Rolipram Improves Outcome in a Rat Model of Infant Sepsis-Induced Cardiorenal Syndrome

Abstract

While the mortality rate associated with sepsis in children has fallen over the years, it still remains unacceptably high. The development of both acute cardiac dysfunction and acute kidney injury during severe sepsis is categorized as type 5 cardiorenal syndrome (CRS) and is poorly understood in infants. To address this lack of understanding and the need for an appropriate animal model in which to conduct relevant preclinical studies, we developed a model of infant sepsis-induced CRS in rat pups then evaluated the therapeutic potential of the phosphodiesterase (PDE) 4 inhibitor, rolipram. Rat pups at 17–18-days old were subjected to cecal ligation and puncture (CLP) to induce fecal polymicrobial sepsis. Uptake of Evans Blue dye was used to assess renal microvascular leakage. Intravital videomicroscopy was used to assess renal microvascular perfusion and oxidant generation. Glomerular filtration rate (GFR) was used to assess renal function. Left ventricular (LV) catheterization and echocardiography were used to assess cardiac function. Impairment of both cardiac and renal function developed rapidly following CLP, indicating type 5 CRS. Most notable were the rapid decline in LV diastolic function, the decline in cardiac output, renal microvascular failure, and the decline in GFR. A dose-response study with rolipram determined 0.1 mg/kg, ip as the lowest most efficacious dose to protect the renal microcirculation. Rolipram was then evaluated using a clinically relevant delayed dosing paradigm (a single dose at 6 h post-CLP). With delayed dosing, rolipram restored the renal microcirculation and reduced microvascular leakage but did not reduce oxidant generation in the kidney nor restore GFR. In contrast, delayed dosing with rolipram restored cardiac function. Rolipram also improved 4-days survival. In summary, CLP in the rat pup produces a clinically relevant pediatric model of sepsis-induced CRS. The PDE4 inhibitor rolipram was effective in improving renal microvascular function and cardiac function, which improved mortality. These findings suggest that rolipram should be evaluated further as adjunctive therapy for the septic infant with CRS.

The Metabolic Basis of Immune Dysfunction Following Sepsis and Trauma

“…Treatment with rolipram improves renal blood flow, protects renal microcirculation and improves glomerular filtrate rate and renal function in a murine model of CLP-induced sepsis, even when administered 6 h after CLP (93). Rolipram treatment also improved renal and cardiac function leading to improved survival in septic rat pups (94). PDE4 inhibitors, rolipram and roflumilast, have been shown to reduce leukocyte-endothelial interactions which inhibits inflammatory cell influx, and reduce capillary leakage during LPS-induced inflammation (95,96).…”

Multifunctional lipid-based nanocarriers with antibacterial and anti‐inflammatory activities for treating MRSA bacteremia in mice

“…5 a and b). This effect was not observed in the group treated with the free drugs, although PDE4 inhibition has been proven to attenuate acute renal failure in sepsis and endotoxemia [ 24 , 61 ].…”

“…One representative PDE4 inhibitor is rolipram, which is a novel PDE4 inhibitor. Rolipram improves cardiac and renal function through the inhibition of cytokine overexpression in a rodent model of sepsis [ 24 , 25 ]. Neutrophils are the most important cell in the host response to bacterial infection [ 26 ], and their migration is a fundamental component of the immune response elicited by bacteremia [ 12 ].…”

Roles of A-Kinase Anchoring Proteins and Phosphodiesterases in the Cardiovascular System

“…The PDE4 family is encoded by four genes, PDE4A , PDE4B , PDE4C and PDE4D [ 178 ] and was shown to be involved in the excitation-contraction coupling regulation, especially in rodents. It has been recently suggested that PDE4 inhibitors could be beneficial in treating sepsis in infants with cardio-renal syndrome (CRS) since they are effective in improving cardiac function in a rat model suffering from sepsis-induced acute cardiac dysfunction and kidney injury [ 179 ]. In addition, PDE4 depletion stabilized the endothelial barrier by reducing the atrial natriuretic peptide (ANP)-induced vascular permeability and, therefore, was efficient in maintaining the plasma volume [ 180 ].…”