Phosphodiesterase 4 inhibition attenuates atrial natriuretic peptide-induced vascular hyperpermeability and loss of plasma volume

Yueh Chen Lin, Haris Samardzic, Roger H. Adamson, Eugene M. Renkin, Joyce F. Clark, Rolf K. Reed, Fitz Roy E Curry

Research output: Contribution to journalArticle

19 Citations (Scopus)

Abstract

Non-technical summary: Natriuretic peptides (such as atrial natriuretic peptide, ANP) are normally present at very low levels in the blood and are part of physiological systems that control blood volume. During diseases such as heart failure and sepsis, circulating levels of ANP increase, leading to an increase in blood vessel permeability and loss of blood fluid volume to the tissues. Other studies show that some inflammatory responses are strongly blocked by increased intracellular cAMP. Here we tested whether rolipram, an inhibitor of the degradation of cAMP, could counteract the movement of protein and fluid out of the blood that is induced by ANP. We found that rolipram almost completely blocked the ANP-induced loss of blood volume. Stabilizing the endothelial barrier by controlling cAMP levels to offset ANP-induced increases in vascular permeability may be part of a strategy to maintain plasma volume in disease states with elevated natriuretic peptides.Abstract Inhibition of phosphodiesterase 4 (PDE4) to increase endothelial cAMP and stabilize the endothelial barrier attenuates acute inflammatory increases in vascular permeability. We extended this approach to attenuate physiological increases in vascular permeability in response to atrial natriuretic peptide (ANP), which acts with the kidney to regulate plasma volume. We measured blood-to-tissue albumin clearance and changes in plasma volume in isoflurane-anaesthetized mice (C57BL/6J) pre-treated with rolipram (8 mg kg-1 i.p., 30 min). Rolipram significantly reduced albumin permeability, measured using a dual-label fluorescence method, in skin and skeletal muscle compared with ANP alone (500 ng kg-1 min-1). Skin and muscle tissue accounted for 70% of the reduction in whole body albumin clearance taking into account albumin clearance in gastrointestinal (GI) tissue, heart and kidney. The action of ANP and rolipram to modify albumin clearances in duodenum and jejunum could be accounted for by local increases in vascular perfusion to increase surface area for exchange. ANP increased haematocrit from 40.6% to 46.8%, corresponding to an average loss of 22% plasma fluid volume (227 μl), and this was almost completely reversed with rolipram. Renal water excretion accounted for less than 30% of plasma fluid loss indicating that reduced albumin permeability and reduced filtration into vasodilated GI tissue were the predominant actions of PDE4 inhibition. Similar fluid retention was measured in mice with endothelial-restricted deletion of the guanylyl cyclase-A receptor for ANP. Stabilizing the endothelial barrier to offset ANP-induced increases in vascular permeability may be part of a strategy to maintain plasma volume.Natriuretic peptides (such as atrial natriuretic peptide, ANP) are normally present at very low levels in the blood and are part of physiological systems that control blood volume. During diseases such as heart failure and sepsis, circulating levels of ANP increase, leading to an increase in blood vessel permeability and loss of blood fluid volume to the tissues. Other studies show that some inflammatory responses are strongly blocked by increased intracellular cAMP. Here we tested whether rolipram, an inhibitor of the degradation of cAMP, could counteract the movement of protein and fluid out of the blood that is induced by ANP. We found that rolipram almost completely blocked the ANP-induced loss of blood volume. Stabilizing the endothelial barrier by controlling cAMP levels to offset ANP-induced increases in vascular permeability may be part of a strategy to maintain plasma volume in disease states with elevated natriuretic peptides.

