title: Rolipram improves renal perfusion and function during sepsis in the mouse.
abstract: Microcirculatory dysfunction is correlated with increased mortality among septic patients and is believed to be a major contributor to the development of acute kidney injury (AKI). Rolipram, a selective phosphodiesterase 4 (PDE4) inhibitor, has been shown to reduce microvascular permeability and in the kidney, increase renal blood flow (RBF). This led us to investigate its potential to improve the renal microcirculation and preserve renal function during sepsis using a murine cecal ligation and puncture (CLP) model to induce sepsis. Rolipram, tested at doses of 0.3-10 mg/kg i.p., acutely restored capillary perfusion in a bell-shaped dose-response effect with 1 mg/kg being the lowest most efficacious dose. This dose also acutely increased RBF despite transiently decreasing mean arterial pressure. Rolipram also reduced renal microvascular permeability. It is noteworthy that delayed treatment with rolipram at 6 hours after CLP restored the renal microcirculation, reduced blood urea nitrogen and serum creatinine, and increased glomerular filtration rate at 18 hours. However, delayed treatment with rolipram did not reduce serum nitrate/nitrite levels, a marker of nitric oxide production, nor reactive nitrogen species generation in renal tubules. These data show that restoring the microcirculation with rolipram, even with delayed treatment, is enough to improve renal function during sepsis despite the generation of oxidants and suggest that PDE4 inhibitors should be evaluated further for their ability to treat septic-induced AKI.
authors.affiliation: Department of Pharmacology and Toxicology (J.H.H, Z.W., N.K.P., P.R.M.) and Pathology (N.G.), University of Arkansas for Medical Sciences, Little Rock, Arkansas.
authors.forename: Joseph H
authors.initials: JH
authors.lastname: Holthoff
authors.forename: Zhen
authors.initials: Z
authors.lastname: Wang
authors.forename: Naeem K
authors.initials: NK
authors.lastname: Patil
authors.forename: Neriman
authors.initials: N
authors.lastname: Gokden
authors.forename: Philip R
authors.initials: PR
authors.lastname: Mayeux
mesh_terms: D058186:Acute Kidney Injury / Q000201:enzymology / Q000503:physiopathology / Q000517:prevention & control*; D000818:Animals; D001783:Blood Flow Velocity / Q000187:drug effects; D004195:Disease Models, Animal; D005919:Glomerular Filtration Rate; D007668:Kidney / Q000098:blood supply / Q000187:drug effects* / Q000201:enzymology / Q000503:physiopathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008833:Microcirculation / Q000187:drug effects; D058988:Phosphodiesterase 4 Inhibitors / Q000008:administration & dosage / Q000627:therapeutic use*; D012079:Renal Circulation / Q000187:drug effects* / Q000502:physiology; D020889:Rolipram / Q000008:administration & dosage / Q000627:therapeutic use*; D018805:Sepsis / Q000188:drug therapy* / Q000201:enzymology / Q000503:physiopathology
chemical_list: D058988:Phosphodiesterase 4 Inhibitors; D020889:Rolipram
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