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S39 The Role Of Soluble Guanylate Cyclase Stimulator Bay 41–2272 On Remodelling Processes Relevant To The Pathogenesis Of Pulmonary Arterial Hypertension
  1. D Shao,
  2. SJ Wort
  1. Imperial College London, London, UK

Abstract

Introduction and objectives Pulmonary arterial hypertension (PAH) is characterised by remodelling of small, muscular pre-capillary blood vessels. The subsequent rise in pulmonary vascular resistance leads to right ventricular failure and death. The aetiology of the remodelling process is largely unknown although defects in the bone morphogenetic protein receptor II (BMPR II) pathway are likely to be involved. Most of the therapies used thus far are aimed at pulmonary vasodilation. However it is unclear how much of the benefit seen with these medications is related to reverse remodelling. Riociguat is a “first in class” drug that stimulates soluble guanylate cyclase, with a consequent increase in cyclic GMP (and vasodilation). Riociguat has recently been shown to improve haemodynamics and exercise capacity in patients with idiopathic PAH and chronic thromboembolic PH (PATENT and CHEST). Here we sought to determine the effects of Bay 41–2272, the tool compound for riociguat, on remodelling processes in pulmonary vascular cells.

Methods We used primary human endothelial (HPAECs) and smooth muscle cells (HPASMCs) as our target cells. Proliferation was measured using the CyQUANT proliferation kit after cells were treated with various concentration of Bay 41–2272 (kind gifted by Bayer Pharmaceuticals Ltd) for 72 h in the presence of 15% serum. Apoptosis was measured using Cell death ELISA kit and DAPI staining after cells were treated with various concentration of Bay 41–2272 for 24 and 48 h in the absence of serum.

Results Bay41–2272 treatment increased HPASMC apoptosis after 24 and 48 h (Figure 1) by Cell death ELISA; this was further confirmed by DNA condensation assay (DAPI staining). Bay 41–2272 treatment also increased HPAEC apoptosis at 24 h. It was not clear at 48 h treatment whether HPAEC cell death was significant in the absence of serum. Bay 41–2272 treatment reduced HPASMC proliferation (Figure 2), but had no effect on HPAECs.

Conclusions Our preliminary indicate that Bay 41–2272 increases apoptosis and inhibits proliferation, at least in HPASMCs, in vitro. Further studies are needed to fully characterise these effects on remodelling processes and to compare sGC stimulators, such as Bay 41–2272 to Type V phosphodiesterases.

Abstract S39 Figure 1

Bay41–2272 induces HPASMCs DNA fragmentation (apoptosis), data were presented as mean±SEM n = 3. **p < 0.005; ***p < 0.001

Abstract S39 Figure 2

Bay41–2272 inhibits HPASMC proliferation, data were presented as mean±SEM, n = 3. *p < 0.05; **p < 0.005; ***p < 0.001

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