Marcella Rocchetti1, Luca Sala1, Riccardo Rizzetto1, Lidia Irene Staszewsky2, Matteo Alemanni1, Vanessa Zambelli3, Ilaria Russo2, Lucio Barile4, Laura Cornaghi5, Claudia Altomare1, Carlotta Ronchi1, Gaspare Mostacciuolo1, Jacopo Lucchetti6, Marco Gobbi6, Roberto Latini2, Antonio Zaza7. 1. Dipartimento di Biotecnologie e Bioscienze, Università degli Studi di Milano - Bicocca, P.za Della Scienza 2, Milano 20126, Italy. 2. Laboratory of Cardiovascular Clinical Pharmacology, Department of Cardiovascular Research, IRCCS-Istituto Mario Negri, Milano, Italy. 3. Dipartimento di Scienze della Salute, Università degli Studi di Milano - Bicocca, Monza, Italy. 4. Molecular Cardiology Laboratory, Fondazione Cardiocentro Ticino, Lugano, Switzerland. 5. Dipartimento di Scienze Biomediche per la Salute, Università degli Studi di Milano, Italy. 6. Molecular Biochemistry and Pharmacology, IRCCS-Istituto Mario Negri, Milano, Italy. 7. Dipartimento di Biotecnologie e Bioscienze, Università degli Studi di Milano - Bicocca, P.za Della Scienza 2, Milano 20126, Italy antonio.zaza@unimib.it.
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. Published on behalf of the European Society of Cardiology. All rights reserved.
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. Published on behalf of the European Society of Cardiology. All rights reserved.
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