CP55940-induced vasorelaxation is endothelial-dependent and mediated by the CB1R through NOS, COX and EDHF pathways in porcine cerebral arteries

Using swine as an experimental model, we examined whether the cannabinoid receptors (CB1R and CB2R) modulated vasomotor tone in isolated pial arteries. It was hypothesized that the CB1R would mediate cerebral artery vasorelaxation in an endothelial-dependent manner. First-order pial arteries were isolated from female Landrace pigs (age = 2 months; N = 27) for wire and pressure myography. Arteries were pre-contracted with a thromboxane A2 analogue (U-46619) and vasorelaxation in response to the CB1R and CB2R receptor agonist CP55940 was examined in the following conditions: 1) untreated; 2) inhibition of the CB1R (AM251); or 3) inhibition of the CB2R receptor (AM630). The data revealed that CP55940 elicits a CB1R-dependent relaxation in pial arteries. CB1R expression was confirmed using immunoblot and immunohistochemical analyses. Subse-quently, the role of different endothelial-dependent pathways in the CB1R-mediated vasorelaxation was exam-ined using: 1) denudation (removal of the endothelium); 2) inhibition of cyclooxygenase (COX; Naproxen); 3) inhibition of nitric oxide synthase (NOS; L-NAME); and 4) combined inhibition of COX + NOS. The data revealed CB1R-mediated vasorelaxation was endothelial-dependent, with contributions from COX-derived prostaglandins, NO, and endothelium-dependent hyperpolarizing factor (EDHF). Pressurized arteries underwent myogenic curves (20-100 mmHg) under the following conditions: 1) untreated; 2) inhibition of the CB1R. The data revealed CB1R inhibition increased basal myogenic tone, but not myogenic reactivity. As the vascular responses were assessed in isolated pial arteries, this work reveals that the CB1R modulates cerebrovascular tone inde-pendently of changes in brain metabolism.

Automated summary

Using swine as an experimental model, this study investigated the modulation of vasomotor tone in isolated pial arteries by cannabinoid receptors (CB1R and CB2R). The results showed that CB1R mediated vasorelaxation in an endothelial-dependent manner. Furthermore, the study revealed that CB1R-mediated vasorelaxation was endothelial-dependent and involved different endothelial-dependent pathways.