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

Abstract

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.

Identification of co-expressed central genes and transcription factors in acute myocardial infarction and diabetic nephropathy

“…OMDM-2 is a cannabinoid transporter inhibitor. Angiotensin II releases endocannabinoids by activating the AT1 receptor [ 59 ]. The mechanism of the cardiovascular system's response to endocannabinoids is complex, and there are still many unsolved mysteries.…”

Why Multitarget Vasodilatory (Endo)cannabinoids Are Not Effective as Antihypertensive Compounds after Chronic Administration: Comparison of Their Effects on Systemic and Pulmonary Hypertension

“…CB 1 Rs are spread all over the body but are mostly found in the central nervous system (CNS), which is the reason for the psychoactivity of THC. As shown in Figure 1, their activation exerts both pro-hypotensive and pro-hypertensive activity [39,45,46,[69][70][71]. The hypotensive effects result mainly from a decrease in noradrenaline release from the sympathetic nerve endings innervating resistance vessels by the activation of presynaptic CB 1 Rs and direct vasodilatory effects determined in various (but not all) vessels [46,58].…”

“…The hypotensive effects result mainly from a decrease in noradrenaline release from the sympathetic nerve endings innervating resistance vessels by the activation of presynaptic CB 1 Rs and direct vasodilatory effects determined in various (but not all) vessels [46,58]. However, it should be remembered that CB 1 Rs are also known for their pro-oxidant and pro-inflammatory effects, and their activation in the CNS leads mainly to a pressor response [39,45,46,71,72]. The highest density of CB 2 Rs occurs in the immune system.…”

“…administration of synthetic cannabinoids or AEA in both anesthetized and conscious animals [69]. Similarly, stimulation of CB 1 Rs in the paraventricular nucleus of the hypothalamus (PVN) causes a pressor response in both anesthetized and conscious rats, clearly suggesting that central mechanisms are responsible for the increased BP induced by cannabinoids [71].…”