Interleukin-1 beta modulates myocardial contraction via dexamethasone sensitive production of nitric oxide

Abstract

Objective: Nitric oxide released by a calcium dependent constitutive NO synthase in endocardial endothelial cells exerts characteristic effects on myocardial contraction. Interleukin 1 beta (IL-1) induces the expression of a different calcium independent NO synthase in several tissues. Activity of the latter enzyme has recently been identified in cardiac myocytes but its functional effects are unknown. The aim of this study was to investigate the effects of IL-1 on contraction of isolated ferret papillary muscle preparations.

Methods: Electrically stimulated preparations were studied in the presence of acebutolol (1 microM), indomethacin (10 microM), and polymyxin (10 micrograms.ml-1). After a 3 h equilibration period, IL-1 (10 ng.ml-1) was added and contractile behaviour monitored over the next 3 h. The following groups were studied: (1) no IL-1; (2) IL-1 alone; (3) IL-1 in the presence of dexamethasone (3 microM); (4) IL-1 in the presence of NG-monomethyl-L-arginine (L-NMMA, 50 microM); (5) IL-1 in the presence of L-NMMA (50 microM) and L-arginine (500 microM). Cyclic GMP content was measured by radioimmunoassay in all preparations.

Results: No significant contractile changes were noted in group 1. In group 2, IL-1 raised myocardial cyclic GMP and induced a progressive abbreviation of isometric twitch, starting 30 min after addition, with a small decrease in peak isometric tension but no change in rate of tension development. These effects were similar to those previously documented for endocardial endothelial NO but were not inhibited by endocardial endothelial denudation. IL-1 effects were inhibited in groups 3 and 4, and partially restored in group 5.

Conclusions: IL-1 activates a dexamethasone sensitive myocardial L-arginine-NO pathway which raises myocardial cyclic GMP and induces marked twitch abbreviation. These effects could potentially lead to cardiac depression by limiting systolic ejection, and may be relevant in conditions where IL-1 levels are increased.