Phosphodiesterase 4 inhibition attenuates plasma volume loss and transvascular exchange in volume expanded mice

Abstract

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 vasodilatation and increasing vascular permeability to water and macromolecules. Previous experiments using mice with selective deletion of ANP receptors in vascular endothelial cells 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. 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 body wt) −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 body wt)−1 h −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 labelled 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, caecum, 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 and observations of elevated central venous pressure after a similar volume expansion in mice with selective deletion of the endothelial ANP receptor. These observations may form the basis for new strategies to retain intravenous fluid containing macromolecules.

Phosphodiesterase 4 Inhibition Dose Dependently Stabilizes Microvascular Barrier Functions and Microcirculation in a Rodent Model of Polymicrobial Sepsis

“…In support of that, it was observed that intraperitoneal application of PD-4-I resulted in attenuation of plasma loss and transvascular fluid exchange in volume-expanded mice (5). Furthermore, PD-4-I application reduced TNF-!…”

Phosphodiesterase‐4 inhibition as a therapeutic approach to treat capillary leakage in systemic inflammation

“…It is meanwhile well established that increased cAMP levels effectively stabilize endothelial barrier properties under resting conditions and in acute inflammation (Adamson et al 1998, 2008; Birukova et al 2004, 2008; Schlegel et al 2008; Baumer et al 2009; Schlegel et al 2009; Schlegel & Waschke, 2009 a ; Spindler et al 2010; Lin et al 2011, 2012). However, because most of these studies were carried out in cell cultures, single vessels in vivo or in isolated organs (Schmidt et al 2008; Schlegel et al 2009; Schlegel & Waschke, 2009 a ; Witzenrath et al 2009), it remained unclear whether the detailed knowledge on cAMP‐induced effects on endothelial barrier functions would finally lead to therapeutic benefits to stabilize capillary leakage in sepsis and acute inflammation.…”

Tonic regulation of vascular permeability

“…The result was retention of a plasma volume expanded state in these mice (Lin et al . ). Strategies based on these observations may improve fluid retention in the vascular space where appropriate before and during surgery.…”

“…, Lin et al . , ). A small number of observations have been made on cultured endothelial cells derived from rat mesenteric microvessels (Baumer et al .…”