Ranolazine prevents INaL enhancement and blunts myocardial remodelling in a model of pulmonary hypertension

Marcella Rocchetti, Luca Sala, Riccardo Rizzetto, Lidia Irene Staszewsky, Matteo Alemanni, Vanessa Zambelli, Ilaria Russo, Lucio Barile, Laura Cornaghi, Claudia Altomare, Carlotta Ronchi, Gaspare Mostacciuolo, Jacopo Lucchetti, Marco Gobbi, Roberto Latini, Antonio Zaza

Research output: Contribution to journalArticle

22 Citations (Scopus)

Abstract

Aims Pulmonary arterial hypertension (PAH) reflects abnormal pulmonary vascular resistance and causes right ventricular (RV) hypertrophy. Enhancement of the late sodium current (INaL) may result from hypertrophic remodelling. The study tests whether: (i) constitutive INaL enhancement may occur as part of PAH-induced myocardial remodelling; (ii) ranolazine (RAN), a clinically available INaL blocker, may prevent constitutive INaL enhancement and PAH-induced myocardial remodelling. Methods and results PAH was induced in rats by a single monocrotaline (MCT) injection [60 mg/kg intraperitoneally (i.p.)]; studies were performed 3 weeks later. RAN (30 mg/kg bid i.p.) was administered 48 h after MCT and washed-out 15 h before studies. MCT increased RV systolic pressure and caused RV hypertrophy and loss of left ventricular (LV) mass. In the RV, collagen was increased; myocytes were enlarged with T-tubule disarray and displayed myosin heavy chain isoform switch. INaL was markedly enhanced; diastolic Ca2+ was increased and Ca2+ release was facilitated. K+ currents were down-regulated and APD was prolonged. In the LV, INaL was enhanced to a lesser extent and cell Ca2+ content was strongly depressed. Electrical remodelling was less prominent than in the RV. RAN completely prevented INaL enhancement and limited most aspects of PAH-induced remodelling, but failed to affect in vivo contractile performance. RAN blunted the MCT-induced increase in RV pressure and medial thickening in pulmonary arterioles. Conclusion PAH induced remodelling with chamber-specific aspects. RAN prevented constitutive INaL enhancement and blunted myocardial remodelling. Partial mechanical unloading, resulting from an unexpected effect of RAN on pulmonary vasculature, might contribute to this effect.

Original languageEnglish
Pages (from-to)37-48
Number of pages12
JournalCardiovascular Research
Volume104
Issue number1
DOIs
Publication statusPublished - Oct 1 2014

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Pulmonary Hypertension
Monocrotaline
Right Ventricular Hypertrophy
pamidronate
Ventricular Pressure
Atrial Remodeling
Lung
Myosin Heavy Chains
Arterioles
Vascular Resistance
Muscle Cells
Ranolazine
Protein Isoforms
Collagen
Sodium
Blood Pressure
Injections

Keywords

  • Hypertrophy
  • Late sodium current
  • Pulmonary hypertension
  • Ranolazine
  • Remodelling

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)
  • Physiology
  • Medicine(all)

Cite this

Rocchetti, M., Sala, L., Rizzetto, R., Irene Staszewsky, L., Alemanni, M., Zambelli, V., ... Zaza, A. (2014). Ranolazine prevents INaL enhancement and blunts myocardial remodelling in a model of pulmonary hypertension. Cardiovascular Research, 104(1), 37-48. https://doi.org/10.1093/cvr/cvu188

Ranolazine prevents INaL enhancement and blunts myocardial remodelling in a model of pulmonary hypertension. / Rocchetti, Marcella; Sala, Luca; Rizzetto, Riccardo; Irene Staszewsky, Lidia; Alemanni, Matteo; Zambelli, Vanessa; Russo, Ilaria; Barile, Lucio; Cornaghi, Laura; Altomare, Claudia; Ronchi, Carlotta; Mostacciuolo, Gaspare; Lucchetti, Jacopo; Gobbi, Marco; Latini, Roberto; Zaza, Antonio.

