Chronic type IV phosphodiesterase inhibition protects glomerular filtration rate and renal and mesenteric blood flow in a zymosan-induced model of multiple organ dysfunction syndrome treated with norepinephrine.
To examine the effects of chronic type IV phosphodiesterase (PDE4) inhibition on renal function and renal and mesenteric vascular resistance and blood flow in a sublethal model of multiple organ dysfunction syndrome (MODS) we used a prospective, randomized, controlled laboratory animal study. Twenty-eight rats had mini-infusion pumps placed to deliver vehicle or PDE4 inhibition with Ro 20-1724 at doses of either 0.3 or 2.0 microg/kg/min. Simultaneously, MODS was induced by intraperitoneal injection of zymosan (0.25 mg/g). Mean arterial blood pressure, heart rate, renal blood flow, and superior mesenteric blood flow (SMABF) were measured at 48 h. Renal vascular resistance (RVR), superior mesenteric artery vascular resistance (SMAVR), and glomerular filtration rate were calculated. A dose-response effect of norepinephrine was also evaluated at 48 h. Chronic Ro 20-1724 treatment prevented norepinephrine-induced vasoconstriction in control rats. Inhibition of PDE4 with Ro 20-1724 (2.0 microg/kg/min) increased urinary cAMP, and attenuated the increase in RVR and SMAVR (p < 0.05) and the decrease in RBF and SMABF (p < 0.05) that occurred from zymosan and norepinephrine. Glomerular filtration rate was also preserved (p < 0. 05), despite a reduction in blood pressure. Chronic PDE4 inhibition protects renal function and mesenteric perfusion during MODS by increasing cAMP in the presence and absence of catecholamines. Higher doses of PDE4 inhibition result in clinically tolerated decreases in mean arterial blood pressure, with improved end-organ function. Chronic PDE4 inhibition is protective, likely through cAMP-mediated attenuation of vasoconstriction.
Thomas
N J
NJ
Center for Clinical Pharmacology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA. nthomas@psu.edu
Carcillo
J A
JA
Herzer
W A
WA
Mi
Z
Z
Jackson
E K
EK
D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors*; D012368:4-(3-Butoxy-4-methoxybenzyl)-2-imidazolidinone / Q000494:pharmacology*; D000316:Adrenergic alpha-Agonists / Q000494:pharmacology; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D000242:Cyclic AMP / Q000652:urine; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D005919:Glomerular Filtration Rate / Q000187:drug effects*; D006339:Heart Rate / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects; D008297:Male; D009102:Multiple Organ Failure / Q000139:chemically induced / Q000188:drug therapy* / Q000503:physiopathology; D009638:Norepinephrine / Q000494:pharmacology; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D012079:Renal Circulation / Q000187:drug effects*; D013152:Splanchnic Circulation / Q000187:drug effects*; D014655:Vascular Resistance / Q000187:drug effects; D015054:Zymosan
D000316:Adrenergic alpha-Agonists; D010726:Phosphodiesterase Inhibitors; D012368:4-(3-Butoxy-4-methoxybenzyl)-2-imidazolidinone; D015054:Zymosan; D000242:Cyclic AMP; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D009638:Norepinephrine