Chronic Cannabidiol Administration Fails to Diminish Blood Pressure in Rats with Primary and Secondary Hypertension Despite Its Effects on Cardiac and Plasma Endocannabinoid System, Oxidative Stress and Lipid Metabolism

Abstract

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.

Cannabidiol Ameliorates Monocrotaline-Induced Pulmonary Hypertension in Rats

“…We are the first researchers who simultaneously determined 13 endocannabinoids and endocannabinoid-related lipids in the lungs (levels of OEA, SEA, HEA, DEA, 2-LG, DHEA, POEA and EPEA have never been determined in the lung). We confirmed that similarly to the lungs of rabbits [ 34 ], rats [ 35 ], mice [ 36 ] and rat hearts [ 16 ], the lungs’ 2-AG concentration was higher (by about 100 times) than the concentration of the well-known endocannabinoid AEA. Moreover, we noticed a similar ordering of endocannabinoid concentrations in rat lungs (the current study) and heart [ 16 ]: 2-AG > PEA ≈ OEA > AEA > LEA ≈ SEA ≈ POEA ≈ NAGly > DHEA ≈ DEA ≈ HEA ≈ 2-LG.…”

“…Chronic CBD 10 mg/kg/day administration was effective in the modification of cardiac and plasma endocannabinoid levels in two models of systemic hypertension [ 16 ] and exerted beneficial cardiovascular effects in diabetic and septic rats, in mice with diabetic- and doxorubicin-induced cardiomyopathy and experimental autoimmune myocarditis (see [ 16 ]). We decided to examine the protective but not therapeutic effect of CBD, because three weeks after MCT administration rats exhibited a higher mortality rate [ 25 ].…”

“…Changes in endocannabinoid levels appear to be dependent on the tissue and the model of hypertension. Thus, cardiac concentrations of AEA, 2-AG and some other endocannabinoids decreased in primary arterial hypertension (spontaneously hypertensive, SHR), but increased in secondary arterial hypertension (deoxycorticosterone (DOCA-salt)) [ 16 ]. In contrast, only POEA and NAGly concentrations decreased in the lungs of PH rats.…”

“…Thus, it reduced by almost by 80% and completely returned to the control value two important changes typical for PH that were stimulated by MCT, namely, (1) elevation in RVSP and (2) decreased blood oxygen saturation, respectively. Interestingly, chronic administration of the same dose of CBD failed to modify blood pressure (BP) and HR in rats with primary (SHR) and secondary (DOCA-salt) hypertension as well as in their normotensive controls [ 16 ]. We confirmed the lack of a CBD influence on the latter cardiovascular parameters of systemic circulation.…”

“…In addition, CBD can modify endocannabinoid levels as a result of inhibition of fatty acid amide hydrolase (FAAH), an enzyme responsible for degradation of anandamide or other endocannabinoids, and/or its interaction with the anandamide membrane transporter. Such model-dependent modification of cardiac and plasma endocannabinoid levels after chronic CBD administration has been demonstrated in experimental hypertension [ 16 ].…”