BAY 41-2272 inhibits the development of chronic hypoxic pulmonary hypertension in rats

Thorsen, Lise Bech Jellesmark; Eskildsen‐Helmond, Yvonne E. G.; Zibrandtsen, Helle; Stasch, Johannes‐Peter; Simonsen, Ulf; Laursen, Britt Elmedal

doi:10.1016/j.ejphar.2010.08.032

Cited by 24 publications

(21 citation statements)

References 26 publications

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“…In the current study, BAY increased both pVASPSer 157 and pVASPSer 239 . These findings differ slightly from that recently reported in a rat model of pulmonary hypertension (Thorsen et al, 2010) whereby BAY induced pVASPSer 239 yet failed to alter pVASPSer 157 ; however, that study was performed in lung homogenates under hypoxia, whereas the current study examined VSM under normoxia; thus, experimental conditions must be considered in cyclic nucleotide studies when using VASP as a "selective" kinase readout.…”

Section: Discussioncontrasting

confidence: 55%

The Soluble Guanylate Cyclase Stimulator BAY 41-2272 Inhibits Vascular Smooth Muscle Growth through the cAMP-Dependent Protein Kinase and cGMP-Dependent Protein Kinase Pathways

Joshi¹,

Martin²,

Fox³

et al. 2011

J Pharmacol Exp Ther

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Vascular smooth muscle (VSM) proliferation and migration are key components in vessel remodeling. Cyclic nucleotide signaling is protective and has long-served as a therapeutic target against undesired VSM growth. The present work analyzed the effects of the soluble guanylate cyclase (sGC) stimulator 3-(4-amino-5-cyclopropylpyrimidine-2-yl)-1-(2-fluorobenzyl)-1H-pyrazolo [3,4-b]pyridine [BAY 41-2272 (BAY)] on VSM growth, and we hypothesize that BAY has the capacity to reduce proliferation and migration via cyclic nucleotide-driven kinase signaling. Perivascular BAY postballoon injury reduced neointimal growth by ϳ40% compared with vehicle controls after 2 weeks. In VSM cells, BAY (10 M) reduced proliferation by ϳ40% after 72 h and migration by ϳ40% after 6 h and ϳ60% after 18 h without deleterious effects on cell viability. cGMP content peaked (248ϫ) 20 min after BAY treatment and remained elevated (140ϫ) through 60 min; however, BAY did not affect cAMP levels compared with controls.Conventional and In-Cell Western analyses showed increases in vasodilator-stimulated phosphoprotein (VASP) phosphorylation (pVASP) at serines 239 (3ϫ) and 157 (2ϫ), respective markers of cGMP-and cAMP-directed protein kinases (PKG and PKA, respectively). The PKG inhibitor YGRKKRRQRRRPPLRKKKKKH peptide (DT-2) completely reversed BAY-mediated increases in pVASPSer 239 and BAY-mediated inhibition of migration. In comparison, the PKA inhibitor peptide PKI further potentiated BAYstimulated pVASPSer 157 and pVASPSer 239 and partially reversed the antiproliferative effects of BAY. This is the first report demonstrating the effectiveness of BAY in reducing neointimal growth with direct evidence for PKG-specific antimigratory and PKAspecific antiproliferative mechanisms. Conclusively, the sGC stimulator BAY reduces VSM growth through cGMP-dependent PKG and PKA processes, providing support for continued evaluation of its clinical utility.

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Section: Discussioncontrasting

confidence: 55%

The Soluble Guanylate Cyclase Stimulator BAY 41-2272 Inhibits Vascular Smooth Muscle Growth through the cAMP-Dependent Protein Kinase and cGMP-Dependent Protein Kinase Pathways

Joshi¹,

Martin²,

Fox³

et al. 2011

J Pharmacol Exp Ther

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“…It was recently demonstrated that BAY increases VASP phosphorylation and attenuates vascular remodeling in the pulmonary vasculature in a hypoxia-induced rat model (Deruelle et al, 2006; Thorsen et al, 2010). In support, we recently demonstrated that BAY increases cAMP, cGMP, VASP phosphorylation and inhibits proliferation of rat A7R5 VSMCs (Mendelev et al, 2009), rat primary VSMCs, and neointimal formation in the rat carotid artery (Joshi et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

Phosphodiesterases Regulate BAY 41-2272-Induced VASP Phosphorylation in Vascular Smooth Muscle Cells

Adderley¹,

Joshi²,

Martin³

et al. 2012

Front. Pharmacol.

