Therapeutic Benefit of the Association of Lodenafil with Mesenchymal Stem Cells on Hypoxia-induced Pulmonary Hypertension in Rats

Abstract

Pulmonary arterial hypertension (PAH) is characterized by the remodeling of pulmonary arteries, with an increased pulmonary arterial pressure and right ventricle (RV) overload. This work investigated the benefit of the association of human umbilical cord mesenchymal stem cells (hMSCs) with lodenafil, a phosphodiesterase-5 inhibitor, in an animal model of PAH. Male Wistar rats were exposed to hypoxia (10% O2) for three weeks plus a weekly i.p. injection of a vascular endothelial growth factor receptor inhibitor (SU5416, 20 mg/kg, SuHx). After confirmation of PAH, animals received intravenous injection of 5.105 hMSCs or vehicle, followed by oral treatment with lodenafil carbonate (10 mg/kg/day) for 14 days. The ratio between pulmonary artery acceleration time and RV ejection time reduced from 0.42 ± 0.01 (control) to 0.24 ± 0.01 in the SuHx group, which was not altered by lodenafil alone but was recovered to 0.31 ± 0.01 when administered in association with hMSCs. RV afterload was confirmed in the SuHx group with an increased RV systolic pressure (mmHg) of 52.1 ± 8.8 normalized to 29.6 ± 2.2 after treatment with the association. Treatment with hMSCs + lodenafil reversed RV hypertrophy, fibrosis and interstitial cell infiltration in the SuHx group. Combined therapy of lodenafil and hMSCs may be a strategy for PAH treatment.

Novel p38 Mitogen-Activated Protein Kinase Inhibitor Reverses Hypoxia-Induced Pulmonary Arterial Hypertension in Rats

“…PH is marked by an increase in pulmonary vascular resistance caused by increased tone and remodeling in intrapulmonary arterioles. The SuHx model exhibits several characteristics of human PH, including histological and hemodynamic alterations [ 29 , 30 , 31 ]. Herein, it was demonstrated that SuHx rats developed PH after 21 days due to slower blood flow through the pulmonary arteries, as indicated by short PAT/PET ratio.…”

“…PH was induced in rats by administration of SU5416 during exposure to hypoxia, which reproduces the severe and persistent vascular remodeling and RV failure similar to late-stage human disease [ 29 , 30 , 58 ]. This rat model, SuHx, develops more severe features than hypoxia only [ 29 , 30 , 31 ] with a progressive proliferative endotheliopathy caused by SU5416 after their return to normoxia [ 29 , 30 ].…”

“…The chamber was opened every 3 days for less than 20 min in order to clean cages and replenish food and water. SuHx rats received weekly intraperitoneal injections of 20 mg/kg SU5416 suspended in SU-vehicle (0.5% carboxymethylcellulose, 0.4% Tween80 and 0.9% benzyl alcohol in isotonic saline) [ 31 ].…”

“…Assessment of pulmonary vascular resistance was performed noninvasively through measurement of PAT obtained by pulsed-wave Doppler TTE at the RV outflow tract (RVOT) [ 29 , 31 , 33 , 34 ]. Values obtained for PAT were normalized to PET, in order to attenuate the influence of possible heart-rate fluctuations unrelated to PH [ 30 , 61 ].…”

Antinociceptive Effect of Lodenafil Carbonate in Rodent Models of Inflammatory Pain and Spinal Nerve Ligation-Induced Neuropathic Pain

“…9,11,12 Lodenafil carbonate is a new dimeric PDE5 inhibitor structurally related to sildenafil and bearing a carbonate bridge. Although its actions on the cardiovascular system were already studied, [13][14][15] the antinociceptive activity of lodenafil carbonate has not yet been investigated, and its study in models of inflammatory and neuropathic pain is of great interest for the development of new therapeutic strategies to alleviate chronic pain.…”