Norepinephrine-induced expression of cytokines in isolated biventricular working rat hearts

The norepinephrine (NE)-induced hypertrophy of the left ventricle (LV) in the rat is associated with increased interleukin (IL)-6 and IL-1β expression. In the present study, a newly established model of isolated biventricular working rat heart was used to examine whether NE may directly induce cytokine mRNA expression in a preparation devoid of other circulating hormonal and humoral factors. Representative hemodynamic parameters and the expression of various cytokines of the isolated biventricular working heart (IBWH) were compared with the respective in vivo results. Systolic pressure (SP) of the right ventricle (RVSP) was higher in the IBWH than in the intact anesthetized rat (42.9 ± 1.89 vs. 32.3 ± 1.06). However, heart rate (HR), LVSP and the maximal rate of pressure development of LV (LV dP/dtmax) were lower. After NE infusion (30 nM), SP and dP/dtmax were increased by 30 and 90%, respectively, in both ventricles. In vivo, the ventricles showed a different response to NE (0.1 mg/kg·h): LVSP increased by 15%, RVSP and RV dP/dtmax was doubled, LV dP/dtmax was tripled. The analysis of cytokine mRNA expression with the RNase protection assay revealed that in vivo IL-6 and IL-1β were increased between 4 and 12 h 80- and 12-fold, respectively, while there was weak expression under control conditions. In the IBWH IL-1α, IL-1β, IL-6 and tumor necrosis factor (TNF)α were increased already during control perfusion. The increase of these stress-activated cytokines indicates that the isolation and perfusion procedure may exert a stress on the heart. NE induced an additional time-dependent increase of IL-6 mRNA after 1 h of infusion. Thus, NE has a direct effect on the cardiac IL-6 expression, which occurred earlier in the in vitro preparation than in the rat heart in vivo.