Monocrotaline-induced pulmonary arterial hypertension: the benefic effects of magnesium sulfate, Rosuvastatin and Sildenafil.

BACKGROUND

Pulmonary arterial hypertension (PAH) is characterized by several maladaptive mechanisms: endothelial dysfunction, oxidative stress, inflammation, pathological remodeling of the pulmonary arterioles, and cellular hypoxia. These mechanisms all favor progressive pulmonary vasculopathy and progressive right ventricle (RV) dysfunction.

AIM

This study aims to characterize the experimental model of monocrotaline-induced PAH in rats. Subsequently, by administering Sildenafil, Rosuvastatin, and Magnesium sulfate, we assessed the animals via ultrasonography and assayed biochemical parameters to evaluate the efficacy of the treatment.

METHODS

42 male Wistar rats were randomly allocated into six equal groups (n=7) and received a single subcutaneous MCT injection (60 mg/kg dose). Drug therapy with Sildenafil, Rosuvastatin, and Magnesium sulfate in different combinations was initiated 14 days after MCT injection. Fulton Index, RV anterior wall thickness, RV internal diameter, and pulmonary arterial acceleration time/ejection time (PAAT/PAET) were measured. The following biochemical parameters were also measured: endothelin 1(ET1), brain natriuretic peptide (BNP), nitric oxide (NO) metabolites, vascular endothelial growth factor (VEGF), and inducible nitric oxide synthase (iNOS).

RESULTS

MCT-PAH was a successful experimental model that has fulfilled anatomical, pressure, and biochemical characteristics supporting this fact. Sildenafil monotherapy does not provide any substantial benefit in reducing MCT-PAH. The additive effects of Rosuvastatin + Sildenafil or Sildenafil + Magnesium sulfate significantly reduced the degree of RV hypertrophy and improved RV systolic pressures. However, there were also modest decreases in biochemical parameters compared to Sildenafil alone. The triple drug combination Sildenafil + Rosuvastatin + Magnesium sulfate shows significant results (p<0,001) compared to the previously described drug combinations. The lowest biochemical parameters were recorded: RV anterior wall thickness, RV internal diameter values, and a significant PAAT/PAET ratio improvement. Thanks to their benefits on vascular pathological remodeling, triple drug combinations implicitly reduce ET1, VEGF, NO metabolites, and iNOS values with statistical significance.

CONCLUSIONS

The beneficial pleiotropic effects of Rosuvastatin combined with Magnesium sulfate (thanks to its potent vasodilator and antioxidant effects) demonstrated its efficacy in this study by improving RV systolic pressures, RV hypertrophy, oxidative stress, and myocardial dysfunction biomarkers.