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.

Inactivation of renal mitochondrial respiratory complexes and manganese superoxide dismutase during sepsis: mitochondria-targeted antioxidant mitigates injury

“…Given the complex and rapid development of sepsis-induced AKI in this model (55), it is not surprising that delayed therapy with Mito-TEMPO did not completely restore GFR. Targeting renal vascular resistance (22) or oxidative stress (23,55) with delayed therapy also only partially restored GFR. These findings support the view that combination therapy will likely be the most efficacious in the septic patient.…”

“…Biotelemetry was used to measure mean arterial pressure (MAP) and heart rate (HR) in conscious mice as described previously (22). Under isoflurane anesthesia, telemetry transmitters (Data Sciences International, St. Paul, MN) were implanted into the carotid artery of mice.…”

“…Glomerular filtration rate (GFR) was measured using FITC-inulin clearance as previously described (22). A 5% FTIC-inulin solution at a dose of 3.74 l/g was administered via the penile vein.…”

The Beneficial Effects of Agomelatine in Experimental Model of Sepsis Related Acute Kidney Injury

“…AKI occurs in nearly half of all septic patients and is associated with increased mortality. [25] It has been suggested that AKI in sepsis is correlated with important destructive effects. While detection of acute lung injury is not easy in early stages, the authors suggested that it can indicate severity of sepsis.…”

Pharmacologic Targeting of Sphingosine-1-Phosphate Receptor 1 Improves the Renal Microcirculation during Sepsis in the Mouse

“…Intravital video microscopy (IVVM) was performed as described previously elsewhere Holthoff et al, 2013). Briefly, after anesthesia with isoflurane, fluorescein isothiocyanate-labeled dextran (2 mmol/kg in 3 ml/kg normal saline) was administered via the penile vein to visualize the capillary vascular space.…”