Cross-Talk between the (Endo)Cannabinoid and Renin-Angiotensin Systems: Basic Evidence and Potential Therapeutic Significance
Krzysztof Mińczuk | Marta Baranowska-Kuczko | Anna Krzyżewska | Eberhard Schlicker | Barbara Malinowska | Baranowska-Kuczko
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. SpeciesModelAgonist Concentration (μM) or DoseEffect(Functional) Antagonist; Concentration In Vitro (μM) or DoseInfluence on the Agonist EffectFinal Conclusion of the AuthorsReferencescells: Chinese hamster; human; African green monkeyCHO; HEK293; COS7 cells (co-expressing AT1Rs and CB1Rs) from ovaries, kidneys, and fibroblasts, respectivelyAng II (0.1)↑2-AG ↔AEA ↑Go protein activationAM251 (10) THL (1)↓Ang II-induced Go protein activationAT1R stimulation leads to DAGL-mediated transactivation of CB1Rs in an autocrine and paracrine manner[33,34]cells: mouseneuro2A cells, a neuroblastoma cell line co-expressing CB1Rs and AT1RsAng II (0.01–10)↑pERK levels via Gαi instead of Gαq the expression of AT1R shifts CB1Rs from an intracellular compartment to the plasma membranelosartan CB1R-targeting siRNA RIM (1) THL (1) HU210 (0.0001)Ang II-induced ↑pERK ↓ by losartan, CB1R-targeting siRNA, RIM, and THL; ↑ by HU210 (occurring in the presence of a very low non-signaling concentration of Ang II only)AT1Rs and CB1Rs form receptor heteromers; blocking CB1R activity prevented the Ang II-mediated pathologic effect[35]cells: ratshepatic stellate cells from control rats (cHSCs) and rats treated with ethanol for 8 months (eHSCs)Ang II (1)CB1R, AT1R and AT1R-CB1 heteromer levels in eHSCs > cHSCs; ↑pERK levels, ↑mitogenic and ↑profibrogenic markers in eHSCs > cHSCsRIM (1)↓Ang II-induced changesBlood Vesselsrats Wistaraortic VSMCsAng II (0.1)↑2-AG level ↑Ca2+ signalTHL (1) JZL184 (1)↓ and ↑ of Ang II-induced 2-AG formation and Ca2+ signal by THL and JZL184, respectivelyAng II stimulates eCB (2-AG) release from the vascular wall that reduces the vasoconstrictor effects of Ang II via CB1R activation (eCBs act as protective negative feedback in response to Ang II)[36]rats and/or miceaortic rings from rats aortic rings from CB1−/− and WT miceAng II (0.001–0.1)concentration-dependent contractionWIN-2 (10) O2050 (1) THL (1) JZL184 (1)vasodilation to WIN-2; not detected in CB1−/− O2050, THL↑ , and JZL184↓ vasoconstrictor effect of Ang II; amplificatory effect of O2050 in WT onlyrats and/or miceskeletal muscle arterioles, saphenous arteriesAng II (0.001–0.1)concentration-dependent contractionWIN-2 (1) O2050 (1) RIM (1) AM251 (1) THL (1)vasodilation to WIN-2; not detected in CB1−/− ↑vasoconstrictor effect of Ang II in WT but not in CB1−/−Ang II stimulates eCB release from the vascular wall that reduces the vasoconstrictor effects of Ang II via CB1R activation (eCBs act as protective negative feedback in response to Ang II)[37]rats Wistarintramural coronary resistance arteriolesAng II (0.0001–10)concentration-dependent contractionWIN-2 (0.0001–1) O2050 (1) THL (1)vasodilatation to WIN-2 reduced by O2050 and AM251 ↑vasoconstrictor effect of Ang IIAng II stimulates eCB release from the vascular wall that reduces the vasoconstrictor effects of Ang II via CB1R activation (eCBs act as protective negative feedback in response to Ang II)[38]rats Wistarpulmonary arteriesAng II (0.0001–0.03)concentration-dependent