We investigated the influence of cannabidiol (CBD) on blood pressure (BP) and heart rate (HR) in spontaneously (SHR) and deoxycorticosterone (DOCA-salt) hypertensive rats. Hypertension was connected with increases in cardiac and plasma markers of lipid peroxidation in both models, whereas cardiac endocannabinoid levels decreased in SHR and increased in DOCA-salt. CBD (10 mg/kg once a day for 2 weeks) did not modify BP and HR in hypertension but counteracted pro-oxidant effects. Moreover, it decreased cardiac or plasma levels of anandamide, 2-arachidonoylglycerol and oleoyl ethanolamide in DOCA-salt and inhibited the activity of fatty acid amide hydrolase (FAAH) in both models. In the respective normotensive control rats, CBD increased lipid peroxidation, free fatty acid levels and FAAH activity. In conclusion, chronic CBD administration does not possess antihypertensive activity in a model of primary and secondary (DOCA-salt) hypertension, despite its antioxidant effect. The latter may be direct rather than based on the endocannabinoid system. The unexpected CBD-related increase in lipid peroxidation in normotensive controls may lead to untoward effects; thus, caution should be kept if CBD is used therapeutically.

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.

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 study evaluates the effect of the peripheral cannabinoid CB₁ receptor antagonist JD5037 in mono- and polytherapy with metformin in rat monocrotaline-induced mild PH. Animals received metformin (100 mg/kg), JD5037 (3 mg/kg), or a combination of both once daily for 21 days. Monocrotaline (60 mg/kg) increased right ventricular (RV) systolic pressure (RVSP), led to RV and lung hypertrophy and remodeling, and decreased oxygen saturation. Metformin partially restored the monocrotaline-induced effects, i.e., decreased RVSP, increased oxygen saturation, and counteracted cardiac fibrotic, hypertrophic, and inflammatory changes. JD5037 modified parameters related to inflammation and/or fibrosis. Only polytherapy with metformin and JD5037 improved Fulton’s index and coronary artery hypertrophy and tended to be more effective than monotherapy against alterations in RVSP, oxygen saturation and coronary artery tunica media vacuolization. In conclusion, monotherapy with JD5037 does not markedly influence the PH-related changes. However, polytherapy with metformin tends to be more efficient than any of these compounds alone.

The enhancement of the endocannabinoid tone might have a beneficial influence on hypertension. Polypharmacology proposes multi-target-directed ligands (MTDLs) as potential therapeutic agents for the treatment of complex diseases. In the present paper, we studied JZL195, a dual inhibitor of the two major endocannabinoid-degrading enzymes, fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL), in spontaneously hypertensive rats (SHR) and normotensive Wistar Kyoto rats (WKY). Hemodynamic parameters were assessed in conscious animals via radiotelemetry and tail-cuff methods and then evaluated by the area under the curve (AUC). Single administration of JZL195 induced dose-dependent weak hypotensive and bradycardic responses in SHR but not in WKY. Similarly, its chronic application revealed only a slight hypotensive potential which, however, effectively prevented the progression of hypertension and did not undergo tolerance. In addition, multiple JZL195 administrations slightly decreased heart rate only in WKY and prevented the gradual weight gain in both groups. JZL195 did not affect organ weights, blood glucose level, rectal temperature and plasma oxidative stress markers. In conclusion, chronic dual FAAH/MAGL inhibition prevents the progression of hypertension in SHR without affecting some basal functions of the body. In addition, our study clearly proves the suitability of AUC for the evaluation of weak blood pressure changes.

Background: Hypoxia is one of the most significant pathogenic factors in cardiovascular diseases. Preclinical studies suggest that nonpsychoactive cannabidiol (CBD) and β-adrenoceptor stimulation might possess cardioprotective potential against ischemia-reperfusion injury. The current study evaluates the influence of hypoxia-reoxygenation (H/R) on the function of atria and ventricular papillary muscles in the presence of CBD and the nonselective β-adrenoceptor agonist isoprenaline (ISO). Methods: The concentration curves for ISO were constructed in the presence of CBD (1 µM) before or after H/R. In chronic experiments (CBD 10 mg/kg, 14 days), the left atria isolated from spontaneously hypertensive (SHR) and their normotensive control (WKY) rats were subjected to H/R following ISO administration. Results: Hypoxia decreased the rate and force of contractions in all compartments. The right atria were the most resistant to hypoxia regardless of prior β-adrenergic stimulation. Previous β-adrenergic stimulation improved recovery in isolated left atria and right (but not left) papillary muscles. Acute (but not chronic) CBD administration increased the effects of ISO in left atria and right (but not left) papillary muscles. Hypertension accelerates left atrial recovery during reoxygenation. Conclusions: H/R directly modifies the function of particular cardiac compartments in a manner dependent on cardiac region and β-adrenergic prestimulation. The moderate direct cardioprotective potential of CBD and β-adrenergic stimulation against H/R is dependent on the cardiac region, and it is less than in the whole heart with preserved coronary flow. In clinical terms, our research expands the existing knowledge about the impact of cannabidiol on cardiac ischemia, the world′s leading cause of death.