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

Aims Pulmonary arterial hypertension (PAH) reflects abnormal pulmonary vascular resistance and causes right ventricular (RV) hypertrophy. Enhancement of the late sodium current (I-NaL) may result from hypertrophic remodelling. The study tests whether: (i) constitutive I-NaL enhancement may occur as part of PAH-induced myocardial remodelling; (ii) ranolazine (RAN), a clinically available I-NaL blocker, may prevent constitutive I-NaL 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 weekslater. 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. I-NaL was markedly enhanced; diastolic Ca2+ was increased and Ca2+ release was facilitated. K+ currents were down-regulated and APD was prolonged. In the LV, I-NaL was enhanced to a lesser extent and cell Ca2+ content was strongly depressed. Electrical remodellingwas less prominent than in the RV. RAN completely prevented I-NaL 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 I-NaL enhancement and blunted myocardial remodelling. Partial mechanical unloading, resulting from an unexpected effect of RAN on pulmonary vasculature, might contribute to this effect.