Frontiers in pharmacology · 2026
Chronic simultaneous inducible nitric oxide synthase (iNOS) and peripheral cannabinoid CB1 receptors blockade ameliorates pulmonary hypertension in monocrotaline-induced rat model.
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Ryszkiewicz Piotr, Remiszewski Patryk, Pędzińska-Betiuk Anna, Mińczuk Krzysztof, Baranowska-Kuczko Marta, Weresa Jolanta, Malinowska Barbara
Аннотация
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 CB1 receptor (CB1R) is associated with pro-inflammatory, pro-fibrotic, and pro-hypertrophic effects. Therefore, we tested the effects of chronic simultaneous iNOS/CB1R 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 CB1R 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/CB1R 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.
METHODS: Rats were injected with monocrotaline or saline (control) and from day 8 after PH induction they received iNOS inhibitor 1400W, peripheral CB1R 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/CB1R 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.