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Ranolazine prevents INaL enhancement and blunts myocardial remodelling in a model of pulmonary hypertension.
Cardiovasc Res. 2014 Oct 01; 104(1):37-48.CR

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 Ca(2+) was increased and Ca(2+) release was facilitated. K(+) currents were down-regulated and APD was prolonged. In the LV, INaL was enhanced to a lesser extent and cell Ca(2+) 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.

Authors+Show Affiliations

Dipartimento di Biotecnologie e Bioscienze, Università degli Studi di Milano - Bicocca, P.za Della Scienza 2, Milano 20126, Italy.Dipartimento di Biotecnologie e Bioscienze, Università degli Studi di Milano - Bicocca, P.za Della Scienza 2, Milano 20126, Italy.Dipartimento di Biotecnologie e Bioscienze, Università degli Studi di Milano - Bicocca, P.za Della Scienza 2, Milano 20126, Italy.Laboratory of Cardiovascular Clinical Pharmacology, Department of Cardiovascular Research, IRCCS-Istituto Mario Negri, Milano, Italy.Dipartimento di Biotecnologie e Bioscienze, Università degli Studi di Milano - Bicocca, P.za Della Scienza 2, Milano 20126, Italy.Dipartimento di Scienze della Salute, Università degli Studi di Milano - Bicocca, Monza, Italy.Laboratory of Cardiovascular Clinical Pharmacology, Department of Cardiovascular Research, IRCCS-Istituto Mario Negri, Milano, Italy.Molecular Cardiology Laboratory, Fondazione Cardiocentro Ticino, Lugano, Switzerland.Dipartimento di Scienze Biomediche per la Salute, Università degli Studi di Milano, Italy.Dipartimento di Biotecnologie e Bioscienze, Università degli Studi di Milano - Bicocca, P.za Della Scienza 2, Milano 20126, Italy.Dipartimento di Biotecnologie e Bioscienze, Università degli Studi di Milano - Bicocca, P.za Della Scienza 2, Milano 20126, Italy.Dipartimento di Biotecnologie e Bioscienze, Università degli Studi di Milano - Bicocca, P.za Della Scienza 2, Milano 20126, Italy.Molecular Biochemistry and Pharmacology, IRCCS-Istituto Mario Negri, Milano, Italy.Molecular Biochemistry and Pharmacology, IRCCS-Istituto Mario Negri, Milano, Italy.Laboratory of Cardiovascular Clinical Pharmacology, Department of Cardiovascular Research, IRCCS-Istituto Mario Negri, Milano, Italy.Dipartimento di Biotecnologie e Bioscienze, Università degli Studi di Milano - Bicocca, P.za Della Scienza 2, Milano 20126, Italy antonio.zaza@unimib.it.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't
Video-Audio Media

Language

eng

PubMed ID

25139747

Citation

Rocchetti, Marcella, et al. "Ranolazine Prevents INaL Enhancement and Blunts Myocardial Remodelling in a Model of Pulmonary Hypertension." Cardiovascular Research, vol. 104, no. 1, 2014, pp. 37-48.
Rocchetti M, Sala L, Rizzetto R, et al. Ranolazine prevents INaL enhancement and blunts myocardial remodelling in a model of pulmonary hypertension. Cardiovasc Res. 2014;104(1):37-48.
Rocchetti, M., Sala, L., Rizzetto, R., Staszewsky, L. I., 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, 104(1), 37-48. https://doi.org/10.1093/cvr/cvu188
Rocchetti M, et al. Ranolazine Prevents INaL Enhancement and Blunts Myocardial Remodelling in a Model of Pulmonary Hypertension. Cardiovasc Res. 2014 Oct 1;104(1):37-48. PubMed PMID: 25139747.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR 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 - Staszewsky,Lidia Irene, 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, Y1 - 2014/08/18/ PY - 2014/8/21/entrez PY - 2014/8/21/pubmed PY - 2015/6/11/medline KW - Hypertrophy KW - Late sodium current KW - Pulmonary hypertension KW - Ranolazine KW - Remodelling SP - 37 EP - 48 JF - Cardiovascular research JO - Cardiovasc Res VL - 104 IS - 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 Ca(2+) was increased and Ca(2+) release was facilitated. K(+) currents were down-regulated and APD was prolonged. In the LV, INaL was enhanced to a lesser extent and cell Ca(2+) 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. SN - 1755-3245 UR - https://www.unboundmedicine.com/medline/citation/25139747/Ranolazine_prevents_INaL_enhancement_and_blunts_myocardial_remodelling_in_a_model_of_pulmonary_hypertension_ L2 - https://academic.oup.com/cardiovascres/article-lookup/doi/10.1093/cvr/cvu188 DB - PRIME DP - Unbound Medicine ER -