Proinflammatory impact of norepinephrine in cardiomyocytes: increased interleukin-6 production, which is suppressed by carvedilol

In severe heart failure elevated plasma/serum levels of both norepinephrine and proinflammatory cytokines have been reported. Several hypotheses have been proposed to explain, why and how cytokine release is triggered in heart failure, one possible player being the neurohumoral dysbalance, while other studies suggest an overspill of cytokines from the failing heart itself. Here we report that norepinephrine in vitro stimulates the release of interleukin-6 (IL-6) from cardiomyocytes (CM), in keeping with a previously unrecognized direct proinflammatory effect of norepinephrine on CM.

Methods

Spontaneously heating neonatal rat CM were incubated for 8–24 h in serum-free medium supplemented with norepinephrine (0.1–1 μM) or without additive, in the absence or presence of carvedilol (10 μM). In some experiments, an inhibitor of phosphodiesterase was simultaneously added. The adrenergic response was documented by monitoring beating rate. Inflammation was assessed by measuring the IL-6 (bioassay) content of culture supernatants.

Results

In numerous experiments, norepinephrine weakly, but reproducible enhanced IL-6 release from cultured CM, resulting in about a doubling of the IL-6 content of culture supernatants after 24 h. The IL-6 release was more pronounced by simultaneous administration of an inhibitor of phosphodiesterase, but suppressed in the presence of carvedilol.

Conclusion

The release of proinflammatory cytokines in heart failure may be directly linked to the enhanced sympathetic tone.