RT Journal Article
SR Electronic
T1 Ranolazine reduces remodeling of the right ventricle and provoked arrhythmias in rats with pulmonary hypertension
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP jpet.114.221861
DO 10.1124/jpet.114.221861
A1 Liles, John T.
A1 Hoyer, Kirsten
A1 Oliver, Jason
A1 Chi, Liguo
A1 Dhalla, Arvinder K.
A1 Belardinelli, Luiz
YR 2015
UL http://jpet.aspetjournals.org/content/early/2015/03/13/jpet.114.221861.abstract
AB Pulmonary arterial hypertension (PAH) is a progressive disease that often results in right ventricular (RV) failure and death. During disease progression, structural and electrical remodeling of the RV impairs pump function, creates pro-arrhythmic substrates and triggers for arrhythmias. Notably, RV failure and lethal arrhythmias are major contributors to cardiac death in patients with PAH that are not directly addressed by currently available therapies. Ranolazine (RAN) is an anti-anginal, anti-ischemic drug that has cardioprotective effects in experimental and clinical settings of left-sided heart dysfunction. RAN also has anti-arrhythmic effects due to inhibition of the late sodium current in cardiomyocytes. We therefore hypothesized that RAN could reduce the maladaptive structural and electrical remodeling of the RV, and prevent triggered ventricular arrhythmias in the monocrotaline rat model of PAH. Indeed, in both in vivo and ex vivo experimental settings, chronic RAN treatment reduced electrical heterogeneity (RV-LV APD dispersion) and shortened QTc intervals in the RV, and normalized RV dysfunction. Chronic RAN also dose-dependently reduced ventricular hypertrophy, reduced circulating levels of BNP, and decreased the expression of fibrotic markers. In addition, the acute administration of RAN prevented isoproterenol-induced VT/VF and subsequent cardiovascular death in rats with established PAH. These results support the notion that RAN can improve the electrical and functional properties of the RV, highlighting its potential benefits in the setting of RV impairment.