Comparison of Macitentan and Bosentan on Right Ventricular Remodeling in a Rat Model of Non-vasoreactive Pulmonary Hypertension

Iglarz, Marc; Landskroner, Kyle; Bauer, Yasmina; Vercauteren, Magali; Rey, Markus; Renault, Bérengère; Studer, R. O.; Vezzali, Enrico; Freti, Diego; Hadana, Hakim; Schläpfer, Manuela; Cattaneo, C; Bortolamiol, Céline; Weber, E.; Whitby, Brian; Delahaye, Stéphane; Wanner, Daniel; Steiner, Pauline; Nayler, Oliver; Hess, Patrick; Clozel, Martine

doi:10.1097/fjc.0000000000000296

Cited by 40 publications

(33 citation statements)

References 36 publications

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“…It would be important to test whether infusion of vasodilators in the Su/Hx model in vivo affects pulmonary arterial pressure. Interestingly, a recent study demonstrated that acute intravenous infusion of the vasodilator agent adenosine caused a dose-dependent reduction in pulmonary artery pressure in anesthetized Wistar rats with Su/Hx-induced PH (Iglarz et al, 2015), suggesting that at an earlier 5-week time point, there is a reactive component of PH in this rat strain. Whether this reactive component of PH to vasodilators could still be observed at a later 7-week time point and in the Sprague-Dawley rat model of Su/Hx remains to be investigated.…”

Section: Pulmonary Vascular Dysfunction In Pulmonary Hypertensionmentioning

confidence: 98%

Impaired Pulmonary Arterial Vasoconstriction and Nitric Oxide–Mediated Relaxation Underlie Severe Pulmonary Hypertension in the Sugen-Hypoxia Rat Model

Christou¹,

Hudalla²,

Michael³

et al. 2017

J Pharmacol Exp Ther

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Pulmonary vasoreactivity could determine the responsiveness to vasodilators and, in turn, the prognosis of pulmonary hypertension (PH). We hypothesized that pulmonary vasoreactivity is impaired, and we examined the underlying mechanisms in the Sugen-hypoxia rat model of severe PH. Male Sprague-Dawley rats were injected with Sugen (20 mg/kg s.c.) and exposed to hypoxia (9% O) for 3 weeks, followed by 4 weeks in normoxia (Su/Hx), or treated with Sugen alone (Su) or hypoxia alone (Hx) or neither (Nx). After hemodynamic measurements, the heart was assessed for right ventricular hypertrophy (Fulton's index); the pulmonary artery, aorta, and mesenteric arteries were isolated for vascular function studies; and contractile markers were measured in pulmonary arteries using quantitative polymerase chain reaction (PCR). Other rats were used for morphometric analysis of pulmonary vascular remodeling. Right ventricular systolic pressure and Fulton's index were higher in Su/Hx versus Su, Hx, and Nx rats. Pulmonary vascular remodeling was more prominent in Su/Hx versus Nx rats. In pulmonary artery rings, contraction to high KCl (96 mM) was less in Su/Hx versus Nx and Su, and phenylephrine-induced contraction was reduced in Su/Hx versus Nx, Hx, and Su. Acetylcholine (ACh)-induced relaxation was less in Su/Hx versus Nx and Hx, suggesting reduced endothelium-dependent vasodilation. ACh relaxation was inhibited by nitric oxide synthase (NOS) and guanylate cyclase blockade in all groups, suggesting a role of the NO-cGMP pathway. Nitrate/nitrite production in response to ACh was less in Su/Hx versus Nx, supporting reduced endothelial NO production. Sodium nitroprusside (10 M) caused less relaxation in Su/Hx versus Nx, Hx, and Su, suggesting a decreased responsiveness of vascular smooth muscle (VSM) to vasodilators. Neither contraction nor relaxation differed in the aorta or mesenteric arteries of all groups. PCR analysis showed decreased expression of contractile markers in pulmonary artery of Su/Hx versus Nx. The reduced responsiveness to vasoconstrictors and NO-mediated vasodilation in the pulmonary, but not systemic, vessels may be an underlying mechanism of severe PH in Su/Hx rats and appears to involve attenuation of the NO relaxation pathway and a switch of pulmonary VSM cells to a synthetic less reactive phenotype.

