Therapeutic efficacy of azaindole-1 in experimental pulmonary hypertension - PubMed (original) (raw)
doi: 10.1183/09031936.00140309. Epub 2010 Jun 7.
D Kosanovic, P K Pamarthi, A Sydykov, Y-J Lai, R Kast, H Schirok, J-P Stasch, H A Ghofrani, N Weissmann, F Grimminger, W Seeger, R T Schermuly
Affiliations
- PMID: 20530035
- DOI: 10.1183/09031936.00140309
Free article
Therapeutic efficacy of azaindole-1 in experimental pulmonary hypertension
B K Dahal et al. Eur Respir J. 2010 Oct.
Free article
Abstract
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.
Similar articles
- The Rho kinase inhibitor azaindole-1 has long-acting vasodilator activity in the pulmonary vascular bed of the intact chest rat.
Pankey EA, Byun RJ, Smith WB 2nd, Bhartiya M, Bueno FR, Badejo AM, Stasch JP, Murthy SN, Nossaman BD, Kadowitz PJ. Pankey EA, et al. Can J Physiol Pharmacol. 2012 Jul;90(7):825-35. doi: 10.1139/y2012-061. Epub 2012 May 16. Can J Physiol Pharmacol. 2012. PMID: 22591047 - [Effects of rosuvastatin on monocrotaline-induced pulmonary artery hypertension in rats].
Li XL, Guan RJ, Xu QH, Wu ZY. Li XL, et al. Zhonghua Xin Xue Guan Bing Za Zhi. 2011 Mar;39(3):247-53. Zhonghua Xin Xue Guan Bing Za Zhi. 2011. PMID: 21609531 Chinese. - Involvement of asymmetric dimethylarginine and Rho kinase in the vascular remodeling in monocrotaline-induced pulmonary hypertension.
Li XH, Peng J, Tan N, Wu WH, Li TT, Shi RZ, Li YJ. Li XH, et al. Vascul Pharmacol. 2010 Nov-Dec;53(5-6):223-9. doi: 10.1016/j.vph.2010.09.002. Epub 2010 Sep 16. Vascul Pharmacol. 2010. PMID: 20840872 - Inhibition of rho kinase attenuates high flow induced pulmonary hypertension in rats.
Li FH, Xia W, Li AW, Zhao CF, Sun RP. Li FH, et al. Chin Med J (Engl). 2007 Jan 5;120(1):22-9. Chin Med J (Engl). 2007. PMID: 17254483 - ROCK Inhibition as Potential Target for Treatment of Pulmonary Hypertension.
Montagnoli TL, da Silva JS, Sudo SZ, Santos AD, Gomide GF, de Sá MPL, Zapata-Sudo G. Montagnoli TL, et al. Cells. 2021 Jun 30;10(7):1648. doi: 10.3390/cells10071648. Cells. 2021. PMID: 34209333 Free PMC article. Review.
Cited by
- Design and synthesis of novel 8-(azaindolyl)-benzoazepinones as potent and selective ROCK inhibitors.
Pala D, Clark D, Edwards C, Pasqua E, Tigli L, Pioselli B, Malysa P, Facchinetti F, Rancati F, Accetta A. Pala D, et al. RSC Med Chem. 2024 Sep 16. doi: 10.1039/d4md00313f. Online ahead of print. RSC Med Chem. 2024. PMID: 39297059 Free PMC article. - Pulmonary Hypertension: Unveiling Molecular Mechanisms, Diagnosis, and Therapeutic Targets.
Gredic M, Hadzic S. Gredic M, et al. J Pers Med. 2023 Sep 28;13(10):1446. doi: 10.3390/jpm13101446. J Pers Med. 2023. PMID: 37888057 Free PMC article. - New Drugs and Therapies in Pulmonary Arterial Hypertension.
Shah AJ, Beckmann T, Vorla M, Kalra DK. Shah AJ, et al. Int J Mol Sci. 2023 Mar 19;24(6):5850. doi: 10.3390/ijms24065850. Int J Mol Sci. 2023. PMID: 36982922 Free PMC article. Review. - Inhibitors of Mitochondrial Dynamics Mediated by Dynamin-Related Protein 1 in Pulmonary Arterial Hypertension.
Xiao F, Zhang R, Wang L. Xiao F, et al. Front Cell Dev Biol. 2022 Jun 30;10:913904. doi: 10.3389/fcell.2022.913904. eCollection 2022. Front Cell Dev Biol. 2022. PMID: 35846374 Free PMC article. Review. - The Isoquinoline-Sulfonamide Compound H-1337 Attenuates SU5416/Hypoxia-Induced Pulmonary Arterial Hypertension in Rats.
Shoji H, Yoshida Y, Sanada TJ, Naito A, Maruyama J, Zhang E, Sumi K, Sakao S, Maruyama K, Hidaka H, Tatsumi K. Shoji H, et al. Cells. 2021 Dec 27;11(1):66. doi: 10.3390/cells11010066. Cells. 2021. PMID: 35011628 Free PMC article.
MeSH terms
Substances
LinkOut - more resources
Full Text Sources
Medical