In: Cardiovascular Research, Vol. 104, No. 1, 01.10.2014, p. 37-48.

Research output: Contribution to journalArticle

Rocchetti, M, Sala, L, Rizzetto, R, Irene Staszewsky, L, Alemanni, M, Zambelli, V, Russo, I, Barile, L, Cornaghi, L, Altomare, C, Ronchi, C, Mostacciuolo, G, Lucchetti, J, Gobbi, M, Latini, R & Zaza, A 2014, 'Ranolazine prevents INaL enhancement and blunts myocardial remodelling in a model of pulmonary hypertension', Cardiovascular Research, vol. 104, no. 1, pp. 37-48. https://doi.org/10.1093/cvr/cvu188
Rocchetti M, Sala L, Rizzetto R, Irene Staszewsky L, Alemanni M, Zambelli V et al. Ranolazine prevents INaL enhancement and blunts myocardial remodelling in a model of pulmonary hypertension. Cardiovascular Research. 2014 Oct 1;104(1):37-48. https://doi.org/10.1093/cvr/cvu188
Rocchetti, Marcella ; Sala, Luca ; Rizzetto, Riccardo ; Irene Staszewsky, Lidia ; Alemanni, Matteo ; Zambelli, Vanessa ; Russo, Ilaria ; Barile, Lucio ; Cornaghi, Laura ; Altomare, Claudia ; Ronchi, Carlotta ; Mostacciuolo, Gaspare ; Lucchetti, Jacopo ; Gobbi, Marco ; Latini, Roberto ; Zaza, Antonio. / Ranolazine prevents INaL enhancement and blunts myocardial remodelling in a model of pulmonary hypertension. In: Cardiovascular Research. 2014 ; Vol. 104, No. 1. pp. 37-48.
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abstract = "Aims Pulmonary arterial hypertension (PAH) reflects abnormal pulmonary vascular resistance and causes right ventricular (RV) hypertrophy. Enhancement of the late sodium current (INaL) may result from hypertrophic remodelling. The study tests whether: (i) constitutive INaL enhancement may occur as part of PAH-induced myocardial remodelling; (ii) ranolazine (RAN), a clinically available INaL blocker, may prevent constitutive INaL enhancement and PAH-induced myocardial remodelling. Methods and results PAH was induced in rats by a single monocrotaline (MCT) injection [60 mg/kg intraperitoneally (i.p.)]; studies were performed 3 weeks later. RAN (30 mg/kg bid i.p.) was administered 48 h after MCT and washed-out 15 h before studies. MCT increased RV systolic pressure and caused RV hypertrophy and loss of left ventricular (LV) mass. In the RV, collagen was increased; myocytes were enlarged with T-tubule disarray and displayed myosin heavy chain isoform switch. INaL was markedly enhanced; diastolic Ca2+ was increased and Ca2+ release was facilitated. K+ currents were down-regulated and APD was prolonged. In the LV, INaL was enhanced to a lesser extent and cell Ca2+ content was strongly depressed. Electrical remodelling was less prominent than in the RV. RAN completely prevented INaL enhancement and limited most aspects of PAH-induced remodelling, but failed to affect in vivo contractile performance. RAN blunted the MCT-induced increase in RV pressure and medial thickening in pulmonary arterioles. Conclusion PAH induced remodelling with chamber-specific aspects. RAN prevented constitutive INaL enhancement and blunted myocardial remodelling. Partial mechanical unloading, resulting from an unexpected effect of RAN on pulmonary vasculature, might contribute to this effect.",
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T1 - Ranolazine prevents INaL enhancement and blunts myocardial remodelling in a model of pulmonary hypertension

