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

Abstract

1 The cardiac depressant actions of TNF were investigated in the isolated perfused rat heart under constant flow (10 ml min~') 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 min) decrease in left ventricular developed pressure (LVDP), which was maintained for 90 min (LVDP after 90 min: control vs TNF; 110 + 4 vs 82±10 mmHg, /0.01). 3 The depression in cardiac function seen with TNF under constant flow conditions, was blocked by the ceramidase inhibitor N-oleoylethanolamine (NOE), 1 //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 coronary flow rate (change in flow 20 min after TNF: control vs TNF; -3.0±0.9 vs -8.7+1.2 ml min"1, P<0.0). 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 than 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 effect, and secondly via an indirect coronary vasoconstriction. © 1999 Stockton Press All rights reserved I.