title: Ranolazine prevents INaL enhancement and blunts myocardial remodelling in a model of pulmonary hypertension.
abstract: OBJECTIVE
  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.
  
  
  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.
  
  
  CONCLUSIONS
  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.affiliation: Dipartimento di Biotecnologie e Bioscienze, Università degli Studi di Milano - Bicocca, P.za Della Scienza 2, Milano 20126, Italy.
authors.forename: Marcella
authors.initials: M
authors.lastname: Rocchetti
authors.affiliation: Dipartimento di Biotecnologie e Bioscienze, Università degli Studi di Milano - Bicocca, P.za Della Scienza 2, Milano 20126, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Sala
authors.affiliation: Dipartimento di Biotecnologie e Bioscienze, Università degli Studi di Milano - Bicocca, P.za Della Scienza 2, Milano 20126, Italy.
authors.forename: Riccardo
authors.initials: R
authors.lastname: Rizzetto
authors.affiliation: Laboratory of Cardiovascular Clinical Pharmacology, Department of Cardiovascular Research, IRCCS-Istituto Mario Negri, Milano, Italy.
authors.forename: Lidia Irene
authors.initials: LI
authors.lastname: Staszewsky
authors.affiliation: Dipartimento di Biotecnologie e Bioscienze, Università degli Studi di Milano - Bicocca, P.za Della Scienza 2, Milano 20126, Italy.
authors.forename: Matteo
authors.initials: M
authors.lastname: Alemanni
authors.affiliation: Dipartimento di Scienze della Salute, Università degli Studi di Milano - Bicocca, Monza, Italy.
authors.forename: Vanessa
authors.initials: V
authors.lastname: Zambelli
authors.affiliation: Laboratory of Cardiovascular Clinical Pharmacology, Department of Cardiovascular Research, IRCCS-Istituto Mario Negri, Milano, Italy.
authors.forename: Ilaria
authors.initials: I
authors.lastname: Russo
authors.affiliation: Molecular Cardiology Laboratory, Fondazione Cardiocentro Ticino, Lugano, Switzerland.
authors.forename: Lucio
authors.initials: L
authors.lastname: Barile
authors.affiliation: Dipartimento di Scienze Biomediche per la Salute, Università degli Studi di Milano, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Cornaghi
authors.affiliation: Dipartimento di Biotecnologie e Bioscienze, Università degli Studi di Milano - Bicocca, P.za Della Scienza 2, Milano 20126, Italy.
authors.forename: Claudia
authors.initials: C
authors.lastname: Altomare
authors.affiliation: Dipartimento di Biotecnologie e Bioscienze, Università degli Studi di Milano - Bicocca, P.za Della Scienza 2, Milano 20126, Italy.
authors.forename: Carlotta
authors.initials: C
authors.lastname: Ronchi
authors.affiliation: Dipartimento di Biotecnologie e Bioscienze, Università degli Studi di Milano - Bicocca, P.za Della Scienza 2, Milano 20126, Italy.
authors.forename: Gaspare
authors.initials: G
authors.lastname: Mostacciuolo
authors.affiliation: Molecular Biochemistry and Pharmacology, IRCCS-Istituto Mario Negri, Milano, Italy.
authors.forename: Jacopo
authors.initials: J
authors.lastname: Lucchetti
authors.affiliation: Molecular Biochemistry and Pharmacology, IRCCS-Istituto Mario Negri, Milano, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Gobbi
authors.affiliation: Laboratory of Cardiovascular Clinical Pharmacology, Department of Cardiovascular Research, IRCCS-Istituto Mario Negri, Milano, Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Latini
authors.affiliation: Dipartimento di Biotecnologie e Bioscienze, Università degli Studi di Milano - Bicocca, P.za Della Scienza 2, Milano 20126, Italy antonio.zaza@unimib.it.
authors.forename: Antonio
authors.initials: A
authors.lastname: Zaza
mesh_terms: D000083:Acetanilides / Q000494:pharmacology*; D000818:Animals; D020013:Calcium Signaling / Q000187:drug effects; D003094:Collagen / Q000378:metabolism; D004195:Disease Models, Animal; D005355:Fibrosis; D006976:Hypertension, Pulmonary / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D017380:Hypertrophy, Right Ventricular / Q000209:etiology / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D008297:Male; D008564:Membrane Potentials; D016686:Monocrotaline; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D018995:Myosin Heavy Chains / Q000378:metabolism; D010879:Piperazines / Q000494:pharmacology*; D011651:Pulmonary Artery / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D000069458:Ranolazine; D051381:Rats; D017207:Rats, Sprague-Dawley; D012964:Sodium / Q000378:metabolism*; D026941:Sodium Channel Blockers / Q000494:pharmacology*; D015222:Sodium Channels / Q000187:drug effects* / Q000378:metabolism; D013997:Time Factors; D066253:Vascular Remodeling / Q000187:drug effects; D014655:Vascular Resistance / Q000187:drug effects; D016278:Ventricular Function, Right / Q000187:drug effects*; D020257:Ventricular Remodeling / Q000187:drug effects*
chemical_list: D000083:Acetanilides; D010879:Piperazines; D026941:Sodium Channel Blockers; D015222:Sodium Channels; D016686:Monocrotaline; D003094:Collagen; D012964:Sodium; D000069458:Ranolazine; D018995:Myosin Heavy Chains
keywords: Hypertrophy; Late sodium current; Pulmonary hypertension; Ranolazine; Remodelling