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Inhibition of cytokine release by and cardiac effects of type IV phosphodiesterase inhibition in early, profound endotoxaemia in vivo.
Clin Exp Pharmacol Physiol 2000; 27(10):787-92CE

Abstract

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/dtmax), 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)-alpha and interleukin (IL)-lbeta). 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 microg/kg per min; a selective PDE4 inhibitor) or its vehicle (DMSO; 1.35 microL/min). 4. At 90 min postadministration, endotoxin significantly increased HR and reduced -dP/dtmax and VEDP and caused a several-fold increase in plasma levels of TNF-alpha, IL-1beta, noradrenaline, adrenaline and PRA. RO20-1724 significantly blunted the endotoxin-induced reduction in -dP/dtmax and decreased endotoxin-induced increases in TNF-alpha and IL-1beta 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.

Authors+Show Affiliations

Center for Clinical Pharmacology, Department of Medicine, University of Pittsburgh Medical Center, Pennsylvania 15213-2582, USA. tofovic@msx.dept-med.pitt.eduNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Comparative Study
Journal Article
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

11022970

Citation

Tofovic, S P., et al. "Inhibition of Cytokine Release By and Cardiac Effects of Type IV Phosphodiesterase Inhibition in Early, Profound Endotoxaemia in Vivo." Clinical and Experimental Pharmacology & Physiology, vol. 27, no. 10, 2000, pp. 787-92.
Tofovic SP, Zacharia LC, Carcillo JA, et al. Inhibition of cytokine release by and cardiac effects of type IV phosphodiesterase inhibition in early, profound endotoxaemia in vivo. Clin Exp Pharmacol Physiol. 2000;27(10):787-92.
Tofovic, S. P., Zacharia, L. C., Carcillo, J. A., & Jackson, E. K. (2000). Inhibition of cytokine release by and cardiac effects of type IV phosphodiesterase inhibition in early, profound endotoxaemia in vivo. Clinical and Experimental Pharmacology & Physiology, 27(10), pp. 787-92.
Tofovic SP, et al. Inhibition of Cytokine Release By and Cardiac Effects of Type IV Phosphodiesterase Inhibition in Early, Profound Endotoxaemia in Vivo. Clin Exp Pharmacol Physiol. 2000;27(10):787-92. PubMed PMID: 11022970.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Inhibition of cytokine release by and cardiac effects of type IV phosphodiesterase inhibition in early, profound endotoxaemia in vivo. AU - Tofovic,S P, AU - Zacharia,L C, AU - Carcillo,J A, AU - Jackson,E K, PY - 2000/10/7/pubmed PY - 2001/2/28/medline PY - 2000/10/7/entrez SP - 787 EP - 92 JF - Clinical and experimental pharmacology & physiology JO - Clin. Exp. Pharmacol. Physiol. VL - 27 IS - 10 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/dtmax), 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)-alpha and interleukin (IL)-lbeta). 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 microg/kg per min; a selective PDE4 inhibitor) or its vehicle (DMSO; 1.35 microL/min). 4. At 90 min postadministration, endotoxin significantly increased HR and reduced -dP/dtmax and VEDP and caused a several-fold increase in plasma levels of TNF-alpha, IL-1beta, noradrenaline, adrenaline and PRA. RO20-1724 significantly blunted the endotoxin-induced reduction in -dP/dtmax and decreased endotoxin-induced increases in TNF-alpha and IL-1beta 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. SN - 0305-1870 UR - https://www.unboundmedicine.com/medline/citation/11022970/Inhibition_of_cytokine_release_by_and_cardiac_effects_of_type_IV_phosphodiesterase_inhibition_in_early_profound_endotoxaemia_in_vivo_ L2 - https://onlinelibrary.wiley.com/resolve/openurl?genre=article&sid=nlm:pubmed&issn=0305-1870&date=2000&volume=27&issue=10&spage=787 DB - PRIME DP - Unbound Medicine ER -