent neuronal NA reuptake. The results showed that in human atrium, hIL-1 beta (3 ng/ml) and hTNF-alpha (0.5 mg/ml) significantly inhibited the S-I release of [H-3]-NA. The inhibitory effect of hIL-1 beta was blocked by human recombinant IL-1 receptor antagonist (50 mg/ml), and by the cyclooxygenase inhibitor, diclofenac (1 mu mol/l), suggesting that hIL-beta inhibited NA release through the formation of prostaglandins. The ability of hIL-1 beta and hTNF-alpha to inhibit NA release suggest that mediators of the immune system produced locally may modulate the activity of the sympathetic nervous system in human atrial appendages.