Sildenafil Prevents and Reverses Transverse-Tubule Remodeling and Ca 2+ Handling Dysfunction in Right Ventricle Failure Induced by Pulmonary Artery Hypertension
| Autor: | Philip N. Sanders, Mark E. Anderson, Yu Ping Xie, Isabella M. Grumbach, Long-Sheng Song, Robert M. Weiss, Biyi Chen, Kathy Zimmerman, Lie Cheng Wang, Ang Guo, Yue Li |
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| Rok vydání: | 2012 |
| Předmět: |
Male
medicine.medical_specialty Sildenafil Hypertension Pulmonary Ventricular Dysfunction Right Piperazines Sildenafil Citrate Article chemistry.chemical_compound Afterload Internal medicine medicine.artery Internal Medicine Animals Medicine Myocyte Myocytes Cardiac Sulfones Rats Wistar Excitation Contraction Coupling Heart Failure Microscopy Confocal Monocrotaline Hypertrophy Right Ventricular Ventricular Remodeling business.industry Endoplasmic reticulum Phosphodiesterase 5 Inhibitors Transverse tubule Myocardial Contraction Rats Disease Models Animal Treatment Outcome Endocrinology medicine.anatomical_structure chemistry Purines Ventricle cGMP-specific phosphodiesterase type 5 Pulmonary artery Cardiology Calcium business |
| Zdroj: | Hypertension. 59:355-362 |
| ISSN: | 1524-4563 0194-911X |
| DOI: | 10.1161/hypertensionaha.111.180968 |
| Popis: | Right ventricular (RV) failure (RVF) is the main cause of death in patients with pulmonary artery hypertension (PAH). Sildenafil, a phosphodiesterase type 5 inhibitor, was approved recently for treatment of PAH patients. However, the mechanisms underlying RV contractile malfunction and the benefits of sildenafil on RV function are not well understood. We aimed to investigate the following: (1) the ultrastructural and excitation-contraction coupling alterations underlying PAH-induced RVF; (2) whether the ultrastructural changes are reversible; and (3) the mechanisms underlying the therapeutic benefits of sildenafil in PAH-RVF. We used a single injection of monocrotaline in Wistar rats to induce pulmonary vascular proliferation, which led to PAH and RVF. RV myocytes displayed severe transverse (T)-tubule loss and disorganization, as well as blunted and dys-synchronous sarcoplasmic reticulum Ca 2+ release. Sildenafil prevented and reversed the monocrotaline-induced PAH and LV filling impairment. Early intervention with sildenafil prevented RV hypertrophy and the development of RVF, T-tubule remodeling, and Ca 2+ handling dysfunction. Although late treatment with sildenafil did not reverse RV hypertrophy in animals with established RVF, RV systolic function was improved. Furthermore, late intervention partially reversed both the impairment of myocyte T-tubule integrity and Ca 2+ handling protein and sarcoplasmic reticulum Ca 2+ release function in monocrotaline-treated rats. In conclusion, PAH-induced increase in RV afterload causes severe T-tubule remodeling and Ca 2+ handling dysfunction in RV myocytes, leading to RV contractile failure. Sildenafil prevents and partially reverses ultrastructural, molecular, and functional remodeling of failing RV myocytes. Reversal of pathological T-tubule remodeling, although incomplete, is achievable without the regression of RV hypertrophy. |
| Databáze: | OpenAIRE |
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