Effects of tumour necrosis factor-alpha on left ventricular function in the rat isolated perfused heart: possible mechanisms for a decline in cardiacfunction

1 The cardiac depressant actions of TNF were investigated in the isolated p erfused rat heart under constant how (10 ml min(-1)) and constant pressure (70 mmHg) conditions, using a recirculating (50 ml) mode of perfusion. 2 Under constant flow conditions TNF (20 ng ml(-1)) caused an early (<25 mi n) decrease in left ventricular developed pressure (LVDP), which was mainta ined for 90 min (LVDP after 90 min: control vs TNF; 110+/-4 vs 82+/-10 mmHg , P<0.01). 3 The depression in cardiac function seen with TNF under constant flow cond itions, was blocked by the ceramidase inhibitor N-oleoylethanolamine (NOE), 1 mu M, (LVDP after 90 min: TNF vs TNF with NOE; 82+/-10 vs 111+/-5 mmHg, P<0.05). 4 In hearts perfused at constant pressure, TNF caused a decrease in coronar y flow rate (change in Bow 20 min after TNF: control vs TNF; -3.0+/-0.9 vs -8.7+/-1.2 ml min(-1), P<0.01). This was paralleled by a negative inotropic effect (change in LVDP 20 min after TNF: control vs TNF; -17+/-7 vs -46+/- 6 mmHg, P<0.01). The decline in function was more rapid and more severe tha n that seen under conditions of constant flow. 5 These data indicate that cardiac function can be disrupted by TNF on two levels, firstly via a direct, ceramidase dependant negative inotropic effec t, and secondly via an indirect coronary vasoconstriction.