The interaction between the endocannabinoid system and the renin angiotensin system and its potential implication for COVID-19 infection – BMC Blogs Network

RAS and COVID-19 infection

The angiotensin converting enzyme 2 (ACE-2), which belongs to the renin angiotensin system (RAS), has been identified as the main entrance for the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) to cause COVID-19 infection in the human body (Fang et al. 2020). The RAS regulates the hemodynamics of the body, it has a very important role in the regulation of blood pressure and it has been related to the pathogenesis of hypertension (Miller and Arnold 2019). Antihypertensive drugs that inhibit either angiotensin converting enzymes (ACE) or angiotensin receptors, have been shown to lead to overexpression of ACE-2 (Fang et al. 2020). The use of ACE inhibitors and angiotensin II receptor blockers (ARBs) has been questioned since overexpression of ACE-2 receptors might result in a worse prognosis of the disease (Fang et al. 2020). However, recent scientific evidence raised the controversy whether ACE-2 receptors are actually downregulated or upregulated by ACE inhibitors and ARBs and whether the use of these drugs form a potential benefit or risk for COVID-19 prognosis (Vaduganathan et al. 2020; Cohen et al. 2020; Curfman 2020; Fosbøl et al. 2020). In fact, a recent retrospective cohort study showed no association between the use of these drugs and the diagnosis or mortality of COVID-19 infection (Fosbøl et al. 2020). Researchers and doctors advise patients who are already taking anti = hypertensive drugs to do not stop the medication. This is because stopping the medication could lead to severe health problems while there is not enough scientific evidence to support a potential risk of its use during COVID-19 disease (Vaduganathan et al. 2020).

Cannabinoids, hypotension and RAS

The ECS has been linked to cardiovascular modulation in multiple studies, including the modulation of blood pressure (Pacher et al. 2018). In fact, cannabis use and isolated cannabinoid administration (either tetrahydrocannabinol (THC) or cannabidiol (CBD)) is known to induce hypotension in healthy users, among other effects on cardiovascular regulation (Pacher et al. 2018). Hypotensive effects of cannabinoids have been reported to be mediated by the activation of cannabinoid receptor 1 (CB1), which is expressed in vascular smooth muscle and endothelial cells (Pacher et al. 2018). The mechanisms underlying the hypotensive effects of cannabinoids are complex, but animal and human studies point to direct vasorelaxation effects induced by the activation of CB1 and/or to the modulation of vasoactive agonists like angiotensin II (Stanley and O’Sullivan 2014). Not only plant-derived cannabinoids have been linked to hypotension, but also hemp seed oil shows hypotensive effects. Interestingly, these hypotensive effects are mediated by ACE inhibition (Girgih et al. 2014; Orio et al. 2017).

We are not aware of any study linking the ECS to the ACE-2 receptor, but we found some connections between the ECS and the RAS, including some links to the ACE receptor. Cross-talk between the ECS and the RAS has been described in several studies using upregulated RAS rat models, showing that CB1 and angiotensin II type 1 receptor (AT1R) form receptor heteromers with functional interactions and suggesting that hypertensive states are related to lower expression of CB1 and higher levels of angiotensin II (Haspula and Clark 2016; Rozenfeld et al. 2011; Schaich et al. 2016). In line with this and with the effects we previously mentioned concerning cannabis use and hypotension, we found a study examining vascular tissues from rats under different CB1 receptor modulations (activation, blockade and knockout) showing that the activation of CB1 reduces vasoconstrictor and hypertensive effects induced by angiotensin II (Szekeres et al. 2012). Since ARBs are used to reduce hypertension by blocking AT1R and CB1 can modulate AT1R, the hypotensive effects followed by CB1 activation might be induced through similar mechanisms. We also know that these CB1-induced hypotensive effects are related to angiotensin II, which is converted from angiotensin I by ACE receptor (Erdös 1976). Thus, it would be interesting to investigate if CB1-induced hypotension is linked to ARB mechanisms and/or ACE inhibition. If this would be the case, the activation of CB1 by cannabinoids like THC might lead to ACE-2 modulation as it has been showed by other antihypertensive drugs.

It is possible that other cannabinoids which show different interactions with CB1 (i.e. CB1 antagonists) could also lead to ACE-2 modulation. Actually, a recent study demonstrated that high-CBD cannabis extracts can modulate ACE-2 expression in artificial 3D human tissue models, suggesting a therapeutic potential in COVID-19 infection (Wang et al. 2020). However, extracts used in the study had different cannabinoid and terpene profiles, resulting in either upregulation or downregulation of ACE-2 expression. Since the total composition of cannabinoids and terpenes of each extract is unknown, it is not possible to determine which combination of active ingredients can actually downregulate or upregulate ACE-2 expression. In any case, this study would reinforce both the link between ECS and RAS and the idea of a potential effect of cannabis use on ACE-2 receptor expression.


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