Chronic simultaneous administration of the iNOS inhibitor 1400W and the peripheral CB1 receptor antagonist JD5037 reduced right ventricular systolic pressure by 32% and mean pulmonary artery pressure by 34% in a rat model of monocrotaline-induced pulmonary hypertension.
Does simultaneous iNOS and CB1 receptor blockade improve hemodynamics and reduce right ventricular hypertrophy in a rat model of monocrotaline-induced pulmonary hypertension?
Dual pharmacological blockade of iNOS and CB1 receptors ameliorates pulmonary hypertension and right ventricular hypertrophy in a preclinical rat model.
Background Pulmonary arterial hypertension (PAH) is a severe multifactorial disease associated with impaired pulmonary hemodynamics, leading to right ventricular (RV) hypertrophy and failure. Induction of inducible nitric oxide synthase (iNOS) and/or activation of cannabinoid CB 1 receptor (CB 1 R) is associated with pro-inflammatory, pro-fibrotic, and pro-hypertrophic effects. Therefore, we tested the effects of chronic simultaneous iNOS/CB 1 R blockade in a rat model of monocrotaline-induced pulmonary hypertension (MCT-PH). Methods Rats were injected with monocrotaline or saline (control) and from day 8 after PH induction they received iNOS inhibitor 1400W, peripheral CB 1 R antagonist JD5037, their combination or relevant vehicles for 17 days. Invasive and non-invasive hemodynamic assessments, biochemical and histological analyses were conducted. Moreover, the contractions of isolated right ventricular papillary muscles in response to β-adrenoreceptor agonist were analyzed. Results 1400W improved MCT-impaired rates in rise/decrease in RV pressure. JD5037 administration reduced MCT-induced increase in mean pulmonary artery pressure (mPAP), RV wall thickness, and improved pulmonary artery Doppler parameters. 1400W + JD5037 combined therapy exerted the most beneficial effects. It reduced RV systolic pressure, mPAP, attenuated RV hypertrophy, with improvement of RV function and blood oxygen saturation. Moreover, it showed anti-inflammatory and anti-remodeling properties. However, no effects on lung hypertrophy, electrocardiographic parameters, and positive inotropic effect of β-adrenoreceptor agonist were revealed. Conclusion Our results demonstrated that dual pharmacological iNOS/CB 1 R blockade is more beneficial in MCT-induced PH amelioration than modulation of any single target alone. Therefore, it could be seen as a promising novel PAH treatment strategy.
Ryszkiewicz et al. (Tue,) conducted a other in Pulmonary arterial hypertension (MCT-induced rat model). 1400W and JD5037 combination vs. Vehicle was evaluated on Right ventricular systolic pressure (RVSP) and mean pulmonary artery pressure (mPAP). Chronic simultaneous administration of the iNOS inhibitor 1400W and the peripheral CB1 receptor antagonist JD5037 reduced right ventricular systolic pressure by 32% and mean pulmonary artery pressure by 34% in a rat model of monocrotaline-induced pulmonary hypertension.