Phosphodiesterase IV inhibitor Rolipram attenuates ANP‐dependent intravascular fluid loss

Abstract

Mice with deletion of the endothelial ANP receptor (guanylyl cyclase A receptor) (EC GC‐A KO mice) have expanded intravascular volumes and retain infused fluid in the vascular space (Schreier et al. Endocrinol 149: 4193, 2008). We have previously demonstrated in isoflurane anesthetized wild type C57BL/6 mice that pretreatment with Rolipram (8 mg/kg IP, 30 min), a phosphodiesterase IV inhibitor that raises intracellular cAMP and stabilizes the endothelial barrier, attenuates the ANP‐dependent increase in vascular permeability (FASEB J 23:950.12, 2009). To test the extent that ANP‐dependent changes in vascular permeability regulate vascular volume, we infused ANP (500 ng/kg·min) and measured a hematocrit increase from 41% to 47%, an 11% reduction in plasma volume. This infusion rate raises plasma ANP to physiological levels near those measured after an acute plasma volume expansion. Rolipram pretreatment completely blocks this ANP‐dependent fluid loss. EC GC‐A KO mice also show no increase in hematocrit with ANP infusion relative to their control littermates. Thus Rolipram appears to be as effective to attenuate ANP‐mediated fluid loss as EC GC‐A KO. We predict that mice similarly pretreated to stabilize the endothelial barrier will retain fluid in the vascular space when given plasma volume expansion. (Supported by pilot funds from Clinical and Translational Science Center, UC Davis UL1 RR024146; NCRR).