The influence of tumour necrosis factor-α on the cardiovascular system of anaesthetized rats

Abstract.

The effects of two vasoactive agents (adenosine A_2A agonist, CGS 21680, and adrenoceptor agonist, noradrenaline) were examined on cardiac output (CO), heart rate (HR), blood pressure (BP), mean circulatory filling pressure (P _mcf), resistance to venous return, arterial resistance, dP/dt, plasma levels of NO₂ ^–/NO₃ ^–, and inducible nitric oxide synthase (iNOS) activity in lungs ex vivo, following treatment with tumour necrosis factor-α (TNF-α; 30 µg/kg) in anaesthetized rats. Treatment with TNF-α produced significant reduction in CO (41±2%), dP/dt (26±3%), BP (26±2%) and P _mcf (27±4%; n=6; mean±SEM), but increased arterial resistance. There were no significant changes in the plasma levels of NO₂ ^–/NO₃ ^– levels over time following treatment with TNF-α, but there was a significant increase (approximately twofold) in the activity of the iNOS in the lungs of animals treated with TNF-α. Administration of CGS 21680 (1.0 µg/kg per min) significantly increased CO (44±6%), HR (12±2%), P _mcf (24±4%) and dP/dt (24±5%) in TNF-α-treated rats. CGS 21680 also significantly reduced arterial resistance (33±2%) without altering resistance to venous return in TNF-α-treated rats. While noradrenaline (1.0 µg/kg per min) infusion did not significantly increase CO, it did significantly increase HR (12±1%), BP (55±9%), P _mcf (47±5%), dP/dt (65±7%), resistance to venous return (64±20%), and arterial resistance (41±16%) in TNF-α-treated animals. The reduction in BP due to administration of TNF-α is the result of significant reduction in CO. Consequently, the decline in CO can be attributed to a combination of a negative inotropic effect as well as a reduction in P _mcf. It is evident that infusion with CGS 21680 could reverse the negative impact of TNF-α on CO by increasing dP/dt, P _mcf and HR as well as a reduction in arterial resistance. The fact that noradrenaline did not significantly increase CO in TNF-α-treated rats can be attributed to increased arterial resistance as well increase in resistance to venous return.