Endothelial nitric oxide synthase‐enhancing G‐protein coupled receptor antagonist inhibits pulmonary artery hypertension by endothelin‐1‐dependent and endothelin‐1‐independent pathways in a monocrotaline model
Open Access
- 30 April 2014
- journal article
- Published by Wiley in The Kaohsiung Journal of Medical Sciences
- Vol. 30 (6), 267-278
- https://doi.org/10.1016/j.kjms.2014.02.014
Abstract
This study investigates whether endothelin-1 (ET-1) mediates monocrotaline (MCT)-induced pulmonary artery hypertension (PAH) and right ventricular hypertrophy (RVH), and if so, whether the G-protein coupled receptor antagonist KMUP-1 (7-{2-[4-(2-chlorobenzene)piperazinyl]ethyl}-1,3-dimethylxanthine) inhibits ET-1-mediated PA constriction and the aforementioned pathological changes. In a chronic rat model, intraperitoneal MCT (60 mg/kg) induced PAH and increased PA medial wall thickening and RV/left ventricle + septum weight ratio on Day 21 after MCT injection. Treatment with sublingual KMUP-1 (2.5 mg/kg/day) for 21 days prevented these changes and restored vascular endothelial nitric oxide synthase (eNOS) immunohistochemical staining of lung tissues. Western blotting analysis demonstrated that KMUP-1 enhanced eNOS, soluble guanylate cyclase, and protein kinase G levels, and reduced ET-1 expression and inactivated Rho kinase II (ROCKII) in MCT-treated lung tissue over long-term administration. In MCT-treated rats, KMUP-1 decreased plasma ET-1 on Day 21. KMUP-1 (3.6 mg/kg) maximally appeared at 0.25 hours in the plasma and declined to basal levels within 24 hours after sublingual administration. In isolated PA of MCT-treated rats, compared with control and pretreatment with l-NG-nitroarginine methyl ester (100 μM), KMUP-1 (0.1-100 μM) inhibited ET-1 (0.01 μM)-induced vasoconstriction. Endothelium-denuded PA sustained higher contractility in the presence of KMUP-1. In a 24-hour culture of smooth muscle cells (i.e., PA smooth muscle cells or PASMCs), KMUP-1 (0.1-10 μM) inhibited RhoA- and ET-1-induced RhoA activation. KMUP-1 prevented MCT-induced PAH, PA wall thickening, and RVH by enhancing eNOS and suppressing ET-1/ROCKII expression. In vitro, KMUP-1 inhibited ET-1-induced PA constriction and ET-1-dependent/independent RhoA activation of PASMCs. In summary, KMUP-1 attenuates ET-1-induced/ET-1-mediated PA constriction, and could thus aid in the treatment of PAH caused by MCT.Keywords
Funding Information
- National Science Council Taiwan (NSC 97-2323-B-037-005, 101-2320-B-037-044, 101-2632-B-037-001-MY2)
This publication has 42 references indexed in Scilit:
- Diversity and modularity of G protein-coupled receptor structuresTrends in Pharmacological Sciences, 2011
- KMUP-1 inhibits pulmonary artery proliferation by targeting serotonin receptors/transporter and NO synthase, inactivating RhoA and suppressing AKT/ERK phosphorylationVascular Pharmacology, 2010
- The xanthine derivative KMUP‐1 inhibits models of pulmonary artery hypertension via increased NO and cGMP‐dependent inhibition of RhoA/Rho kinaseBritish Journal of Pharmacology, 2010
- Endothelin-1 and Serotonin are Involved in Activation of RhoA/Rho Kinase Signaling in the Chronically Hypoxic Hypertensive Rat Pulmonary CirculationJournal of Cardiovascular Pharmacology, 2007
- The importance of endothelin-1 for vascular dysfunction in cardiovascular diseaseCardiovascular Research, 2007
- cGMP‐enhancing‐ and α1A/α1D‐adrenoceptor blockade‐derived inhibition of Rho‐kinase by KMUP‐1 provides optimal prostate relaxation and epithelial cell anti‐proliferation efficacyThe Prostate, 2007
- Rho kinase activation maintains high pulmonary vascular resistance in the ovine fetal lungAmerican Journal of Physiology-Lung Cellular and Molecular Physiology, 2006
- Regulation of cGMP-dependent Protein Kinase Expression by Rho and Krüppel-like Transcription Factor-4Published by Elsevier BV ,2006
- Activation of Soluble Guanylate Cyclase Reverses Experimental Pulmonary Hypertension and Vascular RemodelingCell Metabolism, 2006
- Effects of BAY 41–2272, a soluble guanylate cyclase activator, on pulmonary vascular reactivity in the ovine fetusAmerican Journal of Physiology-Lung Cellular and Molecular Physiology, 2005