ENDOTOXIN AND CYTOKINES INDUCE DIRECT CARDIODEPRESSIVE EFFECTS IN MAMMALIAN CARDIOMYOCYTES VIA INDUCTION OF NITRIC-OXIDE SYNTHASE

In patients with septic shock or inflammatory cardiac diseases like my ocarditis myocardial contractility is depressed. These patients have e levated circulating levels of bacterial endotoxins (lipopolysaccharide s, LPS) and pro-inflammatory cytokines like interleukin-1 beta (IL-alp ha 1 beta) or tumor necrosis factor-alpha (TNF-alpha). It is not clear , whether LPS and/or cytokines have direct inotropic effects on cardio myocytes and whether these effects are mediated via the L-arginine-nit ric oxide synthase (NOS) pathway as demonstrated in vascular smooth mu scle cells. Therefore, we examined the direct effects of LPS, IL-1 bet a and TNF-alpha on contractility and cGMP content in isolated guinea-p ig ventricular cardiomyocytes. Furthermore, the influence of the NOS i nhibitor N-G-nitro-L-arginine (L-NNA) and dexamethasone on these effec ts was studied as well as inducible NOS (iNOS) protein expression. LPS (1000 ng/ml), IL-1 beta (25 ng/ml) and TNF-alpha (100 ng/ml) decrease d contractility by 48%, 55% and 65% and augmented cGMP content by 135% , 88% or 70% after longterm treatment (18 h) in cardiomyocytes, withou t altering contractility or cGMP content after short-term treatment (3 0 min). These effects were blocked by L-NNA (100 mu M) and dexamethaso ne (3 mu M). Furthermore iNOS protein was expressed in LPS- and cytoki ne-treated cardiomyocytes. These findings demonstrate that LPS, IL-1 b eta and TNF-alpha have direct negative inotropic effects on cardiomyoc ytes, which are accompanied by an increase in cGMP content. These effe cts are mediated via de novo synthesis of a myocardial iNOS. The direc t negative inotropic effects of endotoxins and cytokines on cardiomyoc ytes may in part contribute to the contractile dysfunction observed in patients with septic shock or inflammatory cardiac diseases. (C) 1996 Academic Press Limited