TY - JOUR
T1 - Inhibition of cytokine release by and cardiac effects of type IV phosphodiesterase inhibition in early, profound endotoxaemia in vivo
AU - Tofovic, Stevan P.
AU - Zacharia, Lefteris C.
AU - Carcillo, Joseph A.
AU - Jackson, Edwin K.
PY - 2000
Y1 - 2000
N2 - 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 improved early survivability, most likely PDE4 inhibition exerts multiple beneficial effects in endotoxaemia and the purpose of the present study was to test this hypothesis. 2. In study 1, we determined, in anaesthetized rats, the effects of endotoxin (30 mg/kg, i.v.) on cardiac performance parameters (heart rate (HR), ventricular peak systolic pressure (VPSP), maximum positive change in left ventricular 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 activity (PRA) and plasma levels of inflammatory cytokines (tumour necrosis factor (TNF)-α and interleukin (IL)-1β). 3. In study 2, we determined, in anaesthetized rats, whether inhibition of PDE4 attenuates lipopolysaccharide (LPS)-induced changes in the aforementioned parameters of heart performance and neurohumoral status. We compared the changes in these parameters induced by endotoxaemia in animals treated with either RO 20-1724 (10 μg/kg per min; a selective PDE4 inhibitor) or its vehicle (DMSO; 1.35 μL/min). 4. At 90 min postadministration, endotoxin significantly increased HR and reduced -dP/dt(max) and VEDP and caused a several-fold increase in plasma levels of TNF-α, IL-1β, noradrenaline, adrenaline and PRA. RO 20-1724 significantly blunted the endotoxin-induced reduction in -dP/dt(max) and decreased endotoxin-induced increases in TNF-α and IL-1β, without significantly altering endotoxin-induced changes in HR, VEDP, catecholamine levels and PRA. 5. Results from these studies indicate that, in addition to preserving renal function, PDE4 inhibition attenuates inflammatory cytokine release caused by high-dose endotoxin and may have protective effects on diastolic function in early profound endotoxaemia.
AB - 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 improved early survivability, most likely PDE4 inhibition exerts multiple beneficial effects in endotoxaemia and the purpose of the present study was to test this hypothesis. 2. In study 1, we determined, in anaesthetized rats, the effects of endotoxin (30 mg/kg, i.v.) on cardiac performance parameters (heart rate (HR), ventricular peak systolic pressure (VPSP), maximum positive change in left ventricular 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 activity (PRA) and plasma levels of inflammatory cytokines (tumour necrosis factor (TNF)-α and interleukin (IL)-1β). 3. In study 2, we determined, in anaesthetized rats, whether inhibition of PDE4 attenuates lipopolysaccharide (LPS)-induced changes in the aforementioned parameters of heart performance and neurohumoral status. We compared the changes in these parameters induced by endotoxaemia in animals treated with either RO 20-1724 (10 μg/kg per min; a selective PDE4 inhibitor) or its vehicle (DMSO; 1.35 μL/min). 4. At 90 min postadministration, endotoxin significantly increased HR and reduced -dP/dt(max) and VEDP and caused a several-fold increase in plasma levels of TNF-α, IL-1β, noradrenaline, adrenaline and PRA. RO 20-1724 significantly blunted the endotoxin-induced reduction in -dP/dt(max) and decreased endotoxin-induced increases in TNF-α and IL-1β, without significantly altering endotoxin-induced changes in HR, VEDP, catecholamine levels and PRA. 5. Results from these studies indicate that, in addition to preserving renal function, PDE4 inhibition attenuates inflammatory cytokine release caused by high-dose endotoxin and may have protective effects on diastolic function in early profound endotoxaemia.
KW - Adrenergic agonists
KW - Cytokines
KW - Endotoxin
KW - Sepsis
KW - Ventricular function
UR - http://www.scopus.com/inward/record.url?scp=0033798831&partnerID=8YFLogxK
U2 - 10.1046/j.1440-1681.2000.03332.x
DO - 10.1046/j.1440-1681.2000.03332.x
M3 - Article
C2 - 11022970
AN - SCOPUS:0033798831
SN - 0305-1870
VL - 27
SP - 787
EP - 792
JO - Clinical and Experimental Pharmacology and Physiology
JF - Clinical and Experimental Pharmacology and Physiology
IS - 10
ER -