contractionAM251 (1) RHC80267 (40) JZL184 (1) URB597 (1)AM251 and RHC80267 ↑ but JZL184 ↓ vasoconstrictor effect of Ang II; URB597 ↔Ang II stimulates eCB (2-AG) release from the vascular wall that reduces the vasoconstrictor effects of Ang II via CB1R activation (eCBs act as protective negative feedback in response to Ang II)[39]ratsuterine artery from hypertensive TgA and normotensive SD ratsAng II (0.00001–0.01)concentration-dependent contraction, stronger in TgAURB597 (1) JZL184 (1) RIM (1)↓responses to Ang II in SD and TgA ↓responses to Ang II in TgA ↔responses to Ang II in SD and TgAeCBs reduce the Ang II-induced contraction in a CB1R-independent manner in the early stages of hypertensive pregnancy (eCBs act as protective negative feedback in response to Ang II)[40]rats SD miceVSMCs from rat and mouse thoracic aortas with CB1R expressionAng II (1)↑ROS production ↑NADPH oxidase activityRIM (0.1–1) or AM251 (1) CP55940 (1)↓AT1Rs and decrease in the Ang II-induced ↑ROS production and ↑NADPH oxidase activity ↑AT1RsCB1R inhibition (in vitro and in vivo) has atheroprotective effects by down-regulation of AT1Rs, decreased vascular ROS, and thus improved endothelial function in hypercholesterolemic ApoE−/− mice[41]miceApoE−/− treated with a cholesterol-rich dietdevelopment of atherosclerotic plaques, ↓aorta relaxation, ↔aortic AT1R levelRIM (10 mg/kg/day; p.o.) for 12 monthsnormalized the acute pressor response to Ang II in obese rats to the level of lean ratsauthors suggest that chronic CB1R blockade by RIM might reduce vascular AT1R expression; an indirect mechanism related to the decrease in the cholesterol level should also be taken under consideration[49]rats SHR WKYconsciousSHR in comparison to WKY: higher BP, carotid, mesenteric artery: ↑AT1Rs, ↑ACE kidney: ↔AT1Rs, ↔AT2Rs, ↑ACEPEA (30 mg/kg; s.c. for 5 weeks)BP in SHR↓ SHRarteries: ↓AT1Rs, ↓ACE level SHR kidney: ↓AT1Rs, ↑AT2Rs, and ↓ACE level associated with ↓oxidative and nitrosative stressPEA lowers BP and protects against hypertensive renal injury partially via reduction in vascular AT1Rs and Ang II-mediated effects and via modulation of the RAS, leading the AT1/AT2 balance towards an anti-hypertensive status[50,51]rats WKYcultured lymphocytes from WKYAng II (0.01–1)concentration-dependent ↓AEA transporter activity and ↑ROS levellosartan (10 and 100)↓Ang II effects on AEA transporter activity and ROS levelAng II plays a critical role in mediating the decrease in AEA transporter activity in SHR; probably via AT1Rs[52]rats SHR WKYconsciousSHR: ↑plasma Ang II and ↑AEA level; ↓AEA transporter activity in comparison to WKYlosartan (15 or 30 mg/kg; p.o. )↑BP stronger in SHR than in WKYlosartan (20) PD123319 (10) AM251 (30)↓pressor effect of Ang II and CP55940 ↓pressor effect of Ang II and CP55940 ↓pressor effect of Ang IImutual interaction in the PVN between CB1Rs and receptors for Ang II responsible for stimulation of the pressor response (probably via stimulation of CB1R by eCBs released in response to Ang II)[55]micemagnocellular neurosecretory cells from the supraoptic nucleusAng II (0.1)↑frequency of mEPSCsAM251 (2)↑effect of Ang IIeCBs released in response to Ang II modulate the excitatory synaptic inputs via negative feedback[56]rats Wistar mice CB1+/+ CB1−/−consciousAng II (191 pmol/rat; i.c.v.) Ang II (191 pmol/mouse i.c.v.