AU - Rocchetti, Marcella

AU - Sala, Luca

AU - Rizzetto, Riccardo

AU - Irene Staszewsky, Lidia

AU - Alemanni, Matteo

AU - Zambelli, Vanessa

AU - Russo, Ilaria

AU - Barile, Lucio

AU - Cornaghi, Laura

AU - Altomare, Claudia

AU - Ronchi, Carlotta

AU - Mostacciuolo, Gaspare

AU - Lucchetti, Jacopo

AU - Gobbi, Marco

AU - Latini, Roberto

AU - Zaza, Antonio

PY - 2014/10/1

Y1 - 2014/10/1

N2 - Aims Pulmonary arterial hypertension (PAH) reflects abnormal pulmonary vascular resistance and causes right ventricular (RV) hypertrophy. Enhancement of the late sodium current (INaL) may result from hypertrophic remodelling. The study tests whether: (i) constitutive INaL enhancement may occur as part of PAH-induced myocardial remodelling; (ii) ranolazine (RAN), a clinically available INaL blocker, may prevent constitutive INaL enhancement and PAH-induced myocardial remodelling. Methods and results PAH was induced in rats by a single monocrotaline (MCT) injection [60 mg/kg intraperitoneally (i.p.)]; studies were performed 3 weeks later. RAN (30 mg/kg bid i.p.) was administered 48 h after MCT and washed-out 15 h before studies. MCT increased RV systolic pressure and caused RV hypertrophy and loss of left ventricular (LV) mass. In the RV, collagen was increased; myocytes were enlarged with T-tubule disarray and displayed myosin heavy chain isoform switch. INaL was markedly enhanced; diastolic Ca2+ was increased and Ca2+ release was facilitated. K+ currents were down-regulated and APD was prolonged. In the LV, INaL was enhanced to a lesser extent and cell Ca2+ content was strongly depressed. Electrical remodelling was less prominent than in the RV. RAN completely prevented INaL enhancement and limited most aspects of PAH-induced remodelling, but failed to affect in vivo contractile performance. RAN blunted the MCT-induced increase in RV pressure and medial thickening in pulmonary arterioles. Conclusion PAH induced remodelling with chamber-specific aspects. RAN prevented constitutive INaL enhancement and blunted myocardial remodelling. Partial mechanical unloading, resulting from an unexpected effect of RAN on pulmonary vasculature, might contribute to this effect.

AB - Aims Pulmonary arterial hypertension (PAH) reflects abnormal pulmonary vascular resistance and causes right ventricular (RV) hypertrophy. Enhancement of the late sodium current (INaL) may result from hypertrophic remodelling. The study tests whether: (i) constitutive INaL enhancement may occur as part of PAH-induced myocardial remodelling; (ii) ranolazine (RAN), a clinically available INaL blocker, may prevent constitutive INaL enhancement and PAH-induced myocardial remodelling. Methods and results PAH was induced in rats by a single monocrotaline (MCT) injection [60 mg/kg intraperitoneally (i.p.)]; studies were performed 3 weeks later. RAN (30 mg/kg bid i.p.) was administered 48 h after MCT and washed-out 15 h before studies. MCT increased RV systolic pressure and caused RV hypertrophy and loss of left ventricular (LV) mass. In the RV, collagen was increased; myocytes were enlarged with T-tubule disarray and displayed myosin heavy chain isoform switch. INaL was markedly enhanced; diastolic Ca2+ was increased and Ca2+ release was facilitated. K+ currents were down-regulated and APD was prolonged. In the LV, INaL was enhanced to a lesser extent and cell Ca2+ content was strongly depressed. Electrical remodelling was less prominent than in the RV. RAN completely prevented INaL enhancement and limited most aspects of PAH-induced remodelling, but failed to affect in vivo contractile performance. RAN blunted the MCT-induced increase in RV pressure and medial thickening in pulmonary arterioles. Conclusion PAH induced remodelling with chamber-specific aspects. RAN prevented constitutive INaL enhancement and blunted myocardial remodelling. Partial mechanical unloading, resulting from an unexpected effect of RAN on pulmonary vasculature, might contribute to this effect.

KW - Hypertrophy

KW - Late sodium current

KW - Pulmonary hypertension

KW - Ranolazine

KW - Remodelling

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