arachidonyl-2-chloroethylamide and Hypertension

Angiotensin (Ang) II and cannabinoids regulate physiologically relevant astroglial functions via receptor-mediated activation of Mitogen-activated protein kinases (MAPKs). In this study, we investigated the consequences of astroglial Ang II type 1 receptor (AT1R) and Cannabinoid type 1 receptor (CB1R) activation, alone and in combination, on MAPK activation in the presence and absence of hypertensive states. In addition, we also investigated a novel unidirectional crosstalk mechanism between AT1R and CB1R, that involves PKC-mediated phosphorylation of CB1R.. Astrocytes were isolated from the brainstem and cerebellum of Spontaneously hypertensive rats (SHRs) and normotensive Wistar rats. The cells were treated with either 100nM Ang II or 10nM Arachidonyl-2'-chloroethylamide (ACEA), both alone and in combination, for varying time periods, and the extent of phosphorylation of MAPKs, ERK and p38, and the phosphorylated forms of CB1R (p-CB1R), were measured using western blotting.. Ang II treatment resulted in a greater activation of MAPKs in SHR brainstem astrocytes, but not SHR cerebellar astrocytes when compared to Wistar rats. ACEA-mediated MAPK activation was significantly lower in brainstem astrocytes of SHRs when compared to Wistar rats. ACEA negatively modulates AT1R-mediated MAPK activation in both cerebellar and brainstem astrocytes of both models. The effect however was diminished in brainstem astrocytes. Ang II caused a significant increase in phosphorylation of CB1R in cerebellar astrocytes, while its effect was diminished in brainstem astrocytes of both models.. Both Ang II and ACEA-induced MAPK activation were significantly altered in SHR astrocytes when compared to Wistar astrocytes. A possible reduction in CB1R functionality, coupled with a hyperfunctional AT1R in the brainstem, could well be significant factors in the development of hypertensive states. AT1R-mediated phosphorylation of CB1R could be critical for impaired cerebellar development characterized by a hyperactive RAS.

Topics: Angiotensin II; Animals; Arachidonic Acids; Astrocytes; Blood Pressure; Cannabinoids; Disease Models, Animal; Humans; Hypertension; MAP Kinase Kinase 1; Phosphorylation; Rats; Rats, Inbred SHR; Receptor, Angiotensin, Type 1; Receptors, Cannabinoid

Stimulation of cannabinoid type 1 (CB1) receptor in the rostral ventrolateral medulla (RVLM) increases renal sympathetic nerve activity (RSNA) and blood pressure (BP) in rats. Thus, we hypothesized that abnormal expression of CB1 receptor in the RVLM may play a critical role in the pathogenesis of essential hypertension.. We evaluated the effects of intra-RVLM infusions of arachidonyl-2'-chloroethylamide (ACEA), selective CB1 receptor agonist, with or without AM251, selective CB1 receptor antagonist, on BP, heart rate (HR), and RSNA in spontaneously hypertensive rats and wild-type rats. We also assessed the protein level and surface expression of CB1 receptor in the RVLM in these rats.. We found that spontaneously hypertensive rats exhibited higher basal BP, HR, and RSNA than wild-type rats. Furthermore, unilateral intra-RVLM microinjections ACEA (0, 10, or 100 nM/0.5 μl/site) increased BP, HR, and RSNA to a greater extent in spontaneously hypertensive rats than in wild-type rats. These effects were abolished by co-administrations of AM251 (500 nM/0.5 μl/site) into the RVLM. In addition, the protein level of CB1 receptor in the RVLM was robustly increased in spontaneously hypertensive rats, which is correlated with ACEA-induced maximum changes of RSNA, and this was also associated with reduced expression of β-arrestin 2 in the RVLM in spontaneously hypertensive rats. Finally, overexpression of β-arrestin 2 in the RVLM in spontaneously hypertensive rats attenuated BP, HR and RSNA.. Taken together, our results suggested that alterations of CB1 receptor desensitization in the RVLM may play a role in the pathogenesis of essential hypertension.

Topics: Animals; Arachidonic Acids; beta-Arrestin 2; Blood Pressure; Essential Hypertension; Heart Rate; Hypertension; Kidney; Male; Medulla Oblongata; Microinjections; Piperidines; Pyrazoles; Rats; Rats, Inbred SHR; Receptor, Cannabinoid, CB1; Sympathetic Nervous System