The soluble guanylate cyclase activator HMR1766 reverses hypoxia-induced experimental pulmonary hypertension in mice

Weißmann, Norbert; Hackemack, S.; Dahal, Bhola K.; Pullamsetti, Soni Savai; Mittal, Manish; Fuchs, Beate; Medebach, Thomas; Dumitrascu, Rio; Eickels, Martin van; Ghofrani, Hossein Ardeschir; Seeger, Werner; Schermuly, Ralph Theo

doi:10.1152/ajplung.00189.2009

Cited by 34 publications

(28 citation statements)

References 46 publications

(57 reference statements)

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“…The technique of successive hypoxic manoeuvres was employed in isolated, ventilated and buffer-perfused mice lungs to investigate the effect of azaindole-1, fasudil (H139; Sigma-Aldich) and Y-27632 (Y0503; Sigma-Aldich) on acute HPV as described [34]. The ROCK inhibitors were prepared in dimethyl sulphoxide (DMSO).…”

Section: Isolated Murine Lungsmentioning

confidence: 99%

Therapeutic efficacy of azaindole-1 in experimental pulmonary hypertension

Dahal¹,

Kosanovic²,

Pk³

et al. 2010

European Respiratory Journal

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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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Section: Isolated Murine Lungsmentioning

confidence: 99%

Therapeutic efficacy of azaindole-1 in experimental pulmonary hypertension

Dahal¹,

Kosanovic²,

Pk³

et al. 2010

European Respiratory Journal

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“…This might be expected because pulmonary epithelial and endothelial cells express the same constitutive isoform of NOS, namely eNOS. Interestingly, while inhaled NO and stimulation of downstream targets of NO, such as soluble guanylyl cyclase activators, suppress some forms of lung disease and inhibit pulmonary fibrosis, blockade of NO formation was found to be beneficial in other conditions 31. Thus, the role of NO in adaptation of pulmonary structure and function under stress conditions seems to be very complex in nature.…”

Section: Discussionmentioning

confidence: 99%

Effect of nitric oxide deficiency on the pulmonary PTHrP system

Brockhoff

Schreckenberg

Forst

et al. 2016

J Cellular Molecular Medi

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Nitric oxide (NO) deficiency is common in pulmonary diseases, but its effect on pulmonary remodelling is still controversial. As pulmonary parathyroid hormone‐related protein (PTHrP) expression is a key regulator of pulmonary fibrosis and development, the effect of chronic NO deficiency on the pulmonary PTHrP system and its relationship with oxidative stress was addressed. NO bioavailability in adult rats was reduced by systemic administration of L‐NAME via tap water. To clarify the role of NO synthase (NOS)‐3‐derived NO on pulmonary expression of PTHrP, NOS‐3‐deficient mice were used. Captopril and hydralazine were used to reduce the hypertensive effect of L‐NAME treatment and to interfere with the pulmonary renin‐angiotensin system (RAS). Quantitative RT‐PCR and immunoblot techniques were used to characterize the expression of key proteins involved in pulmonary remodelling. L‐NAME administration significantly reduced pulmonary NO concentration and caused oxidative stress as characterized by increased pulmonary nitrite concentration and increased expression of NOX2, p47phox and p67phox. Furthermore, L‐NAME induced the pulmonary expression of PTHrP and of its corresponding receptor, PTH‐1R. Expression of PTHrP and PTH‐1R correlated with the expression of two well‐established PTHrP downstream targets, ADRP and PPARγ, suggesting an activation of the pulmonary PTHrP system by NO deficiency. Captopril reduced the expression of PTHrP, profibrotic markers and ornithine decarboxylase, but neither that of PTH‐1R nor that of ADRP and PPARγ. All transcriptional changes were confirmed in NOS‐3‐deficient mice. In conclusion, NOS‐3‐derived NO suppresses pulmonary PTHrP and PTH‐1R expression, thereby modifying pulmonary remodelling.

