Cross-Talk between the (Endo)Cannabinoid and Renin-Angiotensin Systems: Basic Evidence and Potential Therapeutic Significance

This review is dedicated to the cross-talk between the (endo)cannabinoid and renin angiotensin systems (RAS). Activation of AT₁ receptors (AT₁Rs) by angiotensin II (Ang II) can release endocannabinoids that, by acting at cannabinoid CB₁ receptors (CB₁Rs), modify the response to AT₁R stimulation. CB₁R blockade may enhance AT₁R-mediated responses (mainly vasoconstrictor effects) or reduce them (mainly central nervous system-mediated effects). The final effects depend on whether stimulation of CB₁Rs and AT₁Rs induces opposite or the same effects. Second, CB₁R blockade may diminish AT₁R levels. Third, phytocannabinoids modulate angiotensin-converting enzyme-2. Additional studies are required to clarify (1) the existence of a cross-talk between the protective axis of the RAS (Ang II-AT₂ receptor system or angiotensin 1-7-Mas receptor system) with components of the endocannabinoid system, (2) the influence of Ang II on constituents of the endocannabinoid system and (3) the (patho)physiological significance of AT₁R-CB₁R heteromerization. As a therapeutic consequence, CB₁R antagonists may influence effects elicited by the activation or blockade of the RAS; phytocannabinoids may be useful as adjuvant therapy against COVID-19; single drugs acting on the (endo)cannabinoid system (cannabidiol) and the RAS (telmisartan) may show pharmacokinetic interactions since they are substrates of the same metabolizing enzyme of the transport mechanism.