Inhibition of Na/H exchanger-1 in the right ventricle and lung dysfunction induced by experimental pulmonary arterial hypertension in rats

Abstract

AimsPulmonary arterial hypertension (PAH) is a life-threatening disease that still lacks a direct therapeutic approach targeted to the molecular defects associated with the disease. In this study, we focused on the control of the sodium/hydrogen exchange, which is at the root of impaired regulation of intracellular acidity, as well as of the sodium and calcium intracellular overload. We tested the hypothesis that inhibiting the sodium/hydrogen exchanger isoform 1 (NHE-1) with rimeporide enables the recovery of the pulmonary and right ventricular dysfunction in the Sugen5416/hypoxia rat preclinical model of PAH. Methods and ResultsWe studied 44 rats divided into two broad groups, control, and Sugen5416/hypoxia. After verifying the insurgence of PAH in the Sugen5416/hypoxia group by transthoracic echocardiography and pulse-wave Doppler analysis, two subgroups were assigned to treatment with either 100 mg/kg/day rimeporide or placebo in drinking water for three weeks. The functional, morphological (fibrosis and hypertrophy) and biochemical (inflammation, signalling pathways) myocardial and pulmonary dysfunctions caused by PAH can be at least partially reverted by treatment with rimeporide. Interestingly, the most striking effects of rimeporide were observed in the right ventricle. Rimeporide was able to improve the hemodynamic variables in the pulmonary circulation and the right ventricle, to decrease right ventricle hypertrophy, pulmonary vascular remodelling, inflammation, and fibrosis. No effect of rimeporide is detected in control rats. We also showed that the protective effect of rimeporide was accompanied by a decrease of the p-Akt/Akt ratio and a stimulation of the autophagy flux mainly in the right ventricle. ConclusionBy specifically inhibiting NHE-1, rimeporide at the selected dosage revealed remarkable anti-PAH effects by preventing functional, morphological, and biochemical deleterious effects of PAH on right ventricle and lung. Rimeporide has to be considered as a potential treatment for PAH. Clinical PerspectiveO_ST_ABSWhat is new?C_ST_ABSPulmonary arterial hypertension (PAH) is a disease with a poor survival despite the progress in therapies, the cause of death remains progressive right ventricular failure. The current treatment are essentially pulmonary vasodilators. An ideal drug would show efficacy in pulmonary vasodilation and remodelling but would also have a direct effect on right ventricular function. O_LIRimeporide, a sodium/hydrogen exchanger type 1 (NHE-1), decreases right ventricular hypertrophy, pulmonary vascular remodelling, inflammation, and fibrosis. C_LIO_LIRimeporide is promising as it shows an effect not only on the pulmonary vascular bed but directly on the right ventricle. C_LI What are the clinical implications?By specifically inhibiting NHE-1, rimeporide at the selected dosage revealed remarkable anti-PAH effects by preventing functional, morphological, and biochemical deleterious effects of PAH on right ventricle and lung. O_LIThis offers new possibilities of treatment of pulmonary hypertension. C_LIO_LIA direct effect on right ventricular function and remodelling is extremely attractive for diverse forms of pulmonary hypertension. C_LI