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
Nj. Thomas et al., 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, J PHARM EXP, 296(1), 2001, pp. 168-174
Citations number
36
Categorie Soggetti
Pharmacology & Toxicology
Journal title
JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
To examine the effects of chronic type IV phosphodiesterase (PDE4) inhibiti
on 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 inhib
ition with Ro 20-1724 at doses of either 0.3 or 2.0 mg/kg/min. Simultaneous
ly, MODS was induced by intraperitoneal injection of zymosan (0.25mg/g). Me
an arterial blood pressure, heart rate, renal blood flow, and superior mese
nteric blood flow (SMABF) were measured at 48 h. Renal vascular resistance
(RVR), superior mesenteric artery vascular resistance (SMAVR), and glomerul
ar filtration rate were calculated. A dose-response effect of norepinephrin
e was also evaluated at 48 h. Chronic Ro 20-1724 treatment prevented norepi
nephrine-induced vasoconstriction in control rats. Inhibition of PDE4 with
Ro 20-1724 (2.0 mg/kg/min) increased urinary cAMP, and attenuated the incre
ase 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. Chro
nic PDE4 inhibition protects renal function and mesenteric perfusion during
MODS by increasing cAMP in the presence and absence of catecholamines. Hig
her doses of PDE4 inhibition result in clinically tolerated decreases in me
an arterial blood pressure, with improved end-organ function. Chronic PDE4
inhibition is protective, likely through cAMP-mediated attenuation of vasoc
onstriction.