Effects of tumour necrosis factor-alpha on left ventricular function in the rat isolated perfused heart: possible mechanisms for a decline in cardiac function.
1. The cardiac depressant actions of TNF were investigated in the isolated perfused rat heart under constant flow (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 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, P < 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 microM, (LVDP after 90 min: TNF vs TNF with NOE; 82 +/- 10 vs 11 +/- 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 < 0.01). 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 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.
Department of Pharmacology, University of Bath, Claverton Down.
N J
NJ
Edmunds
H
H
Lal
B
B
Woodward
D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D000077300:Bosentan; D063388:Endocannabinoids; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004983:Ethanolamines / Q000494:pharmacology; D006321:Heart / Q000187:drug effects* / Q000502:physiology; D006339:Heart Rate / Q000187:drug effects; D006352:Heart Ventricles / Q000187:drug effects; D066298:In Vitro Techniques; D007213:Indomethacin / Q000494:pharmacology; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects; D019335:Nitroarginine / Q000494:pharmacology; D009829:Oleic Acids; D010477:Perfusion; D011312:Pressure; D051381:Rats; D017208:Rats, Wistar; D013108:Sphingomyelin Phosphodiesterase / Q000494:pharmacology; D013318:Stroke Volume / Q000187:drug effects / Q000502:physiology; D013449:Sulfonamides / Q000494:pharmacology; D013696:Temperature; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D016276:Ventricular Function; D016277:Ventricular Function, Left / Q000187:drug effects*
D000959:Antihypertensive Agents; D063388:Endocannabinoids; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D004791:Enzyme Inhibitors; D004983:Ethanolamines; D009829:Oleic Acids; D013449:Sulfonamides; D014409:Tumor Necrosis Factor-alpha; C033595:N-oleoylethanolamine; D019335:Nitroarginine; D013108:Sphingomyelin Phosphodiesterase; D000077300:Bosentan; D007213:Indomethacin