Original languageEnglish (US)
Pages (from-to)341-353
Number of pages13
JournalJournal of Physiology
Volume589
Issue number2
DOIs
StatePublished - Jan 2011

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Type 4 Cyclic Nucleotide Phosphodiesterase
Plasma Volume
Atrial Natriuretic Factor
Blood Vessels
Rolipram
Blood Volume
Capillary Permeability
Albumins
Natriuretic Peptides
Permeability
Sepsis
Heart Failure
Kidney
Skin

ASJC Scopus subject areas

  • Physiology

Cite this

Lin, Y. C., Samardzic, H., Adamson, R. H., Renkin, E. M., Clark, J. F., Reed, R. K., & Curry, F. R. E. (2011). Phosphodiesterase 4 inhibition attenuates atrial natriuretic peptide-induced vascular hyperpermeability and loss of plasma volume. Journal of Physiology, 589(2), 341-353. https://doi.org/10.1113/jphysiol.2010.199588

Phosphodiesterase 4 inhibition attenuates atrial natriuretic peptide-induced vascular hyperpermeability and loss of plasma volume. / Lin, Yueh Chen; Samardzic, Haris; Adamson, Roger H.; Renkin, Eugene M.; Clark, Joyce F.; Reed, Rolf K.; Curry, Fitz Roy E.

In: Journal of Physiology, Vol. 589, No. 2, 01.2011, p. 341-353.

Research output: Contribution to journalArticle

Lin, Yueh Chen ; Samardzic, Haris ; Adamson, Roger H. ; Renkin, Eugene M. ; Clark, Joyce F. ; Reed, Rolf K. ; Curry, Fitz Roy E. / Phosphodiesterase 4 inhibition attenuates atrial natriuretic peptide-induced vascular hyperpermeability and loss of plasma volume. In: Journal of Physiology. 2011 ; Vol. 589, No. 2. pp. 341-353.
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T1 - Phosphodiesterase 4 inhibition attenuates atrial natriuretic peptide-induced vascular hyperpermeability and loss of plasma volume

AU - Lin, Yueh Chen

AU - Samardzic, Haris

AU - Adamson, Roger H.

AU - Renkin, Eugene M.

AU - Clark, Joyce F.

AU - Reed, Rolf K.

AU - Curry, Fitz Roy E

PY - 2011/1

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N2 - Non-technical summary: Natriuretic peptides (such as atrial natriuretic peptide, ANP) are normally present at very low levels in the blood and are part of physiological systems that control blood volume. During diseases such as heart failure and sepsis, circulating levels of ANP increase, leading to an increase in blood vessel permeability and loss of blood fluid volume to the tissues. Other studies show that some inflammatory responses are strongly blocked by increased intracellular cAMP. Here we tested whether rolipram, an inhibitor of the degradation of cAMP, could counteract the movement of protein and fluid out of the blood that is induced by ANP. We found that rolipram almost completely blocked the ANP-induced loss of blood volume. Stabilizing the endothelial barrier by controlling cAMP levels to offset ANP-induced increases in vascular permeability may be part of a strategy to maintain plasma volume in disease states with elevated natriuretic peptides.Abstract Inhibition of phosphodiesterase 4 (PDE4) to increase endothelial cAMP and stabilize the endothelial barrier attenuates acute inflammatory increases in vascular permeability. We extended this approach to attenuate physiological increases in vascular permeability in response to atrial natriuretic peptide (ANP), which acts with the kidney to regulate plasma volume. We measured blood-to-tissue albumin clearance and changes in plasma volume in isoflurane-anaesthetized mice (C57BL/6J) pre-treated with rolipram (8 mg kg-1 i.p., 30 min). Rolipram significantly reduced albumin permeability, measured using a dual-label fluorescence method, in skin and skeletal muscle compared with ANP alone (500 ng kg-1 min-1). Skin and muscle tissue accounted for 70% of the reduction in whole body albumin clearance taking into account albumin clearance in gastrointestinal (GI) tissue, heart and kidney. The action of ANP and rolipram to modify albumin clearances in duodenum and jejunum could be accounted for by local increases in vascular perfusion to increase surface area for exchange. ANP increased haematocrit from 40.6% to 46.8%, corresponding to an average loss of 22% plasma fluid volume (227 μl), and this was almost completely reversed with rolipram. Renal water excretion accounted for less than 30% of plasma fluid loss indicating that reduced albumin permeability and reduced filtration into vasodilated GI tissue were the predominant actions of PDE4 inhibition. Similar fluid retention was measured in mice with endothelial-restricted deletion of the guanylyl cyclase-A receptor for ANP. Stabilizing the endothelial barrier to offset ANP-induced increases in vascular permeability may be part of a strategy to maintain plasma volume.Natriuretic peptides (such as atrial natriuretic peptide, ANP) are normally present at very low levels in the blood and are part of physiological systems that control blood volume. During diseases such as heart failure and sepsis, circulating levels of ANP increase, leading to an increase in blood vessel permeability and loss of blood fluid volume to the tissues. Other studies show that some inflammatory responses are strongly blocked by increased intracellular cAMP. Here we tested whether rolipram, an inhibitor of the degradation of cAMP, could counteract the movement of protein and fluid out of the blood that is induced by ANP. We found that rolipram almost completely blocked the ANP-induced loss of blood volume. Stabilizing the endothelial barrier by controlling cAMP levels to offset ANP-induced increases in vascular permeability may be part of a strategy to maintain plasma volume in disease states with elevated natriuretic peptides.

