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

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. 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. 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.

Rocchetti M ，Sala L ，Rizzetto R ，Staszewsky LI ，Alemanni M ，Zambelli V ，Russo I ，Barile L ，Cornaghi L ，Altomare C ，Ronchi C ，Mostacciuolo G ，Lucchetti J ，Gobbi M ，Latini R ，Zaza A ... -  《-》

Pioglitazone alleviates cardiac and vascular remodelling and improves survival in monocrotaline induced pulmonary arterial hypertension.

Behringer A ，Trappiel M ，Berghausen EM ，Ten Freyhaus H ，Wellnhofer E ，Odenthal M ，Blaschke F ，Er F ，Gassanov N ，Rosenkranz S ，Baldus S ，Kappert K ，Caglayan E ... -  《-》

Glycyrrhizin, inhibitor of high mobility group box-1, attenuates monocrotaline-induced pulmonary hypertension and vascular remodeling in rats.

Yang PS ，Kim DH ，Lee YJ ，Lee SE ，Kang WJ ，Chang HJ ，Shin JS ... -  《RESPIRATORY RESEARCH》

Chronic inhibition of phosphodiesterase 5 does not prevent pressure-overload-induced right-ventricular remodelling.

Schäfer S ，Ellinghaus P ，Janssen W ，Kramer F ，Lustig K ，Milting H ，Kast R ，Klein M ... -  《-》

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

Xie YP ，Chen B ，Sanders P ，Guo A ，Li Y ，Zimmerman K ，Wang LC ，Weiss RM ，Grumbach IM ，Anderson ME ，Song LS ... -  《-》