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“…Another technique whereby the sensing catheter is inserted into the jugular vein and forwarded to the right ventricle has also been described in rats 8 and mice. 7 In 2008, Handoko et al described a new surgical technique for implanting the telemetry catheter using a trans-diaphragm approach that is less traumatic for the animals. This technique allows better orientation for introducing the catheter within the right ventricle and especially for further forwarding it into the pulmonary artery, providing a stronger anchorage of the device, which results in a significantly better recovery following surgery.…”

Section: Discussionmentioning

confidence: 99%

“…6 Since then, telemetry has been widely described as a method for measuring RVP and PAP in rodent models of pulmonary hypertension. [7][8][9][10] However, the original procedure of implantable radiotelemetry methodology included extremely invasive thoracic surgery resulting in significant stress, potentially disturbing the cardiovascular system, and in delayed recovery. More recently, a trans-diaphragm surgical technique has been described in rats, avoiding any surgical invasion of the thorax, and resulting in significantly faster recovery of the animals after the surgery.…”

mentioning

confidence: 99%

Measurement of right ventricular pressure by telemetry in conscious moving rabbits

2013

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Implantable radiotelemetry methodology has been used to continuously monitor pulmonary hemodynamics including right ventricular pressure (RVP) or pulmonary arterial pressure (PAP) in conscious, untethered and freely moving animals such as mice and rats. The use of implantable radiotelemetry to monitor RVP or PAP has never previously been described in rabbits. The aim of the present study was to use implantable radiotelemetry to continuously monitor RVP in conscious adult rabbits. Telemetry transmitters were implanted in 44 adult male New Zealand rabbits using a trans-diaphragm approach for the catheter placement. RVP, heart rate (HR) and activity were monitored every 15 min for 20 s. Body mass was recorded once a week. A total of 39 (88%) rabbits were successfully implanted. Thirty rabbits survived the surgical procedure resulting in an overall survival rate of 73%. RVP, HR and activity were long-term monitored in 17 rabbits for an average period of 103 AE 15 days. Weekly body mass follow-up showed that implantable radiotelemetry did not impair the normal development of the animal. Twenty-four-hour period monitoring of RVP, HR and activity showed concomitant changes in RVP, HR and activity according to the dark/light cycle applied to the rabbits. To conclude, implantable radiotelemetry methodology can be safely used to continuously monitor RVP in conscious rabbits. KeywordsTelemetry, right ventricular pressure, pulmonary circulation, rabbit Pulmonary hypertension is a medical condition mainly affecting the pulmonary circulation. Various rodent animal models have been developed to better understand the physiopathology of pulmonary hypertension and to test potential new drugs.1 Hemodynamic data from these animal models are usually restricted to a single measurement of pulmonary arterial pressure (PAP) and/or right ventricular pressure (RVP), in anesthetized, mechanically ventilated and often openchest animals.2,3 More recently, high-resolution echocardiography and magnetic resonance imaging (MRI) techniques have been developed to accurately estimate hemodynamics in small animals including rats, mice and rabbits, and to allow for serial monitoring of experimental pulmonary hypertension.4,5 Although these techniques are non-invasive, they are performed on anesthetized animals, which implies respiratory and cardiovascular depression resulting in various artifacts. Continuous monitoring of RVP and PAP in conscious, untethered and freely moving animals was introduced by Hess et al. in the 1990s and has consequently and considerably improved hemodynamic pulmonary measurement in rodent models of pulmonary hypertension. 6 Since then, telemetry has been widely described as a method for measuring RVP and PAP in rodent models of pulmonary hypertension.7-10 However, the original procedure of implantable radiotelemetry methodology included extremely invasive thoracic surgery resulting in significant stress, potentially disturbing the cardiovascular system, and in delayed recovery. More recently, a trans-diaphragm surgi...

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The soluble guanylate cyclase activator HMR1766 reverses hypoxia-induced experimental pulmonary hypertension in mice

Cited by 34 publications

References 46 publications

Therapeutic efficacy of azaindole-1 in experimental pulmonary hypertension

Therapeutic efficacy of azaindole-1 in experimental pulmonary hypertension

Effect of nitric oxide deficiency on the pulmonary PTHrP system

Measurement of right ventricular pressure by telemetry in conscious moving rabbits

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