CARDIODEPRESSANT EFFECTS OF INTERFERON-GAMMA AND 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 card iomyopathies. We have explored the role of NO synthases (NOSs) in medi ating the cardiodepressant actions of interferon-gamma (IFN-gamma) and lipopolysaccaride LPS) in rat papillary muscle, Muscles from the righ t ventricle were electrically stimulated (0.2 Hz) at 30 degrees C and isometric contraction monitored, Exposure to IFN-gamma and LPS for 15 h in vitro significantly decreased the peak tension (PT for IFN-gamma +LPS, from 0.13 +/- 0.03 to 0.07 +/- 0.02 g) and rate of tension devel opment (dT/dt for IFN-gamma +LPS, from 1.78 +/- 0.36 to 1.17 +/- 0.2 8 g/s) compared to untreated controls, and this was prevented by dexame thasone (1 mu M) and partly reversed by a non-specific NOS inhibitor, N-G-nitro-L-arginine (NOLA, 30 mu M). Likewise, the maximum inotropic response of the papillary muscles to isoprenaline (0.001-10 mu M) decr eased significantly after 15 h treatment with IFN-gamma and LPS (PT fr om 83 +/- 18 to 28 +/- 6%; +dT/dt from 83 +/- 12 to 31 +/- 7%; -dT/dt from 83 +/- 12 to 38 +/- 6%), Again, the depressant effects of IFN-gam ma and LPS on inotropic responsiveness to isoprenaline were completely prevented by pretreatment with dexamethasone (1 mu M), by a specific inhibitor of NOS2, mercaptoethylguanidine (MEG, 30 mu M) and by NOLA. Whereas dexamethasone and NOLA protected against the attenuation of ba seline contractions induced by LPS and IFN-gamma, MEG did not. Western blot analysis of cardiac myocytes showed that there was no constituti ve expression of NOS2, but IFN-gamma and LPS induced expression of NOS 2, and this was prevented by dexamethasone. Thus IFN-gamma, in the pre sence of LPS, reduced papillary muscle contraction and decreased respo nsiveness to beta-adrenoceptor stimulation through induction of NOS2 i n the muscle. Increased NO production may contribute to the cardiac de pression during septic shock and anti-cancer therapy with cytokines, a nd perhaps in heart failure. (C) 1998 Academic Press Limited.