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Section: Pulmonary Vascular Dysfunction In Pulmonary Hypertensionmentioning

confidence: 98%

Impaired Pulmonary Arterial Vasoconstriction and Nitric Oxide–Mediated Relaxation Underlie Severe Pulmonary Hypertension in the Sugen-Hypoxia Rat Model

Christou¹,

Hudalla²,

Michael³

et al. 2017

J Pharmacol Exp Ther

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“…Compound 3 was tested in a head-to-head comparison with macitentan, an orally active, potent, dual endothelin (ET) A and B receptor antagonist currently in use to treat PAH patients. Compared to other endothelin receptor antagonists, macitentan has improved tissue targeting, a longer duration of action and an improved safety profile (DuBrock and Channick, 2014;Iglarz et al, 2015). An interventional treatment regimen was adopted for both macitentan and Compound 3.…”

Section: Discussionmentioning

confidence: 99%

“…Interestingly, we found that also macitentan did not significantly prevent RV hypertrophy despite a trend. Although a positive effect of macitentan against MCT-induced RV hypertrophy was previously reported, it should be noted that the treatment regimen was preventative as started immediately after MCT injection and lasted for 4 weeks (Iglarz et al, 2015). Thus, a clear effect on RV hypertrophy in the MCT rat model may require preventative treatments or interventional treatments lasting longer than 2 weeks.…”

Section: Tablementioning

confidence: 92%

Pharmacological characterization of a highly selective Rho kinase (ROCK) inhibitor and its therapeutic effects in experimental pulmonary hypertension

Cantoni

Cavalli

Pastore

et al. 2019

European Journal of Pharmacology

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Studies on the role of Rho-associated protein kinase (ROCK) in experimental pulmonary artery hypertension (PAH) relies mainly on the use of pharmacological inhibitors. However, interpreting these data is hampered by the lack of specificity of commonly utilized inhibitors. To fill this gap, we have selected and characterized a novel ROCK inhibitor, Compound 3, previously described in a patent. Inhibitory potency of Compound 3 against enzymatic activity of ROCK-1 and 2 (IC 50 = 10 ± 3.1 and 7.8 ± 0.5 nM, respectively) was accompanied by a strong vasodilating effect in phenylephrine pre-contracted isolated rat pulmonary artery rings (IC 50 = 51.7 ± 9.1 nM) as well as in aortic rings (IC 50 = 45.5 ± 1.1 nM). Compound 3 showed a remarkable selectivity towards ROCK 1 and 2 when tested against a large panel (> 400) of human kinases. A partial explanation for its selectivity is provided from docking simulations within ROCK-1. Pharmacokinetic studies showed that Compound 3 is suitable for a twice daily administration without significant accumulation upon repeated dosing. In rats with monocrotaline (MCT)-induced pulmonary hypertension, therapy with Compound 3, (1 and 3 mg/kg, s.c., b.i.d.), started 14 days after induction of the disease, attenuated right ventricle systolic pressure (RVSP) increase. Morphometric histological analysis showed that Compound 3, at both doses, counteracted MCT-induced medial thickening of lung distal arterioles with an effect comparable to macitentan (10 mg/kg, p.o., q.d.). Compound 3 is a potent and highly selective ROCK inhibitor that ameliorates hemodynamic parameters and counteracts pulmonary vascular remodeling in experimental PAH.

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“…5 Characteristic features of this compound are sustained receptor binding and enhanced tissue penetration. 6, 7 Recently, a multi-national phase III trial (SERAPHIN) of this compound was carried out using a primary endpoint reflecting long-term disease progression, and the risk for morbidity and mortality was significantly reduced by 45% on 10 mg macitentan compared with placebo in symptomatic PAH patients. 8 Japanese patients, however, were not enrolled in the multi-national study, and the Japanese regulatory authority proposed a clinical trial with only Japanese patients.…”

Section: Discussionmentioning

confidence: 99%

Efficacy and Safety of a Novel Endothelin Receptor Antagonist, Macitentan, in Japanese Patients With Pulmonary Arterial Hypertension

Tahara

Dobashi

Fukuda

et al. 2016

Circ J

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Comparison of Macitentan and Bosentan on Right Ventricular Remodeling in a Rat Model of Non-vasoreactive Pulmonary Hypertension

Abstract: Supplemental Digital Content Is Available in the Text.

Cited by 40 publications

References 36 publications

Impaired Pulmonary Arterial Vasoconstriction and Nitric Oxide–Mediated Relaxation Underlie Severe Pulmonary Hypertension in the Sugen-Hypoxia Rat Model

Impaired Pulmonary Arterial Vasoconstriction and Nitric Oxide–Mediated Relaxation Underlie Severe Pulmonary Hypertension in the Sugen-Hypoxia Rat Model

Pharmacological characterization of a highly selective Rho kinase (ROCK) inhibitor and its therapeutic effects in experimental pulmonary hypertension

Efficacy and Safety of a Novel Endothelin Receptor Antagonist, Macitentan, in Japanese Patients With Pulmonary Arterial Hypertension

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