Non‐technical summary  When vascular volume is expanded, atrial natriuretic peptide (ANP) released from the heart acts to restore plasma volume by increasing renal water excretion, causing vasodilation and increasing vascular permeability to water and macromolecules. Previous experiments using mice with selective deletion of ANP receptors in vascular endothelial cells (Schreier et al., 2008) emphasized the importance of vascular permeability regulation by ANP in plasma volume restoration because this genetic manipulation of ANP action on vascular permeability limited the restoration of vascular volume after an acute increase in plasma volume. Here we demonstrate retention of intravenously infused fluid in wild‐type mice in which the response to endogenous ANP was attenuated by the pharmacological agent rolipram that stabilized the endothelial barrier by tightening adhesion between adjacent endothelial cells (Curry et al, 2009). The strategy may provide novel approaches to the clinical problem of maintenance of vascular volume after acute intravenous fluid infusion.Abstract  We tested the hypothesis that inhibition of phosphodiesterase 4 (PDE4) with rolipram to increase vascular endothelial cAMP and stabilize the endothelial barrier would attenuate the action of endogenous atrial natriuretic peptide (ANP) to increase vascular permeability to the plasma protein albumin after an acute plasma volume expansion. After rolipram pretreatment (8 mg (kg BW)−1, intraperitoneal, 30 min) more than 95% of the peak increase in plasma volume after volume expansion (4.5% bovine serum albumin, 114 μl (g BW)−1 hr−1, 15 min) remained in the vascular space 75 min after the end of infusion, whereas only 67% of the fluid was retained in volume expanded animals with no rolipram pretreatment. Rolipram significantly decreased 30 min fluorescently labeled albumin clearance (μl (g dry wt)−1) relative to untreated volume expanded controls in skin (e.g., back, 10.4 ± 1.6 vs 19.5 ± 3.6, P= 0.04), muscle (e.g., hamstring, 15.0 ± 1.9 vs 20.8 ± 1.4, P= 0.04) and in colon, cecum, and rectum (average reduction close to 50%). The mass of muscle and skin tissue accounted for 70% of volume expansion dependent albumin shifts from plasma to interstitium. The results are consistent with observations that the PDE4 inhibitor rolipram attenuates ANP induced increases in vascular permeability after infusion of exogenous ANP (Lin et al., 2011) and observations of elevated central venous pressure after a similar volume expansion in mice with selective deletion of the endothelial ANP receptor (Schreier et al., 2008). These observations may form the basis for new strategies to retain intravenous fluid containing macromolecules.