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BAY 41-2272 (BAY), a stimulator of soluble guanylyl cyclase, increases cyclic nucleotides and inhibits proliferation of vascular smooth muscle cells (VSMCs). In this study, we elucidated mechanisms of action of BAY in its regulation of vasodilator-stimulated phosphoprotein (VASP) with an emphasis on VSMC phosphodiesterases (PDEs). BAY alone increased phosphorylation of VASPSer239 and VASPSer157, respective indicators of PKG and PKA signaling. IBMX, a non-selective inhibitor of PDEs, had no effect on BAY-induced phosphorylation at VASPSer239 but inhibited phosphorylation at VASPSer157. Selective inhibitors of PDE3 or PDE4 attenuated BAY-mediated increases at VASPSer239 and VASPSer157, whereas PDE5 inhibition potentiated BAY-mediated increases only at VASPSer157. In comparison, 8Br-cGMP increased phosphorylation at VASPSer239 and VASPSer157 which were not affected by selective PDE inhibitors. In the presence of 8Br-cAMP, inhibition of either PDE4 or PDE5 decreased VASPSer239 phosphorylation and inhibition of PDE3 increased phosphorylation at VASPSer239, while inhibition of PDE3 or PDE4 increased and PDE5 inhibition had no effect on VASPSer157 phosphorylation. These findings demonstrate that BAY operates via cAMP and cGMP along with regulation by PDEs to phosphorylate VASP in VSMCs and that the mechanism of action of BAY in VSMCs is different from that of direct cyclic nucleotide analogs with respect to VASP phosphorylation and the involvement of PDEs. Given a role for VASP as a critical cytoskeletal protein, these findings provide evidence for BAY as a regulator of VSMC growth and a potential therapeutic agent against vasculoproliferative disorders.

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“…Immediately after the surgical procedure was completed, the rats in the sham-operated and the SLDtreated CLP groups received 10-or 20-mg/kg doses of SLD, which were administered with an oral gavage suspended in saline. There are many sildenafil doses for rats, varying from 0·4 mg/kg to 90 mg/kg, with different administration routes [28][29][30][31][32][33]. The reason we selected 10-and 20-mg/kg doses of oral sildenafil is that 10 mg/kg/day of sildenafil would result approximately in the same plasma concentration as 50 mg in humans [34].…”

Section: Sepsis Modelmentioning

confidence: 99%

Sildenafil treatment attenuates lung and kidney injury due to overproduction of oxidant activity in a rat model of sepsis: a biochemical and histopathological study

Çadırcı¹,

Halıcı²,

Odabaşoğlu

et al. 2011

Clinical and Experimental Immunology

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SummarySepsis is a systemic inflammatory response to infection and a major cause of morbidity and mortality. Sildenafil (SLD) is a selective and potent inhibitor of cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase PDE5. We aimed to investigate the protective effects of sildenafil on caecal ligation and puncture (CLP)-induced sepsis in rats. Four groups of rats were used, each composed of 10 rats: (i) 10 mg/kg SLD-treated CLP group; (ii) 20 mg/kg SLD-treated CLP group; (iii) CLP group; and (iv) sham-operated control group. A CLP polymicrobial sepsis model was applied to the rats. All groups were killed 16 h later, and lung, kidney and blood samples were analysed histopathologically and biochemically. Sildenafil increased glutathione (GSH) and decreased the activation of myeloperoxidase (MPO) and of lipid peroxidase (LPO) and levels of superoxide dismutase (SOD) in the septic rats. We observed a significant decrease in LPO and MPO and a decrease in SOD activity in the sildenafil-treated CLP rats compared with the sham group. In addition, 20 mg/kg sildenafil treatment in the sham-operated rats improved the biochemical status of lungs and kidneys. Histopathological analysis revealed significant differences in inflammation scores between the sepsis group and the other groups, except the CLP + sildenafil 10 mg/kg group. The CLP + sildenafil 20 mg/kg group had the lowest inflammation score. Sildenafil treatment decreased the serum tumour necrosis factor (TNF)-a level when compared to the CLP group. Our results indicate that sildenafil is a highly protective agent in preventing lung and kidney damage caused by CLPinduced sepsis via maintenance of the oxidant-anti-oxidant status and decrease in the level of TNF-a.

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BAY 41-2272 inhibits the development of chronic hypoxic pulmonary hypertension in rats

Cited by 24 publications

References 26 publications

The Soluble Guanylate Cyclase Stimulator BAY 41-2272 Inhibits Vascular Smooth Muscle Growth through the cAMP-Dependent Protein Kinase and cGMP-Dependent Protein Kinase Pathways

The Soluble Guanylate Cyclase Stimulator BAY 41-2272 Inhibits Vascular Smooth Muscle Growth through the cAMP-Dependent Protein Kinase and cGMP-Dependent Protein Kinase Pathways

Phosphodiesterases Regulate BAY 41-2272-Induced VASP Phosphorylation in Vascular Smooth Muscle Cells

Sildenafil treatment attenuates lung and kidney injury due to overproduction of oxidant activity in a rat model of sepsis: a biochemical and histopathological study

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