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Phosphodiesterase-type 3 inhibitor potentiates cAMP generation and antiproliferative effects of treprostinil in pulmonary arterial smooth muscle cells from patients with pulmonary hypertension

Patel, J; Orie, N; Clapp, LH; (2010) Phosphodiesterase-type 3 inhibitor potentiates cAMP generation and antiproliferative effects of treprostinil in pulmonary arterial smooth muscle cells from patients with pulmonary hypertension. Presented at: ERS Annual Congress 2010, Barcelona, Spain. Green open access

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Abstract

The prostacyclin class of drugs are used in pulmonary arterial hypertension (PAH), a vascular proliferative disease. While evidence suggests agents improve survival, they eventually stop working. Thus ways are being sort to improve their clinical efficacy. We hypothesised that prostacyclin action could be enhanced by inhibition of phosphodiesterase type 3 (PDE3), a major regulator of cyclic AMP levels in the lung, whose activity appears increased in PAH [1]. Cell proliferation (assessed by cell number) and cyclic AMP assays were performed in pulmonary arterial smooth muscle cells derived from patients with idiopathic PAH (n=6). Treprostinil (1μM) significantly (p<0.001) increased cAMP by 7.0±0.6 fold (n=6) at 30 mins but not thereafter. In the presence of the relatively selective PDE3 inhibitor, cilostamide (1μM), treprostinil produced twice as much cAMP (13.1±0.8 compared to 25.0±2.7 pmol/mg protein, n=3), and levels remained significantly (p<0.05) elevated at 24 hr compared to analogue alone (10.8±1.8 versus 3.22±0.8, pmol/mg protein). Cilostamide (1 & 10μM) also suppressed growth induced by 10% FBS by 20%, as did treprostinil (1μM). The combination however, produced further growth suppression of 35% (p<0.05) and 47% (P<0.001) for low and high PDE inhibitor dose, respectively. In conclusion, PDE3 inhibition may help improve prostacyclin analogue action in IPAH by prolonging elevation in cAMP and enhancing the antiproliferative effects of these agents. Reference: 1. Murray F, et al. Am J Physiol 2007; 292: L294-L303. Supported by an unrestricted educational grant from United Therapeutics.

Type: Conference item (Presentation)
Title: Phosphodiesterase-type 3 inhibitor potentiates cAMP generation and antiproliferative effects of treprostinil in pulmonary arterial smooth muscle cells from patients with pulmonary hypertension
Event: ERS Annual Congress 2010
Location: Barcelona, Spain
Dates: 18 September 2010 - 22 September 2010
Open access status: An open access version is available from UCL Discovery
Publisher version: http://www.ers-education.org/events/international-...
Language: English
Additional information: This version is the version of record. For information on re-use, please refer to the publisher’s terms and conditions.
Keywords: Cyclic AMP, pulmonary arterial smooth muscle cells, hypertension, phosphodiesterase
UCL classification: UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Surgery and Interventional Sci
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Surgery and Interventional Sci > Department of Surgical Biotechnology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Pop Health Sciences > Institute of Cardiovascular Science
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Pop Health Sciences > Institute of Cardiovascular Science > Pre-clinical and Fundamental Science
URI: https://discovery.ucl.ac.uk/id/eprint/1508397
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