AB - Non-technical summary: Natriuretic peptides (such as atrial natriuretic peptide, ANP) are normally present at very low levels in the blood and are part of physiological systems that control blood volume. During diseases such as heart failure and sepsis, circulating levels of ANP increase, leading to an increase in blood vessel permeability and loss of blood fluid volume to the tissues. Other studies show that some inflammatory responses are strongly blocked by increased intracellular cAMP. Here we tested whether rolipram, an inhibitor of the degradation of cAMP, could counteract the movement of protein and fluid out of the blood that is induced by ANP. We found that rolipram almost completely blocked the ANP-induced loss of blood volume. Stabilizing the endothelial barrier by controlling cAMP levels to offset ANP-induced increases in vascular permeability may be part of a strategy to maintain plasma volume in disease states with elevated natriuretic peptides.Abstract Inhibition of phosphodiesterase 4 (PDE4) to increase endothelial cAMP and stabilize the endothelial barrier attenuates acute inflammatory increases in vascular permeability. We extended this approach to attenuate physiological increases in vascular permeability in response to atrial natriuretic peptide (ANP), which acts with the kidney to regulate plasma volume. We measured blood-to-tissue albumin clearance and changes in plasma volume in isoflurane-anaesthetized mice (C57BL/6J) pre-treated with rolipram (8 mg kg-1 i.p., 30 min). Rolipram significantly reduced albumin permeability, measured using a dual-label fluorescence method, in skin and skeletal muscle compared with ANP alone (500 ng kg-1 min-1). Skin and muscle tissue accounted for 70% of the reduction in whole body albumin clearance taking into account albumin clearance in gastrointestinal (GI) tissue, heart and kidney. The action of ANP and rolipram to modify albumin clearances in duodenum and jejunum could be accounted for by local increases in vascular perfusion to increase surface area for exchange. ANP increased haematocrit from 40.6% to 46.8%, corresponding to an average loss of 22% plasma fluid volume (227 μl), and this was almost completely reversed with rolipram. Renal water excretion accounted for less than 30% of plasma fluid loss indicating that reduced albumin permeability and reduced filtration into vasodilated GI tissue were the predominant actions of PDE4 inhibition. Similar fluid retention was measured in mice with endothelial-restricted deletion of the guanylyl cyclase-A receptor for ANP. Stabilizing the endothelial barrier to offset ANP-induced increases in vascular permeability may be part of a strategy to maintain plasma volume.Natriuretic peptides (such as atrial natriuretic peptide, ANP) are normally present at very low levels in the blood and are part of physiological systems that control blood volume. During diseases such as heart failure and sepsis, circulating levels of ANP increase, leading to an increase in blood vessel permeability and loss of blood fluid volume to the tissues. Other studies show that some inflammatory responses are strongly blocked by increased intracellular cAMP. Here we tested whether rolipram, an inhibitor of the degradation of cAMP, could counteract the movement of protein and fluid out of the blood that is induced by ANP. We found that rolipram almost completely blocked the ANP-induced loss of blood volume. Stabilizing the endothelial barrier by controlling cAMP levels to offset ANP-induced increases in vascular permeability may be part of a strategy to maintain plasma volume in disease states with elevated natriuretic peptides.

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