Vasodilatory effects of cannabidiol in human pulmonary and rat small mesenteric arteries: modification by hypertension and the potential pharmacological opportunities

Abstract

Objective: Cannabidiol (CBD) has been suggested as a potential antihypertensive drug. The aim of our study was to investigate its vasodilatory effect in isolated human pulmonary arteries (hPAs) and rat small mesenteric arteries (sMAs). Methods: Vascular effects of CBD were examined in hPAs obtained from patients during resection of lung carcinoma and sMAs isolated from spontaneously hypertensive (SHR); 11-deoxycorticosterone acetate (DOCA-salt) hypertensive rats or their appropriate normotensive controls using organ bath and wire myography, respectively. Results: CBD induced almost full concentration-dependent vasorelaxation in hPAs and rat sMAs. In hPAs, it was insensitive to antagonists of CB 1 (AM251) and CB 2 (AM630) receptors but it was reduced by endothelium denudation, cyclooxygenase inhibitors (indomethacin and nimesulide), antagonists of prostanoid EP 4 (L161982), IP (Cay10441), vanilloid TRPV1 (capsazepine) receptors and was less potent under KCl-induced tone and calciumactivated potassium channel (K Ca) inhibitors (iberiotoxin, UCL1684 and TRAM-34) and in hypertensive, overweight and hypercholesteremic patients. The time-dependent effect of CBD was sensitive to the PPARg receptor antagonist GW9662. In rats, the CBD potency was enhanced in DOCA-salt and attenuated in SHR. The CBDinduced relaxation was inhibited in SHR and DOCA-salt by AM251 and only in DOCA-salt by AM630 and endothelium denudation. Conclusion: The CBD-induced relaxation in hPAs that was reduced in hypertensive, obese and hypercholesteremic patients was endothelium-dependent and mediated via K Ca and IP, EP 4 , TRPV1 receptors. The CBD effect in rats was CB 1-sensitive and dependent on the hypertension model. Thus, modification of CBD-mediated responses in disease should be considered when CBD is used for therapeutic purposes.

The Effects of Cannabidiol, a Non-Intoxicating Compound of Cannabis, on the Cardiovascular System in Health and Disease

“…[8][9][10][11][12][13][14][15][16][17]21,22,26,27,45,46]. The mechanisms through which CBD exerts its effects in the cardiovascular system are underlined [23,30,[47][48][49][50][51][52][53][54][55][56][57]. 1 CBD is a low efficacy partial agonist of GPR18 and antagonizes THC effects (CBD acts as an antagonist); abbreviations: 5-, 12-LOX: 5-,12-Lipoxygenase; 2-AG: 2-Arachidonoylglycerol; 5-HT1A, 2A, 3: Serotonin receptors type 1A, 2A, 3; Abn-CBD: Abnormal-cannabidiol; AEA: Anandamide; A1: Adenosine receptor type 1; CB1, 2: Cannabinoid receptor type 1, 2; COX-1,-2: Cyclooxygenase 1, 2; D2: Dopamine receptor type 2; EMT: Endocannabinoid membrane transporter; EP4: Prostaglandin E receptor 4; FAAH: Fatty acid amide hydrolase; FABP-3,-5,-7: Fatty acid binding protein 3, 5, 7; GABAA: γ-Aminobutyric acid receptor type A; GPR3, 6, 12, 18, 55: G-protein coupled receptor 3, 6, 12, 18, 55; IP: Prostacyclin receptor; PGE: Prostaglandin E; PPAR-γ: Peroxisome proliferator-activated receptor γ; TRPA1: Transient receptor potential ankyrin subfamily member 1; TRPM8: Transient receptor potential melastatin subfamily member 8; TRPV1-4: Transient receptor potential vanilloid subfamily members 1-4; α1-, α1β-, α3-GlyR: α1, α1β-, α3-Glycine receptor; α1-AR: α1-Adrenergic receptor; δ-, μ-OR: δ-, μ-Opioid receptor.…”

“…There are different routes of cannabidiol administration, of which the inhalation (smoking, vaporization or nebulization) and oral (oils, capsules, food and drinks enriched with CBD) routes [8][9][10][11][12][13][14][15][16][17]21,22,26,27,45,46]. The mechanisms through which CBD exerts its effects in the cardiovascular system are underlined [23,30,[47][48][49][50][51][52][53][54][55][56][57]. 1…”

“…After pithing and vagotomy in rats anaesthetised with urethane, i.e., after abolition of reflex responses and the influence of central nervous system on the cardiovascular system, CBD-induced an increase in HR and systolic pressure, whereas a decrease in diastolic pressure probably resulted from vasodilation [52]. 1 concerning only cardiovascular system; 2 effects observed with at least one of the tested doses; 3 patients with glaucoma; 4 TurboCBD TM is a patented capsule formulation of CBD increasing its bioavailability (45 or 90 mg CBD, 600 mg American ginseng, 240 mg Ginkgo biloba, 150 mg organic hemp oil); 5 patients with obsessive-compulsive disorder; 6 pithed and vagotomised rat; 7 patients with epilepsy; 8 patients with dystonic movement disorders; 9 patients with Huntington's disease; 10 patients with schizophrenia; 11 treatment started with 200 mg/day and increased stepwise by 200 mg/day to a daily dose of 800 mg/day (200 mg four times a day) within the first week (in some patients treatment was reduced to 600 mg/day after two weeks due to side effects); 11 The vasodilatory effect of CBD has been demonstrated on isolated human and animal vessels under both physiological (Table 3) [48,56,106] and pathological (see below) conditions and it is probably the most consistent effect of this compound in the cardiovascular system. The mechanism of CBD action on vessels is complex and depends on the examined vascular bed, however, it does not include cannabinoid receptors [48,106], except for isolated human mesenteric arteries, where dependence on CB 1 receptors has been demonstrated [56].…”

“…The mechanism of CBD action on vessels is complex and depends on the examined vascular bed, however, it does not include cannabinoid receptors [48,106], except for isolated human mesenteric arteries, where dependence on CB 1 receptors has been demonstrated [56]. It is worth noting that CBD causes time-dependent vasodilation through nuclear receptors PPAR-γ [48,56,106]. Nevertheless, the vasodilatory action of CBD ex vivo, in most cases, are not translated into systemic blood pressure (no decrease in BP after CBD administration, see above).…”

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

“…Hypertension is a disease with a complex pathomechanism, which includes, among others, changes in the endothelium and redox balance, both within the heart and blood vessels [16,17]. CBD is suggested to be a potential positive modulator of hypertension thanks to its vasodilatory action [3,9,11,18]. Another property that may be of key importance in a potential antihypertensive activity of CBD is its impact on oxidative stress.…”