Sildenafil prevents and reverses transverse-tubule remodeling and Ca 2+ handling dysfunction in right ventricle failure induced by pulmonary artery hypertension

Yu Ping Xie, Biyi Chen, Philip Sanders, Ang Guo, Yue Li, Kathy Zimmerman, Lie Cheng Wang, Robert M. Weiss, Isabella M. Grumbach, Mark E. Anderson, Long Sheng Song

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)355-362
Number of pages8
JournalHypertension
Volume59
Issue number2
DOIs
StatePublished - Feb 1 2012
Externally publishedYes

Keywords

  • Calcium
  • Excitation-contraction coupling
  • PDE5 inhibitor
  • Pulmonary artery hypertension
  • Right ventricle failure
  • T-tubule

ASJC Scopus subject areas

  • Internal Medicine

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