Fifty Years of Monocrotaline-Induced Pulmonary Hypertension

Hill, Nicholas S.; Gillespie, Mark N.; McMurtry, Ivan F.

doi:10.1016/j.chest.2017.10.007

Cited by 44 publications

(41 citation statements)

References 21 publications

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“…Notwithstanding the significance of the findings of this study, it should also be acknowledged that the level of the MCT-induced disease, as demonstrated by the low but consistent increase in mPAP, RVSP and Fulton's Index, was not as severe when compared with previous studies [52,53]. It is acknowledged that the level of PAH disease induced by MCT administration can vary significantly across species, strains and individual animals [51,54]. The more moderate PH induced in this model may account for the lack of significant benefit observed for NTP42 in the Fulton's Index parameter, and for the lack of benefit observed for Selexipag in the RVSP and Fulton's Index parameter.…”

Section: Limitations Of Studymentioning

confidence: 47%

NTP42, a novel antagonist of the thromboxane receptor, attenuates experimentally induced pulmonary arterial hypertension

et al. 2020

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Background: NTP42 is a novel antagonist of the thromboxane prostanoid receptor (TP), currently in development for the treatment of pulmonary arterial hypertension (PAH). PAH is a devastating disease with multiple pathophysiological hallmarks including excessive pulmonary vasoconstriction, vascular remodelling, inflammation, fibrosis, in situ thrombosis and right ventricular hypertrophy. Signalling through the TP, thromboxane (TX) A 2 is a potent vasoconstrictor and mediator of platelet aggregation. It is also a pro-mitogenic, pro-inflammatory and pro-fibrotic agent. Moreover, the TP also mediates the adverse actions of the isoprostane 8-iso-prostaglandin F 2α , a free-radical-derived product of arachidonic acid produced in abundance during oxidative injury. Mechanistically, TP antagonists should treat most of the hallmarks of PAH, including inhibiting the excessive vasoconstriction and pulmonary artery remodelling, in situ thrombosis, inflammation and fibrosis. This study aimed to investigate the efficacy of NTP42 in the monocrotaline (MCT)-induced PAH rat model, alongside current standard-of-care drugs. Methods: PAH was induced by subcutaneous injection of 60 mg/kg MCT in male Wistar-Kyoto rats. Animals were assigned into groups: 1. 'No MCT'; 2. 'MCT Only'; 3. MCT + NTP42 (0.25 mg/kg BID); 4. MCT + Sildenafil (50 mg/kg BID), and 5. MCT + Selexipag (1 mg/kg BID), where 28-day drug treatment was initiated within 24 h post-MCT. Results: From haemodynamic assessments, NTP42 reduced the MCT-induced PAH, including mean pulmonary arterial pressure (mPAP) and right systolic ventricular pressure (RSVP), being at least comparable to the standardof-care drugs Sildenafil or Selexipag in bringing about these effects. Moreover, NTP42 was superior to Sildenafil and Selexipag in significantly reducing pulmonary vascular remodelling, inflammatory mast cell infiltration and fibrosis in MCT-treated animals.

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Section: Limitations Of Studymentioning

confidence: 47%

NTP42, a novel antagonist of the thromboxane receptor, attenuates experimentally induced pulmonary arterial hypertension

et al. 2020

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“…The aim of our study was to examine the potential preventive effect of chronic CBD administration (10 mg/kg/day for three weeks) on changes in pulmonary hemodynamic characteristics, vascular function and morphology, chosen hemostatic and blood morphology parameters and lung endocannabinoid levels induced in an experimental model of PH in rats. We applied the model of MCT-stimulated PH because it shows a selective toxic effect on pulmonary vessels without an effect on systemic vessels and has consistent pathological findings of PAH in humans and it serves as a preclinical model of PAH to test potential therapeutic agents [ 24 , 26 ].…”

Section: Discussionmentioning

confidence: 99%

“…Thus, the aim of our study was to examine the effects of chronic preventive treatment with CBD in rat experimental pulmonary hypertension (PH). Note that the terms “PAH” and “PH” are reserved for the human and experimental conditions, respectively [ 24 , 25 , 26 , 27 ]. To evaluate the efficacy of CBD in PH, right ventricular systolic pressure (RVSP), relaxant-constrictor responses and remodeling of isolated PAs, as well as parameters of hemostasis and levels of endocannabinoids and/or endocannabinoid-like compounds in rat monocrotaline (MCT)-induced PH were measured.…”

