Cardiodepressant Effects of Interferon-γand Endotoxin Reversed by Inhibition of NO Synthase 2 in Rat Myocardium

Endogenous nitric oxide (NO) signalling pathways within the myocardium depress myocardial contractile function in septic shock and some cardiomyopathies. We have explored the role of NO synthases (NOSs) in mediating the cardiodepressant actions of interferon-γ(IFN-γ) and lipopolysaccaride (LPS) in rat papillary muscle. Muscles from the right ventricle were electrically stimulated (0.2 Hz) at 30°C and isometric contraction monitored. Exposure to IFN-γand LPS for 15 hin vitrosignificantly decreased the peak tension (PT for IFN-γ+LPS, from 0.13±0.03 to 0.07±0.02 g) and rate of tension development (dT/dtfor IFN-γ+LPS, from 1.78±0.36 to 1.17±0.28 g/s) compared to untreated controls, and this was prevented by dexamethasone (1μ ) and partly reversed by a non-specific NOS inhibitor, NG-nitro- -arginine (NOLA, 30μ ). Likewise, the maximum inotropic response of the papillary muscles to isoprenaline (0.001–10μ ) decreased significantly after 15 h treatment with IFN-γand LPS (PT from 83±18 to 28±6%; +dT/dtfrom 83±12 to 31±7%; −dT/dtfrom 83±12 to 38±6%). Again, the depressant effects of IFN-γand LPS on inotropic responsiveness to isoprenaline were completely prevented by pretreatment with dexamethasone (1μ ), by a specific inhibitor of NOS2, mercaptoethylguanidine (MEG, 30μ ) and by NOLA. Whereas dexamethasone and NOLA protected against the attenuation of baseline contractions induced by LPS and IFN-γ, MEG did not. Western blot analysis of cardiac myocytes showed that there was no constitutive expression of NOS2, but IFN-γand LPS induced expression of NOS2, and this was prevented by dexamethasone. Thus IFN-γ, in the presence of LPS, reduced papillary muscle contraction and decreased responsiveness toβ-adrenoceptor stimulation through induction of NOS2 in the muscle. Increased NO production may contribute to the cardiac depression during septic shock and anti-cancer therapy with cytokines, and perhaps in heart failure.