Inhibition of cytokine release by and cardiac effects of type IV phosphodiesterase inhibition in early, profound endotoxaemia in vivo

1. In rats, inhibition of type IV phosphodiesterase (PDE4) attenuates acute renal failure and early (hours) mortality induced by high-dose endotoxin. Because it is unlikely that protection of renal function accounts for impro ved early survivability, most likely PDE4 inhibition exerts multiple benefi cial effects in endotoxaemia and the purpose of the present study was to te st this hypothesis. 2. In study 1, we determined, in anaesthetized rats, the effects of endotox in (30 mg/kg, i.v.) on cardiac performance parameters (heart rate (HR), ven tricular peak systolic pressure (VPSP), maximum positive change in left ven tricular pressure with respect to time (+dP/dt), maximum negative change in left ventricular pressure with respect to time (-dP/dt(max)), ventricular end-diastolic pressure (VEDP), ventricular minimum diastolic pressure (VMDP ) and HR-pressure product), plasma catecholamine levels, plasma renin activ ity (PRA) and plasma levels of inflammatory cytokines (tumour necrosis fact or (TNF)-alpha and interleukin (IL)-1 beta). 3. In study 2, we determined, in anaesthetized rats, whether inhibition of PDE4 attenuates lipopolysaccharide (LPS)-induced changes in the aforementio ned parameters of heart performance and neurohumoral status. We compared th e changes in these parameters induced by endotoxaemia in animals treated wi th either RO 20-1724 (10 mu g/kg per min; a selective PDE4 inhibitor) or it s vehicle (DMSO; 1.35 mu L/min). 4. At 90 min postadministration, endotoxin significantly increased HR and r educed -dP/dt(max) and VEDP and caused a several-fold increase in plasma le vels of TNF-alpha, IL-1 beta, noradrenaline, adrenaline and PRA. RO 20-1724 significantly blunted the endotoxin-induced reduction in -dP/dt(max) and d ecreased endotoxin-induced increases in TNF-alpha and IL-1 beta, without si gnificantly altering endotoxin-induced changes in HR, VEDP, catecholamine l evels and PRA. 5. Results from these studies indicate that, in addition to preserving rena l function, PDE4 inhibition attenuates inflammatory cytokine release caused by high-dose endotoxin and may have protective effects on diastolic functi on in early profound endotoxaemia.