Section: Introductionmentioning

confidence: 99%

Cannabidiol Ameliorates Monocrotaline-Induced Pulmonary Hypertension in Rats

Sadowska

Baranowska-Kuczko

Gromotowicz-Popławska

et al. 2020

IJMS

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Cannabidiol (CBD) is known for its vasorelaxant (including in the human pulmonary artery), anti-proliferative and anti-inflammatory properties. The aim of our study was to examine the potential preventive effect of chronic CBD administration (10 mg/kg/day for three weeks) on monocrotaline (MCT)-induced pulmonary hypertension (PH) rats. PH was connected with elevation of right ventricular systolic pressure; right ventricle hypertrophy; lung edema; pulmonary artery remodeling; enhancement of the vasoconstrictor and decreasing vasodilatory responses; increases in plasma concentrations of tissue plasminogen activator, plasminogen activator inhibitor type 1 and leukocyte count; and a decrease in blood oxygen saturation. CBD improved all abovementioned changes induced by PH except right ventricle hypertrophy and lung edema. In addition, CBD increased lung levels of some endocannabinoids (anandamide, N-arachidonoyl glycine, linolenoyl ethanolamide, palmitoleoyl ethanolamide and eicosapentaenoyl ethanolamide but not 2-arachidonoylglycerol). CBD did not affect the cardiopulmonary system of control rats or other parameters of blood morphology in PH. Our data suggest that CBD ameliorates MCT-induced PH in rats by improving endothelial efficiency and function, normalization of hemostatic alterations and reduction of enhanced leukocyte count determined in PH. In conclusion, CBD may be a safe, promising therapeutic or adjuvant therapy agent for the treatment of human pulmonary artery hypertension.

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“…(36,51,53,54) Notwithstanding the significance of the findings of this study, it should also be acknowledged that the level of the MCT-induced disease, as demonstrated by the low but consistent increase in mPAP, RVSP and Fulton's Index, was not as severe when compared with previous studies (33,34). It is acknowledged that the level of PAH disease induced by MCT administration can vary significantly across species, strains and individual animals (35,36). The more moderate PH induced in this model may account for the lack of significant benefit observed for NTP42 in the Fulton's Index parameter, and for the lack of benefit observed for Selexipag in the RVSP and Fulton's Index parameter.…”

Section: Limitations Of Studymentioning

confidence: 63%

NTP42, a novel antagonist of the thromboxane receptor, attenuates experimentally induced pulmonary arterial hypertension

Mulvaney¹,

Reid²,

Bialešová³

et al. 2020

Preprint

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Background NTP42 is a novel antagonist of the thromboxane prostanoid receptor (TP), currently in development for the treatment of pulmonary arterial hypertension (PAH). PAH is a devastating disease with multiple pathophysiological hallmarks including excessive pulmonary vasoconstriction, vascular remodelling, inflammation, fibrosis, in situ thrombosis and right ventricular hypertrophy. Signalling through the TP, thromboxane (TX) A 2 is a potent vasoconstrictor and mediator of platelet aggregation. It is also a pro-mitogenic, pro-inflammatory and pro-fibrotic agent. Moreover, the TP also mediates the adverse actions of the isoprostane 8-iso-prostaglandin F 2α , a free-radical-derived product of arachidonic acid produced in abundance during oxidative injury. Mechanistically, TP antagonists should treat most of the hallmarks of PAH, including inhibiting the excessive vasoconstriction and pulmonary artery remodelling, in situ thrombosis, inflammation and fibrosis. This study aimed to investigate the efficacy of NTP42 in the monocrotaline (MCT)-induced PAH rat model, alongside current standard-of-care drugs. Methods PAH was induced by subcutaneous injection of 60 mg/kg MCT in male Wistar–Kyoto rats. Animals were assigned into groups: 1. ‘No MCT’; 2. ‘MCT Only’; 3. MCT + NTP42 (0.25 mg/kg BID); 4. MCT + Sildenafil (50 mg/kg BID), and 5. MCT + Selexipag (1 mg/kg BID), where 28-day drug treatment was initiated within 24 h post-MCT. Results From haemodynamic assessments , NTP42 reduced the MCT-induced PAH, including mean pulmonary arterial pressure (mPAP) and right systolic ventricular pressure (RSVP), being at least comparable to the standard-of-care drugs Sildenafil or Selexipag in bringing about these effects. Moreover, NTP42 was superior to Sildenafil and Selexipag in significantly reducing pulmonary vascular remodelling, inflammatory mast cell infiltration and fibrosis in MCT-treated animals. Conclusions These findings suggest that NTP42 and antagonism of the TP signalling pathway have a relevant role in alleviating the pathophysiology of PAH, representing a novel therapeutic target with marked benefits over existing standard-of-care therapies.

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Fifty Years of Monocrotaline-Induced Pulmonary Hypertension

Cited by 44 publications

References 21 publications

NTP42, a novel antagonist of the thromboxane receptor, attenuates experimentally induced pulmonary arterial hypertension

NTP42, a novel antagonist of the thromboxane receptor, attenuates experimentally induced pulmonary arterial hypertension

Cannabidiol Ameliorates Monocrotaline-Induced Pulmonary Hypertension in Rats

NTP42, a novel antagonist of the thromboxane receptor, attenuates experimentally induced pulmonary arterial hypertension

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