Alterations of the nitric oxide receptor, soluble guanylate cyclase (sGC) may contribute to the pathophysiology of pulmonary arterial hypertension (PAH). In the present study, the expression of sGC in explanted lung tissue of PAH patients was studied and the effects of the sGC stimulator BAY 63-2521 on enzyme activity, and haemodynamics and vascular remodelling were investigated in two independent animal models of PAH.Strong upregulation of sGC in pulmonary arterial vessels in the idiopathic PAH lungs compared with healthy donor lungs was demonstrated by immunohistochemistry. Upregulation of sGC was detected, similarly to humans, in the structurally remodelled smooth muscle layer in chronic hypoxic mouse lungs and lungs from monocrotaline (MCT)-injected rats. BAY 63-2521 is a novel, orally available compound that directly stimulates sGC and sensitises it to its physiological stimulator, nitric oxide. Chronic treatment of hypoxic mice and MCT-injected rats, with fully established PAH, with BAY 63-2521 (10 mg?kg) partially reversed the PAH, the right heart hypertrophy and the structural remodelling of the lung vasculature.Upregulation of soluble guanylate cyclase in pulmonary arterial smooth muscle cells was noted in human idiopathic pulmonary arterial hypertension lungs and lungs from animal models of pulmonary arterial hypertension. Stimulation of soluble guanylate cyclase reversed right heart hypertrophy and structural lung vascular remodelling. Soluble guanylate cyclase may thus offer a new target for therapeutic intervention in pulmonary arterial hypertension.KEYWORDS: BAY 63-2521, cardiovascular diseases, nitric oxide, pharmacology, pulmonary arterial hypertension, smooth muscle P ulmonary arterial hypertension (PAH) is a disabling disease, with high mortality, characterised by sustained elevation in pulmonary arterial pressure (Ppa) and pulmonary vascular remodelling due to proliferation and migration of pulmonary artery smooth muscle cells (PASMCs) [1]. Imbalance of vasodilatory and vasoconstrictive mediators has been implicated in these changes. Reduced urinary excretion of prostaglandin (PG)I 2 and augmented excretion of thromboxane metabolites were found in patients with idiopathic PAH (IPAH) [2], and immunohistological studies have shown reduced expression of PGI 2 synthase in the pulmonary vessels originating from those patients [3]. Another important mediator in the regulation of vascular tone is nitric oxide (NO), which is synthesised by NO synthases. Local NO production from endothelium and epithelium regulates pulmonary perfusion, depending on alveolar ventilation to assure optimised ventilation/perfusion distribution [4][5][6]. In patients with IPAH, it has been reported that the expression of endothelial NO synthase is downregulated [7], while other reports show an upregulation in plexiform lesions of IPAH patients [8]. However, little is known about the expression and regulation of soluble guanylate cyclase (sGC) which operates as a receptor for NO. Typically, sGC is found as a hetero...

An accumulating body of evidence incriminates Rho kinase (ROCK) in the pathogenesis of pulmonary hypertension (PH). The therapeutic efficacy of azaindole-1, a novel highly selective and orally active ROCK inhibitor, has not yet been investigated in PH.This study aimed to investigate the effects of azaindole-1 on 1) acute hypoxic pulmonary vasoconstriction (HPV), 2) proliferation of pulmonary arterial smooth muscle cells (PASMCs) and 3) animal models of PH.Azaindole-1 significantly inhibited HPV in isolated, ventilated and buffer-perfused murine lungs and proliferation of primary rat PASMCs in vitro. Azaindole-1 was administered orally from 21 to 35 days after monocrotaline (MCT) injection in rats and hypoxic exposure in mice. Azaindole-1 (10 and 30 mg per kg body weight per day in rats and mice, respectively) significantly improved haemodynamics and right ventricular hypertrophy. Moreover, the medial wall thickness and muscularisation of peripheral pulmonary arteries were ameliorated. Azaindole-1 treatment resulted in a decreased immunoreactivity for phospho-myosin phosphatase target subunit 1 and proliferating cell nuclear antigen in pulmonary vessels of MCT-injected rats, suggesting an impaired ROCK activity and reduced proliferating cells.Azaindole-1 provided therapeutic benefit in experimental PH, and this may be attributable to its potent vasorelaxant and antiproliferative effects. Azaindole-1 may offer a useful approach for treatment of PH.KEYWORDS: Azaindole-1, hypoxia, monocrotaline, pulmonary hypertension, Rho kinase P ulmonary arterial hypertension (PAH) is a chronic fatal disease characterised by sustained elevation of pulmonary artery pressure and reduced exercise tolerance. As a consequence, the right ventricular afterload increases and culminates in right ventricular failure. PAH has a complex pulmonary vascular pathophysiology, including vasoconstriction, vascular remodelling and in situ thrombosis. The progressive vascular remodelling, the hallmark of PAH pathology, is attributable to abnormalities in vascular cells, such as increased proliferation and resistance to apoptosis [1][2][3]. However, the precise molecular mechanism is incompletely understood, and so a therapeutic approach for curing this disease is currently sought after.The small GTPase RhoA is one of the members of the Rho protein family that regulate cellular functions such as contraction, motility, proliferation and apoptosis, and Rho kinases (ROCKs) are the best characterised downstream targets for RhoA [4]. Two isoforms of the serine/threonine kinase ROCK have been identified: . ROCKs are ubiquitously expressed in tissues including vasculature and heart. Owing to its role in key cell functions, hyperactive ROCK signalling results in cardiovascular disorders associated with sustained abnormal vasoconstriction and promotion of vascular remodelling [8,9]. Studies on animal models of pulmonary hypertension (PH), such as chronic hypoxia-, monocrotaline (MCT)-, vascular endothelial growth factor receptor inhibition and chron...

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