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Influence of pulmonary hypertension, metformin (MET), JD5037 (JD) and/or their combination on right ventricular remodeling in monocrotaline-induced pulmonary hypertensive (PH) rats and their normotensive controls (CTR). Representative hematoxylin and eosin-stained right ventricle images (100x and 400x magnification); quantitative evaluation is provided in Table 2. MET (100 mg/kg), JD5037 (3 mg/kg) or their combination were administered by oral gavage once daily for 21 days; controls received vehicles (veh) instead.
Source publication
Pulmonary hypertension (PH) is a disease leading to increased pressure in the pulmonary artery and right heart failure. The adenosine monophosphate-activated protein kinase (AMPK) activator, metformin, has a protective effect against PH. CB1 receptor blockade reduces the number of pathological alterations in experimental lung fibrosis. The current...
Contexts in source publication
Context 1
... of PH and drug therapies on the right ventricle As shown in Table 2 and Figure 2, PH caused changes in right ventricle tissue assessed by histological scoring. Compared to the control group, significant alterations can be observed in cardiomyocytes (hypertrophy and hypereosinophilia of cytoplasm, i.e., an increase in the intensity of eosin staining), myocardium (increased waviness of muscle fibers, hyperplasia of connective tissue and extravasation) and coronary arteries (hypertrophy and vacuolization of tunica media and increased infiltration of mononuclear cells). ...
Context 2
... et al. (2021) compared 7 and 20-week-old rats and found that MCT led to a much higher survival rate but also induced less severe PH in older compared to younger rats. This observation also translated into our experience and that of another group using animals from exactly the same source as ours (Hołda et al., 2020a); in both Frontiers in Pharmacology frontiersin.org 09 instances, no animal mortality was observed because of the development of mild PAH. ...
Context 3
... increase in RVSP was associated with a significant enlargement of RV, expressed as Fulton's index, and a tendency of an increase in RV weight/body weight ratio and heart weight/body weight ratio, like in our previous paper (Sadowska et al., 2020). The PH animals also showed increased rates of rise (dP/dt max ) and decrease (dP/dt min ) of right ventricular pressure. ...
Citations
... This drug therefore highlights the beneficial potential of formulating CB1 antagonists that have additional targets, such as AMPK [113]. Interestingly, a recent study examined the effects of JD5037 in combination with metformin, an AMPK activator, in pulmonary hypertension and discovered that the conjunction of these two drugs together proved to be more effective than the monotherapies, highlighting the potential for a CB1/AMPK dual-target drug [122]. A very current issue that has the potential to benefit from a CB1/iNOS hybrid antagonist is the development of the long-term effects of COVID-19, or long "COVID" [123]. ...
Endocannabinoid signaling plays crucial roles in human physiology in the function of multiple systems. The two cannabinoid receptors, CB1 and CB2, are cell membrane proteins that interact with both exogenous and endogenous bioactive lipid ligands, or endocannabinoids. Recent evidence has established that endocannabinoid signaling operates within the human kidney, as well as suggests the important role it plays in multiple renal pathologies. CB1, specifically, has been identified as the more prominent ECS receptor within the kidney, allowing us to place emphasis on this receptor. The activity of CB1 has been repeatedly shown to contribute to both diabetic and non-diabetic chronic kidney disease (CKD). Interestingly, recent reports of acute kidney injury (AKI) have been attributed to synthetic cannabinoid use. Therefore, the exploration of the ECS, its receptors, and its ligands can help provide better insight into new methods of treatment for a range of renal diseases. This review explores the endocannabinoid system, with a focus on its impacts within the healthy and diseased kidney.
... In our previous study CBD reduced the expression of TGF-β1 and Gal-3 in the lungs of rats with MCT-induced PH [45]. Remiszewski et al. [46] showed that chronic administration of the classic cannabinoid type 1 receptor (CB 1 -R) antagonist (JD5037) reduced RV hypertrophy in MCT-induced PH rats, but there was no effect of CB 1 -R antagonist administration on TGF-β1 and Gal-3 expression in the lungs of PH rats. Due to these discrepancies, we hypothesize that in our study CBD reduces the expression of TGF-β1 and Gal-3 through CB 1 -R-independent mechanisms, despite the fact that cannabinoid receptors type 1 and 2 (CB 1,2 -Rs) have been reported to correlate with TGF-β1 and/or Gal-3. ...
Cannabidiol (CBD) is a non-intoxicating compound of Cannabis with anti-fibrotic properties. Pulmonary hypertension (PH) is a disease that can lead to right ventricular (RV) failure and premature death. There is evidence that CBD reduces monocrotaline (MCT)-induced PH, including reducing right ventricular systolic pressure (RVSP), vasorelaxant effect on pulmonary arteries, and decreasing expression of profibrotic markers in the lungs. The aim of our study was to investigate the effect of chronic administration of CBD (10 mg/kg daily for 21 days) on profibrotic parameters in the RVs of MCT-induced PH rats. In MCT-induced PH, we found an increase in profibrotic parameters and parameters related to RV dysfunction, i.e. plasma pro-B-type natriuretic peptide (NT-proBNP), cardiomyocyte width, interstitial and perivascular fibrosis area, amount of fibroblasts and fibronectin, as well as overexpression of the transforming growth of factor β1 (TGF-β1), galectin-3 (Gal-3), suppressor of mothers against decapentaplegic 2 (SMAD2), phosphorylated SMAD2 (pSMAD2) and alpha-smooth muscle actin (α-SMA). In contrast, vascular endothelial cadherin (VE-cadherin) levels were decreased in the RVs of MCT-induced PH rats. Administration of CBD reduced the amount of plasma NT-proBNP, the width of cardiomyocytes, the amount of fibrosis area, fibronectin and fibroblast expression, as well as decreased the expression of TGF-β1, Gal-3, SMAD2, pSMAD2, and increased the level of VE-cadherin. Overall, CBD has been found to have the anti-fibrotic potential in MCT-induced PH. As such, CBD may act as an adjuvant therapy for PH, however, further detailed investigations are recommended to confirm our promising results.
... On the other hand, the peripheral CB 1 R antagonist JD5037 alone tended to lower RVSP only in the MCT-induced model of rat PH. Still, it potentiated the effect of metformin in a combined therapy protocol [151]. Thus, the roles of AEA and CB 1 Rs remain to be examined in detail. ...
Systemic and pulmonary hypertension are multifactorial, high-pressure diseases. The first one is a civilizational condition, and the second one is characterized by a very high mortality rate. Searching for new therapeutic strategies is still an important task. (Endo)cannabinoids, known for their strong vasodilatory properties, have been proposed as possible drugs for different types of hypertension. Unfortunately, our review, in which we summarized all publications found in the PubMed database regarding chronic administration of (endo)cannabinoids in experimental models of systemic and pulmonary hypertension, does not confirm any encouraging suggestions, being based mainly on in vitro and acute in vivo experiments. We considered vasodilator or blood pressure (BP) responses and cardioprotective, anti-oxidative, and the anti-inflammatory effects of particular compounds and their influence on the endocannabinoid system. We found that multitarget (endo)cannabinoids failed to modify higher BP in systemic hypertension since they induced responses leading to decreased and increased BP. In contrast, multitarget cannabidiol and monotarget ligands effectively treated pulmonary and systemic hypertension, respectively. To summarize, based on the available literature, only (endo)cannabinoids with a defined site of action are recommended as potential antihypertensive compounds in systemic hypertension, whereas both mono- and multitarget compounds may be effective in pulmonary hypertension.
