Preclinical Evaluation of the Phosphodiesterase‐4 Inhibitor, Rolipram, in an Infant Model of Sepsis‐Induced Cardiorenal Syndrome

Abstract

Multi‐organ failure is a frequent complication of infant sepsis. Sepsis‐induced cardiorenal syndrome (type 5), defined as development of acute cardiac dysfunction and acute kidney injury, is a frequent complication of infant sepsis that dramatically increases mortality. Septic shock in adults typically presents as a hyperdynamic state with high cardiac output and low systemic vascular resistance. However, most infants with septic shock show low cardiac output and high systemic vascular resistance (cold shock). To define the apparently unique pathogenic mechanisms contributing to renal and cardiac failure during septic shock in infants, and identify targeted therapies to reverse them, we developed a rat pup (17–19 days old) model of infant cardiorenal syndrome induced by cecal ligation and puncture (CLP), a model of infant sepsis that replicates the key cardio‐renal abnormalities. Rolipram is a phosphodiesterase‐4 inhibitor shown to reduce renal vascular resistance and improve microvascular perfusion in an adult mouse model of sepsis. The therapeutic potential of rolipram was evaluated using intravital video microscopy (IVVM) and echocardiography at specific time points following CLP in our rat pup model. A dose‐finding study was completed using IVVM at 6h following CLP that showed that a dose of 0.1 mg/kg, administered at the time of CLP, protected the pups from sepsis‐induced renal hypoperfusion. This dose was then used in further studies. At 18h following CLP, the single dose of rolipram administered at the time of CLP still prevented renal hypoperfusion and also prevented sepsis‐induced decline in stroke volume, left ventricular velocity, fractional shortening, ejection fraction, and most importantly, cardiac output as measured by echocardiography. Rolipram was also able to prevent the increase in blood urea nitrogen, which is used clinically to assess renal function. The protection by rolipram on perfusion and cardiac output indicate that rolipram may be therapeutically beneficial in infant cardiorenal syndrome.Support or Funding InformationCRS supported by T32 GM106999, F31DK104533, AHA PRE20450050; PRM supported by AHA 15GRNT2508025 and UAMS Medical Research Foundation.